Preparation method and application of high-stability empty capsule
By using gelatin and specific auxiliary materials in the preparation process of hollow capsules and using multiple drying cycles, the problem of size changes and sealing of capsules under different humidity conditions is solved, and hollow capsules with high stability and good performance are achieved.
Patent Information
- Application Number
- CN202411835733.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-13
- Publication Date
- 2025-03-21
AI Technical Summary
The capsule will absorb or release moisture under different humidity conditions, resulting in size changes, affecting the filling efficiency and quality of the powder, and the moisture changes affect the sealing of the capsule and the stability of the drug.
Gelatin is used as the film forming agent, and auxiliary materials such as gallic acid, tannin, catechin, maltodextrin and β-cyclodextrin are added. High stability hollow capsules are prepared through specific preparation steps and drying processes. The method includes pretreatment of gelatin, standing of gelatin and multiple drying cycles to improve the stability of the capsule.
Under low humidity or high humidity conditions, the prepared hollow capsules are not prone to water loss or absorb water. After being filled with high humidity-containing powder, the capsule performance remains stable and has good stability and applicability.
Smart Images
Figure CN119656126A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of hollow capsule production, and in particular to a preparation method and application of high-stability hollow capsules. Background Art
[0002] Hard capsules are a solid dosage form for oral administration, designed to encapsulate a solid or semi-solid mixture of active pharmaceutical ingredients and appropriate excipients in a hard hollow gelatin shell. They provide better moisture and light protection before the contents are released, making them widely used in medicines, health foods, and functional foods. Generally speaking, most drugs contained in hollow hard capsules have irritating effects on the esophagus, mucous membranes, etc. After being loaded into the capsule, they protect the drug properties from being destroyed and the patient's digestive system, providing patients with a convenient and safe way of self-administration. The production of hollow hard gelatin capsules is the most widely used hollow hard capsule material in the market for hard capsule processing and manufacturing because of its mature equipment technology and excellent drug release.
[0003] At present, because capsules absorb or release water under different humidity conditions, this will cause the size of the capsule to change, affecting the efficiency and quality of drug powder filling, and the change in moisture will change the tightness of the capsule, thus affecting the sealing of the capsule. In addition, during the production process of capsules, drugs with different moisture contents will be filled. When the moisture content of the filled drug is low, the capsule will release moisture, which will be absorbed by the drug, which may easily cause the hydrolysis of some drugs and affect the efficacy. Summary of the invention
[0004] Technical problem to be solved: In view of the problems existing in the use of capsules in the background technology, the present invention provides a method for preparing and applying high-stability hollow capsules, which are medicinal hollow capsules that can show good stability when filled with low-water-content drugs and in different humidity environments, and have practical positive significance for the rapid development of the pharmaceutical industry.
[0005] Technical solution: The method for preparing a high-stability hollow capsule of the present invention comprises the following steps: Step 1: Weigh a certain amount of gelatin, add 0.5-5% of the auxiliary materials based on the total mass of gelatin, dissolve in 75-90℃ distilled water, and stir until completely dissolved; Step 2: The glue solution prepared in step 1 is placed at 45-60°C and kept warm for 8-12 hours to obtain a stable glue solution; Step 3: Cool the glue solution prepared in step 2 to 40-50° C., dip it into glue for molding, and dry it for 50-200 minutes at a temperature of 25-45° C. and a relative humidity of 30-60% to obtain a capsule cap body glue blank; Step 4: demoulding, cutting and fitting the rubber blank to obtain a hollow capsule with high stability.
[0006] Preferably, the gelatin is bone gelatin, skin gelatin or a combination thereof.
[0007] Preferably, the auxiliary material is a group or combination of gallic acid, tannic acid, catechin, maltodextrin and β-cyclodextrin.
[0008] Preferably, in step 1, 0-20% of the total amount of gelatin is pretreated before adding; The specific steps of the pretreatment are: adding 100-500 L of deionized water to every 1 kg of gelatin, heating in a water bath at 40-60° C. to dissolve, adding 1-10% Ɛ-polylysine, and then adding 1-20 U of microbial glutamine transaminase to react for 6-12 hours, and then inactivating the enzyme at 95° C., and finally adding 1-5% ethyl maltol solution.
[0009] The invention also discloses a high-stability hollow capsule, wherein the hollow capsule is dried multiple times, placed in a high-humidity environment to absorb water, and then dried twice in a repeated cycle. The high-stability hollow capsule is used in the field of drug loading.
[0010] Compared with the prior art, the present invention has the following beneficial effects: The present invention adopts gelatin as a film-forming agent, and adds gallic acid, tannic acid, catechin, maltodextrin, beta-cyclodextrin and other auxiliary materials to prepare hollow capsules. Experiments have confirmed that the hollow capsules are not easy to lose water or absorb water under low humidity or high humidity conditions. After being filled with high hygroscopic powder, the capsules maintain stable performance and have good stability. The hollow capsules can be widely used in the fields of capsule preparations and the like. BRIEF DESCRIPTION OF THE DRAWINGS
[0011] Figure 1 The present invention is a flow chart of the preparation of hollow capsules according to an embodiment of the present invention. DETAILED DESCRIPTION
[0012] To make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the following will be combined with the attached Figure 1 The technical solutions of the embodiments of the present invention are described clearly and completely. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the described embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field belong to the scope of protection of the present invention.
[0013] like Figure 1 As shown, a method for preparing a high-stability hollow capsule of the present invention comprises the following steps: (I) Weigh a certain amount of gelatin, which is one or a combination of bone gelatin and skin gelatin. Pre-treat 0-20% of the total amount of gelatin before adding; the specific steps of pre-treatment are: add 100-500L of deionized water per 1kg of gelatin, heat and dissolve in a water bath at 40-60℃, add 1-10% Ɛ-polylysine, then add 1-20U of microbial glutamine transaminase to react for 6-12h, then inactivate the enzyme at 95℃, and finally add 1-5% ethyl maltol solution. In order to meet the research on the addition of auxiliary materials in the preparation process of gelatin hollow capsules, the amount of pre-treated gelatin and the parameters of the specific preparation steps are set as fixed values in Examples 1-5. It should be noted that the content of deionized water added per 1 kg of gelatin can be 100L, 200L, 300L, 400L, or 500L, the water bath heating dissolution temperature can be 40°C, 50°C, or 60°C, the added content of Ɛ-polylysine can be 1%, 2%, 5%, 8%, or 10%, the added content of microbial glutamine transaminase can be 1U, 2U, 5U, 10U, 15U, or 20U, the reaction time can be 6h, 8h, 10h, or 12h, and the added content of ethyl maltol solution can be 1%, 2%, 3%, 4%, or 5%.
[0014] (ii) Based on the total mass of gelatin, add 0.5-5% of auxiliary materials by mass, the auxiliary materials are one or a combination of gallic acid, tannic acid, catechin, maltodextrin, and β-cyclodextrin. Add untreated gelatin, pretreated gelatin and auxiliary materials into the sol tank, close the valve of the sol tank, inject purified water into the sol tank, inject 3kg of purified water per kilogram of gelatin, heat the circulating water in the interlayer of the sol tank to between 70 and 85°C, control the temperature of the glue solution at about 75-90°C, and stir until it is completely dissolved. Evacuate the sol tank until there are no bubbles in the glue solution, stop evacuating after the temperature drops to 65°C, close the vacuum valve and vacuum pump, and let the obtained glue solution stand at 45-60°C and keep it warm for 8-12 hours to obtain a stable glue solution. Clamp a 220-mesh filter bag onto the glue outlet of the glue sol tank and tighten it. Then place the glue barrel just below the glue outlet, open the glue outlet valve and release the required amount. Cool the glue liquid to 40-50℃, then match the colors and let it stand for natural degassing to obtain the mixed glue, which is ready for dipping in glue. It should be noted that the added content of the auxiliary material can be selected from 0.5%, 1%, 2%, 3%, 4%, and 5%. The type of auxiliary material can be a single component or a combination of gallic acid, tannic acid, catechin, maltodextrin, and β-cyclodextrin. For example, using a single component means that the content of other types is 0; the circulating water heating temperature of the interlayer of the sol tank can be 70°C, 80°C, or 85°C, the glue temperature can be controlled at 75°C, 80°C, or 90°C, the glue standing temperature can be controlled at 45°C, 50°C, 55°C, or 60°C, and the insulation time can be 8h, 9h, 10h, 11h, or 12h; the glue cooling temperature can be 40°C, 45°C, or 50°C; the above parameters can be selected according to needs in Examples 1 to 5.
[0015] (III) Inject the mixed glue into the glue dipping tray, start the mold to automatically dip the glue, and after the mixed glue is solidified on the mold, send it into the low-pressure drying system, dry it at a temperature of 25-45°C and a relative humidity of 30-60% for 50-200 minutes to obtain the capsule cap body rubber blank, and adjust the temperature of the entire drying process according to the parameters of the mixed glue and the changes in the gelatin molecular chain after the mixed glue is dipped in the glue. Among them, the rubber blank drying process is multiple drying, and after drying, it is placed in a high humidity environment to absorb water and then repeated cyclic drying for 2 times. It should be noted that the temperature of the drying system can be 25°C, 30°C, 35°C, 40°C, 45°C, the relative humidity can be 30%, 40%, 50%, 60%, and the drying time can be 50min, 100min, 200min; the above parameters can be selected according to needs in Examples 1-5.
[0016] (iv) cooling, demoulding, cutting, fitting, inspecting and packaging the obtained gelatin blank after drying to obtain a high-stability gelatin hollow capsule, which can be used in the field of drug loading technology.
[0017] Example 1: Figure 1As shown, a method for preparing a high-stability hollow capsule of the present invention comprises the following steps: (I) Weigh a certain amount of gelatin, which is one or a combination of bone gelatin and skin gelatin. Pre-treat 20% of the total amount of gelatin before adding; the specific steps of pre-treatment are: add 500L of deionized water to every 1kg of gelatin, heat it in a 60℃ water bath to dissolve, add 10% Ɛ-polylysine, then add 20U of microbial glutamine transaminase to react for 12h, then inactivate the enzyme at 95℃, and finally add 5% ethyl maltol solution.
[0018] (ii) Based on the total mass of gelatin, add untreated gelatin, pretreated gelatin and 1% gallic acid by mass into the sol tank, close the valve of the sol tank, inject purified water into the sol tank, inject 3kg of purified water per kilogram of gelatin, heat the circulating water in the interlayer of the sol tank to 85℃, control the temperature of the glue solution at about 80℃, and stir until it is completely dissolved. Evacuate the sol tank until there are no bubbles in the glue solution, stop evacuating after cooling to 65℃, close the vacuum valve and vacuum pump, and let the prepared glue solution stand at 60℃ and keep warm for 12h to obtain a stable glue solution. Clamp a 220-mesh filter bag on the glue outlet of the sol tank and clamp it, then place the glue barrel just below the glue outlet, open the glue outlet valve and release it to the required amount, cool the glue solution to 45℃, and then color match and stand for natural degassing to obtain a mixed glue, which is ready for dipping.
[0019] (III) Inject the mixed glue into the glue dipping tray, start the mold to automatically dip the glue, and after the mixed glue is solidified on the mold, send it to the low-pressure drying system and dry it for 100 minutes at a temperature of 28°C and a relative humidity of 45% to obtain the capsule cap body rubber blank. The temperature of the entire drying process is adjusted according to the parameters of the mixed glue and the changes in the gelatin molecular chain after the mixed glue is dipped and molded. Among them, the rubber blank drying process is multiple drying, and after drying, it is placed in a high humidity environment to absorb water and then repeated for 2 cycles of drying.
[0020] (iv) cooling, demoulding, cutting, fitting, inspecting and packaging the obtained gelatin blank after drying to obtain a high-stability gelatin hollow capsule, which can be used in the field of drug loading technology.
[0021] Example 2: Figure 1 As shown, a method for preparing a high-stability hollow capsule of the present invention comprises the following steps: (I) Weigh a certain amount of gelatin, which is one or a combination of bone gelatin and skin gelatin. Pre-treat 0-20% of the total amount of gelatin before adding; the specific steps of pre-treatment are: add 500L of deionized water per 1kg of gelatin, heat in a 60℃ water bath to dissolve, add 10% Ɛ-polylysine, then add 20U of microbial glutamine transaminase to react for 12h, then inactivate the enzyme at 95℃, and finally add 5% ethyl maltol solution.
[0022] (II) Based on the total mass of gelatin, untreated gelatin, pretreated gelatin and 1% tannic acid are added into the sol tank, the valve of the sol tank is closed, purified water is injected into the sol tank, 3kg of purified water is injected into each kilogram of gelatin, the circulating water in the interlayer of the sol tank is heated to 85℃, the temperature of the glue liquid is controlled at about 80℃, and it is stirred until it is completely dissolved. The sol tank is vacuumed until there are no bubbles in the glue liquid, and the vacuuming is stopped after the temperature drops to 65℃, the vacuum valve and vacuum pump are closed, and the prepared glue liquid is allowed to stand and keep warm at 60℃ for 12h to obtain a stable glue liquid. A 220-mesh filter bag is clamped on the glue outlet of the sol tank and clamped, and then the glue barrel is placed directly below the glue outlet, and the glue outlet valve is opened to release the required amount. The glue liquid is cooled to 45℃, and then it is color matched and left to stand for natural degassing to obtain a mixed glue, which is prepared for dipping.
[0023] (III) Inject the mixed glue into the glue dipping tray, start the mold to automatically dip the glue, and after the mixed glue is solidified on the mold, send it to the low-pressure drying system and dry it for 100 minutes at a temperature of 28°C and a relative humidity of 45% to obtain the capsule cap body rubber blank. The temperature of the entire drying process is adjusted according to the parameters of the mixed glue and the changes in the gelatin molecular chain after the mixed glue is dipped and molded. Among them, the rubber blank drying process is multiple drying, and after drying, it is placed in a high humidity environment to absorb water and then repeated for 2 cycles of drying.
[0024] (iv) cooling, demoulding, cutting, fitting, inspecting and packaging the obtained gelatin blank after drying to obtain a high-stability gelatin hollow capsule, which can be used in the field of drug loading technology.
[0025] Example 3: Figure 1 As shown, a method for preparing a high-stability hollow capsule of the present invention comprises the following steps: (I) Weigh a certain amount of gelatin, which is one or a combination of bone gelatin and skin gelatin. Pre-treat 20% of the total amount of gelatin before adding; the specific steps of pre-treatment are: add 500L of deionized water to every 1kg of gelatin, heat it in a 60℃ water bath to dissolve, add 10% Ɛ-polylysine, then add 20U of microbial glutamine transaminase to react for 12h, then inactivate the enzyme at 95℃, and finally add 5% ethyl maltol solution.
[0026] (II) Based on the total mass of gelatin, add untreated gelatin, pretreated gelatin and 1% tannic acid by mass into the sol tank, close the valve of the sol tank, inject purified water into the sol tank, inject 3kg of purified water per kilogram of gelatin, heat the circulating water in the interlayer of the sol tank to 85℃, control the temperature of the glue solution at about 90℃, and stir until it is completely dissolved. Evacuate the sol tank until there are no bubbles in the glue solution, stop evacuating after cooling to 65℃, close the vacuum valve and vacuum pump, and let the prepared glue solution stand at 60℃ and keep warm for 12h to obtain a stable glue solution. Clamp a 220-mesh filter bag on the glue outlet of the sol tank and clamp it, then place the glue barrel just below the glue outlet, open the glue outlet valve and release it to the required amount, cool the glue solution to 45℃, and then color match and stand for natural degassing to obtain a mixed glue, which is ready for dipping.
[0027] (III) Inject the mixed glue into the glue dipping tray, start the mold to automatically dip the glue, and after the mixed glue is solidified on the mold, send it to the low-pressure drying system and dry it for 100 minutes at a temperature of 45°C and a relative humidity of 60% to obtain the capsule cap body rubber blank. The temperature of the entire drying process is adjusted according to the parameters of the mixed glue and the changes in the gelatin molecular chain after the mixed glue is dipped and molded. Among them, the rubber blank drying process is multiple drying, and after drying, it is placed in a high humidity environment to absorb water and then repeated for 2 cycles of drying.
[0028] (iv) cooling, demoulding, cutting, fitting, inspecting and packaging the obtained gelatin blank after drying to obtain a high-stability gelatin hollow capsule, which can be used in the field of drug loading technology.
[0029] Example 4: Figure 1 As shown, a method for preparing a high-stability hollow capsule of the present invention comprises the following steps: (I) Weigh a certain amount of gelatin, which is one or a combination of bone gelatin and skin gelatin. Pre-treat 20% of the total amount of gelatin before adding; the specific steps of pre-treatment are: add 500L of deionized water to every 1kg of gelatin, heat it in a 60℃ water bath to dissolve, add 10% Ɛ-polylysine, then add 20U of microbial glutamine transaminase to react for 12h, then inactivate the enzyme at 95℃, and finally add 5% ethyl maltol solution.
[0030] (II) Based on the total mass of gelatin, add untreated gelatin, pretreated gelatin and 4% maltodextrin by mass into the sol tank, close the valve of the sol tank, inject purified water into the sol tank, inject 3kg of purified water for every kilogram of gelatin, heat the circulating water in the interlayer of the sol tank to 85℃, control the temperature of the glue solution at about 90℃, and stir until it is completely dissolved. Evacuate the sol tank until there are no bubbles in the glue solution, stop evacuating after cooling to 65℃, close the vacuum valve and vacuum pump, and let the prepared glue solution stand at 60℃ and keep warm for 12h to obtain a stable glue solution. Clamp a 220-mesh filter bag on the glue outlet of the sol tank and clamp it, then place the glue barrel just below the glue outlet, open the glue outlet valve and release it to the required amount, cool the glue solution to 45℃, and then color match and stand for natural degassing to obtain a mixed glue, which is ready for dipping.
[0031] (III) Inject the mixed glue into the glue dipping tray, start the mold to automatically dip the glue, and after the mixed glue is solidified on the mold, send it to the low-pressure drying system and dry it for 100 minutes at a temperature of 45°C and a relative humidity of 60% to obtain the capsule cap body rubber blank. The temperature of the entire drying process is adjusted according to the parameters of the mixed glue and the changes in the gelatin molecular chain after the mixed glue is dipped and molded. Among them, the rubber blank drying process is multiple drying, and after drying, it is placed in a high humidity environment to absorb water and then repeated for 2 cycles of drying.
[0032] (iv) cooling, demoulding, cutting, fitting, inspecting and packaging the obtained gelatin blank after drying to obtain a high-stability gelatin hollow capsule, which can be used in the field of drug loading technology.
[0033] Example 5: Figure 1 As shown, a method for preparing a high-stability hollow capsule of the present invention comprises the following steps: (I) Weigh a certain amount of gelatin, which is one or a combination of bone gelatin and skin gelatin. Pre-treat 20% of the total amount of gelatin before adding; the specific steps of pre-treatment are: add 500L of deionized water to every 1kg of gelatin, heat it in a 60℃ water bath to dissolve, add 10% Ɛ-polylysine, then add 20U of microbial glutamine transaminase to react for 12h, then inactivate the enzyme at 95℃, and finally add 5% ethyl maltol solution.
[0034] (II) Based on the total mass of gelatin, untreated gelatin, pretreated gelatin, and 1% gallic acid, 0.5% tannic acid, 1.5% catechin, 2.5% maltodextrin, and 1% β-cyclodextrin are added to the sol tank, the valve of the sol tank is closed, purified water is injected into the sol tank, and 3 kg of purified water is injected into each kilogram of gelatin. The circulating water in the interlayer of the sol tank is heated to 85°C, so that the temperature of the gelatin solution is controlled at about 90°C, and stirred until it is completely dissolved. The sol tank is vacuumed until there are no bubbles in the gelatin solution. After the temperature drops to 65°C, the vacuuming is stopped, the vacuum valve and vacuum pump are closed, and the prepared gelatin solution is left to stand and kept warm at 60°C for 12 hours to obtain a stable gelatin solution. Clamp a 220-mesh filter bag onto the glue outlet of the glue sol tank and tighten it. Then place the glue barrel just below the glue outlet, open the glue outlet valve and release the required amount. Cool the glue liquid to 45°C, match the colors, and let it stand for natural degassing to obtain the mixed glue, which is ready for dipping in glue.
[0035] (III) Inject the mixed glue into the glue dipping tray, start the mold to automatically dip the glue, and after the mixed glue is solidified on the mold, send it to the low-pressure drying system and dry it for 100 minutes at a temperature of 45°C and a relative humidity of 60% to obtain the capsule cap body rubber blank. The temperature of the entire drying process is adjusted according to the parameters of the mixed glue and the changes in the gelatin molecular chain after the mixed glue is dipped and molded. Among them, the rubber blank drying process is multiple drying, and after drying, it is placed in a high humidity environment to absorb water and then repeated for 2 cycles of drying.
[0036] (iv) cooling, demoulding, cutting, fitting, inspecting and packaging the obtained gelatin blank after drying to obtain a high-stability gelatin hollow capsule, which can be used in the field of drug loading technology.
[0037] Comparative Example 1: Based on the total mass of gelatin, gelatin and 1% gallic acid by mass are placed in a sol tank, all valves of the sol tank are closed, purified water is injected into the sol tank, 3kg of purified water is injected into each kilogram of gelatin, and the circulating water in the interlayer of the sol tank is heated to 85°C, so that the temperature of the glue solution is controlled at about 80°C, and stirred until it is completely dissolved. The sol tank is vacuumed until there are no bubbles in the glue solution, and the vacuuming is stopped after the temperature drops to 65°C, the vacuum valve and vacuum pump are closed, and a 220-mesh filter bag is clamped on the glue outlet of the sol tank and clamped, and then the glue barrel is placed directly below the glue outlet, and the glue outlet valve is opened to release the required amount; after color matching and natural degassing, a mixed glue is obtained, which is prepared for dipping. The mixed glue is injected into the glue dipping tray, and the mold is turned on to automatically dip the glue. After the mixed glue is solidified on the mold, it is sent to the production line drying system and dried for 100 minutes at a drying temperature of 28°C and a drying humidity of 45%. After drying, it is placed in a high humidity environment to absorb water and then repeated for 2 cycles of drying. The temperature of the entire drying process is adjusted according to the parameters of the mixed glue and the changes in the gelatin molecular chain after the mixed glue is dipped and formed. The rubber blank obtained after drying is cooled, demoulded, cut, fitted, inspected, and packaged to obtain high-stability gelatin hollow capsules.
[0038] Comparative Example 2: Based on the total mass of gelatin, gelatin and 1% mass fraction of gallic acid are placed in a sol tank, all valves of the sol tank are closed, purified water is injected into the sol tank, 3kg of purified water is injected into each kilogram of gelatin, and the circulating water in the interlayer of the sol tank is heated to between 85℃, so that the temperature of the glue liquid is controlled at about 80℃, and stirred until it is completely dissolved. The sol tank is vacuumed until there are no bubbles in the glue liquid, and the vacuum is stopped after the temperature drops to 65℃, the vacuum valve and the vacuum pump are closed, and a 220-mesh filter bag is clamped on the glue outlet of the sol tank and clamped, and then the glue barrel is placed directly below the glue outlet, and the glue outlet valve is opened to the required amount; then the color is matched, and the natural degassing is allowed to stand to obtain a mixed glue, which is prepared for dipping. The mixed glue is injected into the dipping tray, and the mold is automatically dipped in glue when the machine is turned on. After the mixed glue is solidified on the mold, it is sent to the production line drying system and dried for 100 minutes at a drying temperature of 28℃ and a drying humidity of 45%. The temperature of the whole drying process is adjusted according to the parameters of the mixed glue and the changes of the gelatin molecular chain after the mixed glue is dipped and formed. The obtained rubber blank after drying is cooled, demoulded, cut, fitted, inspected and packaged to obtain high-stability gelatin hollow capsules.
[0039] (I) Performance analysis of hollow capsules of Examples 1 to 5 and Comparative Examples 1 to 2: (1) Analysis of water loss rate of hollow capsules in low humidity environment: The hollow capsules obtained in Examples 1 to 5 and Comparative Examples 1 to 2 and the purchased common hollow capsules were placed under conditions of 25° C. and 60% humidity for 24 hours and weighed to obtain a mass of m1. The hollow capsules were then placed under conditions of 40° C. and 20% humidity for 24 hours and weighed to obtain a mass of m2. .
[0040] (2) Analysis of water loss rate of hollow capsules in high humidity environment: The hollow capsules obtained in Examples 1 to 5 and Comparative Examples 1 to 2 and the purchased common hollow capsules were placed under conditions of 25° C. and 45% humidity for 24 hours and weighed to obtain a mass of m1. The hollow capsules were then placed under conditions of 40° C. and 80% humidity for 24 hours and weighed to obtain a mass of m2. .
[0041] Table 1 Experimental results of hollow capsules obtained in Examples 1 to 5 and Comparative Examples 1 to 2:
[0042] .
[0043] As shown in Table 1, the water loss and water gain of the hollow capsules in Examples 1 to 5 under low humidity and high humidity environments are better than those of ordinary hollow capsules, and the hollow capsules in Example 4 have good performance under both low humidity and high humidity conditions. It can be seen that the addition of auxiliary materials such as maltodextrin and tannic acid can improve the stability of the hollow capsules under low humidity or high humidity conditions.
[0044] (3) Powder filling: The Chinese medicinal powder was filled into the hollow capsules obtained in Examples 1 to 5 and Comparative Examples 1 to 2 and purchased common hollow capsules to prepare capsule preparations with each capsule filled with 0.45 g of Chinese medicinal powder.
[0045] (4) Analysis of water loss in capsule preparations: The mass of the hollow capsule before filling with medicinal powder is weighed as m1. After the hollow capsule is filled with Chinese medicinal powder and placed in a specific environment for a period of time, the mass of the hollow capsule after the medicinal powder is weighed is m2. .
[0046] Table 2 Water loss results of hollow capsules obtained in Examples 1 to 5 and Comparative Examples 1 to 2:
[0047] .
[0048] (5) Analysis of the brittleness of empty capsules: Take 50 hollow capsules obtained in Examples 1 to 5 and Comparative Examples 1 to 2 and 50 ordinary hollow capsules purchased, and put them one by one into a glass tube (inner diameter 24 mm, length 200 mm) erected on a wooden board (thick bottom 2 cm), and let a cylindrical weight (made of polytetrafluoroethylene, with a diameter of 22 mm and a weight of 20±0.1 g) fall freely from the mouth of the glass tube to see if the capsules are broken. If broken, no more than 5 capsules (quality standard) shall be allowed.
[0049] Table 3 Results of brittleness analysis of hollow capsules obtained in Examples 1 to 5 and Comparative Examples 1 to 2:
[0050] .
[0051] As shown in Tables 2 and 3, the water loss of the hollow capsules of Example 5 after filling with medicinal powder is minimal, and its friability ratio is also relatively good, which indicates that the addition of auxiliary materials such as maltodextrin and tannic acid can effectively improve the water loss after filling with Chinese medicinal powder and improve the friability of the capsules.
[0052] (II) Stability analysis of linaclotide capsules: (1) Filling of linaclotide powder: The linaclotide powder was weighed and filled into the hollow capsules obtained in Examples 1 to 5 and the purchased common hollow capsules to prepare capsule preparations containing 0.290 mg of linaclotide per capsule.
[0053] (2) Stability test of linaclotide capsules: Seven capsules of the same type prepared as above and 2 g of silica gel desiccant were placed in a sealed bottle, and the bottle was stored under hot and humid conditions of 40°C and 75% RH for 2 months. The contents of related substances in each linaclotide capsule at 0 month, 1 month and 2 month and the purity of the linaclotide capsule were detected by HPLC, and the average values were calculated. The results are shown in Table 4 below.
[0054] Table 4 Stability results of linaclotide capsules obtained in Examples 1 to 5 and Comparative Examples 1 to 2:
[0055] .
[0056] As shown in Table 4, the content of impurity Cys1-IMD in the linaclotide capsules prepared in Example 5 is significantly lower than that in ordinary capsules, and the chromatographic purity of the linaclotide capsules of Examples 1 to 3 is significantly higher than that of purchased ordinary capsules, indicating that the addition of excipients such as maltodextrin and tannic acid can improve the stability of hollow capsules, reduce their water release, and thus reduce the effect of water on the drug.
[0057] The above are preferred embodiments of the present invention. It should be pointed out that, for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.
Claims
1. A method for preparing high-stability hollow capsules, characterized in that: The following steps are involved: Step 1: Weigh a certain amount of gelatin, add 0.5-5% of the auxiliary materials based on the total mass of gelatin, dissolve in 75-90℃ distilled water, and stir until completely dissolved; Step 2: The glue solution prepared in step 1 is placed at 45-60°C and kept warm for 8-12 hours to obtain a stable glue solution; Step 3: Cool the glue solution prepared in step 2 to 40-50° C., dip it into glue for molding, and dry it for 50-200 minutes at a temperature of 25-45° C. and a relative humidity of 30-60% to obtain a capsule cap body glue blank; Step 4: demoulding, cutting and fitting the rubber blank to obtain a hollow capsule with high stability.
2. The method for preparing the high-stability hollow capsule according to claim 1, characterized in that: The gelatin is one or a combination of bone gelatin and skin gelatin.
3. The method for preparing the high-stability hollow capsule according to claim 1, characterized in that: The auxiliary material is a group or combination of gallic acid, tannic acid, catechin, maltodextrin and beta-cyclodextrin.
4. The method for preparing high-stability hollow capsules according to claim 1, characterized in that: In step 1, 0-20% of the total amount of gelatin is pretreated before adding; The specific steps of the pretreatment are: adding 100-500 L of deionized water to every 1 kg of gelatin, heating in a water bath at 40-60° C. to dissolve, adding 1-10% Ɛ-polylysine, and then adding 1-20 U of microbial glutamine transaminase to react for 6-12 hours, and then inactivating the enzyme at 95° C., and finally adding 1-5% ethyl maltol solution.
5. A high-stability hollow capsule prepared by the preparation method according to any one of claims 1 to 4.
6. The high stability hollow capsule according to claim 5, characterized in that: The hollow capsule drying process is multiple drying, after drying, it is placed in a high humidity environment to absorb water and then repeated drying for two times.
7. Use of the high-stability hollow capsule according to claim 6 in the field of drug loading.