Process for the preparation of enteric seamless microcapsules in one step and its application

Abstract

The present application relates to the technical field of microcapsule preparation, in particular to a one-step process for preparing enteric seamless microcapsules and application thereof.The preparation process comprises the following steps: preparing a wall material liquid and a core material liquid, dropping the wall material liquid and the core material liquid into a cooling liquid through a concentric nozzle to form microcapsules, filtering and collecting the microcapsules and placing them in a room temperature drying device for 2-4 hours to obtain enteric seamless microcapsules; the wall material liquid and the core material liquid are respectively introduced into the outer layer and the inner layer of the concentric nozzle; the cooling liquid is an enteric coating powder solution.The raw material ratio of the wall material liquid, the core material liquid and the cooling liquid is optimized, the wall material liquid and the core material liquid are simultaneously dropped into the cooling liquid through the concentric nozzle, and the obtained seamless microcapsules have enteric solubility, can resist gastric juice erosion and only disintegrate rapidly in the intestinal environment; the process has simple preparation steps, is fast, has high product yield, is safe and has wide application.

Description

Technical Field

[0001] This invention relates to the field of microcapsule formulation technology, specifically to a one-step process for preparing enteric-coated seamless microcapsules and its application. Background Technology

[0002] Microencapsulation technology is a technique that uses natural or synthetic polymers to encapsulate solid or liquid core substances into tiny capsules with a diameter of less than 5000 μm. It is commonly used to protect sensitive bioactive substances. Currently, microencapsulation technology is widely used in animal science, livestock production, and the pharmaceutical field.

[0003] Microbiome transplantation (CMPT) has become a hot research focus in recent years. This technology involves extracting gut microbiota from a healthy donor, preparing it into a suspension or oral capsule, and then transplanting it to the patient to restore gut microbiota homeostasis and treat related diseases. The main dosage forms for microbiome transplantation are suspensions and oral capsules. Suspensions are primarily used for invasive transplantation procedures such as nasoenteric tubes and gastroscopy / colonoscopy, while oral capsules are simply swallowed by the patient. Compared to invasive transplantation methods, oral capsules offer a better patient experience, higher compliance, and greater acceptance. However, current oral capsules are too large, making them difficult for children or people with swallowing difficulties to swallow. Furthermore, existing capsule manufacturing processes use liquid paraffin as a coolant, which is difficult to clean and prone to residue, potentially causing adverse reactions such as diarrhea, nausea, and vomiting. In addition, current manufacturing processes cause the outer layer of the capsule to dissolve rapidly when soaked in warm water or warm milk at around 40°C, leading to capsule disintegration and the release of the contents before reaching the intestines, reducing the effectiveness of the treatment.

[0004] Therefore, it is necessary to develop an enteric-coated seamless microcapsule that can reach and release completely into the intestinal environment. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides a one-step process for preparing enteric-coated seamless microcapsules and its applications. The seamless microcapsules prepared by this process are enteric-coated, resistant to gastric acid erosion, and remain intact in warm water without dissolving, rapidly disintegrating only in the intestinal environment. Furthermore, this process is simpler, faster, and has wider applicability.

[0006] To achieve the above objectives, the present invention provides the following technical solution: The first aspect of the present invention provides a one-step process for preparing enteric seamless microcapsules, comprising the following steps: preparing a wall material liquid and a core material liquid; dripping the wall material liquid and the core material liquid into a cooling liquid through a concentric dropper to form microcapsules; filtering and collecting the microcapsules and drying them at room temperature for 2-4 hours to obtain enteric seamless microcapsules. The wall material liquid and the core material liquid are respectively introduced into the outer and inner layers of the concentric dripper; The coolant is an enteric-coated powder solution; the particle size of the enteric seamless microcapsules is 2-3 mm.

[0007] Furthermore, the enteric coating powder solution is obtained by dissolving the enteric coating powder in an ethanol solution with a mass concentration of 85-90%; the enteric coating powder is food-grade. The use of 85-90% ethanol in this technical solution reduces the cooling oil cleaning step in conventional microcapsule preparation processes, achieves residue-free results, and simplifies and safes the process. In some specific embodiments, coating components such as zein, shellac, cellulose acetate phthalate, etc., or other functional components can be added to the cooling liquid to improve the functionality of the microcapsules.

[0008] Furthermore, the preparation method of the wall material liquid is as follows: first, prepare a 40% gelatin solution; after gelling, add L-type carrageenan, K-type carrageenan, pectin, and low-acyl gellan gum respectively, stir until completely dissolved, and let stand to defoam, thus obtaining the final product. Pectin has good stability under acidic conditions and is not easily affected by pH changes. Adding a certain amount can effectively improve the stability of microcapsules in gastric juice. At the same time, pectin is also a dietary fiber, which is beneficial to human health and can act as a prebiotic to promote the growth of probiotics. Carrageenan and gellan gum have good stability under acidic and high-temperature conditions and are not easily decomposed. Adding a certain amount can significantly improve the stability of microcapsules in gastric juice and high-temperature environments.

[0009] Furthermore, the gelatin is BL200.

[0010] Furthermore, the amount of L-type carrageenan added is 0.1-1% of the mass of the gelatin solution; the amount of K-type carrageenan added is 0.1-1% of the mass of the gelatin solution; the amount of pectin added is 1-5% of the mass of the gelatin solution; and the amount of low-acyl gellan gum added is 0.1-0.2% of the mass of the gelatin solution.

[0011] Furthermore, the preparation method of the core material liquid is as follows: soybean lecithin, mono- and diglyceride fatty acid esters, and the contents are added to an oil solvent and stirred until uniformly mixed. Soybean lecithin, as an emulsifier and stabilizer, can prevent precipitation of the contents in the core material liquid during the preparation process, and can also act as an antioxidant to prevent the contents from being oxidized; mono- and diglyceride fatty acid esters, as emulsifiers and stabilizers, can also act as dispersants, promoting uniform distribution of the contents in the core material liquid, so that the quality of the finally prepared seamless capsules is stable and controllable.

[0012] Furthermore, the oil solvent is one or more of refined vegetable oil, shortening, lard, coconut oil, and butter; the amount of soybean lecithin added is 0.1% of the mass of the oil solvent; the amount of mono- and diglyceride fatty acid esters added is 0.5% of the mass of the oil solvent; and the amount of the contents added is 20-40% of the mass of the oil solvent.

[0013] Furthermore, the contents are one or more of the following: probiotic freeze-dried powder, intestinal flora freeze-dried powder, other active ingredients or pharmaceutical ingredients, and must be passed through a 100-mesh sieve before use.

[0014] A second aspect of the present invention also provides the application of the above-described process in the preparation of seamless microcapsules for improving gut microbiota.

[0015] A third aspect of the present invention also provides the application of the above-described process in the preparation of seamless microcapsules for the treatment of intestinal-related diseases.

[0016] The beneficial effects of this invention are: This invention optimizes the raw material ratio of the wall material liquid, core material liquid, and coolant. The wall material liquid and core material liquid are simultaneously introduced into the coolant through concentric droppers, allowing for rapid solidification into seamless microcapsules, forming double-layered concentric microcapsules. Simultaneously, the enteric coating component in the coolant adheres to and coats the solidified wall material surface, forming the outermost enteric coating layer. The resulting seamless microcapsules have three layers, exhibit enteric properties, resist gastric acid erosion, and remain intact in 40°C warm water without dissolving, only rapidly disintegrating in the intestinal environment. This invention's process is simpler, faster, has a higher yield, and is safer. It can be widely used in the preparation of seamless microcapsules for gut microbiota and other treatments of intestinal-related diseases. Attached Figure Description

[0017] Figure 1 This is a process flow diagram of the one-step preparation of enteric-coated seamless microcapsules according to the present invention; Figure 2 This is a schematic diagram of the structure of the one-step method for preparing enteric-coated seamless microcapsules according to the present invention; Figure 3 This is a comparison diagram of the seamless microcapsules of the present invention and conventional seamless capsules incubated in gastric juice for 3 hours, where a is the seamless microcapsule of Example 1 of the present invention and b is a commercially available conventional seamless capsule.

[0018] The present invention will be further described below with reference to the accompanying drawings and embodiments. Detailed Implementation

[0019] To better illustrate the technical solution of the present invention, the following will explain the solution of the present invention in conjunction with embodiments. Those skilled in the art will understand that the following embodiments are only for illustrating the present invention and should not be considered as limiting the scope of the present invention. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques described in literature or reference books in the field or according to the product instructions. Reagents or instruments used, unless otherwise specified, are all conventional products.

[0020] The above-described technical features of the present invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions.

[0021] This invention specifically provides a one-step process for preparing enteric-coated seamless microcapsules, the specific process flow of which is as follows: Figure 1 As shown, the process includes the following steps: preparing wall material liquid and core material liquid; dripping the wall material liquid and core material liquid into the coolant through a concentric dropper to form microcapsules; filtering and collecting the microcapsules and drying them at room temperature for 2-4 hours to obtain enteric-coated seamless microcapsules with three layers: the innermost layer is the core material, the middle layer is the wall material, and the outermost layer is the enteric coating. A schematic diagram of its structure is shown below. Figure 2 As shown. Specifically, the enteric-coated seamless microcapsules have a particle size of 2-3 mm, making them easy for children and people with swallowing difficulties to take, resulting in good compliance.

[0022] Specifically, the wall material liquid and the core material liquid are respectively filled into the outer and inner layers of the concentric dripper.

[0023] The preparation method of the wall material liquid is as follows: First, prepare a 40% gelatin solution. After the gel has dissolved, add L-type carrageenan, K-type carrageenan, pectin, and low-acyl gellan gum respectively, stirring until completely dissolved. Let it stand to defoam, and the liquid is obtained. More specifically, the gelatin is BL200; the amount of L-type carrageenan added is 0.5-1% of the mass of the gelatin solution; the amount of K-type carrageenan added is 0.1-1% of the mass of the gelatin solution; the amount of pectin added is 1-5% of the mass of the gelatin solution; and the amount of low-acyl gellan gum added is 0.1-0.2% of the mass of the gelatin solution.

[0024] The preparation method of the core material solution is as follows: Soybean lecithin, mono- and diglycerides of fatty acids, and the contents are added to an oil solvent and stirred until homogeneous. More specifically, the oil solvent is one or more of refined vegetable oil, shortening, lard, coconut oil, and butter; the amount of soybean lecithin added is 0.1% of the mass of the oil solvent; the amount of mono- and diglycerides of fatty acids added is 0.5% of the mass of the oil solvent; and the amount of the contents added is 20-40% of the mass of the oil solvent. Furthermore, the contents are lyophilized probiotic powder, lyophilized intestinal flora powder, other active ingredients, or pharmaceutical ingredients, and must be passed through a 100-mesh sieve before use.

[0025] Specifically, the coolant is an enteric coating powder solution; the enteric coating powder solution is obtained by dissolving the enteric coating powder in an ethanol solution with a mass concentration of 85-90%; the enteric coating powder is a food-grade coating powder; the present invention uses an ethanol solution as a solvent for the enteric coating powder, which is safe, leaves no residue, and can reduce the cooling oil cleaning steps in conventional microcapsule preparation processes, making it more convenient.

[0026] The following is a further explanation with reference to specific embodiments.

[0027] Example 1 The process for preparing seamless microcapsules of enteric-coated gut microbiota in one step includes the following steps: The prepared wall material liquid and core material liquid were respectively loaded into the outer and inner layers of the concentric dropper, and then dripped into the cooling liquid through the concentric dropper to form microcapsules. The microcapsules were filtered, collected, and dried at room temperature for 3 hours to obtain seamless microcapsules of enteric intestinal flora.

[0028] The preparation method of the wall material liquid is as follows: First, prepare a 40% BL200 gelatin solution. After the gel is dissolved, add 0.5% L-type carrageenan, 1% K-type carrageenan, 2% pectin, and 0.2% low-acyl gellan gum by mass of the gelatin solution. Stir until completely dissolved, let stand to defoam, and the liquid is obtained. The preparation method of the core material liquid is as follows: add 0.1% soybean lecithin, 0.5% mono- and diglyceride fatty acid esters, and 40% lyophilized intestinal flora powder (passed through a 100-mesh sieve) by mass to refined vegetable oil, and stir until evenly mixed to obtain the core material liquid. Preparation of coolant: Dissolve food-grade coating powder in 90% ethanol solution to obtain the coolant.

[0029] Example 2 The one-step process for preparing seamless microcapsules of enteric probiotics includes the following steps: The prepared wall material liquid and core material liquid were respectively loaded into the outer and inner layers of the concentric dropper, and then dripped into the cooling liquid through the concentric dropper to form microcapsules. The microcapsules were filtered, collected, and dried at room temperature for 4 hours to obtain seamless microcapsules of enteric probiotics.

[0030] The preparation method of the wall material liquid is as follows: First, prepare a 40% BL200 gelatin solution. After the gel is dissolved, add 0.1% L-type carrageenan, 0.5% K-type carrageenan, 5% pectin, and 0.1% low-acyl gellan gum by mass of the gelatin solution respectively. Stir until completely dissolved, let stand to defoam, and the liquid is obtained. The preparation method of the core material liquid is as follows: add 0.1% of soybean lecithin, 0.5% of mono- and diglycerides of fatty acids and 30% of Bifidobacterium probiotic freeze-dried powder (passed through a 100-mesh sieve) to shortening, and stir until evenly mixed to obtain the core material liquid. Preparation of coolant: Dissolve food-grade coating powder in 88% ethanol solution to obtain the coolant.

[0031] Example 3 A one-step process for preparing seamless microcapsules of enteric digestive enzymes includes the following steps: The prepared wall material liquid and core material liquid are respectively loaded into the outer and inner layers of the concentric dropper, and then dripped into the cooling liquid through the concentric dropper to form microcapsules. The microcapsules are filtered, collected, and dried at room temperature for 2-4 hours to obtain seamless microcapsules of enteric probiotics.

[0032] The preparation method of the wall material liquid is as follows: First, prepare a 40% BL200 gelatin solution. After the gel is dissolved, add 1% L-type carrageenan, 0.1% K-type carrageenan, 1% pectin, and 0.2% low-acyl gellan gum by mass of the gelatin solution. Stir until completely dissolved, let stand to defoam, and the liquid is obtained. The preparation method of the core material liquid is as follows: add 0.1% soybean lecithin, 0.5% mono- and diglyceride fatty acid esters, and 20% lyophilized digestive enzyme powder (passed through a 100-mesh sieve) by weight to coconut oil, and stir until they are evenly mixed. Preparation of coolant: Dissolve food-grade coating powder in 85% ethanol solution to obtain the coolant.

[0033] Comparative Example 1 The process for preparing seamless microcapsules of enteric flora in one step differs from that in Example 1 in that the preparation method of the wall material solution is as follows: first, prepare a 40% BL200 gelatin solution, and after gelling, add 0.5% L-type carrageenan, 1% K-type carrageenan, and 0.2% low-acyl gellan gum by mass of the gelatin solution, stir until completely dissolved, and let stand to defoam, and the result is obtained. The rest is the same as in Example 1.

[0034] Comparative Example 2 The process for preparing seamless microcapsules of enteric flora in one step differs from that in Example 1 in that the preparation method of the wall material solution is as follows: first, prepare a 40% BL200 gelatin solution, and after gelling, add 2% pectin and 0.2% low acyl gellan gum by weight of the gelatin solution, stir until completely dissolved, and let stand to defoam, and the result is obtained. The rest is the same as in Example 1.

[0035] Comparative Example 3 The process for preparing seamless microcapsules of enteric flora in one step differs from that in Example 1 in that the preparation method of the wall material solution is as follows: first, prepare a 40% BL200 gelatin solution, and after gelling, add 0.5% L-type carrageenan, 1% K-type carrageenan, and 2% pectin by weight of the gelatin solution, stir until completely dissolved, and let stand to defoam, and the result is obtained. The rest is the same as in Example 1.

[0036] Comparative Example 4 The process for preparing seamless microcapsules of enteric flora in one step differs from that in Example 1 in that the wall material liquid is a 40% BL2000 gelatin solution and the coolant is liquid paraffin; otherwise, it is the same as in Example 1.

[0037] Comparative Example 5 The process for preparing seamless microcapsules of enteric flora in one step differs from that in Example 1 in that the preparation method of the core material liquid is as follows: soybean lecithin and contents are added to an oil solvent and stirred until they are mixed evenly. The rest is the same as in Example 1.

[0038] Comparative Example 6 The process for preparing seamless microcapsules of enteric flora in one step differs from that in Example 1 in that the preparation method of the core material liquid is as follows: mono- and diglyceride fatty acid esters and contents are added to an oil solvent and stirred until they are mixed evenly. The rest is the same as in Example 1.

[0039] Test case 1. Testing the gastric acid resistance of enteric-coated seamless microcapsules The dried enteric-coated seamless microcapsules from Example 1 and commercially available conventional probiotic microcapsules were respectively incubated in simulated gastric fluid, and their disintegration was observed. The results showed that the conventional probiotic microcapsules began to disintegrate after approximately 2.5 hours and completely disintegrated after approximately 4 hours, while the enteric-coated seamless microcapsules prepared in this invention showed no disintegration after 4 hours of incubation in gastric fluid. A comparison image after 3 hours of incubation in gastric fluid is shown below. Figure 3 As shown.

[0040] The artificial gastric juice is prepared according to the formula in the Chinese Pharmacopoeia. Take 16.4 mL of dilute hydrochloric acid, add about 800 mL of water and 10 g of pepsin, shake well and then dilute with water to 1000 mL.

[0041] 2. Disintegration of enteric-coated seamless microcapsules upon soaking in warm water The dried enteric-coated seamless microcapsules from Example 1 and commercially available seamless capsules were soaked in warm water (40°C) and warm milk (40°C) respectively, and the disintegration was observed. The results are shown in Table 1.

[0042] Table 1. Stability in warm water and warm milk

[0043] As can be seen from the results in Table 1, the enteric-coated seamless microcapsules of the present invention remained intact after being soaked in warm water (40°C) and warm milk (40°C) for 30 minutes, while conventional seamless capsules partially or completely disintegrated in the outer layer after 15 minutes. This indicates that the enteric-coated seamless microcapsules prepared by the present invention have better stability in warm water and warm milk.

[0044] 3. Observe the stability of microcapsules prepared with different wall material liquid formulations and cooling liquid formulations in gastric juice and high temperature environment. The microcapsules obtained in Example 1 and Comparative Examples 1-4 were incubated in artificial gastric juice and soaked in warm water, respectively, and the disintegration was observed. The results are shown in Table 2.

[0045] Table 2. Stability in gastric juice and warm water at 40°C

[0046] The results in Table 2 show that the wall material solutions in Comparative Examples 1-3 lacked pectin, carrageenan, and low-acyl gellan gum, respectively, resulting in a decrease in their stability under gastric juice and high-temperature conditions. This indicates that the simultaneous addition of certain amounts of pectin, carrageenan, and low-acyl gellan gum can improve the stability of microcapsules under gastric juice and high-temperature conditions, suggesting a synergistic effect among the three. In Comparative Example 4, the microcapsules prepared using conventional microencapsulation methods exhibited a more significant decrease in stability under gastric juice and high-temperature conditions because the wall material solution only used gelatin and the coolant was paraffin. Furthermore, the paraffin required washing, which was not only cumbersome but also prone to leaving residues. In contrast, the optimized wall material solution and coolant of this invention effectively improved the gastric acid resistance and high-temperature resistance of the microcapsules, and required no washing with no residues.

[0047] 3. Observe the encapsulation of microcapsules prepared with different core material liquid formulations. The appearance and yield of the microcapsules obtained in Example 1 and Comparative Examples 5 and 6 are shown in Table 3 (wherein, yield = number of qualified microcapsules / total number of microcapsules prepared).

[0048] Table 3. Microcapsule appearance and yield

[0049] As can be seen from the results in Table 3, the core material liquid formulations of Comparative Examples 5 and 6 lacked soybean lecithin and mono- and diglyceride fatty acid esters, respectively. Compared with Example 1, Comparative Examples 5 and 6 showed changes in appearance, including cracking, leakage of core material, and irregular appearance. In addition, obvious particulate matter and dropper blockage occurred during the preparation process, resulting in failure to form the desired shape. The main reason for this is that the lack of soybean lecithin or mono- and diglyceride fatty acid esters caused the core material components to agglomerate and disperse unevenly during the preparation and dissolution process, thus affecting the yield. In contrast, the present invention adds soybean lecithin and mono- and diglyceride fatty acid esters to the core material liquid, which promotes uniform dispersion of the freeze-dried powder, prevents agglomeration and precipitation, and makes the seamless microcapsules of stable quality and high yield.

[0050] In summary, this invention optimizes the raw material ratio of wall material liquid, core material liquid, and coolant, and simultaneously drips the wall material liquid and core material liquid into the coolant through concentric droppers. The seamless microcapsules produced in one step have enteric properties, can resist gastric acid erosion, rapidly disintegrate only in the intestinal environment, have good temperature resistance, high yield, are safe, and have wide applications.

[0051] Finally, it should be emphasized that the above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention can have various changes and modifications. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A one-step process for preparing enteric-coated seamless microcapsules, characterized in that, Includes the following steps: Prepare wall material liquid and core material liquid, and drip the wall material liquid and core material liquid into the cooling liquid through a concentric dropper to form microcapsules. Filter and collect the microcapsules and dry them at room temperature for 2-4 hours to obtain enteric seamless microcapsules. The wall material liquid and the core material liquid are respectively introduced into the outer and inner layers of the concentric dripper; The coolant is an enteric-coated powder solution.

2. The process for preparing enteric-coated seamless microcapsules in one step according to claim 1, characterized in that, The enteric coating powder solution is obtained by dissolving the enteric coating powder in an ethanol solution with a mass concentration of 85-90%; the enteric coating powder is a food-grade coating powder.

3. The process for preparing enteric-coated seamless microcapsules in one step according to claim 1, characterized in that, The preparation method of the wall material liquid is as follows: first prepare a 40% gelatin solution, and after it has dissolved, add L-type carrageenan, K-type carrageenan, pectin and low-acyl gellan gum respectively, stir until completely dissolved, let stand to defoam, and the liquid is obtained.

4. The process for preparing enteric-coated seamless microcapsules in one step according to claim 3, characterized in that, The gelatin is BL200.

5. The one-step process for preparing enteric-coated seamless microcapsules according to claim 3, characterized in that, The amount of L-type carrageenan added is 0.1-1% of the mass of the gelatin solution; the amount of K-type carrageenan added is 0.1-1% of the mass of the gelatin solution; the amount of pectin added is 1-5% of the mass of the gelatin solution; and the amount of low-acyl gellan gum added is 0.1-0.2% of the mass of the gelatin solution.

6. The process for preparing enteric-coated seamless microcapsules in one step according to claim 1, characterized in that, The preparation method of the core material liquid is as follows: soybean lecithin, mono- and diglyceride fatty acid esters, and contents are added to an oil solvent and stirred until they are evenly mixed.

7. The process for preparing enteric-coated seamless microcapsules in one step according to claim 6, characterized in that, The oil solvent is one or more of refined vegetable oil, shortening, lard, coconut oil, and butter; the amount of soybean lecithin added is 0.1% of the mass of the oil solvent; the amount of mono- and diglyceride fatty acid esters added is 0.5% of the mass of the oil solvent; and the amount of the contents added is 20-40% of the mass of the oil solvent.

8. The process for preparing enteric-coated seamless microcapsules in one step according to claim 6, characterized in that, The contents are one or more of probiotic freeze-dried powder and intestinal flora freeze-dried powder, and must be passed through a 100-mesh sieve before use.

9. The application of a one-step process for preparing enteric-coated seamless microcapsules as described in any one of claims 1-8 in the preparation of seamless microcapsules for improving gut microbiota.

10. The application of a one-step process for preparing enteric-coated seamless microcapsules as described in any one of claims 1-8 in the preparation of seamless microcapsules for treating intestinal-related diseases.

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