Production process of colonic-soluble hydroxypropyl methylcellulose hollow capsule

Abstract

The invention discloses a production process of a colonic-soluble hydroxypropyl methylcellulose hollow capsule, which comprises the following steps: selecting two kinds of hydroxypropyl methylcellulose with different viscosity specifications to be compounded as capsule wall material main materials, and matching with a plasticizer, an enteric-soluble pore-foaming agent, a gel and an antioxidant; the preparation method comprises the following steps: dissolving high-viscosity hydroxypropyl methylcellulose in warm water, adding a solution obtained by dissolving low-viscosity hydroxypropyl methylcellulose in water, continuously stirring to form a uniform solution, sequentially adding a plasticizer, an enteric-coated pore-foaming agent, a gelling agent and an antioxidant, uniformly stirring, filtering to obtain a clarified capsule material liquid, and stirring and mixing through a stirring mechanism; injecting the capsule material liquid into a forming machine, uniformly coating the capsule material liquid on the surface of a mold, and performing pre-solidification shaping and drying to form a capsule body and a capsule cap; quantitatively spraying the functional inner coating solution on the inner walls of the capsule body and the capsule cap, and drying to form a functional inner coating; coating liquid is sprayed on the outer walls of the capsule body and the capsule cap and dried, and coating layers are formed outside the capsule body and the capsule cap.

Description

Technical Field

[0001] This invention relates to the field of capsule manufacturing technology, and more specifically, to a manufacturing process for colonically coagulated hydroxypropyl methylcellulose empty capsules. Background Technology

[0002] In oral drug delivery systems, empty capsules are widely used in clinical practice due to their advantages such as masking drug odors, improving drug stability, and ease of administration. Among these, colon-targeted delivery systems enable precise drug release in the colon, which is of great significance for the treatment of colon-specific diseases such as ulcerative colitis and Crohn's disease. Simultaneously, it avoids gastrointestinal irritation caused by premature drug release in the stomach or small intestine, thus improving drug efficacy and patient tolerability.

[0003] Existing hydroxypropyl methylcellulose colonic-coated empty capsules are prepared using hydroxypropyl methylcellulose of a single viscosity specification. The capsule material is prone to problems such as poor formability, insufficient mechanical strength, or uncontrolled dissolution rate, making it difficult to balance the forming quality of the capsule material with colonic dissolution performance. Summary of the Invention

[0004] The purpose of this invention is to overcome the shortcomings of the prior art and provide a production process for colon-coated hydroxypropyl methylcellulose empty capsules.

[0005] To achieve the above objectives, the present invention adopts the following technical solution:

[0006] This invention discloses a manufacturing process for colon-coated hydroxypropyl methylcellulose empty capsules, comprising the following steps:

[0007] Two different viscosities of hydroxypropyl methylcellulose were selected as the main encapsulation material, along with plasticizers, enteric pore-forming agents, gelling agents, and antioxidants. High-viscosity hydroxypropyl methylcellulose was dissolved in warm water, followed by the addition of a solution of low-viscosity hydroxypropyl methylcellulose dissolved in water, and stirring continued to form a homogeneous solution. Then, plasticizers, enteric pore-forming agents, gelling agents, and antioxidants were added sequentially and stirred until homogeneous. After filtration, a clear encapsulation material solution was obtained. The encapsulation material solution was injected into a molding machine to evenly coat the mold surface. After pre-curing, fixing, and drying, the capsule body and cap were formed. A functional inner coating solution was quantitatively sprayed onto the inner wall of the capsule body and cap and dried to form a functional inner coating. A coating solution was sprayed onto the outer wall of the capsule body and cap and dried to form a coating layer. The capsule bodies and caps were subjected to vibration screening and near-infrared spectroscopy scanning to remove unqualified products.

[0008] Further, by weight, it contains 80-100 parts hydroxypropyl methylcellulose, 5-15 parts plasticizer, 2-8 parts enteric pore-forming agent, 1-5 parts gelling agent, and 0.1-0.5 parts antioxidant.

[0009] Furthermore, the viscosity of high-viscosity hydroxypropyl methylcellulose is 4000-50000 mPa·s, and the viscosity of low-viscosity hydroxypropyl methylcellulose is 50-400 mPa·s, with a mass ratio of 1:2 to 2:1.

[0010] Furthermore, the plasticizer is one or a mixture of glycerol, polyethylene glycol, and triethyl citrate.

[0011] Furthermore, the antioxidant is tert-butyl-p-hydroxyanisole or di-tert-butyl-p-cresol.

[0012] Furthermore, the pre-setting and fixing conditions are a temperature of 50-60℃, a relative humidity of 40-50%, and a time of 1-3 minutes.

[0013] Furthermore, the drying conditions are a temperature of 35-45℃, a relative humidity of 25-35%, and a time of 1-2 hours.

[0014] Furthermore, the functional inner coating solution is an aqueous solution of sodium alginate or a carbomer aqueous dispersion with a mass concentration of 1-5%, and is dried at 35-45℃ for 10-20 minutes after spraying.

[0015] Further, the coating solution includes a first coating solution and a second coating solution. The first coating solution is sprayed and dried to form a first coating layer, and then the second coating solution is sprayed and dried to form a second coating layer. The first coating solution, by mass parts, consists of: 5-8 parts acrylic resin, 1-2 parts polyethylene glycol, 1-2 parts talc, and 85-92 parts 85% ethanol aqueous solution. The first coating layer is an anti-gastric juice layer. The second coating solution, by mass parts, consists of: 3-6 parts acrylic resin, 2-4 parts acrylic resin, 1-3 parts pH-sensitive polymer, 0.5-2 parts enzyme-sensitive material, 1-2 parts polyethylene glycol, and 82-90 parts 85% ethanol aqueous solution. The second coating layer is an enteric coating layer.

[0016] Furthermore, the pH-sensitive polymer is shellac or hydroxypropyl methylcellulose acetate succinate; the enzyme-sensitive material is amylose or calcium pectin.

[0017] The beneficial effects of this invention are: by using two types of hydroxypropyl methylcellulose with different viscosities, the film-forming properties and mechanical strength of the capsule material are balanced; the high-viscosity hydroxypropyl methylcellulose provides a good supporting skeleton for the capsule material, ensuring that the capsule body and capsule cap are not easily deformed after molding; the low-viscosity hydroxypropyl methylcellulose improves the fluidity and uniformity of the capsule material liquid, so that the capsule material liquid can be evenly coated on the mold surface, and after pre-curing and drying, it forms capsule bodies and capsule caps with uniform size and smooth surface, effectively reducing the defect rate such as excessive brittleness and dimensional deviation. Attached Figure Description

[0018] Figure 1 This is a schematic diagram of one structure of the stirring mechanism in this embodiment;

[0019] Figure 2 This is a schematic diagram of one structure of the auxiliary mixing tank in this embodiment;

[0020] Figure 3 for Figure 1 Enlarged view of point A in the middle;

[0021] Figure 4 for Figure 1 Enlarged diagram of point B in the middle.

[0022] Attached reference numerals: 1. Outer mixing tank; 2. Inner mixing tank; 3. Connecting plate; 4. Guide surface; 5. Drive motor one; 6. Agitator two; 7. Mounting box; 8. Agitator one; 9. Tank body; 10. Outer rim ring; 11. Tank lid; 12. Gear ring; 13. Agitator motor one; 14. Agitator; 15. Connecting rod; 16. Liquid supply pump; 17. Liquid outlet pipe; 18. Sleeve; 19. Agitator rod; 20. Support ring; 21. 1. Drive motor 2; 22. Drive gear 1; 23. Through hole; 24. Vertical rod 1; 25. Vertical rod 2; 26. Mounting cavity; 27. Opening; 28. Gear ring; 29. ​​Fixed seat; 30. Stirring motor 2; 31. Drive gear 2; 32. Connecting block; 33. Fixed screw; 34. Drive motor 3; 35. Driving bevel gear; 36. Rotating shaft; 37. Driven bevel gear; 38. Guide block; 39. Guide surface. Detailed Implementation

[0023] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0024] An enteric-coated hydroxypropyl methylcellulose empty capsule, wherein the capsule ingredients, by weight, include 80-100 parts hydroxypropyl methylcellulose, 5-15 parts plasticizer, 2-8 parts enteric pore-forming agent, 1-5 parts gelling agent, and 0.1-0.5 parts antioxidant. The manufacturing process includes the following steps:

[0025] Two different viscosity grades of hydroxypropyl methylcellulose were selected as the main capsule material. The high-viscosity hydroxypropyl methylcellulose had a viscosity of 4000-50000 mPa·s, while the low-viscosity hydroxypropyl methylcellulose had a viscosity of 50-400 mPa·s, with a mass ratio of 1:2 to 2:1. The high-viscosity hydroxypropyl methylcellulose provides sufficient mechanical strength and forming support for the capsule wall, preventing capsule breakage and deformation during filling and transportation. The low-viscosity hydroxypropyl methylcellulose improves the fluidity and coating uniformity of the capsule material liquid, ensuring consistent capsule wall thickness. The two viscosities of hydroxypropyl methylcellulose work synergistically to maximize their advantages.

[0026] The plasticizer is one or a mixture of glycerol, polyethylene glycol, and triethyl citrate. Further, the antioxidant is tert-butyl-p-hydroxyanisole or di-tert-butyl-p-cresol.

[0027] After dissolving high-viscosity hydroxypropyl methylcellulose (HPMC) in warm water, a solution of low-viscosity HPMC in water is added and stirred to form a homogeneous solution. This stepwise dissolution method effectively avoids localized agglomeration and incomplete dissolution caused by the difference in dissolution rates between the two HPMCs of different viscosities.

[0028] Then, plasticizer, enteric pore-forming agent, gelling agent, and antioxidant are added in sequence and stirred evenly. After filtration, a clear capsule material solution is obtained. This step is carried out in a stirring mechanism.

[0029] The encapsulating material liquid is injected into the molding machine, allowing it to be evenly coated onto the mold surface. After pre-setting and drying, the encapsulation body and cap are formed. The pre-setting conditions are: temperature 50-60℃, relative humidity 40-50%, and time 1-3 minutes. The drying conditions are: temperature 35-45℃, relative humidity 25-35%, and time 1-2 hours.

[0030] A functional inner coating solution, such as sodium alginate aqueous solution or carbomer aqueous dispersion, is quantitatively sprayed onto the inner wall of the capsule body and capsule cap and dried at 35-45℃ for 10-20 minutes to form a functional inner coating. The solution mass concentration is 1-5%.

[0031] Sodium alginate or carbomer both have excellent intestinal mucosal adhesion properties, which can prolong the retention time of the capsule in the colon and improve drug absorption efficiency. At the same time, the inner coating can form the first physical barrier, reducing the erosion of the drug in the capsule by the gastric and small intestinal environment. It is especially suitable for protecting acid- and enzyme-sensitive protein and polypeptide drugs, thus broadening the scope of application of the capsule.

[0032] The capsule body and cap are sprayed with a first coating solution and dried, followed by a second coating solution and dried. This process is done using a spray method, forming a double-layer coating on the capsule body and cap. The first coating solution, by weight, consists of: 5-8 parts acrylic resin, 1-2 parts polyethylene glycol, 1-2 parts talc, and 85-92 parts 85% ethanol aqueous solution. This first coating layer acts as a gastric juice barrier, rapidly solidifying in the acidic gastric juice environment to form a dense protective film, effectively preventing premature swelling of the capsule wall or drug leakage. The second coating solution, by weight, consists of: 3-6 parts acrylic resin, 2-4 parts acrylic resin, 1-3 parts pH-sensitive polymer, 0.5-2 parts enzyme-sensitive material, 1-2 parts polyethylene glycol, and 82-90 parts 85% ethanol aqueous solution. This second coating layer is an enteric coating.

[0033] The synergistic effect of pH-sensitive polymers and enzyme-sensitive materials allows the drug to dissolve only in the weakly alkaline environment of the colon and under the enzymatic action of specific bacterial flora. Combined with the microporous channels formed by enteric pore-forming agents, this enables precise and rapid release of the drug in the colon, significantly improving the bioavailability of the drug at the lesion site.

[0034] pH-sensitive polymers are shellac or hydroxypropyl methylcellulose acetate succinate; enzyme-sensitive materials are amylose or calcium pectin.

[0035] Vibration screening is used to select the capsule body and capsule cap. Vibration screening can efficiently remove defective products that are broken or deformed. Near-infrared spectroscopy scanning is also performed to detect the uniformity of the capsule wall and coating layer thickness, ensuring the uniformity of the final product and thus obtaining qualified capsule bodies and capsule caps.

[0036] Stirring mechanism such as Figures 1-4 As shown, the system includes an outer mixing tank 1, a secondary mixing tank mounted on top of the outer mixing tank 1, and an inner mixing tank 2 installed inside the outer mixing tank 1. High-viscosity hydroxypropyl methylcellulose and water are mixed in the outer mixing tank 1, while low-viscosity hydroxypropyl methylcellulose and water are mixed in the secondary mixing tank. The mixture in the secondary mixing tank then enters the outer mixing tank 1 and mixes with the mixture in the outer mixing tank 1, thus completing the mixing of the two solutions. Several connecting plates 3 connect the outer wall of the inner mixing tank 2 and the inner wall of the outer mixing tank 1. The connecting plates 3 are vertically arranged, and the shape of the inner mixing tank 2 follows the shape of the inner wall of the outer mixing tank 1, forming a flow channel between the outer wall of the inner mixing tank 2 and the inner wall of the outer mixing tank 1. The flow channel includes a horizontal channel at the bottom and a vertical channel at the outer periphery. A guide surface 4 is provided at the connection between the horizontal and vertical channels to guide the flow of the solution, allowing the solution flowing along the horizontal channel to flow into and along the vertical channel.

[0037] A through hole 23 is provided at the bottom center of the connecting plate 3, so that the interior of the inner stirring tank 2 is connected to the flow channel. The solution entering the interior of the inner stirring tank 2 from the flow channel can return to the flow channel through the through hole 23, so that the solution can circulate.

[0038] A drive motor 5 is installed inside the outer mixing tank 1 at the guide surface 4. The drive motor 5 drives the stirring paddle 6. The drive motor 5 drives the stirring paddle 6 to run, and the stirring paddle 6 generates lift on the solution located at the junction of the horizontal and vertical channels, allowing the solution to flow upward along the vertical channel.

[0039] The outer stirring tank 1 includes a guide block 38, which is located at the top of the inner side of the outer stirring tank 1. The guide block 38 includes a guide surface 39 at the bottom, which can guide the solution flowing along the vertical channel, so that the solution flows towards the middle and lower direction, that is, the solution flows into the inner stirring tank 2.

[0040] The auxiliary mixing tank includes a tank body 9 and a lid 11 mounted on the upper part of the tank body 9. A stirring motor 13 is mounted on the upper part of the lid 11, and the stirring motor 13 drives a stirrer 14. The stirrer 14 and the stirring motor 13 are located on both sides of the lid 11. When the lid 11 is closed on the tank body 9, the stirrer 14 is located inside the tank body 9. A liquid supply pump 16 is installed at the bottom of the tank body 9. The liquid supply pump 16 is a submersible pump that can work normally when it is in the solution. The liquid supply pump 16 is connected to an outlet pipe 17, which extends out of the tank body 9. A connecting rod 15 is connected to the lower part of the tank body 9 and passes through a through hole 23. An installation box 7 is installed at the bottom of the outer mixing tank 1. The lower end of the connecting rod 15 is fixedly connected to the top of the installation box 7. A stirring paddle 8 is installed on the installation box 7, and the stirring paddle 8 is oriented in the same direction as the outlet pipe 17. The agitator 8 includes a rotating shaft 36, which is rotatably mounted on the side wall of the mounting box 7. One end of the rotating shaft 36, located inside the mounting box 7, is connected to a driven bevel gear 37. A drive motor 34 is mounted at the bottom of the connecting rod 15. The drive motor 34 drives a driving bevel gear 35, which is located inside the mounting box 7 and meshes with the driven bevel gear 37. Through the engagement of the driving bevel gear 35 and the driven bevel gear 37, the drive motor 34 can drive the agitator 8 to rotate.

[0041] When the agitator 8 is running, it pushes the solution in the middle of the bottom of the outer mixing tank 1 into the horizontal channel and flows along the horizontal channel. The solution then rises along the vertical channel and reaches the position of the outlet pipe 17 of the auxiliary mixing tank, where it can come into contact with the solution flowing out from the outlet pipe 17, thereby achieving preliminary mixing.

[0042] A support ring 20 is installed on the top of the outer mixing tank 1, and the tank body 9 is set through the support ring 20. The tank body 9 includes an outer edge ring 10, which rests on the support ring 20, allowing the tank body 9 to rotate within the support ring 20. A gear ring 12 is installed on the outer circumference of the outer edge ring 10. A second drive motor 21 is installed on the top of the outer mixing tank 1, and the second drive motor 21 drives a first drive gear 22, which meshes with the gear ring 12. The second drive motor 21 drives the first drive gear 22 to rotate, which in turn drives the meshing gear ring 12 to rotate, thereby causing the tank body 9 to rotate.

[0043] As the barrel 9 rotates, the position of the outlet pipe 17 changes. Simultaneously, the barrel 9, via the connecting rod 15, drives the mounting box 7 to rotate, changing the orientation of the stirring paddle 8. This allows the solution at different locations within the outer stirring barrel 1 to come into contact with and mix with the solution discharged from the outlet pipe 17, resulting in better mixing of the solutions in the outer stirring barrel 1 and the barrel 9.

[0044] A stirring element is installed on the connecting rod 15. The mixed solution enters the inner stirring tank 2, where the stirring element on the connecting rod 15 agitates the solution, ensuring uniform mixing. The stirring element includes a sleeve 18 fitted onto the connecting rod 15, with several stirring rods 19 connected to its outer circumference. Inner extension rings are provided at the upper and lower ends of the sleeve 18, and an annular groove is formed on the outer circumference of the connecting rod 15. The inner extension ring portion is located within the annular groove, allowing the sleeve 18 to rotate around the connecting rod 15 without shifting.

[0045] The connecting rod 15 includes a first vertical rod 24 connected to the bottom of the barrel 9 and a second vertical rod 25 connected to the top of the mounting box 7. The first vertical rod 24 and the second vertical rod 25 are connected by several connecting blocks 32. A fixing screw 33 is installed on the connecting block 32. At least one fixing screw 33 is screwed into the first vertical rod 24 and at least one fixing screw 33 is screwed into the second vertical rod 25. The bottom of the first vertical rod 24 has a mounting cavity 26. An opening 27 is opened on the side wall of the first vertical rod 24 corresponding to the position of the mounting cavity 26. The opening 27 connects the outside of the first vertical rod 24 with the mounting cavity 26. A toothed ring 28 is provided on the inner wall of the sleeve 18 corresponding to the position of the opening 27. A second stirring motor 30 is fixedly installed in the mounting cavity 26 by a fixing seat 29. The second stirring motor 30 is driven by a second driving gear 31. Part of the second driving gear 31 passes through the opening 27 so that the second driving gear 31 can mesh with the toothed ring 28. The stirring motor 20 drives the driving gear 21 to rotate. The driving gear 21, through its cooperation with the gear ring 28, drives the sleeve 18 to rotate. The sleeve 18 then drives the stirring rod 19 to rotate, thereby stirring the solution entering the inner stirring tank 2 and the solution located in the inner stirring tank 2, so that the solution can be mixed evenly.

[0046] The above description is merely a preferred embodiment of the present invention. The scope of protection of the present invention is not limited to the above embodiments. All technical solutions falling within the scope of the present invention's concept are within the scope of protection of the present invention. It should be noted that for those skilled in the art, any improvements and modifications made without departing from the principles of the present invention should also be considered within the scope of protection of the present invention.

Claims

1. A manufacturing process for colon-coated hydroxypropyl methylcellulose empty capsules, characterized in that, Includes the following steps: Two different viscosity grades of hydroxypropyl methylcellulose were selected as the main material for the capsule, along with plasticizers, enteric pore-forming agents, gelling agents, and antioxidants. After dissolving high-viscosity hydroxypropyl methylcellulose in warm water, a solution of low-viscosity hydroxypropyl methylcellulose in water is added and stirred to form a homogeneous solution. Then, plasticizer, enteric pore-forming agent, gelling agent, and antioxidant are added in sequence and stirred evenly. After filtration, a clear capsule material solution is obtained. The encapsulation liquid is injected into the molding machine, so that the encapsulation liquid is evenly coated on the mold surface. After pre-curing, fixing and drying, the encapsulation body and the encapsulation cap are formed. A functional inner coating solution is quantitatively sprayed onto the inner wall of the capsule body and capsule cap and dried to form a functional inner coating. The outer walls of the capsule body and capsule cap are sprayed with a coating liquid and dried to form a coating layer on the capsule body and capsule cap. The capsule body and capsule cap are subjected to vibration screening and near-infrared spectroscopy scanning to remove unqualified products.

2. The production process of colon-coated hydroxypropyl methylcellulose empty capsules according to claim 1, characterized in that, High-viscosity hydroxypropyl methylcellulose has a viscosity of 4000-50000 mPa·s, while low-viscosity hydroxypropyl methylcellulose has a viscosity of 50-400 mPa·s, with a mass ratio of 1:2 to 2:

1.

3. The production process of colon-coated hydroxypropyl methylcellulose empty capsules according to claim 1, characterized in that, The plasticizer is one or a mixture of glycerol, polyethylene glycol, and triethyl citrate.

4. The production process of colon-coated hydroxypropyl methylcellulose empty capsules according to claim 1, characterized in that, The antioxidant is tert-butyl-p-hydroxyanisole or di-tert-butyl-p-cresol.

5. The production process of colon-coated hydroxypropyl methylcellulose empty capsules according to claim 1, characterized in that, The pre-setting and fixing conditions are: temperature 50-60℃, relative humidity 40-50%, and time 1-3 min.

6. The production process of colon-coated hydroxypropyl methylcellulose empty capsules according to claim 1, characterized in that, The drying conditions are: temperature 35-45℃, relative humidity 25-35%, and time 1-2 hours.

7. The production process of colon-coated hydroxypropyl methylcellulose empty capsules according to claim 1, characterized in that, The functional inner coating solution is an aqueous solution of sodium alginate or a carbomer aqueous dispersion with a mass concentration of 1-5%. After spraying, it is dried at 35-45℃ for 10-20 minutes.

8. The production process of colon-coated hydroxypropyl methylcellulose empty capsules according to claim 1, characterized in that, The coating solution includes a first coating solution and a second coating solution. The first coating solution is sprayed and dried to form a first coating layer, and then the second coating solution is sprayed and dried to form a second coating layer. The first coating solution, by mass parts, consists of: 5-8 parts acrylic resin, 1-2 parts polyethylene glycol, 1-2 parts talc, and 85-92 parts 85% ethanol aqueous solution. The first coating layer is an anti-gastric juice layer. The second coating solution, by mass parts, consists of: 3-6 parts acrylic resin, 2-4 parts acrylic resin, 1-3 parts pH-sensitive polymer, 0.5-2 parts enzyme-sensitive material, 1-2 parts polyethylene glycol, and 82-90 parts 85% ethanol aqueous solution. The second coating layer is an enteric coating layer.

9. The production process of colon-coated hydroxypropyl methylcellulose empty capsules according to claim 8, wherein the pH-sensitive polymer is shellac or hydroxypropyl methylcellulose acetate succinate; and the enzyme-sensitive material is amylose or calcium pectin.

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