Smeglutide coated chip and preparation method thereof
Through the double-layer structure design of the semaglutide-coated chip, the absorption enhancer and alkalizer in the outer shell layer are used to regulate the gastric environment, thereby solving the problem of low bioavailability of semaglutide tablets and achieving higher bioavailability and reducing medication costs.
Patent Information
- Application Number
- CN202510793022.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-06-13
- Publication Date
- 2025-09-05
AI Technical Summary
The existing polypeptide drug semaglutide tablets have the problems of low bioavailability and high medication cost.
The double-layer structure design of the semaglutide-coated chip is adopted, which consists of a core layer and an outer shell layer. The outer shell layer contains a second absorption enhancer and an alkalinizer. By releasing the second absorption enhancer and alkalinizer in the gastric juice, the pH value in the stomach is increased, the activity of pepsin is reduced, and the permeability of the gastric mucosa is adjusted, thereby controlling the release time of semaglutide and ensuring its release in a stable gastric environment.
Significantly improve the bioavailability of semaglutide, reduce oral dosage, and reduce medication costs.
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Figure CN120585771A_ABST
Abstract
Description
Technical Field
[0001] The present application relates to the field of medical technology, and in particular to a semaglutide-coated chip and a preparation method thereof. Background Art
[0002] The human stomach contains a lot of gastric acid and pepsin. Polypeptide drugs have low resistance to enzymes and are easily degraded by gastrointestinal digestive enzymes and hydrolases in body fluids, thus losing their activity. Their oral bioavailability is extremely low, making their clinical application difficult.
[0003] Currently, the absolute oral bioavailability of the commercially available peptide drug semaglutide tablets is only 0.4% to 1%, which is much lower than the bioavailability of the injection (about 89% for subcutaneous injection). In order to achieve therapeutic effects, the oral dose needs to be significantly increased clinically, and a large amount of the expensive absorption enhancer SNAC (300 mg / tablet) must be added, which greatly increases the patient's medication cost (annual cost exceeds US$10,000).
[0004] It can be seen that the existing polypeptide drug semaglutide tablets have the problems of low bioavailability and high medication cost. Summary of the Invention
[0005] In view of this, the purpose of this application is to provide a semaglutide-coated chip and a preparation method thereof, aiming to solve the problems of low bioavailability and high medication cost of the polypeptide drug semaglutide tablets in the prior art.
[0006] To achieve the above-mentioned invention objectives, the technical solutions adopted in this application are as follows:
[0007] In a first aspect, the embodiments of the present application provide a semaglutide-encapsulated chip, comprising a core layer and an outer shell layer;
[0008] The core layer includes an active ingredient and core excipient ingredients, wherein the active ingredient is semaglutide; the core excipient ingredients include a first absorption enhancer;
[0009] The shell layer comprises a second absorption enhancer, an alkalizing agent and shell auxiliary material components, wherein the alkalizing agent is selected from arginine, lysine, histidine, meglumine, sodium hydroxide, sodium carbonate, sodium citrate, triethanolamine and ammonia water;
[0010] The first absorption enhancer and the second absorption enhancer are selected from sodium 8-(2-hydroxybenzamido)octanoate, Tween 80, sodium lauryl sulfate, sodium caprate, polyglyceryl-3 diisostearate, oleic acid, lauric acid, sodium deoxycholate, sodium cholate, polyoxyethylene (35) castor oil, PEG-vitamin E succinate, PEG-vitamin D3 succinate, pluronic, methoxy polyethylene glycol-polycaprolactone copolymer, sucrose fatty acid ester, polyethylene glycol 15-hydroxystearate, polyethylene glycol caprylate and polyethylene glycol glyceride;
[0011] The mass ratio of the first absorption enhancer to the second absorption enhancer is 0-95:10-90.
[0012] In a second aspect, the present invention provides a method for preparing a semaglutide-coated chip according to the first aspect, comprising the following steps:
[0013] The active ingredient and the tablet excipient ingredients are mixed, granulated, and tableted to form a tablet core layer, wherein the diameter of the tablet core layer is 2 mm to 9 mm;
[0014] The second absorption enhancer, the alkalizing agent and the shell auxiliary material components are mixed and granulated to obtain the shell layer material;
[0015] The core layer is coated with the shell layer material to form a shell layer by pressing on the surface of the core layer to obtain a semaglutide-coated core chip; the semaglutide-coated core chip has a diameter of 6 mm to 13 mm and a hardness of 50 N to 250 N.
[0016] Compared with the prior art, the technical solution provided by the embodiments of the present application has at least the following beneficial effects:
[0017] The semaglutide-coated chip provided in the embodiment of the present application adopts a double-layer structure (also known as a "tablet-in-tablet" structure) consisting of a core layer (inner layer) and an outer shell layer (outer layer), so that after oral administration, the outer shell layer contacts the gastric juice for the first time and releases the second absorption enhancer, alkalizer and other ingredients therein, thereby increasing the pH value in the stomach, reducing the activity of pepsin and regulating the permeability of the gastric mucosa; and the core layer is wrapped in the center by the outer shell layer, and the active ingredient (semaglutide) and the like therein will be exposed and released only after the outer shell layer disintegrates. Since there is a time lag in the release of the components of the core layer and the components of the outer shell layer in the stomach, the release time of the components of the core layer is later than the release time of the components of the outer shell layer, so that different release behaviors can be achieved in the "same preparation unit", so that semaglutide is in a relatively stable gastric environment throughout the release process, significantly improving the bioavailability of the preparation, so it is expected to significantly reduce the oral dose, thereby reducing the cost of medication. BRIEF DESCRIPTION OF THE DRAWINGS
[0018] In order to more clearly illustrate the technical solutions in the embodiments of the present application, the following briefly introduces the drawings required for use in the embodiments or descriptions of the prior art. Obviously, the drawings described below are only some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without any creative work.
[0019] Figure 1 Schematic diagram of the cross-sectional structure of a semaglutide-encapsulated chip provided in one embodiment of the present application. DETAILED DESCRIPTION
[0020] In order to make the technical problems, technical solutions and beneficial effects to be solved by this application more clearly understood, the following is a further detailed description of this application in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain this application, but the implementation methods of this application are not limited thereto.
[0021] Unless otherwise defined, the technical terms used in the following examples have the same meanings as commonly understood by those skilled in the art. The experimental reagents used in the following examples, unless otherwise specified, are conventional biochemical reagents; the amounts of the experimental reagents used, unless otherwise specified, are the amounts used in routine experimental procedures; and the experimental methods, unless otherwise specified, are conventional methods.
[0022] Figure 1 Schematic diagram of the cross-sectional structure of a semaglutide-encapsulated chip provided in one embodiment of the present application.
[0023] See also Figure 1 In the first aspect, an embodiment of the present application provides a semaglutide-coated chip, comprising a core layer 101 and an outer shell layer 102; the core layer 101 comprises an active ingredient and core excipient ingredients, the active ingredient being semaglutide; the core excipient ingredients comprise a first absorption enhancer.
[0024] The shell layer 102 includes a second absorption enhancer, an alkalizer, and shell auxiliary material components. The alkalizer is selected from arginine, lysine, histidine, meglumine, sodium hydroxide, sodium carbonate, sodium citrate, triethanolamine, and ammonia water.
[0025] The first absorption enhancer and the second absorption enhancer are selected from sodium 8-(2-hydroxybenzamido) caprylate (hereinafter referred to as "SNAC"), Tween 80, sodium lauryl sulfate, sodium caprate, polyglyceryl-3 diisostearate, oleic acid, lauric acid, sodium deoxycholate, sodium cholate, polyoxyethylene (35) castor oil, polyethylene glycol-vitamin E succinate, polyethylene glycol-vitamin D3 succinate, Pluronic, methoxy polyethylene glycol-polycaprolactone copolymer, sucrose fatty acid ester, polyethylene glycol 15-hydroxystearate, and polyethylene glycol caprylate.
[0026] The mass ratio of the first absorption enhancer to the second absorption enhancer is 0-95:10-90.
[0027] In some embodiments, the first absorption enhancer is a combination of sodium 8-(2-hydroxybenzamido)octanoate and at least one of Tween 80, sodium deoxycholate, and polyglycerol-3 diisostearate.
[0028] In some embodiments, the second absorption enhancer is a combination of sodium 8-(2-hydroxybenzamido)octanoate and at least one of Tween 80, sodium deoxycholate, and polyglyceryl-3 diisostearate.
[0029] In some embodiments, the alkalizing agent is at least one of arginine, meglumine, sodium carbonate, and sodium citrate.
[0030] In some embodiments, the second absorption enhancer is a combination of sodium 8-(2-hydroxybenzamido)octanoate, Tween 80, sodium deoxycholate, and polyglyceryl-3 diisostearate.
[0031] SNAC is a weakly basic compound. The carboxylate ion (-COO - ) can react with hydrogen ions (H + ) binds to the stomach, neutralizing gastric acid and raising the local pH in the stomach, thereby reducing the activity of pepsin. This in turn inhibits pepsin's ability to hydrolyze proteins, reducing the degradation of peptide drugs by pepsin. Furthermore, SNAC can be inserted into the lipid bilayer of the cell membrane of gastric mucosal cells, enhancing cell membrane stability, thereby regulating gastric mucosal permeability, increasing membrane fluidity, and promoting the transport of peptides across the cell membrane.
[0032] The molecular structure of Tween 80 (polysorbate 80) contains hydroxyl groups and ether bonds, which makes it weakly alkaline in solution and can neutralize small amounts of gastric acid, thus helping to increase the pH value in the stomach. Furthermore, Tween 80 is a non-ionic surfactant that forms an adsorption layer on the surface of pepsin molecules, altering the surface charge and hydrophobicity of the enzyme molecules and interfering with the binding of the enzyme to the substrate (protein), thereby inhibiting the activity of pepsin and reducing the degradation of peptide drugs by pepsin. Tween 80 can penetrate into the lipid bilayer of the cell membrane of gastric mucosal cells, increasing the fluidity of the lipids and thus changing the permeability of the cell membrane.
[0033] Sodium deoxycholate is a strong base and weak acid salt. The hydroxide ions it produces can combine with hydrogen ions (H+) in the stomach, thereby neutralizing gastric acid and increasing the local pH value of the stomach. Secondly, sodium deoxycholate can strongly bind to the hydrophobic region in the pepsin molecule, destroying the secondary, tertiary and quaternary structures of the enzyme molecule, causing the denaturation and inactivation of pepsin, which is beneficial to reduce the degradation of peptide drugs by pepsin.
[0034] Polyglyceryl-3 diisostearate can neutralize small amounts of gastric acid, helping to increase the pH value in the stomach. Secondly, polyglyceryl-3 diisostearate is an oil-soluble emulsifier that forms a hydrophobic physical barrier on the surface of pepsin, hindering its contact with protein substrates, thereby inhibiting its hydrolytic activity and helping to reduce the degradation of peptide drugs by pepsin. The fatty acid chains of polyglyceryl-3 diisostearate can interact with the cell membrane lipids of gastric mucosal cells, filling the gaps in the lipid bilayer, enhancing the density and stability of the cell membrane, and thus regulating the permeability of the gastric mucosa.
[0035] By using a composition of sodium 8-(2-hydroxybenzamido)octanoate, Tween 80, sodium deoxycholate, and polyglycerol-3 diisostearate as the second absorption enhancer, the components have a synergistic effect, which can comprehensively increase the pH value in the stomach, reduce the activity of pepsin, and regulate the permeability of the gastric mucosa. When the outer shell layer disintegrates and the core layer is exposed to begin releasing the active ingredient (semaglutide), semaglutide can remain in a relatively stable gastric environment from beginning to end, thereby significantly improving its bioavailability.
[0036] In some embodiments, the core excipient components further include a first diluent, a first lubricant, a first binder, and a first disintegrant.
[0037] In some embodiments, the shell excipient components further include a second diluent, a second lubricant, a second binder, and a second disintegrant.
[0038] In some embodiments, the core layer includes the following components, calculated by mass percentage (i.e., the mass of each component in the core layer accounts for the percentage of the total mass of the core layer): 1% to 30% of semaglutide, 0% to 95% of a first absorption enhancer, 0% to 95% of a first diluent, 0% to 5% of a first lubricant, 0% to 60% of a first binder, and 0% to 8% of a first disintegrant.
[0039] In some embodiments, the shell layer includes the following components, calculated by mass percentage (i.e., the mass of each component in the shell layer accounts for the percentage of the total mass of the shell layer): 10% to 90% of a second absorption enhancer, 0% to 30% of an alkalizer, 0% to 90% of a second diluent, 0% to 5% of a second lubricant, 0% to 20% of a second binder, and 0% to 8% of a second disintegrant.
[0040] In some embodiments, the first diluent is selected from starch, lactose, dextrin, sucrose, microcrystalline cellulose, calcium hydrogen phosphate, and mannitol.
[0041] Optionally, the first diluent is at least one of lactose, microcrystalline cellulose, and mannitol.
[0042] In some embodiments, the first lubricant is selected from talc, magnesium stearate, stearic acid, hydrogenated castor oil, sucrose stearate, and colloidal silicon dioxide.
[0043] Optionally, the first lubricant is at least one of magnesium stearate and colloidal silicon dioxide.
[0044] In some embodiments, the first binder is selected from povidone, hydroxypropyl cellulose, hypromellose, polyvinyl alcohol, starch, and polyethylene glycol.
[0045] Optionally, the first binder is at least one of povidone, hypromellose, and polyethylene glycol.
[0046] In some embodiments, the first disintegrant is selected from sodium carboxymethyl starch, sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, and starch.
[0047] Optionally, the first disintegrant is at least one of low-substituted hydroxypropyl cellulose and cross-linked polyvinylpyrrolidone.
[0048] In some embodiments, the weight ratio of the core layer to the shell layer is 247-273:565-735.
[0049] In a second aspect, the present invention also provides a method for preparing the semaglutide-coated chip according to the first aspect, comprising the following steps:
[0050] S1. The active ingredient and the tablet excipient ingredients are mixed, granulated, and tableted to form a tablet core layer, wherein the diameter of the tablet core layer is 2 mm to 9 mm (for example, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, or 9 mm, etc.).
[0051] S2. Mixing and granulating the second absorption enhancer, the alkalizing agent and the shell auxiliary material components to obtain the outer shell material;
[0052] S3. The core layer is coated with the shell layer material to form a shell layer by pressing on the surface of the core layer to obtain a semaglutide-coated chip; the semaglutide-coated chip has a diameter of 6 mm to 13 mm (for example, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm or 13 mm, etc.), and a hardness of 50 N to 250 N (for example, 50 N, 60 N, 70 N, 80 N, 90 N, 100 N, 110 N, 150 N, 180 N, 200 N or 250 N, etc.).
[0053] In some embodiments, in step S1 above, the active ingredient and the tablet core excipient ingredients can be directly mixed, and then granules can be prepared using a conventional wet granulation or dry granulation process. The granules are then compressed using a tablet press to form a tablet core layer. The tablet core layer can be a plain tablet or a coated tablet.
[0054] Optionally, the diameter of the core layer is 5 mm to 7 mm, for example, 5 mm, 6 mm or 7 mm.
[0055] In some embodiments, in the above step S2, the second absorption enhancer, the alkalizing agent and the shell layer auxiliary material components can be directly mixed, and then granulated using a conventional wet granulation or dry granulation process to obtain the shell layer material.
[0056] In some embodiments, in the above step S3, a chip-coated tablet press can be used. First, the outer shell material prepared in the above step S2 is pre-filled, then the core layer prepared in the above step S1 is filled, and then the outer shell material prepared in the above step S2 is filled, and finally the semaglutide-coated chip is formed by pressing.
[0057] Optionally, the diameter of the semaglutide package chip is 9 mm to 12 mm, for example, 9 mm, 10 mm, 11 mm or 12 mm.
[0058] Optionally, the hardness of the semaglutide package chip is 60-150N, for example, 60N, 70N, 80N, 90N, 100N, 110N, 120N, 130N, 140N or 150N.
[0059] In some embodiments, the second absorption enhancer is a mixture of sodium 8-(2-hydroxybenzamido)octanoate, Tween 80, sodium deoxycholate, and polyglycerol-3 diisostearate.
[0060] The above-mentioned step of mixing and granulating the second absorption enhancer, alkalizing agent and shell auxiliary material components to obtain the outer shell material specifically includes:
[0061] Sodium 8-(2-hydroxybenzamido)octanoate is mixed with a water-soluble carrier and spray-dried to obtain a solid dispersion;
[0062] Using β-cyclodextrin to include the solid dispersion to obtain a water-soluble inclusion compound;
[0063] The water-soluble inclusion compound is mixed with Tween 80, sodium deoxycholate, and polyglycerol-3 diisostearate to obtain a compound;
[0064] The compound is mixed with an alkalizing agent and shell auxiliary material components, and granulated to obtain an outer shell material.
[0065] As an example, in the first step, sodium 8-(2-hydroxybenzamido)octanoate is mixed with a water-soluble carrier (such as polyvinyl pyrrolidone, copovidone, etc.) to obtain a first mixed solution, and then the first mixed solution is spray-dried to obtain a solid dispersion. The second step is to add β-cyclodextrin to deionized water, heat it to 50℃~70℃, and stir until it is completely dissolved to form a saturated or nearly saturated solution, thereby obtaining a first solution; the solid dispersion prepared above is dissolved in a phosphate buffer solution with a pH of 7.0 to obtain a second solution; the second solution is slowly added dropwise to the first solution and mixed evenly to form a second mixed solution; the second mixed solution is ultrasonicated at a temperature of 30℃~50℃ for 10~60 minutes, after which the ultrasonicated second mixed solution is cooled to 24℃~28℃, filtered under reduced pressure to collect the precipitate, and washed with cold water 2~3 times to remove the unencapsulated β-cyclodextrin and solid dispersion; finally, the precipitate is vacuum dried to constant weight at a vacuum drying temperature of 40℃~60℃ to obtain a water-soluble inclusion complex. The third step is to mix the water-soluble inclusion complex with Tween 80, sodium deoxycholate, and polyglycerol-3 diisostearate to obtain a compound. The fourth step is to mix the compound obtained in the third step with the alkalizer and the shell auxiliary material components, and granulate them to obtain the shell layer material.
[0066] In some embodiments, in the second step, β-cyclodextrin can be replaced by hydroxypropyl-β-cyclodextrin or methyl-β-cyclodextrin.
[0067] In the embodiment of the present application, on the one hand, by mixing sodium 8-(2-hydroxybenzamido)octanoate with a water-soluble carrier and spray drying to form a solid dispersion, the crystal structure of SNAC can be destroyed, the lattice energy of SNAC can be reduced, and it is beneficial to improve its dissolution rate and solubility in an acidic environment. On the other hand, by using the hydrophobic cavity of β-cyclodextrin to encapsulate (inclusion) the solid dispersion, a water-soluble inclusion compound is formed, and the hydroxyl groups of β-cyclodextrin interact with water molecules in the outer layer to improve the overall solubility. Finally, the water-soluble inclusion compound is compounded with Tween 80, sodium deoxycholate, and polyglycerol-3 diisostearate in a specific ratio to form a compound, which can effectively increase the pH value in the stomach, reduce the activity of pepsin, and regulate the permeability of the gastric mucosa, so that when the core layer is exposed after the outer shell disintegrates and begins to release the active ingredient (semaglutide), semaglutide can be in a relatively stable gastric environment from beginning to end, thereby significantly improving its bioavailability.
[0068] The efficiency of preparing the water-soluble inclusion complex can be improved by adding β-cyclodextrin to deionized water and heating to dissolve it to obtain a first solution, adding the solid dispersion to a neutral phosphate buffer to dissolve it to obtain a second solution, and then mixing the first and second solutions and ultrasonically treating them.
[0069] The present application has been subjected to multiple tests, and part of the test results are cited as a reference to further describe the invention in detail, which will be described in detail in conjunction with specific embodiments.
[0070] The core layer prescriptions provided in Examples 1 to 5 are shown in Table 1 (the mass of each component of the core layer accounts for the percentage of the total mass of the core layer), the shell layer material prescriptions provided in Examples 1 to 5 are shown in Table 2 (the mass of each component of the shell layer material accounts for the percentage of the total mass of the shell layer material), and the shell layer material prescriptions provided in Examples 6 to 8 are shown in Table 3 (the mass of each component of the shell layer material accounts for the percentage of the total mass of the shell layer material).
[0071] Table 1 Tablet core layer formulations of Examples 1 to 5
[0072]
[0073]
[0074] Table 2 Shell material prescription of Examples 1 to 5
[0075]
[0076] Table 3 Shell material prescription of Examples 6 to 8
[0077]
[0078] Example 1
[0079] The formulation of the core layer 1 provided in this embodiment is shown in Table 1. The preparation method of the core layer 1 is as follows:
[0080] In the first step, the active ingredient, the first binder, and the first diluent are mixed using a hopper mixer, and then the first lubricant is added and the mixing is continued to obtain a total mixed material.
[0081] In the second step, the total mixed material is placed in a tablet press and punched into tablets using a 7 mm round punch, so that each tablet contains 7 mg of semaglutide, the tablet weight is controlled to be 130 mg ± 5%, and the hardness is 20N to 50N, to obtain the tablet core layer 1.
[0082] The recipe of the outer shell material 1 provided in this embodiment is shown in Table 2. The preparation method of the outer shell material 1 is as follows:
[0083] In the first step, SNAC (sodium 8-(2-hydroxybenzamido)octanoate) is mixed with a water-soluble carrier (polyvinyl pyrrolidone) to obtain a first mixed solution, and then the first mixed solution is spray-dried to obtain a solid dispersion; wherein the weight ratio of SNAC to polyvinyl pyrrolidone is 1:5.
[0084] In the second step, β-cyclodextrin is added to deionized water, heated to 50°C, and stirred until completely dissolved to form a saturated or nearly saturated solution to obtain a first solution; the solid dispersion prepared in the first step is dissolved in phosphate buffer (pH 7.0) to obtain a second solution, wherein the mass volume ratio of the solid dispersion to the phosphate buffer is 1g:10mL, and the second solution is slowly added dropwise to the first solution and mixed evenly to form a second mixed solution; the second mixed solution is ultrasonicated at a temperature of 40°C for 30 minutes, and then the ultrasonicated second mixed solution is cooled to 25°C, and the precipitate is collected by filtration under reduced pressure, and the precipitate is washed with cold water 2 to 3 times to remove unencapsulated β-cyclodextrin and solid dispersion; finally, the precipitate is vacuum dried to constant weight at a vacuum drying temperature of 50°C to obtain a water-soluble inclusion complex.
[0085] In the third step, the water-soluble inclusion compound, the second diluent and the second disintegrant prepared in the second step are placed in a wet granulation pot, mixed evenly, and purified water is added to perform wet granulation to obtain wet granules.
[0086] The fourth step is to dry the wet granules in a fluidized bed or oven to reduce the moisture content to less than 5%, thereby obtaining a crude dry granule product.
[0087] The fifth step is to place the dry granule crude product in a finishing machine, use a 1.2 mm screen, control the speed to 500 rpm for granulation, and obtain dry granules.
[0088] In the sixth step, the dry particles obtained in the fifth step, the alkalizer, and the second lubricant are placed in a hopper mixer and mixed evenly to obtain the outer shell material 1.
[0089] The preparation method of the semaglutide-coated chip 1 provided in this embodiment is as follows:
[0090] The core layer 1 and shell layer material 1 prepared above were placed in a tablet press and pressed using an 11 mm round punch. Specifically, the tablet press cavity was first pre-filled with the shell layer material 1 prepared above, followed by the core layer 1, and then the shell layer material 1. Finally, the tablets were pressed to form semaglutide-coated core chips 1. The filling amount of the shell layer material 1 was 350 mg, the tablet weight variation was controlled to ±5%, and the hardness was controlled to be between 60N and 150N.
[0091] Example 2
[0092] The formulation of the core layer 2 provided in this embodiment is shown in Table 1. The core layer 2 was prepared by referring to the preparation method of the core layer 1 in Example 1.
[0093] The recipe of the outer shell material 2 provided in this example is shown in Table 2. The outer shell material 2 was prepared by referring to the preparation method of the outer shell material 1 in Example 1.
[0094] The core layer 2 and the outer shell layer material 2 were used to prepare the semaglutide-encapsulated chip 2 by referring to the preparation method of the semaglutide-encapsulated chip 1 in Example 1.
[0095] Example 3
[0096] The formulation of the core layer 3 provided in this embodiment is shown in Table 1. The core layer 3 was prepared by referring to the preparation method of the core layer 1 in Example 1.
[0097] The recipe of the outer shell material 3 provided in this example is shown in Table 2. The outer shell material 3 was prepared by referring to the preparation method of the outer shell material 1 in Example 1.
[0098] The core layer 3 and the outer shell layer material 3 were used to prepare the semaglutide-encapsulated chip 3 by referring to the preparation method of the semaglutide-encapsulated chip 1 in Example 1.
[0099] Example 4
[0100] The formulation of core layer 4 provided in this example is shown in Table 1. The preparation method of core layer 4 is substantially the same as that of core layer 1 in Example 1, except that: in the first step, the active ingredient, the first binder, the first diluent, the first disintegrant, and the first absorption enhancer are mixed using a hopper mixer, and then the first lubricant is added and mixing is continued to obtain a total mixed material.
[0101] The recipe of the outer shell material 4 provided in this embodiment is shown in Table 2, and its preparation method is as follows:
[0102] In the first step, SNAC is mixed with a water-soluble carrier (polyvinyl pyrrolidone) to obtain a first mixed solution, and then the first mixed solution is spray-dried to obtain a solid dispersion; wherein the weight ratio of SNAC to polyvinyl pyrrolidone is 1:5.
[0103] In the second step, β-cyclodextrin is added to deionized water, heated to 50°C, and stirred until completely dissolved to form a saturated or nearly saturated solution to obtain a first solution; the solid dispersion prepared in the first step is dissolved in phosphate buffer (pH 7.0) to obtain a second solution, wherein the mass volume ratio of the solid dispersion to the phosphate buffer is 1g:10mL, and the second solution is slowly added dropwise to the first solution and mixed evenly to form a second mixed solution; the second mixed solution is ultrasonicated at a temperature of 40°C for 30 minutes, and then the ultrasonicated second mixed solution is cooled to 25°C, and the precipitate is collected by filtration under reduced pressure, and the precipitate is washed with cold water 2 to 3 times to remove unencapsulated β-cyclodextrin and solid dispersion; finally, the precipitate is vacuum dried to constant weight at a vacuum drying temperature of 50°C to obtain a water-soluble inclusion complex.
[0104] The third step is to mix the water-soluble inclusion compound prepared in the second step with Tween 80, sodium deoxycholate and polyglycerol-3 diisostearate to obtain a compound.
[0105] In the fourth step, the compound prepared in the third step, the second diluent and the second disintegrant are placed in a wet granulation pot, mixed evenly, and purified water is added to perform wet granulation to obtain wet granules.
[0106] The fifth step is to dry the wet granules in a fluidized bed or oven to reduce the moisture content to less than 5% to obtain a crude dry granule product.
[0107] In the sixth step, the crude dry granules obtained in the fifth step are placed in a finishing machine, sieved with a 1.2 mm screen, and sized at a speed of 500 rpm to obtain dry granules.
[0108] In the seventh step, the dry particles obtained in the sixth step, the alkalizing agent, and the second lubricant are placed in a hopper mixer and mixed evenly to obtain the outer shell material 4.
[0109] The core layer 4 and the outer shell layer material 4 were used to prepare the semaglutide-encapsulated chip 4 by referring to the preparation method of the semaglutide-encapsulated chip 1 in Example 1.
[0110] Example 5
[0111] The recipe of the core layer 5 provided in this embodiment is shown in Table 1. The core layer 5 was prepared by referring to the preparation method of the core layer 4 in Example 4.
[0112] The recipe of the outer shell material 5 provided in this embodiment is shown in Table 2. The outer shell material 5 was prepared by referring to the preparation method of the outer shell material 4 in Example 4.
[0113] The core layer 5 and the outer shell layer material 5 were used to prepare the semaglutide-coated chip 5 by referring to the preparation method of the semaglutide-coated chip 4 in Example 4.
[0114] Example 6
[0115] The formulation and preparation method of the core layer 6 provided in this embodiment are the same as those of the core layer 1 in Example 1.
[0116] The recipe of the outer shell material 6 provided in this embodiment is shown in Table 3, and its preparation method is as follows:
[0117] In the first step, SNAC is mixed with a water-soluble carrier (polyvinyl pyrrolidone) to obtain a first mixed solution, and then the first mixed solution is spray-dried to obtain a solid dispersion; wherein the weight ratio of SNAC to polyvinyl pyrrolidone is 1:5.
[0118] In the second step, β-cyclodextrin is added to deionized water, heated to 50°C, and stirred until completely dissolved to form a saturated or nearly saturated solution to obtain a first solution; the solid dispersion prepared in the first step is dissolved in phosphate buffer (pH 7.0) to obtain a second solution, wherein the mass volume ratio of the solid dispersion to the phosphate buffer is 1g:10mL, and the second solution is slowly added dropwise to the first solution and mixed evenly to form a second mixed solution; the second mixed solution is ultrasonicated at a temperature of 40°C for 30 minutes, and then the ultrasonicated second mixed solution is cooled to 25°C, and the precipitate is collected by filtration under reduced pressure, and the precipitate is washed with cold water 2 to 3 times to remove unincluded β-cyclodextrin and solid dispersion; finally, the precipitate is vacuum dried to constant weight, and the vacuum drying temperature is 50°C to obtain a water-soluble inclusion complex.
[0119] In the third step, the water-soluble inclusion compound, the second diluent and the second disintegrant prepared in the second step are placed in a wet granulation pot, mixed evenly, and purified water is added to perform wet granulation to obtain wet granules.
[0120] The fourth step is to dry the wet granules in a fluidized bed or oven to reduce the moisture content to less than 5%, thereby obtaining a crude dry granule product.
[0121] The fifth step is to place the dry granule crude product in a finishing machine, use a 1.2 mm screen, control the speed to 500 rpm for granulation, and obtain dry granules.
[0122] In the sixth step, the dry particles obtained in the fifth step and the second lubricant are placed in a hopper mixer and mixed evenly to obtain the outer shell material 6.
[0123] The core layer 6 and the outer shell layer material 6 were used to prepare the semaglutide-encapsulated chip 6 by referring to the preparation method of the semaglutide-encapsulated chip 1 in Example 1.
[0124] Example 7
[0125] The formulation and preparation method of the core layer 7 provided in this embodiment are the same as those of the core layer 2 in Example 2.
[0126] The recipe of the outer shell material 7 provided in this embodiment is shown in Table 3. The outer shell material 7 was prepared by referring to the preparation method of the outer shell material 6 in Example 6.
[0127] The core layer 7 and the outer shell layer material 7 were used to prepare the semaglutide-encapsulated chip 7 by referring to the preparation method of the semaglutide-encapsulated chip 1 in Example 1.
[0128] Example 8
[0129] The formulation and preparation method of the core layer 8 provided in this embodiment are the same as those of the core layer 3 in Example 3.
[0130] The recipe of the outer shell material 8 provided in this embodiment is shown in Table 3. The outer shell material 8 was prepared by referring to the preparation method of the outer shell material 6 in Example 6.
[0131] The core layer 8 and the outer shell layer material 8 were used to prepare the semaglutide-encapsulated chip 8 by referring to the preparation method of the semaglutide-encapsulated chip 1 in Example 1.
[0132] Example 9
[0133] The formulation and preparation method of the core layer 9 provided in this embodiment are the same as those of the core layer 1 in Example 1.
[0134] The prescription and preparation method of the outer shell material 9 provided in this embodiment are the same as the prescription and preparation method of the outer shell material 7 in Example 7.
[0135] The core layer 9 and the outer shell layer material 9 were used to prepare the semaglutide-encapsulated chip 9 by referring to the preparation method of the semaglutide-encapsulated chip 1 in Example 1.
[0136] Example 10
[0137] The formulation and preparation method of the core layer 10 provided in this embodiment are the same as those of the core layer 1 in Example 1.
[0138] The prescription and preparation method of the outer shell material 10 provided in this embodiment are the same as the prescription and preparation method of the outer shell material 8 in Example 8.
[0139] The core layer 10 and the outer shell layer material 10 were used to prepare the semaglutide-encapsulated chip 10 by referring to the preparation method of the semaglutide-encapsulated chip 1 in Example 1.
[0140] Example 11
[0141] The formulation and preparation method of the core layer 11 of this embodiment are the same as those of the core layer 1 of Example 1.
[0142] The recipe of the shell material 11 of this embodiment is the same as that of the shell material 1 of Example 1. The preparation method of the shell material 11 is as follows:
[0143] In the first step, SNAC, the second diluent, and the second disintegrant are placed in a wet granulation pot, mixed evenly, and purified water is added to perform wet granulation to obtain wet granules.
[0144] In the second step, the wet granules are dried in a fluidized bed or oven to reduce the moisture content to less than 5%, thereby obtaining the crude dry granules.
[0145] The third step is to place the dry granule crude product in a finishing machine, use a 1.2 mm screen, control the speed to 500 rpm for granulation, and obtain dry granules.
[0146] In the fourth step, the dry particles obtained in the fifth step, the alkalizer, and the second lubricant are placed in a hopper mixer and mixed evenly to obtain the outer shell material 11.
[0147] The core layer 11 and the outer shell layer material 11 were used to prepare the semaglutide-encapsulated chip 11 by referring to the preparation method of the semaglutide-encapsulated chip 1 in Example 1.
[0148] Example 12
[0149] The formulation and preparation method of the core layer 12 of this embodiment are the same as those of the core layer 2 of Example 2.
[0150] The prescription and preparation method of the outer shell material 12 provided in this embodiment are the same as the prescription and preparation method of the outer shell material 6 in Example 6.
[0151] The core layer 12 and the outer shell layer material 12 were used to prepare the semaglutide-encapsulated chip 12 by referring to the preparation method of the semaglutide-encapsulated chip 1 in Example 1.
[0152] Example 13
[0153] The formulation and preparation method of the core layer 13 of this embodiment are the same as those of the core layer 3 of Example 3.
[0154] The prescription and preparation method of the outer shell material 13 provided in this embodiment are the same as the prescription and preparation method of the outer shell material 6 in Example 6.
[0155] The core layer 13 and the outer shell layer material 13 were used to prepare the semaglutide-encapsulated chip 13 by referring to the preparation method of the semaglutide-encapsulated chip 1 in Example 1.
[0156] Example 14
[0157] The formulation and preparation method of the core layer 14 of this embodiment are the same as those of the core layer 1 of Example 1.
[0158] The prescription and preparation method of the outer shell material 14 provided in this embodiment are the same as the prescription and preparation method of the outer shell material 2 in Example 2.
[0159] The core layer 14 and the outer shell layer material 14 were used to prepare the semaglutide-encapsulated chip 14 by referring to the preparation method of the semaglutide-encapsulated chip 1 in Example 1.
[0160] Example 15
[0161] The formulation and preparation method of the core layer 15 of this embodiment are the same as those of the core layer 1 of Example 1.
[0162] The prescription and preparation method of the outer shell material 15 provided in this embodiment are the same as the prescription and preparation method of the outer shell material 3 in Example 3.
[0163] The core layer 15 and the outer shell layer material 15 were used to prepare the semaglutide-encapsulated chip 15 by referring to the preparation method of the semaglutide-encapsulated chip 1 in Example 1.
[0164] Example 16
[0165] The formulation and preparation method of the core layer 16 of this embodiment are the same as those of the core layer 1 of Example 1.
[0166] The prescription and preparation method of the outer shell material 16 provided in this embodiment are the same as the prescription and preparation method of the outer shell material 4 in Example 4.
[0167] The core layer 16 and the outer shell layer material 16 were used to prepare the semaglutide-encapsulated chip 16 by referring to the preparation method of the semaglutide-encapsulated chip 1 in Example 1.
[0168] Test Example 1: Tablet Core Layer Dissolution Test
[0169] 1. Test sample: core layer 1 to core layer 5 prepared in Examples 1 to 5.
[0170] 2. Test Method: Dissolution and Release Test Method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method 2) was used for the test. Dissolution Conditions: Phosphate buffer solution (pH 6.8) was used as the dissolution medium, the rotation speed was 70 min / rpm, and samples were collected at 10, 15, 30, 45, and 60 minutes.
[0171] 3. The test results are shown in Table 4.
[0172] Table 4 Dissolution of core layers 1 to 5
[0173]
[0174]
[0175] As shown in Table 4, in the dissolution medium of phosphate buffer solution (pH 6.8), the dissolution rates of the core layers 1 to 5 prepared in Examples 1 to 5 can all reach more than 80% at 45 min, and the dissolution rates of the core layers 2 to 5 prepared in Examples 2 to 5 can all reach more than 100% at 45 min.
[0176] Comparing Examples 1 to 3, it can be seen that when the amount of the first binder is reduced and the amount of the first diluent is increased, the dissolution rate of the resulting core layer increases. When the amount of the first binder is reduced to 0, the dissolution rate of the core layer significantly increases. Therefore, the dissolution rate of the core layer can be adjusted by adjusting the amounts of the first binder and first diluent in the core layer formulation, thereby obtaining core layers with different release rates.
[0177] Test Example 2: Animal Test
[0178] 1. Test samples: semaglutide-coated chips 1 to 16 prepared in Examples 1 to 16, and commercially available ordinary semaglutide tablets (plain tablets), all with a specification of 7 mg / tablet.
[0179] 2. Test Methods: 34 male and 34 female Beagle dogs were used as test animals, weighing 10 to 12.8 kg during the test period. During the test period, the 34 male and 34 female Beagle dogs were randomly divided into 17 groups, numbered 1 to 17, with two male and two female Beagle dogs in each group. Beagle dogs in Groups 1 to 17 were orally administered with commercially available plain semaglutide tablets or semaglutide-coated chips 1 to 16, respectively. The whole tablet was administered orally (via gavage tube), with one tablet taken with approximately 15 mL of water. The dogs fasted for at least 12 hours before administration and were fed 5 hours after administration. Blood was collected before administration and at 0.25 h, 0.5 h, 1 h, 1.5 h, 2 h, 4 h, 8 h, 24 h, 48 h, 72 h, 120 h, 168 h, and 216 h after administration to determine blood drug concentration. The drug concentration and time data were used to calculate the metabolic kinetic parameters according to the non-compartmental model method using WinNonlin6.4 software to calculate the area under the curve (AUC). 0-t .
[0180] 3. The test results are shown in Table 5.
[0181] Table 5 Bioavailability results of semaglutide package chips 1 to 16 and commercially available ordinary semaglutide tablets (plain tablets)
[0182] Test samples <![CDATA[AUC 0-t ]]> T / R (%) Commercially available ordinary semaglutide tablets (plain tablets) 5.18 - Example 1 (Semaglutide package chip 1) 31.09 600.19 Example 2 (Semaglutide package chip 2) 16.04 309.65 Example 3 (Semaglutide package chip 3) 21.89 422.59 Example 4 (Semaglutide package chip 4) 27.88 538.22 Example 5 (Semaglutide package chip 5) 28.03 541.12 Example 6 (Semaglutide package chip 6) 10.99 212.16 Example 7 (Semaglutide package chip 7) 19.87 383.59 Example 8 (Semaglutide package chip 8) 22.15 427.61 Example 9 (Semaglutide Package Chip 9) 20.58 397.3 Example 10 (Semaglutide package chip 10) 18.72 361.39 Example 11 (Semaglutide package chip 11) 9.16 176.83 Example 12 (Semaglutide package chip 12) 15.67 302.51 Example 13 (Semaglutide package chip 13) 21.09 407.14 Example 14 (Semaglutide package chip 14) 27.98 540.15 Example 15 (Semaglutide package chip 15) 36.66 707.72 Example 16 (Semaglutide Package Chip 16) 38.25 738.42
[0183] As shown in Table 5, the area under the drug-dose curve (AUC) of the semaglutide-coated chips 1 to 16 prepared in Examples 1 to 16 of the present application for Beagle dogs is significantly greater than that of the commercially available ordinary semaglutide tablets (plain tablets), and the bioavailability is significantly improved, which is 176.83% to 738.42% compared to the commercially available ordinary semaglutide tablets (plain tablets). It can be seen that the examples of the present application adopt a double-layer structure (also known as a "tablet-in-tablet" structure) consisting of a core layer (inner layer) and an outer shell layer (outer layer), and utilize the release lag of the outer shell layer and the core layer to keep semaglutide in a relatively stable gastric environment throughout the release process, significantly improving the bioavailability of the preparation, and thus it is expected to significantly reduce the oral dose, thereby reducing the cost of medication.
[0184] Comparison of Examples 1, 14, and 15 shows that the type of alkalizing agent in the outer shell material significantly affects the bioavailability of the semaglutide-coated chip. When sodium citrate is used as the alkalizing agent, the bioavailability of the semaglutide-coated chip is the highest.
[0185] Comparing Examples 6, 9, and 10, it can be seen that the ratio of the second absorption enhancer to the second diluent in the outer shell material significantly affects the bioavailability of the semaglutide-coated chip. When the ratio of the second absorption enhancer to the second diluent is close to 1:1, the bioavailability of the semaglutide-coated chip is higher.
[0186] By comparing Examples 1 and 11, it can be seen that by first mixing sodium 8-(2-hydroxybenzamido)octanoate with a water-soluble carrier and spray-drying to form a solid dispersion, and then using the hydrophobic cavity of β-cyclodextrin to encapsulate (inclusion) the solid dispersion to form a water-soluble inclusion complex, the bioavailability of the prepared semaglutide-coated chip can be significantly improved.
[0187] By comparing Examples 1 and 16, it can be seen that by first mixing sodium 8-(2-hydroxybenzamido)octanoate with a water-soluble carrier and spray-drying to form a solid dispersion, and then using the hydrophobic cavity of β-cyclodextrin to encapsulate (inclusion) the solid dispersion to form a water-soluble inclusion complex, and then compounding the water-soluble inclusion complex with Tween 80, sodium deoxycholate, and polyglycerol-3 diisostearate, the bioavailability of the prepared semaglutide-coated chip can be further improved.
[0188] Comparing Examples 6, 12, and 13, it is clear that the amount of the first adhesive in the core layer significantly impacts the bioavailability of semaglutide-coated chips. The bioavailability of semaglutide-coated chips increases as the amount of the first adhesive decreases. Therefore, by controlling the amount of the first adhesive, coated chips with varying release profiles can be achieved.
[0189] The above embodiments are only used to illustrate the technical solutions of the present application, rather than to limit them. Although the present application has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. These modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the various embodiments of the present application, and should all be included in the scope of protection of the present application.
Claims
1. A semaglutide package chip, characterized in that: including a core layer and a shell layer; The core layer includes an active ingredient and core excipient ingredients, wherein the active ingredient is semaglutide; the core excipient ingredients include a first absorption enhancer; The shell layer comprises a second absorption enhancer, an alkalizing agent and shell auxiliary material components, wherein the alkalizing agent is selected from arginine, lysine, histidine, meglumine, sodium hydroxide, sodium carbonate, sodium citrate, triethanolamine and ammonia water; The first absorption enhancer and the second absorption enhancer are selected from sodium 8-(2-hydroxybenzamido)octanoate, Tween 80, sodium lauryl sulfate, sodium caprate, polyglyceryl-3 diisostearate, oleic acid, lauric acid, sodium deoxycholate, sodium cholate, polyoxyethylene (35) castor oil, polyethylene glycol-vitamin E succinate, polyethylene glycol-vitamin D3 succinate, pluronic, methoxy polyethylene glycol-polycaprolactone copolymer, sucrose fatty acid ester, polyethylene glycol 15-hydroxystearate, polyethylene glycol caprylate and polyethylene glycol glyceryl ester; The mass ratio of the first absorption enhancer to the second absorption enhancer is 0-95:10-90.
2. The semaglutide package chip according to claim 1, characterized in that The first absorption enhancer is a combination of sodium 8-(2-hydroxybenzamido)octanoate and at least one of Tween 80, sodium deoxycholate, and polyglycerol-3 diisostearate; The second absorption enhancer is a combination of sodium 8-(2-hydroxybenzamido)octanoate and at least one of Tween 80, sodium deoxycholate, and polyglycerol-3 diisostearate; The alkalizing agent is at least one of arginine, meglumine, sodium carbonate and sodium citrate.
3. The semaglutide package chip according to claim 2, characterized in that: The second absorption enhancer is a composition of sodium 8-(2-hydroxybenzamido)octanoate, Tween 80, sodium deoxycholate and polyglycerol-3 diisostearate.
4. The semaglutide package chip according to claim 1, characterized in that The tablet core auxiliary material components also include a first diluent, a first lubricant, a first binder and a first disintegrant; The shell excipient components further include a second diluent, a second lubricant, a second binder and a second disintegrant.
5. The semaglutide package chip according to claim 4, characterized in that The core layer comprises the following components by mass percentage: 1% to 30% of semaglutide, 0% to 95% of a first absorption enhancer, 0% to 95% of a first diluent, 0% to 5% of a first lubricant, 0% to 60% of a first binder, and 0% to 8% of a first disintegrant; The outer shell layer comprises the following components: 10% to 90% of a second absorption enhancer, 0% to 30% of an alkalizer, 0% to 90% of a second diluent, 0% to 5% of a second lubricant, 0% to 20% of a second binder, and 0% to 8% of a second disintegrant.
6. The semaglutide package chip according to claim 4, characterized in that The first diluent is selected from starch, lactose, dextrin, sucrose, microcrystalline cellulose, calcium hydrogen phosphate, and mannitol; The first lubricant is selected from talc, magnesium stearate, stearic acid, hydrogenated castor oil, sucrose stearate, and colloidal silicon dioxide; The first binder is selected from povidone, hydroxypropyl cellulose, hypromellose, polyvinyl alcohol, starch, polyethylene glycol; The first disintegrant is selected from sodium carboxymethyl starch, sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, and starch.
7. The semaglutide package chip according to claim 6, characterized in that: The first diluent is at least one of lactose, microcrystalline cellulose, and mannitol; The first lubricant is at least one of magnesium stearate and colloidal silicon dioxide; The first binder is at least one of povidone, hypromellose, and polyethylene glycol; The first disintegrant is at least one of low-substituted hydroxypropyl cellulose and cross-linked polyvinylpyrrolidone.
8. The semaglutide package chip according to claim 1, characterized in that: The weight ratio of the core layer to the outer shell layer is 247-273:565-735.
9. A method for preparing a semaglutide-coated chip according to any one of claims 1 to 8, characterized in that: The steps include: The active ingredient and the tablet excipient ingredients are mixed, granulated, and tableted to form a tablet core layer, wherein the diameter of the tablet core layer is 2 mm to 9 mm; The second absorption enhancer, the alkalizing agent and the shell auxiliary material components are mixed and granulated to obtain the shell layer material; The core layer is coated with the shell layer material to form a shell layer by pressing on the surface of the core layer to obtain a semaglutide-coated core chip; the semaglutide-coated core chip has a diameter of 6 mm to 13 mm and a hardness of 50 N to 250 N.
10. The method for preparing the semaglutide-coated chip according to claim 9, characterized in that: The second absorption enhancer is a compound of sodium 8-(2-hydroxybenzamido)octanoate, Tween 80, sodium deoxycholate, and polyglycerol-3 diisostearate; The second absorption enhancer, the alkalizing agent and the shell auxiliary material components are mixed and granulated to obtain the shell layer material, including: Sodium 8-(2-hydroxybenzamido)octanoate is mixed with a water-soluble carrier and spray-dried to obtain a solid dispersion; Using β-cyclodextrin to include the solid dispersion to obtain a water-soluble inclusion compound; The water-soluble inclusion compound is mixed with Tween 80, sodium deoxycholate, and polyglycerol-3 diisostearate to obtain a compound; The compound is mixed with an alkalizing agent and shell auxiliary material components, and granulated to obtain an outer shell material.