An Omeprazole Enteric-coated Composition and Its Preparation Method

Abstract

This invention discloses an omeprazole enteric-coated composition, which is prepared by hot melt extrusion of omeprazole, a solid lipid carrier, a surfactant, a pH-sensitive polymer, and a plasticizer to form a biphase matrix structure with the pH-sensitive polymer as the continuous phase and the omeprazole-containing lipid phase as the dispersed phase. The preparation method is also disclosed, thereby achieving gastric protection of omeprazole, rapid intestinal release, and good storage stability.

Description

Technical Field

[0001] This invention relates to chemical and pharmaceutical technologies, specifically to an enteric-coated omeprazole formulation and its preparation method, which can be used to treat various acid-related diseases. Background Technology

[0002] Omeprazole is a benzimidazole-based first-generation proton pump inhibitor (PPI) with the strongest acid-suppressing activity among all marketed drugs. Omeprazole exerts its effect by selectively and irreversibly inhibiting the proton pump in the vesicle membrane of gastric parietal cells. This inhibition is irreversible, and the effect of omeprazole on acid secretion is clinically indistinguishable regardless of secretory stimulation. The irreversible binding of omeprazole to the proton pump cannot be reversed by washing and is rapidly converted to its active form in the gastric wall by cytochrome P450. Omeprazole is clinically used in enteric-coated capsules. It is used to treat gastric ulcers, duodenal ulcers, reflux esophagitis, and Zollinger-Ellison syndrome (gastrinoma). Omeprazole is also used in combination with one or more appropriate antibiotics to eradicate Helicobacter pylori and related ulcers. Omeprazole was the first PPI approved for marketing in the European Union in 1988. In the same year, it was marketed in China under the brand name Losec.

[0003] Because omeprazole contains a sulfinyl (sulfoxide) group, this compound is chemically extremely unstable and easily degraded by temperature, humidity, and acid. It is a weakly basic compound and readily decomposes in strongly acidic gastric juices, leading to drug inactivation. This compound is also extremely sensitive to light, undergoing rapid photolysis in solution. Therefore, the drug must be stored at low temperatures and protected from light. Furthermore, omeprazole is poorly soluble in water, exhibiting strong hydrophobicity and poor compatibility with other reagents (including liquids), making its industrial production difficult, resulting in low yields and failure to meet quality control standards. Its production technology has significant inherent risks, and quality fluctuations are likely to occur between batches of finished products.

[0004] Omeprazole is unstable in stomach acid and decomposes in an acidic environment. Therefore, it is necessary to protect the drug from stomach acid before administration and ensure its smooth delivery to the intestines for release and absorption. Most commercially available omeprazole products contain enteric polymers to achieve this. In the prior art, omeprazole enteric-coated capsules are made by filling omeprazole into enteric granules and then encapsulating them in a capsule shell. Most commercially available granules are made using an extrusion-spheronization process combined with fluidized bed coating. Granular enteric-coated formulations have advantages such as good acid resistance, timely and sufficient drug release, and high stability.

[0005] However, existing omeprazole enteric-coated capsules still have the following shortcomings in preparation and application:

[0006] (1) Omeprazole is easily degraded by humid and hot conditions during pellet preparation and coating, especially when the thickness of the isolation layer and enteric coating layer is not well controlled, the stability of the drug is difficult to guarantee.

[0007] (2) When the extrusion spheronization method is used to prepare pellet cores, different excipients are incompatible during the extrusion spheronization process, which can easily lead to powdering or pellet core breakage, poor fluidity, and affect the uniformity of subsequent coating and the dissolution time of micro pellets, resulting in poor disintegration power and unfavorable dissolution of the main drug.

[0008] (3) Existing generic formulations differ significantly from original formulations in their in vitro drug release behavior, which may pose a risk of clinical bioequivalence. Factors such as the selection of coating materials and coating weight gain in the preparation process have a significant impact on the drug release behavior of the formulation.

[0009] (4) Enteric coating technology has high requirements. Poor coating integrity can lead to premature release and degradation of the drug in the stomach, while excessive coating may affect the local release and absorption of the drug in the intestine. Some formulations have problems with insufficient or untimely release after oral administration, which affects the clinical efficacy of the drug.

[0010] (5) Although hot melt extrusion technology has advantages such as continuous production and avoidance of large amounts of solvent use, it has been used in the development of some drug formulations. However, for drugs such as omeprazole that are sensitive to acidic environments and processing conditions, how to achieve stability improvement, gastric protection and rapid intestinal release under hot melt extrusion conditions through the synergistic design of excipient system and process route is still a technical problem that needs to be solved in this field.

[0011] Therefore, developing an omeprazole enteric-coated composition, capsule, and preparation method with good stability, controllable drug release behavior, and simple preparation process remains a technical problem that urgently needs to be solved by those skilled in the art. Summary of the Invention

[0012] To address the aforementioned problems in the prior art, this invention provides an omeprazole enteric-coated composition, its preparation method, and its applications. This invention utilizes a combination of a specific solid lipid carrier, surfactant, pH-sensitive polymer, and plasticizer, along with a drug lipid pre-concentration and hot-melt extrusion process, to form a biphasic matrix structure with the pH-sensitive polymer as the continuous phase and the omeprazole-containing lipid phase as the dispersed phase. This achieves gastric protection of omeprazole, rapid intestinal release, and good storage stability.

[0013] The purpose of this invention is to provide an omeprazole enteric-coated composition, wherein the omeprazole enteric-coated composition is obtained by hot melt extrusion of omeprazole, a solid lipid carrier, a surfactant, a pH-sensitive polymer, and a plasticizer, forming a biphase matrix structure with the pH-sensitive polymer as the continuous phase and the omeprazole-containing lipid phase as the dispersed phase; wherein, by weight, the omeprazole enteric-coated composition comprises the following components: 10-30 parts of omeprazole; 80-120 parts of solid lipid carrier; surfactant... The agent comprises 0.1 to 1.5 parts; pH-sensitive polymer comprises 30 to 60 parts; plasticizer comprises 0.1 to 2 parts; wherein the solid lipid carrier is composed of polyethylene glycol glycerol laurate and glycerol behenate, and the weight ratio of polyethylene glycol glycerol laurate to glycerol behenate is 1:(1 to 3); the surfactant is composed of poloxamer 188 and vitamin E polyethylene glycol succinate, and the weight ratio of poloxamer 188 to vitamin E polyethylene glycol succinate is (1 to 3):1.

[0014] Furthermore, in the omeprazole enteric-coated composition, the ratio of polyethylene glycol glycerol laurate to glycerol behenate is 1:2.

[0015] Furthermore, in the omeprazole enteric-coated composition, the ratio of poloxamer 188 to vitamin E polyethylene glycol succinate is 2:1.

[0016] Furthermore, in the omeprazole enteric-coated composition, the pH-sensitive polymer is selected from one or at least two of methacrylic acid-ethyl acrylate copolymer, hydroxypropyl methylcellulose acetate succinate, and hydroxypropyl methylcellulose phthalate.

[0017] Furthermore, in the omeprazole enteric-coated composition, the plasticizer is triethyl citrate. According to the release determination method in the Chinese Pharmacopoeia, after treatment in an acidic medium with pH 1.0–1.5 for 2 hours, the cumulative release of omeprazole is not higher than 10%. After being transferred to a buffer medium with pH 6.5–7.0 for 30 minutes, the cumulative release is not less than 80%. Moreover, after being stored at 40℃±2℃ and relative humidity 75%±5% for 3 months, the increase in total impurity content is not higher than 0.20%.

[0018] Furthermore, an omeprazole enteric-coated capsule is obtained by adding an appropriate amount of lubricant to the omeprazole enteric-coated composition and filling it into a hard capsule.

[0019] Furthermore, the preparation method of the omeprazole enteric-coated composition specifically includes the following steps:

[0020] (1) Weigh out the following ingredients according to the formula: omeprazole, solid lipid carrier, surfactant, pH-sensitive polymer and plasticizer;

[0021] (2) Omeprazole, solid lipid carrier and surfactant are melt-mixed at 60-70°C to prepare drug lipid preconcentrate;

[0022] (3) The drug lipid preconcentrate is mixed with pH-sensitive polymer and plasticizer, and then extruded by twin screw hot melt extrusion at 90-120°C to obtain extrudate, so that the lipid phase containing omeprazole is dispersed in the continuous phase of pH-sensitive polymer.

[0023] (4) Cool and granulate the extrudate obtained in step (3) to obtain the omeprazole enteric-coated composition.

[0024] Furthermore, in step (2), the omeprazole enteric-coated composition is prepared by melting and mixing omeprazole, a solid lipid carrier, and a surfactant at 65°C to obtain a drug lipid pre-concentrate.

[0025] Furthermore, in step (3), the omeprazole enteric-coated composition is prepared by mixing the drug lipid pre-concentrate with the pH-sensitive polymer and plasticizer, and then extruding it using a twin-screw hot melt extrusion at 110°C to obtain the extrudate, thereby dispersing the omeprazole-containing lipid phase in the continuous phase of the pH-sensitive polymer.

[0026] Furthermore, the use of the omeprazole enteric-coated composition, or omeprazole enteric-coated capsules, in the preparation of medicaments for the treatment of gastric ulcers, duodenal ulcers, reflux esophagitis, Zollinger-Ellison syndrome, and Helicobacter pylori-associated acid secretion disorders.

[0027] Compared with the prior art, the present invention has at least the following beneficial effects:

[0028] 1. Improving the stability of omeprazole in formulations: This invention uses polyethylene glycol glycerol laurate and behenicol glycerol laurate to construct a solid lipid carrier, and combines it with poloxamer 188 and vitamin E polyethylene glycol succinate to form a drug lipid pre-concentrate. This allows omeprazole to be preferentially dispersed in the lipid microenvironment, which can reduce the chance of the drug being directly exposed to an adverse environment during subsequent hot-melt processing, thereby helping to inhibit degradation, reduce impurity generation, and improve formulation stability.

[0029] 2. Balancing gastric protection and rapid intestinal release: This invention utilizes a pH-sensitive polymer to construct a continuous phase, effectively limiting drug release in acidic media and reducing the risk of omeprazole degradation in the acidic gastric environment. Under the corresponding pH conditions in the intestine, the pH-sensitive polymer swells and / or dissolves, promoting rapid drug release. Therefore, the composition of this invention achieves a cumulative release of no more than 10% in acidic media over 2 hours, and a cumulative release of no less than 80% after transfer to a buffer medium with a pH of 6.5–7.0 within 30 minutes.

[0030] 3. Reducing the adverse effects of traditional coating processes: Existing omeprazole enteric-coated formulations typically rely on an isolation layer and an enteric coating layer for acid resistance protection. The preparation process usually involves wet granulation, coating, and other steps, which can easily introduce humid and heat factors and increase process complexity. This invention uses drug lipid pre-concentration combined with hot-melt extrusion to construct the enteric matrix structure, reducing the adverse effects of traditional multi-layer coating processes on drug stability and process consistency. This simplifies the preparation process and improves batch-to-batch quality stability.

[0031] 4. The process offers good controllability and is suitable for industrial-scale preparation: This invention first prepares a pre-concentrated drug lipid compound, which is then hot-melt extruded with a pH-sensitive polymer and a plasticizer. This helps control the heating process of the drug under high temperature and high shear conditions, reducing the risk of local degradation that may be caused by direct blending extrusion. Furthermore, the process steps are clear, and the parameters are easy to control, making it suitable for continuous and large-scale production.

[0032] 5. Superior overall performance of the formulation: The omeprazole enteric-coated composition of the present invention has good acid resistance, rapid intestinal drug release behavior and low impurity growth level, which can better meet the dual requirements of stability and release behavior of oral omeprazole enteric-coated formulations. Attached Figure Description

[0033] Figure 1 A bar chart comparing the acid resistance release rates of each embodiment and the comparative example in the acidic stage (pH 1.2);

[0034] Figure 2 This is a comparison graph showing the cumulative release rates of each embodiment and the comparative example during the buffering phase (pH 6.8).

[0035] Figure 3 The graph shows the stability (impurity content) changes of each embodiment and comparative example under light conditions.

[0036] Figure 4 A bar chart comparing the increase in total impurities in each example and comparative example over 3 months in accelerated stability testing (40℃ / RH75%).

[0037] Figure 5This is a comparison chart showing the impact of the pre-concentration process (Example 1) and the direct blending process (Comparative Example 3) on the core performance of the formulation. Detailed Implementation

[0038] The present invention will be described in detail below with reference to specific embodiments. The following embodiments will help those skilled in the art to further understand the present invention, but do not limit the present invention in any way. It should be noted that those skilled in the art can make several modifications and improvements without departing from the concept of the present invention. These all fall within the protection scope of the present invention. The present invention will be further described below with reference to examples:

[0039] Unless otherwise specified, all raw materials used in the following examples are commercially available.

[0040] in:

[0041] Omeprazole is a pharmaceutical-grade active pharmaceutical ingredient;

[0042] Polyethylene glycol glyceryl laurate can be used as a Gelucire-type material;

[0043] Glyceryl behenate can be Compritol 888 ATO;

[0044] Poloxamer 188 is a pharmaceutical grade excipient;

[0045] Vitamin E polyethylene glycol succinate is pharmaceutical grade TPGS;

[0046] pH-sensitive polymers can be selected from methacrylic acid-ethyl acrylate copolymer, hydroxypropyl methylcellulose acetate succinate, or hydroxypropyl methylcellulose phthalate.

[0047] Triethyl citrate is a pharmaceutical-grade plasticizer.

[0048] The "biphase matrix structure" described in this invention refers to the following: under scanning electron microscopy, a continuous phase framework formed by a pH-sensitive polymer can be observed, in which a lipid phase is distributed in the form of dispersed microregions; and by DSC detection, the characteristic melting peak of omeprazole is weakened or disappears, indicating that the drug exists at least partially in the lipid phase in an amorphous or molecularly dispersed state.

[0049] Unless otherwise specified, "parts" in the following embodiments refer to parts by weight.

[0050] The omeprazole enteric-coated composition of the present invention can be prepared according to the following steps:

[0051] (1) Weigh out the following ingredients according to the formula: omeprazole, solid lipid carrier, surfactant, pH-sensitive polymer and plasticizer;

[0052] (2) After heating the solid lipid carrier to a molten state, add omeprazole and surfactant, mix at 60-70°C to make omeprazole uniformly dispersed in the lipid system, and obtain drug lipid preconcentrate;

[0053] (3) After the drug lipid preconcentrate is mixed evenly with pH-sensitive polymer and plasticizer, it is added to a twin-screw hot melt extruder and hot melt extruded at 90-120°C to obtain the extrudate;

[0054] (4) After cooling the extrudate, crush and granulate it to obtain the omeprazole enteric-coated composition;

[0055] (5) If necessary, add an appropriate amount of lubricant to the obtained composition and fill it into an empty capsule shell to obtain omeprazole enteric-coated capsules.

[0056] Preferably, the mixing temperature in step (2) is 65°C; the hot melt extrusion temperature in step (3) is 110°C; and the residence time of the material in the hot melt extruder does not exceed 10 minutes.

[0057] Example 1: Preparation of Omeprazole Enteric-coated Capsules

[0058] 1. Formula Composition

[0059] By weight, it includes the following components:

[0060] 20 parts of omeprazole

[0061] 30 parts of polyethylene glycol glyceryl laurate

[0062] 60 parts of behenicol glyceryl ester

[0063] Polosham 188 0.67 copies

[0064] Vitamin E polyethylene glycol succinate 0.33 parts

[0065] 40 parts of methacrylic acid-ethylacrylic acid copolymer

[0066] 0.8 parts of triethyl citrate

[0067] The total amount of solid lipid carrier is 90 parts, and the weight ratio of polyethylene glycol glycerol laurate to behenicol glycerol laurate is 1:2; the total amount of surfactant is 1.0 part, and the weight ratio of poloxamer 188 to vitamin E polyethylene glycol succinate is 2:1.

[0068] 2. Preparation method

[0069] (1) Weigh each component according to the above formula;

[0070] (2) Add polyethylene glycol glycerol laurate and glycerol behenate to a mixing container and heat to 65°C to melt them;

[0071] (3) Add omeprazole, poloxamer 188 and vitamin E polyethylene glycol succinate to the molten lipid, stir and mix at 65°C for 20 minutes to make the drug uniformly dispersed in the lipid system and obtain the drug lipid preconcentrate.

[0072] (4) Mix the drug lipid preconcentrate with methacrylic acid-ethyl acrylate copolymer and triethyl citrate evenly;

[0073] (5) Add the mixture to a twin-screw hot melt extruder and perform hot melt extrusion at 110°C, controlling the material residence time to not exceed 10 minutes;

[0074] (6) After cooling the extrudate to room temperature, pulverize it and granulate it through a 20-mesh sieve to obtain the omeprazole enteric-coated composition;

[0075] (7) Add an appropriate amount of lubricant to the obtained composition and fill it into an empty capsule shell to obtain omeprazole enteric-coated capsules.

[0076] Example 2: Preparation of Omeprazole Enteric-coated Capsules

[0077] 1. Formula Composition

[0078] By weight, it includes the following components:

[0079] 10 parts of omeprazole

[0080] 30 parts of polyethylene glycol glyceryl laurate

[0081] 90 parts of behenicol glyceryl ester

[0082] Polosham 188 0.50 copies

[0083] Vitamin E polyethylene glycol succinate 0.50 parts

[0084] 30 parts of hydroxypropyl methylcellulose acetate succinate

[0085] 1.0 part of triethyl citrate

[0086] The total amount of solid lipid carrier is 120 parts, and the weight ratio of polyethylene glycol glycerol laurate to behenicol glycerol laurate is 1:3; the total amount of surfactant is 1.0 part, and the weight ratio of poloxamer 188 to vitamin E polyethylene glycol succinate is 1:1.

[0087] 2. Preparation method

[0088] The preparation method is the same as in Example 1, except that the pH-sensitive polymer used is hydroxypropyl methylcellulose acetate succinate; and the hot-melt extrusion temperature is controlled at 105°C. After cooling and granulation, an omeprazole enteric-coated composition is obtained, an appropriate amount of lubricant is added, and it is then encapsulated for later use.

[0089] Example 3: Preparation of Omeprazole Enteric-coated Capsules

[0090] 1. Formula Composition

[0091] By weight, it includes the following components:

[0092] 30 parts of omeprazole

[0093] 40 parts of polyethylene glycol glyceryl laurate

[0094] 40 parts of behenicol glyceryl ester

[0095] Polosham 188 0.75 copies

[0096] Vitamin E polyethylene glycol succinate 0.25 parts

[0097] 35 parts of hydroxypropyl methylcellulose phthalate

[0098] 0.5 parts of triethyl citrate

[0099] The total amount of solid lipid carrier is 80 parts, and the weight ratio of polyethylene glycol glycerol laurate to behenicol glycerol laurate is 1:1; the total amount of surfactant is 1.0 part, and the weight ratio of poloxamer 188 to vitamin E polyethylene glycol succinate is 3:1.

[0100] 2. Preparation method

[0101] The preparation method is the same as in Example 1, except that: the pH-sensitive polymer used is hydroxypropyl methylcellulose phthalate; the melt mixing temperature is 60°C; and the hot melt extrusion temperature is 100°C.

[0102] After cooling and granulation, an omeprazole enteric-coated composition is obtained. An appropriate amount of lubricant is added, and the mixture is then encapsulated for later use.

[0103] Comparative Example 1: A single solid lipid carrier + a single surfactant system

[0104] 1. Formula Composition

[0105] By weight, it includes the following components:

[0106] 20 parts of omeprazole

[0107] 90 parts of polyethylene glycol glyceryl laurate

[0108] Polosham 188 1.0 copies

[0109] 40 parts of methacrylic acid-ethylacrylic acid copolymer

[0110] 0.8 parts of triethyl citrate

[0111] 2. Preparation method

[0112] Prepared according to the method of Example 1, except that the solid lipid carrier uses only polyethylene glycol glycerol laurate and does not contain glycerol behenate; the surfactant uses only poloxamer 188 and does not contain polyethylene glycol succinate vitamin E.

[0113] Comparative Example 2: Another single solid lipid carrier + single surfactant system

[0114] 1. Formula Composition

[0115] By weight, it includes the following components:

[0116] 20 parts of omeprazole

[0117] 90 parts of behenicol glyceryl ester

[0118] Vitamin E polyethylene glycol succinate 1.0 part

[0119] 40 parts of methacrylic acid-ethylacrylic acid copolymer

[0120] 0.8 parts of triethyl citrate

[0121] 2. Preparation method

[0122] Prepared according to the method of Example 1, except that the solid lipid carrier uses only glyceryl behenate and does not contain polyethylene glycol glycerate laurate; the surfactant uses only vitamin E polyethylene glycol succinate and does not contain poloxamer 188.

[0123] Comparative Example 3: Direct blending hot melt extrusion without drug lipid pre-concentration

[0124] 1. Formula Composition

[0125] The formula is exactly the same as in Example 1.

[0126] 2. Preparation method

[0127] Prepared according to the formulation of Example 1, except that the drug lipid pre-concentrate is not prepared in advance. Instead, omeprazole, polyethylene glycol glycerol laurate, behenicol glycerol laurate, poloxamer 188, vitamin E polyethylene glycol succinate, methacrylate-ethyl acrylate copolymer and triethyl citrate are mixed at one time and directly added to a twin-screw hot melt extruder for hot melt extrusion. The other conditions are the same as in Example 1.

[0128] Comparative Example 4: The ratio of polyethylene glycol glycerol laurate to glycerol behenate exceeds the scope of the claims.

[0129] Preparation of Omeprazole Enteric-coated Capsules

[0130] 1. Formula Composition

[0131] By weight, it includes the following components:

[0132] 20 parts of omeprazole

[0133] 15 parts of polyethylene glycol glyceryl laurate

[0134] 75 parts of behenicol glyceryl ester

[0135] Polosham 188 0.67 copies

[0136] Vitamin E polyethylene glycol succinate 0.33 parts

[0137] 40 parts of methacrylic acid-ethylacrylic acid copolymer

[0138] 0.8 parts of triethyl citrate

[0139] The total amount of solid lipid carrier is 90 parts, and the weight ratio of polyethylene glycol glycerol laurate to behenicol glycerol laurate is 1:5; the total amount of surfactant is 1.0 part, and the weight ratio of poloxamer 188 to vitamin E polyethylene glycol succinate is 2:1.

[0140] 2. Preparation method

[0141] Prepared according to the formulation of Example 1.

[0142] Comparative Example 5: The ratio of poloxamer 188 to vitamin E polyethylene glycol succinate exceeds the scope of the claims.

[0143] 1. Formula Composition

[0144] By weight, it includes the following components:

[0145] 20 parts of omeprazole

[0146] 30 parts of polyethylene glycol glyceryl laurate

[0147] 60 parts of behenicol glyceryl ester

[0148] Polosham 188 0.83 copies

[0149] Vitamin E polyethylene glycol succinate 0.17 parts

[0150] 40 parts of methacrylic acid-ethylacrylic acid copolymer

[0151] 0.8 parts of triethyl citrate

[0152] The total amount of solid lipid carrier is 90 parts, and the weight ratio of polyethylene glycol glycerol laurate to behenicol glycerol laurate is 1:2; the total amount of surfactant is 1.0 part, and the weight ratio of poloxamer 188 to vitamin E polyethylene glycol succinate is 5:1.

[0153] 2. Preparation method

[0154] Prepared according to the formulation of Example 1.

[0155] Comparative Example 6: The total amount of solid lipid carrier used is less than the lower limit of the claims.

[0156] 1. Formula Composition

[0157] By weight, it includes the following components:

[0158] 20 parts of omeprazole

[0159] 16.7 parts of polyethylene glycol glycerol lauryl acid

[0160] Glyceryl behenate 33.3 parts

[0161] Polosham 188 0.67 copies

[0162] Vitamin E polyethylene glycol succinate 0.33 parts

[0163] 40 parts of methacrylic acid-ethylacrylic acid copolymer

[0164] 0.8 parts of triethyl citrate

[0165] The total amount of solid lipid carrier is 50 parts, and the weight ratio of polyethylene glycol glycerol laurate to behenicol glycerol laurate is 1:2; the total amount of surfactant is 1.0 part, and the weight ratio of poloxamer 188 to vitamin E polyethylene glycol succinate is 2:1.

[0166] 2. Preparation method

[0167] Prepared according to the formulation of Example 1.

[0168] Comparative Example 7: The amount of pH-sensitive polymer used was lower than the lower limit of the claims.

[0169] 1. Formula Composition

[0170] By weight, it includes the following components:

[0171] 20 parts of omeprazole

[0172] 30 parts of polyethylene glycol glyceryl laurate

[0173] 60 parts of behenicol glyceryl ester

[0174] Polosham 188 0.67 copies

[0175] Vitamin E polyethylene glycol succinate 0.33 parts

[0176] 15 parts of methacrylic acid-ethylacrylic acid copolymer

[0177] 0.8 parts of triethyl citrate

[0178] The total amount of solid lipid carrier is 90 parts, and the weight ratio of polyethylene glycol glycerol laurate to behenicol glycerol laurate is 1:2; the total amount of surfactant is 1.0 part, and the weight ratio of poloxamer 188 to vitamin E polyethylene glycol succinate is 2:1.

[0179] 2. Preparation method

[0180] Prepared according to the formulation of Example 1.

[0181] Comparative Example 8: No plasticizer added

[0182] 1. Formula Composition

[0183] By weight, it includes the following components:

[0184] 20 parts of omeprazole

[0185] 30 parts of polyethylene glycol glyceryl laurate

[0186] 60 parts of behenicol glyceryl ester

[0187] Polosham 188 0.67 copies

[0188] Vitamin E polyethylene glycol succinate 0.33 parts

[0189] 40 parts of methacrylic acid-ethylacrylic acid copolymer

[0190] No triethyl citrate or other plasticizers are added.

[0191] 2. Preparation method

[0192] Prepared according to the method of Example 1, except that no plasticizer is added. The upper limit of torque is appropriately increased during hot melt extrusion to ensure that the material can be extruded, while the other conditions are the same.

[0193] Comparative Example 9: Using a non-pH-sensitive polymer as a substitute

[0194] 1. Formula Composition

[0195] By weight, it includes the following components:

[0196] 20 parts of omeprazole

[0197] 30 parts of polyethylene glycol glyceryl laurate

[0198] 60 parts of behenicol glyceryl ester

[0199] Polosham 188 0.67 copies

[0200] Vitamin E polyethylene glycol succinate 0.33 parts

[0201] 40 parts of ethyl cellulose

[0202] 0.8 parts of triethyl citrate

[0203] In this example, ethyl cellulose is used instead of the methacrylic acid-ethyl acrylate copolymer in Example 1.

[0204] 2. Preparation method

[0205] Prepared according to the method of Example 1, except that the polymer used was replaced with ethyl cellulose, and all other conditions were the same.

[0206] Example 4: Release Rate Study

[0207] 1. Detection Method

[0208] The omeprazole enteric-coated compositions (not filled into empty capsules) obtained in Examples 1-3 and Comparative Examples 1-9 were respectively tested for release rate according to the release rate determination method in General Chapter 0931, Method II of the 2020 edition of the Chinese Pharmacopoeia.

[0209] The specific conditions are as follows:

[0210] Acidic stage: Medium: 0.1 mol / L hydrochloric acid solution (pH approximately 1.2); Temperature: 37±0.5℃; Rotation speed: 100 rpm; Processing time: 2 hours; Samples were taken at 0.5 hours and 2 hours respectively.

[0211] Buffering phase: After the acidic phase, the pH of the solution was adjusted to 6.8 using sodium hydroxide; the measurement continued, and samples were taken at 5, 10, 20, 30, 45 and 60 minutes after pH adjustment; the omeprazole content was determined by high performance liquid chromatography and the cumulative release was calculated.

[0212] 2. Results are shown in Table 1-2 or Figure 1-2 .

[0213] Table 1 Results of acid resistance release during the acid phase

[0214]

[0215] Table 2. Release results during the buffer phase (cumulative dissolution after pH adjustment to 6.8)

[0216]

[0217] 3. Results Analysis

[0218] From Table 1 and Table 2, we can see that:

[0219] In Examples 1-3 of this invention, after treatment in an acidic medium (pH 1.2) for 2 hours, the cumulative release of omeprazole was no higher than 10% (4.2%, 5.8%, and 6.5%, respectively), demonstrating good gastric protective ability. After transfer to a pH 6.8 buffer for 30 minutes, the cumulative release reached 98.7%, 99.4%, and 98.9%, respectively, all above 80%, indicating near-complete release and rapid intestinal release. The cumulative release decreased slightly at 45 and 60 minutes, possibly related to omeprazole degradation. Comparative Example 1 (single lipid carrier + single surfactant) achieved a cumulative release of 12.6% in the acidic phase after 2 hours, exceeding the 10% limit, indicating that the lipid's protective ability relative to omeprazole decreased without the barrier effect of behenicol ester. In the buffer phase after 30 minutes, the cumulative release was only 78.2%, below 80%. Comparative Example 2 (another group with a single lipid carrier and a single surfactant) showed a similar pattern, with a cumulative release of 13.8% in the acidic phase after 2 hours and only 73.8% in the buffer phase after 30 minutes. This indicates that the single lipid carrier and single surfactant prevented the release of omeprazole into the intestine in a pH 6.8 buffer solution. Comparative Examples 1-2 showed a slight decrease in cumulative release at 60 minutes, possibly due to the degradation of already released drug, while the remaining drug could not be released further due to the matrix structure. Comparative Example 3 (direct blending and hot-melt extrusion without pre-concentration) showed a cumulative release as high as 14.5% in the acidic phase after 2 hours and 81.5% in the buffer phase after 30 minutes, still lower than Examples 1-3. The cumulative release reached its peak at 84.6% in the buffer phase after 45 minutes. This indicates that by directly blending and hot-melt extruding all components without a drug lipid pre-concentration step, omeprazole cannot fully enter the lipid phase to form an effective biphasic matrix structure, resulting in significant deterioration of both acid resistance and intestinal release. The results of Comparative Example 4 indicate that when the ratio of polyethylene glycol glycerol laurate to glyceryl behenate exceeds the range of 1:(1-3), the insufficient proportion of the hydrophilic block of polyethylene glycol glycerol laurate affects the molecular-level dispersion of omeprazole in the lipid phase. Simultaneously, excessive glyceryl behenate leads to increased crystallinity and rigidity of the lipid matrix, decreasing interfacial compatibility with the pH-sensitive polymer. Ultimately, this results in lower acid resistance and intestinal release rates compared to Example 1. This demonstrates that the ratio range of 1:(1-3) in the claims is not arbitrarily chosen, but rather an optimal range based on the synergistic function of the two lipid materials. The results of Comparative Example 5 indicate that polyethylene glycol succinate for vitamin E not only acts as a surfactant in the system of this invention, but its vitamin E groups also possess antioxidant protection functions, inhibiting the oxidative degradation of the sulfinyl group of omeprazole. When its proportion is insufficient, this protective effect is weakened. Furthermore, excessive poloxamer 188 increases the hydrophilicity of the lipid system, making it easier for acidic media to penetrate the matrix, thus weakening the acid resistance effect.The synergistic ratio of the two surfactants within the range of (1–3):1 is a crucial condition for achieving optimal formulation performance. The results of Comparative Example 6 indicate that the amount of solid lipid carrier needs to reach a certain threshold to ensure sufficient molecular-level dispersion of omeprazole in the lipid phase. When the total amount of lipid carrier is only 50 parts, compared to 20 parts of omeprazole, the amount of lipid carrier is insufficient to construct complete lipid microdomains, causing some omeprazole to be directly embedded in the polymer continuous phase in microcrystal form (a weak omeprazole melting peak may appear in DSC detection), losing the protection of the lipid phase and significantly reducing acid resistance. In Comparative Example 7, after the amount of pH-sensitive polymer was reduced to 15 parts, the cumulative release in the acidic phase increased significantly to 12.6% after 2 hours. Although the cumulative release in the buffer solution reached 72.4% after 30 minutes, its protective ability in the stomach was clearly insufficient, indicating that the amount of polymer continuous phase must reach a certain level to form an effective acid-resistant barrier. In Comparative Example 8, without the addition of plasticizer, the processability of the extrudate deteriorated, and the release rate of the resulting formulation increased to 13.1% in the acidic stage, decreased to 81.4% in the buffer solution after 30 minutes, and decreased to 94.5% in the buffer solution after 45 minutes. This indicates that the plasticizer helps improve the polymer processing performance and matrix structure integrity, thereby improving acid resistance and release consistency. In Comparative Example 9, after replacing the methacrylic acid-ethyl acrylate copolymer with the non-pH-sensitive polymer ethyl cellulose, although Comparative Example 9 still showed a certain inhibitory effect in the acidic stage, its cumulative release rate after 2 hours was 11.8%, which is still higher than the preferred standard of this invention. Moreover, its cumulative release rate in the pH 6.8 buffer solution after 30 minutes was only 79.5%, showing obvious insufficient release. This indicates that the pH-sensitive polymer described in this invention is essential for achieving the technical effect of "protection in the stomach and rapid release in the intestine".

[0220] Example 5: Stability Experiment

[0221] 1. Light stability test

[0222] The samples from Examples 3 and Comparative Examples 1-9 (omeprazole enteric-coated compositions not filled into empty capsules) were placed under light (4500-5000 lx), and the total impurity content was measured periodically. The results are shown in Table 3 or Figure 3 .

[0223] Table 3 Results of light stability test (impurity content, %)

[0224]

[0225] 2. Accelerated stability test

[0226] Accelerated testing was conducted on all samples at 40℃±2℃ and 75%±5% relative humidity. Samples were taken at 0 months, 1 month, 2 months, and 3 months, and the total impurity content was determined by high performance liquid chromatography. The results are shown in Table 4 or [Table data would be inserted here]. Figure 4 .

[0227] Table 4. Results of accelerated stability test (total impurity content, %)

[0228]

[0229] 3. Results Analysis

[0230] (1) Regarding light stability: After 120 days of light exposure, the total impurity content of Examples 1-3 remained at an extremely low level (0.29%–0.34%). The impurity increase was more pronounced in Comparative Examples 1-9, with the impurity content of Comparative Examples 1-2 increasing significantly after 60 days, reaching 0.77% and 0.68% respectively at 120 days. Comparative Example 3 performed the worst, with an impurity content of 0.85% at 120 days.

[0231] (2) Regarding accelerated stability: After being stored at 40℃±2℃ and 75%±5% relative humidity for 3 months, the total impurity increase values ​​of Examples 1-3 of the present invention were 0.14%, 0.18%, and 0.19%, respectively, all not exceeding 0.20%, showing good storage stability. The impurity increase of Comparative Examples 1-9 was more obvious, among which the impurity increase value of Comparative Example 3 (direct blending and hot melt extrusion without pre-concentration) was as high as 0.55%, which was nearly 3 times that of Example 1.

[0232] (3) The above results indicate that the dual solid lipid carrier system, dual surfactant system, and drug lipid pre-concentration combined with hot melt extrusion process adopted in this invention work synergistically to reduce omeprazole degradation and improve the storage stability of the formulation. Among them, the drug lipid pre-concentration step makes a particularly significant contribution to stability (Comparative Example 3 vs. Example 1).

[0233] Example 6: Special Investigation on the Effect of Drug Lipid Pre-concentration Process

[0234] 1. Experimental Design

[0235] Example 1 and Comparative Example 3 were selected for comparison to evaluate the effect of the drug lipid pre-concentration step on formulation performance. Example 1 used a process of "preparing the drug lipid pre-concentrate first, and then hot-melt extruding it with a pH-sensitive polymer and a plasticizer"; Comparative Example 3 used a process of "direct hot-melt extrusion after one-time blending of all components".

[0236] Both have the same formula composition, only the preparation process is different.

[0237] 2. The comparison results are shown in Table 5 or... Figure 5 .

[0238] Table 5. Effects of pre-concentration process on formulation performance

[0239]

[0240] 3. Results Analysis

[0241] The results showed that, under identical formulation conditions, whether or not a drug lipid pre-concentration step was used had a significant impact on the performance of the final formulation:

[0242] (1) Acid resistance: The acid phase release of Example 1 was only 4.2%, while that of Comparative Example 3 was as high as 14.5%, a difference of 3.5 times. This indicates that the pre-concentration step allows omeprazole to fully enter the lipid phase and form an effective biphasic matrix structure after hot melt extrusion, thereby significantly improving the acid resistance protection effect.

[0243] (2) Enteric release: Example 1 released 98.7% in buffer solution in 30 minutes, while Comparative Example 3 released only 88.5%. It is speculated that the pre-concentration step makes the lipid phase more uniformly dispersed, which can expose and release the drug more quickly after the pH-sensitive polymer swells / dissolves.

[0244] (3) Stability: The increase in impurities in Example 1 over 3 months was only 0.14%, while that in Comparative Example 3 was as high as 0.55%, a difference of more than 3 times. This indicates that the pre-concentration step provides more favorable lipid microenvironment protection for omeprazole, reducing the risk of degradation during processing and storage.

[0245] In summary, the drug lipid pre-concentration step is not simply a change in the mixing order, but rather a fundamental difference at the level of formulation microstructure. It enables omeprazole to achieve more complete dispersion and encapsulation in the lipid phase, thereby obtaining better protection and superior release behavior in the final biphasic matrix.

[0246] Example 7: Microstructure and Phase Characterization

[0247] 1. Scanning electron microscopy (SEM) observation

[0248] The extruded omeprazole enteric-coated composition obtained in Example 1 was subjected to liquid nitrogen brittle fracture, and its cross-section was observed by scanning electron microscopy. The results showed that the cross-section of the extruded composition exhibited obvious two-phase structural characteristics, in which the polymer matrix formed a continuous and smooth skeletal phase (continuous phase), while the lipid regions were uniformly dispersed in the continuous polymer phase in the form of spherical nano or submicron droplets / microregions, confirming the formation of the "two-phase matrix structure" described in this invention. In contrast, the cross-section of Comparative Example 3 (direct blend) showed rough, irregular aggregates with blurred phase separation boundaries.

[0249] 2. Differential Scanning Calorimetry (DSC) Analysis

[0250] DSC analysis was performed on the omeprazole active pharmaceutical ingredient, the drug lipid pre-concentrate obtained in Example 1, and the final enteric-coated composition. The omeprazole active pharmaceutical ingredient exhibited a sharp, characteristic melting endothermic peak at approximately 158°C. However, in the DSC spectra of the drug lipid pre-concentrate and the final composition of Example 1, this characteristic melting peak of omeprazole completely disappeared. This indicates that, through the pre-concentration process, omeprazole was molecularly dispersed or amorphously dissolved in the solid lipid carrier, thereby avoiding crystal form changes or localized high-concentration degradation of the drug during subsequent extrusion and release.

[0251] The specific embodiments of the present invention have been described above. It should be understood that the present invention is not limited to the specific embodiments described above, and those skilled in the art can make various modifications or variations within the scope of the claims, which do not affect the essence of the present invention.

Claims

1. An enteric composition of omeprazole, characterized in that, The omeprazole enteric-coated composition is prepared by hot melt extrusion of omeprazole, a solid lipid carrier, a surfactant, a pH-sensitive polymer, and a plasticizer, forming a biphase matrix structure with the pH-sensitive polymer as the continuous phase and the omeprazole-containing lipid phase as the dispersed phase. The omeprazole enteric-coated composition comprises, by weight, the following components: 10-30 parts omeprazole; 80-120 parts solid lipid carrier; 0.1-1.5 parts surfactant; 30-60 parts pH-sensitive polymer; and 0.1-2 parts plasticizer. The solid lipid carrier is composed of polyethylene glycol glycerol laurate and glycerol behenate, with a weight ratio of PEG-glycerol laurate to glycerol behenate of 1:(1-3). The surfactant is composed of poloxamer 188 and vitamin E polyethylene glycol succinate, with a weight ratio of poloxamer 188 to vitamin E polyethylene glycol succinate of (1-3):

1.

2. The enteric omeprazole composition according to claim 1, characterized in that, The ratio of polyethylene glycol glycerol laurate to behenicol glycerol laurate is 1:

2.

3. The enteric omeprazole composition according to claim 1, wherein The ratio of poloxamer 188 to vitamin E polyethylene glycol succinate is 2:

1.

4. The enteric composition of omeprazole according to any one of claims 1 to 3, characterized in that, The pH-sensitive polymer is selected from one or at least two of methacrylic acid-ethyl acrylate copolymer, hydroxypropyl methylcellulose acetate succinate, and hydroxypropyl methylcellulose phthalate.

5. The enteric composition of omeprazole according to any one of claims 1 to 3, wherein The plasticizer is triethyl citrate. According to the release rate determination method in the Chinese Pharmacopoeia, the cumulative release of omeprazole in the enteric-coated composition is not higher than 10% after treatment in an acidic medium with pH 1.0 to 1.5 for 2 hours, and the cumulative release is not lower than 80% after being transferred to a buffer medium with pH 6.5 to 7.0 for 30 minutes. Furthermore, after the enteric-coated composition of omeprazole is placed at 40℃±2℃ and relative humidity 75%±5% for 3 months, the increase in total impurity content is not higher than 0.20%.

6. An omeprazole enteric-coated capsule, characterized in that, The omeprazole enteric-coated composition according to any one of claims 1-3 is obtained by adding an appropriate amount of lubricant and filling it into hard capsules.

7. The omeprazole enteric-coated composition according to any one of claims 1-3, characterized in that, The preparation method specifically includes the following steps: (1) Weigh out the following ingredients according to the formula: omeprazole, solid lipid carrier, surfactant, pH-sensitive polymer and plasticizer; (2) Omeprazole, solid lipid carrier and surfactant are melt-mixed at 60-70°C to prepare drug lipid preconcentrate; (3) The drug lipid preconcentrate is mixed with pH-sensitive polymer and plasticizer, and then extruded by twin screw hot melt extrusion at 90-120°C to obtain extrudate, so that the lipid phase containing omeprazole is dispersed in the continuous phase of pH-sensitive polymer. (4) Cool and granulate the extrudate obtained in step (3) to obtain the omeprazole enteric-coated composition.

8. The omeprazole enteric-coated composition according to claim 7, characterized in that, In step (2), omeprazole, solid lipid carrier and surfactant are melt-mixed at 65°C to obtain drug lipid preconcentrate.

9. The omeprazole enteric-coated composition according to claim 7, characterized in that, In step (3), the drug lipid pre-concentrate is mixed with pH-sensitive polymer and plasticizer, and then extruded using a twin-screw hot melt extrusion at 110°C to obtain an extrudate, so that the lipid phase containing omeprazole is dispersed in the continuous phase of pH-sensitive polymer.

10. Use of the omeprazole enteric-coated composition according to any one of claims 1 to 3, or the omeprazole enteric-coated capsule according to claim 6, in the preparation of a medicament for treating gastric ulcers, duodenal ulcers, reflux esophagitis, Zollinger-Ellison syndrome, and Helicobacter pylori-associated acid secretion disorders.

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