Pharmaceutical formulation

Abstract

A pharmaceutical formulation according to some embodiments comprises: an immediate-release part for eluting an active ingredient in a pH-independent manner; and an enteric part for eluting the active ingredient in a pH-dependent manner, wherein the active ingredient may comprise a proton pump inhibitor, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. Some embodiments of the present invention enable immediate absorption of drugs while maintaining prolonged pharmacological efficacy.

Description

pharmaceutical preparations

[0001] The present invention relates to a pharmaceutical preparation comprising a proton pump inhibitor.

[0002] This disclosure claims the benefit of priority to Republic of Korea Patent Application No. 10-2024-0066394, filed May 22, 2024, the entire contents of which are incorporated by reference herein.

[0003] Proton pump inhibitors (PPIs) are drugs that suppress gastric acid secretion by inhibiting the enzyme H+ / K+-ATPase, which is involved in gastric acid secretion. Therefore, PPIs are effective in treating conditions such as indigestion, gastroesophageal reflux disease (GERD), laryngeal reflux disease (GERD), and peptic ulcer disease.

[0004] PPIs, such as dexlansoprazole, lansoprazole, ilaprazole, pantoprazole, rabeprazole, and esomeprazole, are benzimidazole-based prodrugs. These PPIs are highly unstable in acidic environments and are easily degraded by gastric acid as they pass through the stomach. Therefore, the following attempts have been made in the past.

[0005] Korean Patent No. 10-2146395 proposes a formulation containing sodium bicarbonate, which neutralizes gastric acid. However, the formulation contains only 800 mg of sodium bicarbonate, resulting in poor patient compliance. Furthermore, the formulation's efficacy is short-lived, failing to alleviate patients' nocturnal symptoms.

[0006] Meanwhile, South Korean Patent No. 10-1061750 (Dexilant DR Capsule, Takeda Pharmaceutical Company) proposes a capsule containing two granules that release the drug at different pH levels and at different times. However, since both granules in this capsule release the drug at pH 5.5 or higher, immediate absorption of the drug is not achieved.

[0007] Accordingly, there is a need to develop pharmaceutical formulations that have excellent patient compliance, long-lasting efficacy, and immediate drug absorption.

[0008] The technical idea of ​​the present invention aims to solve a problem by providing a pharmaceutical preparation that has excellent patient compliance, long-lasting efficacy, and allows immediate absorption of the drug.

[0009] Some embodiments of the present invention that can solve the above-described problems are as follows.

[0010] According to some embodiments, a pharmaceutical preparation comprises a rapid-release portion that releases an active ingredient in a pH-independent manner; and an enteric portion that releases an active ingredient in a pH-dependent manner; wherein the active ingredient may comprise a proton pump inhibitor, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

[0011] In some embodiments, the active ingredient can be eluted at a pH ranging from 1.0 to 8.5.

[0012] In some embodiments, the active ingredient can be dissolved in a range of pH 4.0 to pH 8.5.

[0013] In some embodiments, the rapid release agent may include a pH adjusting agent.

[0014] In some embodiments, the pH adjusting agent may include one or more of magnesium hydroxide, magnesium carbonate, magnesium oxide, calcium carbonate, sodium bicarbonate, sodium biphosphate, and sodium carbonate.

[0015] In some embodiments, the pH adjusting agent may include one or more of magnesium hydroxide, magnesium carbonate, magnesium oxide, and calcium carbonate.

[0016] In some embodiments, the pH adjusting agent may include magnesium hydroxide.

[0017] In some embodiments, the amount of the pH regulator may be in the range of 200 mg to 500 mg.

[0018] In some embodiments, the long-lasting portion may include a long-lasting coating layer.

[0019] In some embodiments, the enteric coating layer can be dissolved in a range of pH 4.0 to pH 8.5.

[0020] In some embodiments, the enteric coating layer may include one or more of polyvinyl acetate phthalate, methacrylic acid copolymer, methacrylic acid-ethyl acrylate copolymer, methyl methacrylate-ethyl acrylate copolymer, methacrylic acid-methyl methacrylate copolymer, hypromellose, hypromellose phthalate, hypromellose acetate succinate, cellulose acetate, cellulose acetate phthalate, cellulose acetate succinate, carboxymethylethyl cellulose, ethyl cellulose, ethyl acrylate-methyl methacrylate-trimethylammonium ethyl methacrylate chloride copolymer, and shellac.

[0021] In some embodiments, the long-lasting coating layer may comprise a methacrylic acid copolymer.

[0022] In some embodiments, the enteric coating layer may additionally comprise polysorbate 80.

[0023] In some embodiments, the immediate release portion may be an immediate release tablet, the enteric coating portion may be an enteric coating tablet, and the pharmaceutical formulation may be a capsule.

[0024] In some embodiments, the proton pump inhibitor may include one or more of dexlansoprazole, lansoprazole, ilaprazole, pantoprazole, rabeprazole, and esomeprazole.

[0025] In some embodiments, the proton pump inhibitor may comprise dexlansoprazole.

[0026] In some embodiments, the pharmaceutically acceptable solvate of the proton pump inhibitor may comprise dexlansoprazole 1.5 hydrate.

[0027] In some embodiments, the active ingredient may include low-substituted hydroxypropyl cellulose, tromethamine, microcrystalline cellulose, crospovidone, and sodium stearyl fumarate.

[0028] In some embodiments, the enteric portion may include tromethamine, hypromellose, sodium lauryl sulfate, low-substituted hydroxypropyl cellulose, sodium starch glycolate, and sodium stearyl fumarate.

[0029] In some embodiments, the total weight of the pharmaceutical formulation may be less than or equal to 750 mg.

[0030] In some embodiments, the content of the long-lasting coating layer may be in the range of 10 parts by weight to 70 parts by weight based on 100 parts by weight of the active ingredient included in the long-lasting portion.

[0031] In some embodiments, the content of the enteric coating layer may be in the range of 2 parts by weight to 35 parts by weight based on 100 parts by weight of the portion of the enteric part excluding the enteric coating layer.

[0032] Some embodiments of the present invention enable immediate absorption of the drug while maintaining a prolonged therapeutic effect. Some embodiments of the present invention also exhibit excellent patient compliance.

[0033] The effects of the embodiments of the present invention are not limited to the effects mentioned above, and other effects not mentioned can be clearly derived and understood by those skilled in the art to which the embodiments of the present invention pertain from the following description. In other words, unintended effects resulting from practicing the embodiments of the present invention can also be clearly derived and understood by those skilled in the art to which the embodiments of the present invention pertain.

[0034] FIG. 1 is a schematic diagram illustrating a pharmaceutical formulation according to some embodiments.

[0035] Figure 2 is a graph showing the dissolution patterns under acidic conditions and buffer conditions of Examples 1 to 4.

[0036] The terms or words used in this specification should not be interpreted as limited to their usual or dictionary meanings, but should be interpreted in a meaning that conforms to the technical idea of ​​the present invention based on the principle that the inventor can appropriately define the meaning of the terms or words to explain his or her own invention in the best way.

[0037] In this specification, it should be understood that terms such as "include" or "have" are intended to specify the presence of a feature, number, step, operation, component, part or combination thereof described in the specification, but do not preclude the possibility of the presence or addition of one or more other features, numbers, steps, operations, components, parts or combinations thereof. In addition, when it is said that a part such as a layer, film, region or plate is "on" another part, this includes not only the case where it is "directly above" the other part, but also the case where there is another part in between. Conversely, when it is said that a part such as a layer, film, region or plate is "under" another part, this includes not only the case where it is "directly below" the other part, but also the case where there is another part in between.

[0038] It should be understood that the examples and drawings are merely examples of the present invention and do not represent all of the technical ideas of the present invention, and that various equivalents and modifications may be substituted for them.

[0039] When describing the present invention, if it is determined that a detailed description of a known configuration or function may obscure the gist of the present invention, the detailed description will be omitted.

[0040] Since the drawings are provided to more completely explain the present invention to those skilled in the art, the shape, size, and number of components in the drawings may be exaggerated, omitted, or schematically illustrated for clearer explanation. The shape, size, ratio, and number of each component in the drawings do not entirely reflect the actual shape, size, ratio, and number of each component.

[0041]

[0042] FIG. 1 is a schematic diagram illustrating a pharmaceutical formulation according to some embodiments.

[0043] Referring to Figure 1, the pharmaceutical preparation (10) includes a rapid-release part (11) and an enteric part (12).

[0044] Since the pharmaceutical preparation (10) includes a rapid-release portion (11), when a human ingests the pharmaceutical preparation (10), the active ingredient can be immediately absorbed into the body. Since the pharmaceutical preparation (10) includes an enteric portion (12), when a human ingests the pharmaceutical preparation (10), the medicinal effect can last for a long time.

[0045]

[0046] The fast-acting part (11) and the long-acting part (12) contain a proton pump inhibitor, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient.

[0047] In some embodiments, the proton pump inhibitor may comprise one or more of dexlansoprazole, lansoprazole, ilaprazole, pantoprazole, rabeprazole, and esomeprazole. In some embodiments, the proton pump inhibitor may comprise dexlansoprazole. In some embodiments, the pharmaceutically acceptable salt may comprise a salt derived from a pharmaceutically acceptable organic acid, inorganic acid, or base. In some embodiments, the pharmaceutically acceptable solvate of the proton pump inhibitor may be dexlansoprazole 1.5 hydrate.

[0048]

[0049] In some embodiments, the content of the active ingredient included in the rapid release portion (11) may be in the range of 5 mg to 25 mg. In some embodiments, the content of the active ingredient included in the rapid release portion (11) may be in the range of 10 mg to 20 mg.

[0050] In some embodiments, the content of the active ingredient included in the long-term portion (11) may be in the range of 30 mg to 70 mg. In some embodiments, the content of the active ingredient included in the long-term portion (11) may be in the range of 40 mg to 60 mg.

[0051]

[0052] The human digestive system is composed of the stomach, small intestine (duodenum, jejunum, ileum), and large intestine, and the pH of each is different. In this specification, the phrase "the active ingredient is dissolved independently of pH" in the rapid-release part (11) means that the rapid-release part (11) dissolves the active ingredient regardless of the pH of the digestive organ. In this specification, the phrase "the active ingredient is dissolved dependently on pH" in the enteric-coated part (12) means that the enteric-coated part (12) dissolves or does not dissolve the active ingredient depending on the pH of the digestive organ.

[0053] In some embodiments, the release portion (11) can release the active ingredient in the stomach, small intestine, or large intestine. In some embodiments, the enteric portion (12) can release the active ingredient in the small intestine and / or large intestine without releasing the active ingredient in the stomach.

[0054] In some embodiments, the release portion (11) can release the active ingredient in a range of pH 1.0 to pH 8.5. In some embodiments, the enteric portion can release the active ingredient in a range of pH 4.0 to pH 8.5.

[0055]

[0056] In some embodiments, the release agent (11) may include a pH regulator. In some embodiments, the pH regulator may neutralize an acidic environment when the release agent (11) is exposed to the acidic environment, thereby preventing the active ingredient from decomposing.

[0057] In some embodiments, the pH adjusting agent may include one or more of a metallic antacid or a non-metallic antacid. In some embodiments, the pH adjusting agent may include one or more of magnesium hydroxide, magnesium carbonate, magnesium oxide, calcium carbonate, sodium bicarbonate, sodium biphosphate, and sodium carbonate. In some embodiments, the pH adjusting agent may include one or more of magnesium hydroxide, magnesium carbonate, magnesium oxide, and calcium carbonate. In some embodiments, the pH adjusting agent may include magnesium hydroxide.

[0058] In some embodiments, the content of the pH adjusting agent may be in the range of 200 mg to 500 mg. If the content of the pH adjusting agent is too low, when the rapid release portion (11) is exposed to an acidic environment, the acidic environment may not be sufficiently neutralized, thereby failing to prevent the decomposition of the active ingredient. If the content of the pH adjusting agent is too high, the size of the pharmaceutical preparation (10) may increase, which may reduce patient compliance.

[0059] In some embodiments, the amount of the pH regulator may be 250 mg or more. In some embodiments, the amount of the pH regulator may be 300 mg or more. In some embodiments, the amount of the pH regulator may be 310 mg or more. In some embodiments, the amount of the pH regulator may be 450 mg or less. In some embodiments, the amount of the pH regulator may be 400 mg or less. In some embodiments, the amount of the pH regulator may be 330 mg or less.

[0060]

[0061] In some embodiments, the enteric portion (12) may include an enteric coating layer. The enteric coating layer may prevent the enteric portion (12) from dissolving the active ingredient even when the enteric portion (12) is exposed to an acidic environment.

[0062] In some embodiments, the enteric coating layer can be dissolved in a range of pH 4.0 to pH 8.5. Accordingly, as described above, the enteric portion (12) can dissolve the active ingredient in a range of pH 4.0 to pH 8.5.

[0063] In some embodiments, the enteric coating layer may include one or more of polyvinyl acetate phthalate, a methacrylic acid copolymer, a methacrylic acid-ethyl acrylate copolymer, a methyl methacrylate-ethyl acrylate copolymer, a methacrylic acid-methyl methacrylate copolymer, hypromellose, hypromellose phthalate, hypromellose acetate succinate, cellulose acetate, cellulose acetate phthalate, cellulose acetate succinate, carboxymethylethyl cellulose, ethyl cellulose, an ethyl acrylate-methyl methacrylate-trimethylammonium ethyl methacrylate chloride copolymer, and shellac. In some embodiments, the enteric coating layer may include a methacrylic acid copolymer. In some embodiments, the enteric coating layer may include Opadry Enteric 95O available from Colorcon.

[0064] In some embodiments, the enteric coating layer comprises sodium lauryl sulfate and derivatives thereof, poloxamer and derivatives thereof, medium chain triglycerides (MCT), labrasol, transcutol, labrafil, labrafac, poloxamer, various polysorbates [e.g., polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan monopalmitate (Tween 40), polyoxyethylene sorbitan monostearate (Tween 60), and polyoxyethylene sorbitan monooleate (Tween 80)], sorbitan esters [e.g., sorbitan monolaurate (Span 20), sorbitan monopalmitate (Span 40), Sorbitan monostearate (Span 60), sorbitan monooleate (Span 80), sorbitan trilaurate (Span 25), sorbitan trioleate (Span 85), sorbitan tristearate (Span 65)], cremophor, PEG-60 hydrogenated castor oil, PEG-40 hydrogenated castor oil, sodium lauryl glutamate, disodium cocoamphodiacetate, and fumed silica (colloidal silica). In some embodiments, the enteric coating layer may include polysorbate 80.

[0065] In some embodiments, the content of the enteric coating layer may be in the range of 10 parts by weight to 70 parts by weight based on 100 parts by weight of the active ingredient included in the enteric portion (12). If the content of the enteric coating layer is too low, the enteric portion (12) may dissolve the active ingredient too quickly in the range of pH 4.0 to pH 8.5. If the content of the enteric coating layer is too high, the enteric portion (12) may dissolve the active ingredient too slowly in the range of pH 4.0 to pH 8.5.

[0066] In some embodiments, the content of the enteric coating layer may be 15 parts by weight or more with respect to 100 parts by weight of the active ingredient included in the enteric portion (12). In some embodiments, the content of the enteric coating layer may be 20 parts by weight or more with respect to 100 parts by weight of the active ingredient included in the enteric portion (12). In some embodiments, the content of the enteric coating layer may be 25 parts by weight or more with respect to 100 parts by weight of the active ingredient included in the enteric portion (12). In some embodiments, the content of the enteric coating layer may be 30 parts by weight or more with respect to 100 parts by weight of the active ingredient included in the enteric portion (12). In some embodiments, the content of the enteric coating layer may be 65 parts by weight or less with respect to 100 parts by weight of the active ingredient included in the enteric portion (12). In some embodiments, the content of the enteric coating layer may be 60 parts by weight or less with respect to 100 parts by weight of the active ingredient included in the enteric portion (12). In some embodiments, the content of the enteric coating layer may be 55 parts by weight or less with respect to 100 parts by weight of the active ingredient included in the enteric portion (12). In some embodiments, the content of the enteric coating layer may be 50 parts by weight or less with respect to 100 parts by weight of the active ingredient included in the enteric portion (12). In some embodiments, the content of the enteric coating layer may be 45 parts by weight or less with respect to 100 parts by weight of the active ingredient included in the enteric portion (12). In some embodiments, the content of the enteric coating layer may be 40 parts by weight or less with respect to 100 parts by weight of the active ingredient included in the enteric portion (12). In some embodiments, the content of the long-lasting coating layer may be 35 parts by weight or less with respect to 100 parts by weight of the active ingredient included in the long-lasting portion (12).

[0067] In some embodiments, the content of the enteric coating layer may be in the range of 2 parts by weight to 35 parts by weight based on 100 parts by weight of the portion of the enteric coating layer excluding the enteric coating layer among the enteric portions (12). If the content of the enteric coating layer is too low, the enteric portions (12) may dissolve the active ingredient too quickly in the range of pH 4.0 to pH 8.5. If the content of the enteric coating layer is too high, the enteric portions (12) may dissolve the active ingredient too slowly in the range of pH 4.0 to pH 8.5.

[0068] In some embodiments, the content of the enteric coating layer may be 5 parts by weight or more with respect to 100 parts by weight of the portion of the enteric portion (12) excluding the enteric coating layer. In some embodiments, the content of the enteric coating layer may be 7 parts by weight or more with respect to 100 parts by weight of the portion of the enteric portion (12) excluding the enteric coating layer. In some embodiments, the content of the enteric coating layer may be 9 parts by weight or more with respect to 100 parts by weight of the portion of the enteric portion (12) excluding the enteric coating layer. In some embodiments, the content of the enteric coating layer may be 11 parts by weight or more with respect to 100 parts by weight of the portion of the enteric portion (12) excluding the enteric coating layer. In some embodiments, the content of the enteric coating layer may be 13 parts by weight or more with respect to 100 parts by weight of the portion of the enteric portion (12) excluding the enteric coating layer. In some embodiments, the content of the enteric coating layer may be 30 parts by weight or less relative to 100 parts by weight of the portion of the enteric portion (12) excluding the enteric coating layer. In some embodiments, the content of the enteric coating layer may be 25 parts by weight or less relative to 100 parts by weight of the portion of the enteric portion (12) excluding the enteric coating layer. In some embodiments, the content of the enteric coating layer may be 20 parts by weight or less relative to 100 parts by weight of the portion of the enteric portion (12) excluding the enteric coating layer. In some embodiments, the content of the enteric coating layer may be 17 parts by weight or less relative to 100 parts by weight of the portion of the enteric portion (12) excluding the enteric coating layer. In some embodiments, the immediate-release portion (11) may be a tablet, a granule, a powder, a pill, a liquid, a pellet, a soft capsule, or a hard capsule. In some embodiments, the immediate-release portion (11) may be an immediate-release tablet. In Fig. 2, the release unit (11) is depicted as a single solid formulation, but this is merely exemplary. In some embodiments, the release unit (11) may include a plurality of tablets, a plurality of soft capsules, or a plurality of hard capsules.As a non-limiting example, the release portion (11) may comprise two tablets, one containing the active ingredient and the other containing a pH modifier. In some embodiments, the enteric portion (12) may be a tablet, granule, powder, pill, liquid, pellet, soft capsule, or hard capsule. In some embodiments, the enteric portion (12) may be an enteric tablet.

[0069] In some embodiments, the release unit (11) may include a coating layer. In some embodiments, the coating layer may be configured to provide color to the tablet or prevent the tablet from sticking. In some embodiments, the coating layer may include one or more of polyvinyl alcohol, hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose, and ethyl cellulose. In some embodiments, the coating layer may include polyvinyl alcohol. In some embodiments, the coating layer may include talc, titanium dioxide, sodium lauryl sulfate, and glycerol monocaprylocaprate. In some embodiments, the coating layer may include Opadry AMB II Yellow from Colorcon.

[0070] In some embodiments, the enteric coating portion (12) may include a first coating layer and a second coating layer. In some embodiments, the first coating layer may be configured to provide color to the tablet or prevent the tablet from sticking. In some embodiments, the first coating layer may include one or more of hypromellose, hydroxypropylcellulose, hydroxyethylcellulose, ethylcellulose, and polyvinyl alcohol. In some embodiments, the first coating layer may include hypromellose. In some embodiments, the first coating layer may include Opadry Yellow from Colorcon. In some embodiments, the second coating layer may be located on the surface of the second coating layer. In some embodiments, the second coating layer may be the enteric coating layer described above.

[0071]

[0072] In some embodiments, the immediate release portion (11) may include low-substituted hydroxypropyl cellulose, tromethamine, microcrystalline cellulose, crospovidone, and sodium stearyl fumarate. In some embodiments, the enteric portion (12) may include tromethamine, hypromellose, sodium lauryl sulfate, low-substituted hydroxypropyl cellulose, sodium starch glycolate, and sodium stearyl fumarate. The materials described above are merely examples of additives that may be included in the immediate release portion (11) or the enteric portion (12) in some embodiments. That is, in addition to the materials described above, additives commonly used in the pharmaceutical industry may also be included in the immediate release portion (11) or the enteric portion (12) as needed.

[0073]

[0074] In some embodiments, the pharmaceutical formulation (10) may be a tablet or a capsule. In some embodiments, the pharmaceutical formulation (10) may be a capsule. The capsule may protect the immediate-release portion (11) and the enteric-coated portion (12). The capsule may prevent the immediate-release portion (11) and the enteric-coated portion (12) from being exposed to the outside in the mouth or esophagus. The capsule may allow the immediate-release portion (11) and the enteric-coated portion (12) to be exposed to the outside in the stomach. In some embodiments, the pharmaceutical formulation (10) may be a soft capsule or a hard capsule. In some embodiments, the pharmaceutical formulation (10) may be a hard capsule.

[0075] In some embodiments, the total weight of the pharmaceutical formulation (10) may be 750 mg or less. Accordingly, the pharmaceutical formulation (10) may have excellent patient compliance. In some embodiments, the total weight of the pharmaceutical formulation (10) may be 700 mg or less. In some embodiments, the total weight of the pharmaceutical formulation (10) may be 650 mg or less. In some embodiments, the total weight of the pharmaceutical formulation (10) may be 400 mg or more. In some embodiments, the total weight of the pharmaceutical formulation (10) may be 450 mg or more. In some embodiments, the total weight of the pharmaceutical formulation (10) may be 500 mg or more. In some embodiments, the total weight of the pharmaceutical formulation (10) may be 550 mg or more. In some embodiments, the total weight of the pharmaceutical formulation (10) may be 600 mg or more.

[0076]

[0077] Test 1: Comparative test of acid neutralization effect according to type of pH adjuster

[0078] The pH regulators listed in Table 1 below were added to a solution (≒ pH 1.5) containing 100 mL of a pH 1.2 solution and 200 mL of purified water, and after waiting a sufficient amount of time, the pH of the solution was measured. The total amount of pH regulators was 320 mg.

[0079] pH adjusterMagnesium hydroxideMagnesium carbonateSodium bicarbonateSodium biphosphateSodium carbonateSodium carbonateMagnesium oxideCalcium carbonate solution pH 10.402.51.821.642.229.612.32

[0080] Through Test 1, it was confirmed that magnesium hydroxide, magnesium carbonate, magnesium oxide, calcium carbonate, sodium carbonate, sodium bicarbonate, and sodium biphosphate all have the property of neutralizing acids, thereby changing the pH value and having a pH control effect.

[0081] Test 2: Comparison of the dissolution patterns of the enteric part according to the composition of the enteric coating layer

[0082] In order for the efficacy to last for a long time, the time interval between the first release start time of the active ingredient by the immediate-release part (the time when the slope first starts to rise steeply on the graph where the X-axis is time and the Y-axis is blood drug concentration) and the second release start time of the active ingredient by the sustained-release part (the time when the slope second starts to rise steeply on the graph where the X-axis is time and the Y-axis is blood drug concentration) should be about 2 to about 3 hours. If the above time interval is about 2 to about 3 hours, the T of the formulation max The T of typical PPI preparations is about 4 to 6 hours. max The drug is released from the bloodstream at a significantly delayed rate of approximately 1 hour. This delays the drug's elimination from the bloodstream, allowing the drug to have a prolonged effect.

[0083] Since the first release of the active ingredient by the fast-acting agent occurs almost immediately after taking the preparation, the time for the start of the release of the active ingredient in the body after taking the long-acting agent must be about 2 to 3 hours so that the drug effect can last for a long time.

[0084]

[0085] <In vitro 용출 시험 조건>

[0086] Dissolution solution: 900 mL of pH 7.0, 0.144% (w / v) SLS solution

[0087] Device: Basket method, 75±2rpm

[0088] Temperature: 37±0.5 ℃

[0089] The effluent has a pH of 7.0, simulating conditions within the small intestine.

[0090]

[0091] <in vitro 약물 방출 시간으로부터 예측되는 체내 약물 방출 시간>

[0092] Since the dissolution rate under in vitro dissolution test conditions is approximately twice that under small intestinal conditions, the onset time of active ingredient release in the in vitro dissolution test is multiplied by 2. Then, considering that the residence time in the stomach is 1 hour, 1 hour is added. The predicted onset time of active ingredient release in the body after taking the formulation, based on the onset time of active ingredient release in the in vitro dissolution test, is as shown in Table 2 below. Ultimately, the desirable drug release time in the in vitro dissolution test is approximately 30 to 60 minutes.

[0093]

[0094] In vitro dissolution test, start time of active ingredient release (minutes) 0153045607590 Start time of active ingredient release in the body after taking the preparation (minutes) 6090120150180210240

[0095] The following manufacturing examples 1 to 4 were prepared.

[0096] Manufacturing Example 1

[0097] The surface of the tablet containing dexlansoprazole was coated with 10 mg of Opadry Enteric 950 (methacrylic acid copolymer) and 0.5 mg of polysorbate 80.

[0098]

[0099] Manufacturing Example 2

[0100] The surface of tablets containing dexlansoprazole was coated with 5 mg of Opadry Enteric 950 (methacrylic acid copolymer) and 5.0 mg of Opadry Enteric 920 (hypromellose phthalate).

[0101]

[0102] Manufacturing Example 3

[0103] The surface of the tablet containing dexlansoprazole was coated with 5.0 mg of Opadry Enteric 950 (methacrylic acid copolymer) and 5.0 mg of Acrylise (methacrylic acid-ethyl acrylate copolymer).

[0104]

[0105] Manufacturing Example 4

[0106] The surface of the tablet containing dexlansoprazole was coated with 5.0 mg of Opadry Enteric 950 (methacrylic acid copolymer) and 5.0 mg of Opadry (hypromellose).

[0107]

[0108] The in vitro dissolution tests described above were performed for Manufacturing Examples 1 to 4. The results are shown in Table 3 below.

[0109]

[0110] Classification Manufacturing Example 1 Manufacturing Example 2 Manufacturing Example 3 Manufacturing Example 4 Dexlansoprazole uncoated tablet (mg) 100.0 OPADRY Enteric 95 0 (mg) 15.0 7.5 7.5 7.5 OPADRY Enteric 92 0 (mg) - 7.5 - Acryl-EZE (mg) - 7.5 - OPADRY (mg) - 7.5 polysorbate 80 (mg) 0.75 - Active ingredient release start time in in vitro dissolution test (minutes) About 35 About 60 About 45 About 20 Expected drug release time in the body (minutes) About 130 About 180 About 150 About 100

[0111] Through Test 2, it was confirmed that the dissolution patterns of Manufacturing Examples 1 and 3 were superior to those of Manufacturing Examples 2 and 4.

[0112] Test 3: Comparative test of coating quality and ease of handling according to the composition of the long-lasting coating layer

[0113] The coating quality and ease of handling of Manufacturing Examples 1 and 3 were compared. The comparison results confirmed that Manufacturing Example 1 had superior coating quality and was easier to handle than Manufacturing Example 3.

[0114]

[0115] Test 4: Comparison of dissolution patterns according to the content of the enteric coating layer

[0116] The following examples 1 to 4 were prepared.

[0117]

[0118] Examples 1 to 4

[0119] A tablet containing 16.10 mg of dexlansoprazole 1.5 hydrate, 320 mg of magnesium hydroxide, low-substituted hydroxypropyl cellulose, tromethamine, microcrystalline cellulose, crospovidone, and sodium stearyl fumarate was prepared. The tablet was coated with Opadry AMB II Yellow to prepare an immediate-release tablet.

[0120] A tablet containing 48.29 mg of dexlansoprazole 1.5 hydrate, tromethamine, hypromellose, sodium lauryl sulfate, low-substituted hydroxypropyl cellulose, sodium starch glycolate, and sodium stearyl fumarate was prepared. The content of the tablet was 107.5 mg. The tablet was first coated with Opadry Yellow and second coated (enteric coating) with Opadry Enteric Clear 950 and polysorbate 80 to prepare an enteric-coated tablet.

[0121] The coated tablets and enteric tablets were encapsulated inside hard capsules.

[0122] However, only the content of the long-term coating layer of Examples 1 to 4 was changed as shown in Table 4 below.

[0123]

[0124] -Example 1Example 2Example 3Example 4Content of active ingredient in enteric-coated tablet (mg) 48.29 48.29 48.29 48.29 Content of uncoated tablet in enteric-coated tablet (mg) 107.5 107.5 107.5 107.5 Content of enteric coating layer (mg) 8.19 16.38 24.57 32.76 Weight part of enteric coating layer per 100 weight parts of active ingredient in enteric-coated tablet 17.0 33.95 0.96 7.8 Weight part of enteric coating layer per 100 weight parts of uncoated tablet in enteric-coated tablet 7.6 15.22 2.93 0.5

[0125] Dissolution tests were conducted for Examples 1 to 4. The specific dissolution test conditions were as follows. Dissolution tests were conducted for 60 minutes under acidic conditions, followed by 120 minutes under buffer conditions. The test results are shown in Table 5 and Figure 2 below.

[0126] <Dissolution conditions>

[0127] Dissolution solution:

[0128] - Acidic conditions: pH 2.0, 200 mL of 0.144% (w / v) SLS solution

[0129] - Buffer conditions: pH 7.0, 500 mL of 0.144% (w / v) SLS solution

[0130] Device: Basket method, 75±2rpm

[0131] Temperature: 37±0.5 ℃

[0132]

[0133] Dissolution time Acidic condition Dissolution (%) Buffer condition Dissolution (%) 0 2 0 4 0 6 0 1 5 3 0 4 5 6 0 7 5 9 0 1 0 5 1 2 0 Example 10.0 18.7 2 1.2 2 3 2 7 3 3 5 2 5 3 6 7 3 4 8 7 8 9 3 5 9 6 7 9 8 2 Example 20.0 18.3 2 0 9 2 4 1 2 7 3 2 9 8 3 4 0 5 2 4 7 1 3 8 8 9 4 3 9 7 2 Example 30.0 18.9 2 1.3 2 3 7 2 5 12 7 3 2 7 8 2 9 4 5 5 6 8 4 8 4 9 5 3 Example 40.019.620.623.425.427.527.928.129.849.470.782.6

[0134] The immediate-release tablet contains 16.10 mg of the active ingredient, and the enteric-coated tablet contains 48.29 mg of the active ingredient. Therefore, the weight % of the active ingredient of the immediate-release tablet is 25 wt % and the weight % of the enteric-coated tablet is 75 wt % based on the amount of the active ingredient of the entire formulation. It was confirmed that a significant amount of the active ingredient was dissolved within 60 minutes in all of Examples 1 to 4 under acidic conditions (more than 23 wt % out of 25 wt % was dissolved). This confirmed that the dissolution of the immediate-release tablet occurred smoothly, and that the acidic environment neutralization effect of the pH adjuster was effectively demonstrated during the dissolution process, so that the active ingredient was not decomposed and the dissolution rate did not decrease.

[0135] Under buffer conditions, it was confirmed that the dissolution of the active ingredient began in Example 1 at 15 to 30 minutes, Example 2 at 30 to 45 minutes, Example 3 at 60 to 75 minutes, and Example 4 at 75 to 90 minutes (about 5 wt % dissolution out of 75 wt %, 25% deducted from the values ​​in Table 5).

[0136] As described above, the start time of release of the active ingredient in the desirable in vitro dissolution test is about 30 to about 60 minutes, and thus it was confirmed that the dissolution profile of Example 2 was superior to that of Examples 1, 3, and 4.

[0137]

[0138] The above description is intended solely to illustrate the present invention. The scope of the present invention should be interpreted in accordance with the claims, and all technical ideas within the scope equivalent or equivalent thereto should be construed as being included within the scope of the present invention.

[0139]

[0140] [Explanation of symbols]

[0141] Pharmaceutical preparations: 10

[0142] Quick release: 11

[0143] Jang Yong-bu: 12

Claims

1. A rapid release component that releases the active ingredient independently of pH; and Contains an enteric part that dissolves the active ingredient in a pH-dependent manner; A pharmaceutical preparation comprising the above active ingredient, a proton pump inhibitor, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof.

2. In paragraph 1, The above-mentioned active ingredient is a pharmaceutical preparation that dissolves the active ingredient in a range of pH 1.0 to pH 8.

5.

3. In paragraph 1, The above-mentioned long-acting part is a pharmaceutical preparation that dissolves the active ingredient in a range of pH 4.0 to pH 8.

5.

4. In paragraph 1, The above-mentioned pharmaceutical preparation containing a pH regulator.

5. In paragraph 4, A pharmaceutical preparation comprising the pH adjusting agent at least one of magnesium hydroxide, magnesium carbonate, magnesium oxide, calcium carbonate, sodium bicarbonate, sodium biphosphate and sodium carbonate.

6. In paragraph 4, A pharmaceutical preparation comprising the pH adjusting agent at least one of magnesium hydroxide, magnesium carbonate, magnesium oxide and calcium carbonate.

7. In paragraph 4, The above pH adjusting agent is a pharmaceutical preparation containing magnesium hydroxide.

8. In paragraph 6, A pharmaceutical preparation wherein the content of the pH regulator is in the range of 200 mg to 500 mg.

9. In paragraph 1, The above-mentioned pharmaceutical preparation comprises an enteric coating layer.

10. In paragraph 9, The above-mentioned enteric coating layer is a pharmaceutical preparation that dissolves in the range of pH 4.0 to pH 8.

5.

11. In paragraph 9, A pharmaceutical preparation wherein the enteric coating layer comprises at least one of polyvinyl acetate phthalate, a methacrylic acid copolymer, a methacrylic acid-ethyl acrylate copolymer, a methyl methacrylate-ethyl acrylate copolymer, a methacrylic acid-methyl methacrylate copolymer, hypromellose, hypromellose phthalate, hypromellose acetate succinate, cellulose acetate, cellulose acetate phthalate, cellulose acetate succinate, carboxymethylethyl cellulose, ethyl cellulose, an ethyl acrylate-methyl methacrylate-trimethylammonium ethyl methacrylate chloride copolymer, and shellac.

12. In paragraph 9, A pharmaceutical preparation wherein the above-mentioned enteric coating layer comprises a methacrylic acid copolymer.

13. In paragraph 12, A pharmaceutical preparation wherein the above-mentioned enteric coating layer additionally contains polysorbate 80.

14. In paragraph 1, The above-mentioned part is a fast-acting agent, The above-mentioned long-term care is long-term care, The above pharmaceutical preparation is a pharmaceutical preparation in capsule form.

15. In paragraph 1, The above proton pump inhibitor is a pharmaceutical preparation comprising at least one of dexlansoprazole, lansoprazole, ilaprazole, pantoprazole, rabeprazole, and esomeprazole.

16. In paragraph 1, The above proton pump inhibitor is a pharmaceutical preparation containing dexlansoprazole.

17. In paragraph 1, A pharmaceutical preparation comprising a pharmaceutically acceptable solvate of the above proton pump inhibitor is dexlansoprazole 1.5 hydrate.

18. In paragraph 1, The above-mentioned pharmaceutical preparation comprising low-substituted hydroxypropyl cellulose, tromethamine, microcrystalline cellulose, crospovidone and sodium stearyl fumarate.

19. In paragraph 1, The above-mentioned long-acting part is a pharmaceutical preparation comprising tromethamine, hypromellose, sodium lauryl sulfate, low-substituted hydroxypropyl cellulose, sodium starch glycolate and sodium stearyl fumarate.

20. In paragraph 8, A pharmaceutical preparation having a total weight of 750 mg or less.

21. In paragraph 9, A pharmaceutical preparation in which the content of the above-mentioned enteric coating layer is in the range of 10 parts by weight to 70 parts by weight based on 100 parts by weight of the active ingredient included in the above-mentioned portion.

22. In paragraph 9, A pharmaceutical preparation in which the content of the enteric coating layer is in the range of 2 to 35 parts by weight based on 100 parts by weight of the portion excluding the enteric coating layer among the enteric portions.

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