Application of hydrotalcite and ursodesoxycholic acid oral suspension composition

Abstract

The invention discloses application of hydrotalcite and an ursodesoxycholic acid oral suspension composition, a suspension is composed of two parts, namely a drug-loaded pellet and an inactive particle, the drug-loaded pellet is composed of a drug-loaded pellet core and a taste-masking coating layer, and the taste-masking coating layer comprises zein, hydrotalcite, an anti-sticking agent and a plasticizer; the inactive particles comprise a filling agent, a suspending aid and essence. The drug-loaded pellet of the ursodesoxycholic acid oral suspension composition is composed of a drug-loaded pellet core and a taste-masking coating layer, ursodesoxycholic acid is contained in the drug-loaded pellet core, and hydrotalcite serving as a pore-foaming agent is contained in the taste-masking coating layer. Therefore, when the composition medicine is taken, whether the film-forming material zein or the pore-foaming agent is not dissolved in water during taking, and after the composition medicine reaches the stomach, hydrotalcite can generate neutralization reaction with gastric acid to play a role of the pore-foaming agent, so that quick release of the composition medicine is ensured.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical preparations, in particular to the application of hydrotalcite and an ursodeoxycholic acid oral suspension composition. Background Art

[0002] Ursodeoxycholic acid (UDCA), with the chemical name 3α, 7β-dihydroxy-5β-cholestane-24-acid, is one of the components of human bile acid and an endogenous substance in the human body. It can promote the excretion of endogenous bile acid, increase the proportion of hydrophilic bile acid, protect liver cells and bile duct cells from toxic bile acid, prevent hydrophobic bile acid from interfering with mitochondrial membrane, inhibit liver cell apoptosis, significantly improve liver function, and has the effects of immunoregulation and cell protection. It is currently widely used as a drug for cholesterol gallstones, cholestatic liver disease (such as primary biliary cirrhosis), and bile reflux gastritis.

[0003] Ursodeoxycholic acid preparations were first developed by Japan's Tanabe Mitsubishi in the 1960s and approved for marketing in Japan. The dosage forms include tablets and granules, and the specifications are 50mg and 100mg. Later, ursodeoxycholic acid capsules developed by ALLERGAN SALES LLC were approved in the United States in 1987, and the specifications are 150mg and 300mg. In the 1990s, ursodeoxycholic acid capsules (specification: 250mg) developed by Dr. FalkPharma GmbH were approved for marketing in Europe and were approved for import in China in 1994.

[0004] The above-mentioned tablets and capsules approved for marketing are not suitable for children, the elderly and other patients with dysphagia. However, the instructions for the granules developed by Japan's Tanabe Mitsubishi, which are suitable for patients with dysphagia, clearly state that they taste bitter, thus limiting their clinical application.

[0005] In the late 1990s, Dr. Falk Pharma GmbH developed an oral suspension of ursodeoxycholic acid, which was approved for marketing in Europe. This greatly improved the compliance issues of ursodeoxycholic acid tablets and capsules due to swallowing difficulties for children and elderly patients, but it still failed to solve the problem of bitter taste. The main reason is that ursodeoxycholic acid tastes extremely bitter. Although the original research added more flavoring agents and flavors to the suspension, it still could not cover up the persistent discomfort caused by taking the medicine, such as the bitter taste that could not be removed in the mouth for a long time after multiple gargles.

[0006] Patent document CN201710812340.8 discloses a dry suspension of ursodeoxycholic acid and a preparation method thereof, characterized in that the composition is added with a suspending agent, a thickener, a glidant, and a flavoring agent, and the dry suspension prepared by this technology cannot effectively mask the taste. Patent document CN201910274440.9 discloses a preparation method of ursodeoxycholic acid preparation that uses lipid reticular inclusion technology to mask the bitter taste, but this technology fails to completely isolate the bitter ursodeoxycholic acid from the oral saliva, that is, a small amount of ursodeoxycholic acid may still directly contact the oral cavity during clinical use and produce a strong bitter taste. Patent document CN202210850056 discloses an oral solution of ursodeoxycholic acid and a preparation method thereof, wherein the composition is prepared into an inclusion compound by modified cyclodextrin and ursodeoxycholic acid, thereby simultaneously achieving the effects of solubilizing ursodeoxycholic acid and reducing bitterness, but it can only slightly reduce the bitterness, and the oral solution is inconvenient to carry. Patent document CN202111230180.9 discloses an ursodeoxycholic acid nanosuspension and its preparation method and application. The nanosuspension is prepared by medium grinding and can be further made into an oral suspension or dry suspension. However, the ursodeoxycholic acid preparation prepared by this technology has not completely solved the bitterness problem. Patent document CN202011146484.2 discloses a plant protein-ursodeoxycholic acid sustained-release nanoparticle composite microcapsule and a preparation method thereof; its preparation method first uses an anti-solvent precipitation method to self-assemble plant protein and ursodeoxycholic acid into nanoparticles, and then uses biomaterials to coat the nanoparticles to obtain plant protein-ursodeoxycholic acid sustained-release nanoparticle composite microcapsules. Its main purpose is to obtain an ursodeoxycholic acid preparation with significant sustained-release drug delivery characteristics, and its defect is that the prepared microcapsules have a low drug loading.

[0007] The use of a taste-masking coating that is insoluble in water (drug dispersion medium when taken clinically) but soluble in gastric acid is a good technical choice. This technology can ensure that the drug does not dissolve in the oral cavity when taken and plays a taste-masking role, and at the same time, the drug can be quickly dissolved and released when it reaches the stomach after taking it. For example, Chinese patent CN114617856A discloses a solid-liquid suspension Chinese medicine preparation, comprising solid Chinese medicine micro-pill particles and a liquid semi-liquid part, wherein the solid Chinese medicine micro-pill particles are composed of a pellet core and a coating layer, wherein the coating layer is characterized by using a water-insoluble coating material such as corn oxime, ethyl cellulose or shellac, and a gastric-soluble water-insoluble inorganic or organic pore-forming agent, such as sodium carbonate, calcium carbonate, ultrafine microcrystalline cellulose, gelatin, sodium alginate, dextrin, etc. However, the use of sodium carbonate, calcium carbonate, etc. as pore-forming agents will cause excessively rapid gas production and a large amount of gas production due to their rapid neutralization reaction with gastric acid, which will cause certain damage to the gastric mucosa, resulting in frequent symptoms of abdominal distension, belching, and rebound increase in gastric acid secretion in patients. It is especially unsuitable for patients with underlying diseases such as acute and chronic gastritis, reflux esophagitis, gastric or duodenal ulcers; in addition, sodium carbonate is a relatively large challenge to the production process and storage stability of preparations due to its strong hygroscopicity. The use of ultrafine microcrystalline cellulose, gelatin, sodium alginate, dextrin, etc. as pore-forming agents is difficult to act as a pore-forming agent for drugs that need to be released quickly because of their slow dissolution rate in the stomach. Summary of the invention

[0008] The invention provides an application of hydrotalcite and an ursodeoxycholic acid oral suspension composition, so as to solve the technical problem that the existing ursodeoxycholic acid preparation adopts sodium carbonate, calcium carbonate and the like as a pore-forming agent, which is easy to cause damage to the gastric mucosa, and solves the technical problem that the composition cannot simultaneously have the effects of strong taste masking effect, convenient for patients with dysphagia to take, convenient to carry, capable of rapid release in the stomach without causing damage to the gastric mucosa, and being suitable for patients with gastric diseases and ordinary patients.

[0009] According to one aspect of the present invention, there is provided a use of hydrotalcite as a porogen.

[0010] Furthermore, the hydrotalcite is used as a pore-forming agent in an ursodeoxycholic acid oral suspension composition, wherein the weight percentage of hydrotalcite: ursodeoxycholic acid is 3% to 6%: 100%.

[0011] According to another aspect of the present invention, an ursodeoxycholic acid oral suspension composition is provided, wherein the suspension consists of two parts: drug-loaded micropellets and inactive granules, wherein the drug-loaded micropellets consist of a drug-loaded pellet core and a taste-masking coating layer, wherein the taste-masking coating layer comprises zein, aluminum carbonate, an anti-adherent agent and a plasticizer; and the inactive granules comprise a filler, a suspending agent and a flavor.

[0012] Furthermore, the mass ratio of the drug-loaded pellets: inactive particles is (550-600): (1000-4000);

[0013] In the drug-loaded pellets, the mass ratio of the drug-loaded pellet core to the taste-masking coating layer is 500:(50-100), wherein:

[0014] In the drug-loaded pill core, the mass ratio of ursodeoxycholic acid: filler: disintegrant: binder is (50-300): (40-240): (5-30): (5-30);

[0015] In the taste-masking coating layer, the mass ratio of zein: aluminum carbonate: anti-sticking agent: plasticizer is (25-50): (7.5-15): (8-35): (1-5).

[0016] Furthermore, in the inactive particles, the weight percentages of filler: suspending agent: flavor are (84.5% to 96.95%): (3% to 10%): (0.05% to 0.5%).

[0017] Furthermore, the disintegrant in the drug-loaded pill core is selected from one or more of cross-linked sodium carboxymethyl cellulose, cross-linked calcium carboxymethyl cellulose, cross-linked polyvinyl pyrrolidone, and sodium carboxymethyl starch;

[0018] The binder in the drug-loaded pill core is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, and fully pregelatinized starch.

[0019] Furthermore, the particle size of the hydrotalcite is D90≤10 microns;

[0020] The anti-sticking agent in the taste-masking coating layer is selected from one or more of talc and magnesium stearate;

[0021] The plasticizer in the taste-masking coating layer is selected from triethyl citrate.

[0022] Furthermore, the filler in the inactive particles is selected from one or more of anhydrous glucose or its hydrate, anhydrous sucrose or its hydrate, mannitol, xylitol, and sorbitol;

[0023] The suspending agent in the inactive particles is selected from one of microcrystalline cellulose-sodium carboxymethylcellulose complex and xanthan gum;

[0024] The flavor in the inactive particles is fruit flavor.

[0025] Furthermore, a single dosage unit of the suspension contains 50 to 300 mg of ursodeoxycholic acid, and more preferably 250 mg.

[0026] Furthermore, the average diameter of the drug-loaded pellets is 0.2 to 1.5 mm, and more preferably 0.4 to 1.0 mm.

[0027] The present invention has the following beneficial effects:

[0028] 1. The present invention uses medicinal hydrotalcite as an auxiliary material to release a pore-forming agent, and the amount of hydrotalcite used to release the pore-forming agent is controlled at 3% to 6% of the amount of ursodeoxycholic acid used as the active ingredient. The carbonate of hydrotalcite itself is used to neutralize gastric acid. The neutralization reaction produces carbon dioxide to rapidly disintegrate the drug-loaded micropills, so that gastric juice can enter the micropills. At the same time, the carbonate accounts for a small proportion by weight in the hydrotalcite molecule and contains alkaline ions: aluminum ions and magnesium ions. The intensity of the neutralization reaction is milder than that of substances such as calcium carbonate and sodium carbonate.

[0029] 2. The drug-loaded pellets of the ursodeoxycholic acid oral suspension composition of the present invention are composed of a drug-loaded pellet core and a taste-masking coating layer, wherein ursodeoxycholic acid is in the drug-loaded pellet core, and aluminum carbonate is used as a taste-masking coating to release a pore-forming agent in the taste-masking coating layer, so that when the drug composition is taken, both the film-forming material zein and the pore-forming agent are insoluble in water when taken, and after the drug composition reaches the stomach, the aluminum carbonate can react with gastric acid to play a role as a pore-forming agent, thereby ensuring the rapid release of the drug composition.

[0030] 3. The present invention adopts a preparation composition structure of drug-loaded micropellets (composed of a drug-loaded micropellet core and a taste-masking coating layer) + inactive particles. The prepared ursodeoxycholic acid oral suspension composition has the effects of strong taste-masking effect, convenient for patients with dysphagia to take, convenient to carry, rapid release in the stomach without damaging the gastric mucosa, and being suitable for both patients with gastric diseases and ordinary patients. The drug-loaded micropellets mainly play a taste-masking role, and the inactive particles mainly play a suspending role and further improve the taste. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] The drawings constituting a part of this application are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention. In the drawings:

[0032] Figure 1 It is the average cumulative dissolution curve of Comparative Example 1, Comparative Example 2, Comparative Example 3 and Example 28. DETAILED DESCRIPTION

[0033] The embodiments of the present invention are described in detail below with reference to the accompanying drawings. However, the present invention can be implemented in many different ways as defined and covered below.

[0034] An embodiment of the first aspect of the present invention provides a use of aluminum carbonate as a pore-forming agent for taste-masking coating release.

[0035] Acid-resistant gastric mucosal protective agent aluminum magnesium carbonate [chemical structure: Al2Mg6(OH) 16 CO3·4H2O】, because it has carbonate, it can neutralize gastric acid. At the same time, the carbonate accounts for a small proportion by weight in the aluminum carbonate molecule and contains alkaline ions: aluminum ions and magnesium ions. The intensity of the neutralization reaction is milder than that of calcium carbonate, sodium carbonate and other substances, and the amount of gas produced by the neutralization reaction is also less than that of calcium carbonate, sodium carbonate and other substances. Aluminum carbonate is clinically used for acute and chronic gastritis, reflux esophagitis, gastric or duodenal ulcers, stomach discomfort symptoms related to gastric acid, such as stomach pain, heartburn, acid belching, fullness, etc., as well as to prevent gastric mucosal damage caused by non-steroidal drugs. Representative pharmaceutical preparations are aluminum carbonate tablets "Daxi (Bayer Pharmaceuticals), specification 500mg, the conventional dosage is 1-2 tablets at a time, 3-4 times a day, that is, the daily dose is 1.5g to 4g. Aluminum carbonate is almost not absorbed in the gastrointestinal tract, and the concentrations of magnesium and aluminum in plasma and urine remain within the normal range. The main mechanisms of aluminum carbonate in treating gastric diseases and protecting gastric mucosa are: (1) neutralizing gastric acid and forming a bicarbonate reservoir in the stomach; (2) inhibiting the activity of pepsin; (3) promoting the synthesis of prostaglandins in the mucosa; (4) releasing epithelial growth factor; (5) releasing basic fibroblast growth factor (bFGF).

[0036] In the prior art, aluminum carbonate is also often used as an alkalizing agent to adjust the pH value of the solution; aluminum carbonate is also used in combination with other drugs for treating gastritis or gastric ulcers to adjust gastric acid through the weak alkalinity of aluminum carbonate, thereby adjusting the pH value of gastric juice to a more suitable range.

[0037] The present invention uses aluminum carbonate as an auxiliary material, a taste-masking coating and a pore-forming agent, and the amount of aluminum carbonate is controlled to be 3% to 6% of the amount of the active ingredient ursodeoxycholic acid. The carbonate group of aluminum carbonate itself is used to neutralize gastric acid to produce carbon dioxide, so that the drug-loaded micropills are rapidly disintegrated, allowing gastric juice to enter the micropills, thereby releasing ursodeoxycholic acid.

[0038] In this embodiment, the hydrotalcite is used as a taste-masking coating release pore-forming agent in an ursodeoxycholic acid oral suspension composition, wherein the weight percentage of hydrotalcite: ursodeoxycholic acid is 3% to 6%: 100%.

[0039] As a weak acid drug, ursodeoxycholic acid has a certain degree of irritation to the gastric mucosa after taking it; at the same time, the instructions for its capsule preparation clearly point out that it should not be taken at the same time with antacids containing aluminum hydroxide and / or montmorillonite (aluminum oxide), because these drugs can combine with ursodeoxycholic acid in the intestine, thereby hindering absorption (the principle is speculated to be: ursodeoxycholic acid combines with antacids to form ursodeoxycholic acid aluminum salt or dissociated ursodeoxycholic acid with stronger polarity; and highly polar substances are not easy to pass through biological membranes, thus affecting absorption), affecting the efficacy. After analyzing the above principles and clinical use experience, the above antacids include aluminum magnesium carbonate.

[0040] The inventors of the present invention unexpectedly discovered through a large number of test screenings that when aluminum carbonate is used as a release pore-forming agent of a taste-masking coating layer and its dosage is controlled at 3% to 6% of the dosage of the active ingredient ursodeoxycholic acid, it will not only have no effect on the efficacy of the ursodeoxycholic acid preparation, but also can alleviate the irritation of ursodeoxycholic acid to the gastric mucosa.

[0041] The amount of hydrotalcite as the porogen must be controlled at 3% to 6%, preferably 4% to 5%, of the amount of ursodeoxycholic acid as the active ingredient. If the amount is too low, the effect of releasing the porogen cannot be achieved and the dissolution is slow. If the amount is too high, the absorption of ursodeoxycholic acid is affected due to the excessive amount of hydrotalcite, because part of the hydrotalcite that has not yet reacted with gastric acid to neutralize is combined with the active ingredient ursodeoxycholic acid to form a more polar aluminum salt of ursodeoxycholic acid or dissociated ursodeoxycholic acid. However, highly polar substances are not easy to pass through biological membranes, thereby affecting absorption, so that a small amount of ursodeoxycholic acid will not be absorbed.

[0042] The present invention adopts hydrotalcite, a gastric mucosal protective agent, as an auxiliary material for releasing a pore-forming agent for the first time, and its usage amount is much lower than its clinical usage amount. For example, the usage amount of hydrotalcite in a single dose in the present invention does not exceed 15 mg, which is much lower than the single dose of 500 mg of hydrotalcite tablets, a clinical product. Thus, it not only exerts its function as a pharmaceutical auxiliary material for releasing a pore-forming agent, but also exerts its medicinal function (dual use of pharmaceutical auxiliary), overcomes the problem of rapid release of the ursodeoxycholic acid oral suspension composition in the stomach after taste-masking coating, and also takes into account overcoming the damage of ursodeoxycholic acid preparations to the gastric mucosa, further improves the applicable population of patients and medication compliance, thereby improving the advantages of clinical use.

[0043] According to another aspect of the present invention, an ursodeoxycholic acid oral suspension composition is provided, wherein the suspension consists of two parts: drug-loaded micropellets and inactive granules, wherein the drug-loaded micropellets consist of a drug-loaded pellet core and a taste-masking coating layer, wherein the taste-masking coating layer comprises zein, aluminum carbonate, an anti-adherent agent and a plasticizer; and the inactive granules comprise a filler, a suspending agent and a flavor.

[0044] The drug-loaded pellets of the ursodeoxycholic acid oral suspension composition described above are composed of a drug-loaded pellet core and a taste-masking coating layer, wherein ursodeoxycholic acid is in the drug-loaded pellet core, and hydrotalcite as a releasing pore-forming agent is in the taste-masking coating layer, so that when the drug of the composition is taken, neither the film-forming material zein nor the releasing pore-forming agent is dissolved in the water when taken, and after the drug of the composition reaches the stomach, hydrotalcite can react with gastric acid to react with the releasing pore-forming agent (after the neutralization reaction, gastric juice can enter the interior of the pellet, and the carbon dioxide generated by the neutralization reaction can cause the drug-loaded pellet to disintegrate rapidly), thereby ensuring the rapid release of the drug of the composition.

[0045] The ursodeoxycholic acid oral suspension composition, during the production, preparation and storage, both ursodeoxycholic acid and hydrotalcite are present in solid form, and the two do not interact with each other; when the preparation is placed in a strong acidic environment (such as a gastric acid environment), hydrotalcite first reacts with gastric acid to neutralize, thereby achieving a pore-forming agent effect and producing a certain gastric mucosal protective effect. As the neutralization reaction of hydrotalcite occurs, its pore-forming agent effect is revealed, and the drug-loaded pill core contacts with gastric juice, disintegrates, and each component (including ursodeoxycholic acid) is dissolved successively.

[0046] In this embodiment, the mass ratio of the drug-loaded pellets: inactive particles is (550-600): (1000-4000); preferably (550-600): (2000-3000).

[0047] In the drug-loaded pellets, the mass ratio of the drug-loaded pellet core to the taste-masking coating layer is 500:(50-100), preferably 500:(50-75). In the drug-loaded pellet core, the mass ratio of ursodeoxycholic acid: filler: disintegrant: binder is (50-300):(40-240):(5-30):(5-30).

[0048] In the taste-masking coating layer, the mass ratio of zein: hydrotalcite: anti-adherent agent: plasticizer is (25-50): (7.5-15): (8-35): (1-5), preferably (30-50): (10-15): (8-35): (3-5).

[0049] In this embodiment, the weight percentage of filler: suspending agent: flavor in the inactive particles is (84.5% to 96.95%): (3% to 10%): (0.05% to 0.5%), preferably (91.5% to 96.95%): (5% to 8%): (0.3% to 0.5%).

[0050] In this embodiment, the disintegrant in the drug-loaded pill core is selected from one or more of cross-linked sodium carboxymethyl cellulose, cross-linked calcium carboxymethyl cellulose, cross-linked polyvinyl pyrrolidone, and sodium carboxymethyl starch; preferably cross-linked sodium carboxymethyl cellulose.

[0051] The binder in the drug-loaded pill core is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, and fully pregelatinized starch, preferably hydroxypropyl methylcellulose.

[0052] In this embodiment, the particle size of the hydrotalcite is D90≤10 microns; the particle size of ursodeoxycholic acid is D90≤30 microns;

[0053] The anti-sticking agent in the taste-masking coating layer is selected from one or more of talc and magnesium stearate; preferably talc;

[0054] The plasticizer in the taste-masking coating layer is selected from triethyl citrate.

[0055] In this embodiment, the filler in the inactive particles is selected from one or more of anhydrous glucose or its hydrate, anhydrous sucrose or its hydrate, mannitol, xylitol, and sorbitol; preferably, glucose;

[0056] The suspending agent in the inactive particles is selected from one of microcrystalline cellulose-sodium carboxymethylcellulose complex and xanthan gum; microcrystalline cellulose-sodium carboxymethylcellulose complex is further preferred, and microcrystalline cellulose-sodium carboxymethylcellulose complex with model RC611 is further preferred;

[0057] The flavor in the inactive particles is a fruit flavor, which is selected from lemon flavor, banana flavor, strawberry flavor, orange flavor and other fruit flavors.

[0058] In this embodiment, the ursodeoxycholic acid contained in a single dosage unit of the suspension is 50-300 mg, and more preferably 250 mg.

[0059] In this embodiment, the average diameter of the drug-loaded pellets is 0.2-1.5 mm, and more preferably 0.4-1.0 mm.

[0060] In this embodiment, the drug-loaded pellet core can be prepared by using an extrusion-spheronization process or a centrifugal granulation process.

[0061] In this embodiment, the drug-loaded micropellets are prepared by coating the drug-loaded pill core with a taste-masking layer using a fluidized bed coating process; the suspension consists of two parts: drug-loaded micropellets and inactive granules, and is packaged in divided doses using a granule filling machine with a dual-station filling function.

[0062] Examples 1-6 provide a formula for a drug-loaded pellet core, as shown in Table 1:

[0063] Table 1 is the formula of the drug-loaded pellet core of Examples 1-6

[0064]

[0065] In Table 1, the preparation process of Examples 1-4 is:

[0066] After preparing micronized ursodeoxycholic acid (D90≤30 microns), filler (microcrystalline cellulose or pregelatinized starch), disintegrant (cross-linked sodium carboxymethyl cellulose or cross-linked polyvinyl pyrrolidone or sodium carboxymethyl starch) according to the formula ratio in the above table, place in a high-speed stirring granulation device, add a binder aqueous solution (hydroxypropyl methylcellulose aqueous solution or hydroxypropyl cellulose aqueous solution or povidone K30 aqueous solution) for wet granulation to obtain a wet soft material. The wet soft material is placed in an extrusion device equipped with a screen (screen aperture 0.4 or 0.5 or 0.6 mm) to extrude strip or rod-shaped particles, and then the strip or rod-shaped particles are placed in a spheronizer for spheronization and drying to obtain drug-loaded pellets, sieved, and 24-40 meshes are collected to obtain drug-loaded pill cores.

[0067] In Table 1, the preparation process of Examples 5-6 is:

[0068] Micronized ursodeoxycholic acid (D90≤30 microns), filler (microcrystalline cellulose or pregelatinized starch), disintegrant (cross-linked sodium carboxymethyl cellulose or cross-linked polyvinyl pyrrolidone or sodium carboxymethyl starch) are prepared according to the formula ratio in the above table, placed in a mixing device for uniform mixing, and then discharged. The material is then placed in a centrifugal granulation device, the equipment is started, and an aqueous binder solution (hydroxypropyl methylcellulose aqueous solution or hydroxypropyl cellulose aqueous solution or povidone K30 aqueous solution) is sprayed in an atomized manner for centrifugal preparation, granulation, and drying to obtain drug-loaded pellets, which are sieved and 24-40 mesh pieces are collected to obtain drug-loaded pill cores.

[0069] Examples 7-13 provide a formulation of drug-loaded pellets, as shown in Table 2:

[0070] Table 2 is the formula of the drug-loaded pellets of Examples 7-13

[0071]

[0072] In Table 2, the preparation process of Examples 7-10:

[0073] The film-forming material (zein), plasticizer (triethyl citrate), release pore-forming agent (aluminum carbonate (D90≤10 microns)), and anti-adhesive agent (talc) are prepared in an amount of 1.05 to 1.2 times the prescription ratio in the above table (the purpose of increasing the preparation amount by 5% to 20% is to ensure the coating weight gain of the taste-masking coating layer due to spray loss in the coating process; the coating is terminated by reaching the target coating weight gain), and then dissolved or uniformly dispersed in a 70% (v / v) ethanol solution of 10 times the amount of the aforementioned materials under stirring to obtain a taste-masking coating solution, which is continuously stirred and set aside.

[0074] The drug-loaded pill cores of Example 1 were placed in a fluidized bed coating device with a bottom spray coating device, the equipment was started, and the air volume was controlled appropriately to make it in a fluidized state, and the material temperature was preheated to above 30°C, and then the air volume was controlled appropriately, the material temperature was within the range of 20-45°C, and the humidity was within the range of 6-15 g / m 3 The taste-masking coating liquid is sprayed in a suitable spraying speed within a certain range and the atomization pressure is 0.1-0.3 MPa. The taste-masking coating is carried out according to the following process parameters until the target coating weight gain is achieved, and the pellets are dried, discharged, sieved, and 20-40 mesh are collected to obtain the drug-loaded pellets.

[0075] In Table 2, the preparation process of Examples 11-13:

[0076] The film-forming material (zein), plasticizer (triethyl citrate), release pore-forming agent (aluminum carbonate (D90≤10 microns)), and anti-adhesive agent (talc) are prepared in an amount of 1.05 to 1.2 times the prescription ratio in the above table (the purpose of increasing the preparation amount by 5% to 20% is to ensure the coating weight gain of the taste-masking coating layer due to spray loss in the coating process; the coating is terminated by reaching the target coating weight gain), and then dissolved or uniformly dispersed in a 70% (v / v) ethanol solution of 10 times the amount of the aforementioned materials under stirring to obtain a taste-masking coating solution, which is continuously stirred and set aside.

[0077] The drug-loaded pellet core of Example 1 was placed in a centrifugal granulation device, the equipment was started, and the material temperature was preheated to above 30°C, and then the appropriate air volume, material temperature within the range of 20-45°C, and humidity within the range of 6-15 g / m 3 The taste-masking coating liquid is sprayed in a suitable spraying speed within a certain range and the atomization pressure is 0.1-0.3 MPa. The taste-masking coating is carried out according to the following process parameters until the target coating weight gain is achieved, and the pellets are dried, discharged, sieved, and 20-40 mesh are collected to obtain the drug-loaded pellets.

[0078] Examples 14-16 provide a formulation of drug-loaded pellets, as shown in Table 3:

[0079] Table 3 is the formula of the drug-loaded pellets of Examples 14-16

[0080]

[0081] In Table 3, the preparation process of Examples 14-16:

[0082] The film-forming material (zein), plasticizer (triethyl citrate), release pore-forming agent (aluminum carbonate (D90≤10 microns)), and anti-adhesive agent (talc) are prepared in an amount of 1.05 to 1.2 times the prescription ratio in the above table (the purpose of increasing the preparation amount by 5% to 20% is to ensure the coating weight gain of the taste-masking coating layer due to spray loss in the coating process; the coating is terminated by reaching the target coating weight gain), and then dissolved or uniformly dispersed in a 70% (v / v) ethanol solution of 10 times the amount of the aforementioned materials under stirring to obtain a taste-masking coating solution, which is continuously stirred and set aside.

[0083] The pill cores of the corresponding embodiments in the above table are placed in a fluidized bed coating device with a bottom spray coating device, the equipment is started, the air volume is controlled appropriately to make it in a fluidized state, and the material temperature is preheated to above 30°C, and then the air volume is controlled appropriately, the material temperature is within the range of 20-45°C, and the humidity is within the range of 6-15g / m 3 The taste-masking coating liquid is sprayed in a suitable spraying speed within a certain range and the atomization pressure is 0.1-0.3 MPa. The taste-masking coating is carried out according to the following process parameters until the target coating weight gain is achieved, and the pellets are dried, discharged, sieved, and 20-40 mesh are collected to obtain the drug-loaded pellets.

[0084] Examples 17-18 provide a formulation of drug-loaded pellets, as shown in Table 4:

[0085] Table 4 is the formula of the drug-loaded pellets of Examples 17-18

[0086]

[0087] In Table 4, the preparation process of Examples 17 to 18:

[0088] The film-forming material (zein), plasticizer (triethyl citrate), release pore-forming agent (aluminum carbonate (D90≤10 microns)), and anti-adhesive agent (talc) are prepared in an amount of 1.05 to 1.2 times the prescription ratio in the above table (the purpose of increasing the preparation amount by 5% to 20% is to ensure the coating weight gain of the taste-masking coating layer due to spray loss in the coating process; the coating is terminated by reaching the target coating weight gain), and then dissolved or uniformly dispersed in 70% (v / v) ethanol, which is 10 times the amount of the above materials, under stirring to obtain a taste-masking coating solution, which is continuously stirred and set aside.

[0089] The pill cores of the corresponding embodiments in the above table are placed in a fluidized bed coating device with a bottom spray coating device, the equipment is started, the air volume is controlled appropriately to make it in a fluidized state, and the material temperature is preheated to above 30°C, and then the air volume is controlled appropriately, the material temperature is within the range of 20-45°C, and the humidity is within the range of 6-15g / m 3The taste-masking coating liquid is sprayed in a suitable spraying speed within a certain range and the atomization pressure is 0.1-0.3 MPa. The taste-masking coating is carried out according to the following process parameters until the target coating weight gain is achieved, and the pellets are dried, discharged, sieved, and 20-40 mesh are collected to obtain the drug-loaded pellets.

[0090] Examples 19 to 22 provide a formulation of an inactive particle, as shown in Table 5:

[0091] Table 5 is a formula table of the inactive particles in Examples 19 to 22

[0092]

[0093]

[0094] In Table 5, the preparation process of Examples 19 to 22:

[0095] Prepare glucose, suspending agent and lemon essence according to the prescription ratio in the above table, pass through a 60-mesh sieve, and mix thoroughly with a mixing device to obtain inactive granules.

[0096] Examples 23 to 26 provide a formulation of inactive particles, as shown in Table 6:

[0097] Table 6 is a formula table of the inactive particles in Examples 23 to 26

[0098]

[0099] In Table 6, the preparation process of Examples 23 to 26:

[0100] Prepare glucose, suspending agent and lemon essence according to the prescription ratio in the above table, pass through a 60-mesh sieve, and mix thoroughly with a mixing device to obtain inactive granules.

[0101] Examples 27 to 35 provide a formulation of an ursodeoxycholic acid oral suspension composition, as shown in Table 7:

[0102] Table 7 is a formula table of ursodeoxycholic acid oral suspension compositions in Examples 27 to 35

[0103]

[0104] In Table 7, the preparation processes of Examples 27 to 35 are:

[0105] The drug-loaded micropellets and inactive granules of the corresponding examples are prepared according to the prescription ratio in the above table, passed through a 60-mesh sieve, and packaged in doses into pharmaceutical composite films using a granule filling machine with a double-station filling function, and sealed to obtain the finished suspension.

[0106] Examples 36 to 39 provide a formulation of an ursodeoxycholic acid oral suspension composition, as shown in Table 8:

[0107] Table 8 is a formula table of ursodeoxycholic acid oral suspension compositions in Examples 36 to 39

[0108]

[0109] In Table 8, the preparation processes of Examples 36 to 39 are:

[0110] The drug-loaded micropellets and inactive granules of the corresponding examples are prepared according to the prescription ratio in the above table, passed through a 60-mesh sieve, and packaged in doses into pharmaceutical composite films using a granule filling machine with a double-station filling function, and sealed to obtain the finished suspension.

[0111] Comparative Example 1

[0112] The existing ursodeoxycholic acid oral suspension has a specification of 250 mg / 5 ml, which is produced by the original research company Dr. Falk Pharma GmbH with the trade name Ursofalk and is marketed in Germany; batch number: 220064A.

[0113] Comparative Example 2

[0114] Ursodeoxycholic acid capsules, specification: 250 mg, originally produced by Losan Pharma GmbH, trade name Ursofalk, marketed in China; batch number: L230005A.

[0115] Comparative Example 3

[0116] The preparation process of the suspension in this comparative example is the same as that in Example 28, and the formulation and process of the drug-loaded micropellets are basically the same as those in Example 7, except that the taste-masking coating layer does not contain the porogen aluminum magnesium carbonate, and in order to ensure the consistency of the weight gain of the taste-masking coating layer with that in Example 7 (generally speaking, the consistency of coating weight gain is one of the key process factors affecting release), the amount of anti-adhesive talc is increased.

[0117] Comparative Example 4

[0118] The preparation process of the suspension in this comparative example is the same as that of Example 28, and the formulation and process of the drug-loaded micropellets are basically the same as those of Example 7, the only difference being that the film-forming material is replaced by hydroxypropyl methylcellulose from zein.

[0119] Comparative Example 5

[0120] The preparation process of the suspension of this comparative example is the same as that of Example 28, and the formulation and process of the drug-loaded micropellets are basically the same as those of Example 7, except that the amount of the porogen aluminum carbonate magnesium in the taste-masking coating layer is adjusted to 1% of the amount of ursodeoxycholic acid, and at the same time, in order to ensure the consistency of the weight gain of the taste-masking coating layer with that of Example 7 (generally speaking, the consistency of coating weight gain is one of the key process factors affecting release), the amount of anti-adhesive talc is increased.

[0121] Comparative Example 6

[0122] The preparation process of the suspension in this comparative example is the same as that of Example 28, and the formulation and process of the drug-loaded micropellets are basically the same as those of Example 7, except that the amount of the pore-forming agent aluminum carbonate magnesium in the taste-masking coating layer is adjusted to 10% of the amount of ursodeoxycholic acid.

[0123] See Table 9 for details.

[0124] Table 9 is a formula table of the ursodeoxycholic acid oral suspension composition in Comparative Examples 3-6

[0125]

[0126]

[0127] Test example

[0128] Taste evaluation 1 (subjective taste evaluation method):

[0129] 20 volunteers were selected to take and taste the above-mentioned Example preparations and Comparative Examples 1, 3, and 4, respectively, and then the volunteers filled in the taste information according to the following form. The implementation points and evaluation results are detailed as follows:

[0130] (1) Comparative Example 1 (commercially available preparation; ursodeoxycholic acid oral suspension): 5 ml (i.e., containing 250 mg ursodeoxycholic acid) was directly taken orally. Taking here means that the drug was spit out about 30 seconds after entering the mouth (not swallowed into the esophagus), and the mouth was rinsed with no less than 200 ml of water;

[0131] (2) Dosage of Examples 27-39 and Comparative Examples 3-4: Pour 1 bag (containing 250 mg ursodeoxycholic acid) into a container containing 15 ml of water, stir well, let stand for 30 minutes and then take orally (the purpose of standing for 30 minutes is to simulate the longest conventional clinical administration time). Taking here means that the drug is spit out about 30 seconds after entering the mouth (not swallowed into the esophagus), and rinse the mouth with no less than 200 ml of water.

[0132] (3) To avoid the interference of bitterness on the taste evaluation, the taste evaluation test of Comparative Examples 1 and 4 was carried out on the first day; Comparative Example 3 and Examples 27 to 30 were carried out on the second day; Examples 31 to 35 were carried out on the third day; and Examples 36 to 40 were carried out on the fourth day.

[0133] See Table 10 for details.

[0134] Table 10 is the mouthfeel evaluation results of the suspensions of Comparative Examples 1, 3-4 and Examples 27-39

[0135]

[0136]

[0137]

[0138] From the above table, we can see that:

[0139] (1) The aroma of Comparative Example 1 (commercially available preparation; ursodeoxycholic acid oral suspension) and Comparative Example 4 (film-forming material: hydroxypropyl methylcellulose) was acceptable, but the sweet taste at the entrance did not cover up the bitter taste. The reason why Comparative Example 4 did not cover up the bitter taste was that hydroxypropyl methylcellulose could be dissolved in water, thereby causing part of ursodeoxycholic acid to be released and dissolved, which in turn caused the bitter taste to come out.

[0140] (2) Examples 27 to 39 and Comparative Example 3 (without a pore-forming agent) all performed well in terms of aroma, bitter / sweet taste, oral aftertaste, etc. The results showed that the ursodeoxycholic acid preparation prepared by the present invention can completely mask the taste and has a good taste.

[0141] Taste evaluation 2 (dissolution test method):

[0142] According to the second method (paddle method) of dissolution determination in Appendix II of the 2020 edition of the Chinese Pharmacopoeia, the compositions prepared in Examples 27 to 39 and Comparative Examples 3 to 4 were respectively subjected to dissolution tests with a dissolution medium of 900 ml of purified water, a paddle speed of 75 rpm, and a water temperature of 37±0.5°C, and samples were taken at 30 minutes to detect the dissolution amount, as shown in the following table. If the dissolution amount in 30 minutes is less than 5%, it is considered to have an excellent taste-masking effect; if it is less than 10%, it is considered to have a good taste-masking effect; if it is greater than 10%, it is considered to have a poor taste-masking effect. See Table 11 for details.

[0143] Table 11 is the taste evaluation results of the suspensions in Comparative Examples 3-4 and Examples 27-39

[0144]

[0145]

[0146] Dissolution test

[0147] (1) Description of the dissolution test method selection: Due to the poor solubility of ursodeoxycholic acid in the low pH range and good solubility in the high pH range, its absorption characteristics in vivo show a bimodal phenomenon, that is, a small part is dissolved and absorbed in the stomach to small intestine segment, showing the first absorption peak, and most of it is dissolved and absorbed in the high pH (pH7-8) colon segment and presents a second absorption peak. In order to better simulate the in vivo dissolution environment, the present invention adopts dissolution in 0.1 mol / L hydrochloric acid medium to simulate the disintegration and dissolution in the stomach, and then dissolves in pH7.5 medium to simulate the dissolution in the colon segment. The specific dissolution method is as follows:

[0148] (2) Dissolution test method: The dissolution of samples of Comparative Examples 1 to 3, Comparative Examples 5 to 6, and Examples 27 to 39 was determined according to the dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules, 0931, Method 2, Method 1 (Pulp Method)).

[0149] (3) Dissolution conditions: 300 ml of 0.1 mol / L hydrochloric acid solution containing 0.5% SDS was used as the dissolution medium, the rotation speed was 50 rpm, and the operation was carried out according to the law. After 30 minutes, samples were taken. After sampling, 700 ml of 0.086 mol / L disodium hydrogen phosphate solution preheated to 37°C ± 0.5°C was added to each dissolution cup, and the pH was adjusted to 7.5 ± 0.05 with 2 mol / L sodium hydroxide solution. The mixture was mixed well, the rotation speed was kept unchanged, and the operation was continued according to the law. Samples were taken after 5, 10, 15, 20, 30, 45, and 60 minutes, respectively. After sampling, the dissolution amount was detected and the average cumulative dissolution rate was calculated. The specific data are shown in Table 12.

[0150] The average cumulative dissolution curves of Comparative Example 1, Comparative Example 2, Comparative Example 3 and Example 28 are shown in the attached Figure 1 .

[0151] Table 12 shows the dissolution test results of the suspensions in Comparative Examples 1-2, 3, 5-6 and Examples 27-39

[0152]

[0153] The results show that the compositions prepared in Examples 27 to 39 and Comparative Example 6 exhibit similar dissolution behavior in a 0.1 mol / L hydrochloric acid solution containing 0.5% SDS and a pH 7.5 phosphate medium as compared with Comparative Examples 1 and 2, and exhibit better dissolution as compared with Comparative Examples 3 and 5; Comparative Example 3 hardly dissolves due to the absence of a pore-forming agent; Comparative Example 5 dissolves significantly slower than Examples 27 to 39 due to the small amount of aluminum carbonate magnesium released as the pore-forming agent.

[0154] Biomembrane permeability evaluation (oil-water partition coefficient determination) test

[0155] (1) Description of the selection of biomembrane permeability evaluation method: Ursodeoxycholic acid is a weak acid drug. The instructions for its capsule preparation clearly state that it should not be taken simultaneously with antacids containing aluminum hydroxide and / or montmorillonite (aluminum oxide), because these drugs can bind to ursodeoxycholic acid in the intestine, thereby hindering absorption (the principle is speculated to be: ursodeoxycholic acid binds to antacids to form more polar ursodeoxycholic acid aluminum salt or dissociated ursodeoxycholic acid; and highly polar substances are not easy to pass through the biomembrane, thus affecting absorption), affecting the efficacy. Based on the analysis of the above principle and clinical use experience, the above antacids include aluminum carbonate.

[0156] Through the above principle analysis, the permeability of biomembranes can be evaluated by detecting the polarity of substances, and one of the commonly used methods to determine the polarity of substances is to determine the oil-water partition coefficient. The oil-water partition coefficient (oil-water partition coefficient) is the logarithm of the ratio of the partition coefficients of a substance in n-octanol and water. It reflects the distribution of a substance in the oil and water phases, usually expressed by the logP value. The smaller the logP value, the stronger its hydrophilicity; conversely, the larger the logP value, the stronger its lipophilicity. The oil-water partition coefficient has a certain reference value for evaluating the absorption and distribution of substances in the body. Substances with a large oil-water partition coefficient can easily pass through biomembranes. The specific determination method is as follows:

[0157] (2) Oil-water partition coefficient determination method:

[0158] Measure 200 mL of the dissolution endpoint solution of Comparative Example 6 under the above dissolution test (i.e., the dissolution solution after 60 minutes of dissolution in a pH 7.5 phosphate medium) and place it in a beaker, add 200 mL of n-octanol, stir and mix in a 37°C water bath for 4 hours, then place it in an extraction separator and let it stand for 24 hours, take the aqueous phase layer (lower layer) to detect the equilibrium concentration (cw) of ursodeoxycholic acid in the aqueous phase. Then, take the mass concentration of the dissolution endpoint solution as the initial concentration, calculate the equilibrium concentration (co) of ursodeoxycholic acid in the n-octanol phase, i.e., the oil phase, and finally calculate the oil-water partition coefficient (P, co / cw) and the logarithmic value logP. The results are shown in Table 13 below.

[0159] Table 13 shows the results of the biofilm permeability test

[0160]

[0161] The above table shows that the oil-water partition coefficient of the dissolution of the composition prepared in Example 28 (the amount of aluminum carbonate is 6% of the amount of ursodeoxycholic acid) and Comparative Example 5 (the amount of aluminum carbonate is 1% of the amount of ursodeoxycholic acid) under pH 7.5 is about 0.39-0.42, while the oil-water partition coefficient of the dissolution of the composition prepared in Comparative Example 6 (the amount of aluminum carbonate is 10% of the amount of ursodeoxycholic acid) under pH 7.5 is significantly lower than that of Example 28 and Comparative Example 5, that is, the polarity of the dissolution of the composition prepared in Comparative Example 6 is stronger, and the reason is presumably that the excess aluminum carbonate combines with ursodeoxycholic acid to form a more polar ursodeoxycholic acid aluminum salt or dissociated ursodeoxycholic acid.

[0162] Suspension performance evaluation (sedimentation volume ratio)

[0163] (1) Sedimentation volume ratio test method: The sedimentation volume ratio of the compositions prepared in Comparative Example 1 and Examples 27 to 39 was determined according to the sedimentation volume ratio determination method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0123), wherein the compositions prepared in Examples 27 to 39 were prepared before the determination: 1 bag was taken, 5 ml of purified water was added, and the mixture was shaken and then tested according to the above method. A sedimentation volume ratio of not less than 0.90 was considered to be in compliance with the regulations. The determination results are detailed in Table 14.

[0164] Table 14 Evaluation results of suspension performance of Comparative Example 1 and Examples 27-39

[0165]

[0166]

[0167] The results show that the sedimentation volume ratios of the compositions prepared in Examples 27 to 39 and Comparative Example 1 all meet the requirements, that is, the suspension properties can meet the clinical administration requirements.

[0168] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. An application of magnesium aluminum carbonate as a porogen.

2. The use according to claim 1, characterized in that: The hydrotalcite is used as a pore-forming agent in an ursodeoxycholic acid oral suspension composition, wherein the weight percentage of hydrotalcite: ursodeoxycholic acid is 3%-6%:100%.

3. An ursodeoxycholic acid oral suspension composition, characterized in that: The suspension consists of two parts: drug-loaded micropellets and inactive particles. The drug-loaded micropellets consist of a drug-loaded pellet core and a taste-masking coating layer, wherein the taste-masking coating layer comprises zein, aluminum carbonate, an anti-adhesive agent and a plasticizer; and the inactive particles comprise a filler, a suspending agent and a flavor.

4. The ursodeoxycholic acid oral suspension composition according to claim 3, characterized in that: The mass ratio of the drug-loaded pellets to the inactive particles is (550-600): (1000-4000); In the drug-loaded pellets, the mass ratio of the drug-loaded pellet core to the taste-masking coating layer is 500:(50-100), wherein: In the drug-loaded pill core, the mass ratio of ursodeoxycholic acid: filler: disintegrant: binder is (50-300): (40-240): (5-30): (5-30); In the taste-masking coating layer, the mass ratio of zein: aluminum carbonate: anti-sticking agent: plasticizer is (25-50): (7.5-15): (8-35): (1-5).

5. The ursodeoxycholic acid oral suspension composition according to claim 4, characterized in that: In the inactive particles, the weight percentages of filler: suspending agent: flavor are (84.5% to 96.95%): (3% to 10%): (0.05% to 0.5%).

6. The ursodeoxycholic acid oral suspension composition according to claim 4, characterized in that: The disintegrant in the drug-loaded pill core is selected from one or more of cross-linked sodium carboxymethyl cellulose, cross-linked calcium carboxymethyl cellulose, cross-linked polyvinyl pyrrolidone, and sodium carboxymethyl starch; The binder in the drug-loaded pill core is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, and fully pregelatinized starch.

7. The ursodeoxycholic acid oral suspension composition according to claim 4, characterized in that: The particle size of the hydrotalcite is D90≤10 microns; The anti-sticking agent in the taste-masking coating layer is selected from one or more of talc and magnesium stearate; The plasticizer in the taste-masking coating layer is selected from triethyl citrate.

8. The ursodeoxycholic acid oral suspension composition according to claim 4, characterized in that: The filler in the inactive particles is selected from one or more of anhydrous glucose or its hydrate, anhydrous sucrose or its hydrate, mannitol, xylitol, and sorbitol; The suspending agent in the inactive particles is selected from one of microcrystalline cellulose-sodium carboxymethylcellulose complex and xanthan gum; The flavor in the inactive particles is fruit flavor.

9. The ursodeoxycholic acid oral suspension composition according to claim 4, characterized in that: A single dosage unit of the suspension contains 50 to 300 mg of ursodeoxycholic acid.

10. The ursodeoxycholic acid oral suspension composition according to claim 4, characterized in that: The average diameter of the drug-loaded micropellets is 0.2 to 1.5 mm.

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