High-water-solubility drug gastric floating double-layer sustained release tablet and preparation method thereof

Abstract

The invention relates to the technical field of oral sustained-release preparations containing high-water-solubility drugs, in particular to a high-water-solubility drug gastric floating double-layer sustained-release tablet and a preparation method thereof. The double-layer sustained-release tablet comprises a drug layer and a floating layer, the medicine-containing layer is prepared from a high-water-solubility medicine, a hydrophilic polymer gel material I, a disintegrating agent, a foaming agent, an adhesive, an anti-sticking agent and a filling agent; the floating layer is prepared from a hydrophilic polymer gel material II, a disintegrating agent, a foaming agent, an adhesive, an anti-sticking agent, a floating aid and a filling agent. The high-water-solubility medicine is used as an active ingredient, a gel framework material is applied, a double-layer tablet form is adopted, the medicine storage effect is achieved through the medicine-containing layer, the tablet floating effect is achieved through the floating layer, the medicine permeability is adjusted through the low-pH environment in the stomach, the permeability is improved, and high medicine loading capacity and slow release of the high-water-solubility medicine are achieved.

Description

Technical Field

[0001] The invention relates to the technical field of oral sustained-release preparations containing highly water-soluble drugs, and in particular to a highly water-soluble drug gastric floating double-layer sustained-release tablet and a preparation method thereof. Background Art

[0002] The drug release rate of the monolayer hydrophilic gel skeleton sustained-release tablet is first-order or pseudo-first-order release. Its release characteristics are faster in the early stage and slower in the later stage, which is not conducive to the stable control of blood drug concentration. For drugs with high water solubility, the monolayer gel skeleton has insufficient control over the release rate. In the early stage of drug release, the drug on the surface is released before the hydration gel layer is formed, resulting in faster initial release. In order to control the initial release, an excessive amount of sustained-release material is generally added. However, in this case, in the later stage of release, due to the reduction of the drug diffusion concentration difference, the release rate decreases, which is easy to cause incomplete release.

[0003] As a highly water-soluble model drug, loxoprofen sodium is very soluble in water and easily soluble in ethanol. The preparation currently used in clinical practice is a common immediate-release preparation, Loxoprofen developed by Sankyo Co., Ltd. of Japan, with a specification of 60 mg and three doses per day, which is easy to cause fluctuations in blood drug concentration and increase the occurrence of adverse reactions. Therefore, it is necessary to make it into a sustained-release preparation to reduce the number of dosing times, maintain a stable blood drug concentration, reduce the occurrence of adverse reactions, and improve patient compliance.

[0004] Generally, highly water-soluble drugs are difficult to make into sustained-release dosage forms due to their excellent hydrophilicity. There are several studies on the preparation of sustained-release dosage forms of highly water-soluble drugs in the prior art. However, due to their high solubility, most preparations show burst release within the first 2 hours, which may cause unexpected side effects and damage to patients. Some highly hydrophilic drugs have moderate solubility under acidic conditions and are easily converted into their molecular form under acidic conditions, making them more easily absorbed by the human body. Therefore, making them into gastric floating tablets is not only conducive to providing a relatively stable and ideal release effect, but also can improve patient compliance and improve bioavailability. Summary of the invention

[0005] The purpose of the present invention is to overcome the above-mentioned defects of the prior art and provide a gastric floating double-layer sustained-release tablet of a highly water-soluble drug and a preparation method thereof.

[0006] The present invention uses highly water-soluble drugs as active ingredients, uses hydrophilic polymer gel materials as skeleton materials, and adopts a double-layer tablet form. The drug-containing layer realizes the drug storage effect, and the floating layer realizes the tablet floating effect. The low pH environment in the stomach is used to adjust the drug permeability to improve its permeability. An alkaline foaming agent is used to provide an alkaline microenvironment for the tablet to adjust the drug release. A low-density material bleaching agent is used to adjust the density of the floating layer, so that the floating layer acts as a float valve and floats on the water surface, while the drug-containing layer is located below the water surface. The present invention realizes high drug loading and skeleton sustained release of highly water-soluble drugs, increases the dosage of each drug tablet, prolongs the drug action time, maintains a stable blood drug concentration for a long time, improves the bioavailability of the drug, reduces gastrointestinal reactions, reduces the number of drug administrations, is easy for the human body to swallow, and improves the patient's medication compliance.

[0007] In order to achieve the above object, the technical solution of the present invention is as follows:

[0008] The present invention provides a highly water-soluble drug gastric floating double-layer sustained-release tablet, comprising: a drug-containing layer and a floating layer;

[0009] The drug-containing layer is composed of highly water-soluble drugs, hydrophilic polymer gel material I, disintegrants, foaming agents, adhesives, anti-adhesive agents, and fillers;

[0010] The floating layer is composed of hydrophilic polymer gel material II, disintegrant, foaming agent, adhesive, anti-adhesive agent, bleaching aid and filler.

[0011] In the above technical solution, further, the highly water-soluble drug accounts for 15% to 25% of the total weight of the sustained-release tablet.

[0012] In the above technical solution, further, the highly water-soluble drug includes one of loxoprofen sodium, diclofenac sodium, sodium salicylate, sodium valproate, and ketoprofen. In the present invention, the highly water-soluble drug refers to a series of drugs with high solubility in water, but its solubility will change due to pH changes.

[0013] In the above technical solution, further, the hydrophilic polymer gel material I is at least one of HPMC E50, HPMC K4M, HPMC K10M, HPMC K15M, HPC HF, HPC MF, HEC 250L, HEC 250M, PEO WSR Coagulant, Carbopol 974P NF, and SAL PH172, and the weight proportion of the hydrophilic polymer gel material I in the drug-containing layer is 5% to 15%;

[0014] The hydrophilic polymer gel material II is at least one of HPMC K100M, HPC HXF, HEC 250H, HEC 250HHX, CMC, CMC-Na, PEO WSR-303, Carbopol 974P NF, SAL PH175 and SAL PH176, and the weight proportion of the hydrophilic polymer gel material II in the floating layer is 20% to 35%;

[0015] The drug-containing layer selects a low-viscosity hydrophilic polymer gel material as a skeleton sustained-release material to control the stable release of highly water-soluble drugs in the early and middle stages, preferably hydroxypropyl methylcellulose with low viscosity, such as E50, K4M, K10M, and K15M; the floating layer selects a high-viscosity hydrophilic polymer gel material, preferably hydroxypropyl methylcellulose with high viscosity, such as K100M, which can float quickly in the early stage and act as a floating valve that can provide long-term floating ability to carry the entire tablet floating on the water surface. As the release time increases, the drug-containing layer gradually dissolves slowly, and the release resistance to the highly water-soluble drugs in the drug-containing layer gradually decreases, effectively solving the problem of the release rate decreasing in the later stage when the hydrophilic gel material in the single-layer tablet plays a floating and sustained-release role at the same time, thereby ensuring that the release rate is relatively constant throughout the drug release cycle and the drug residue is very small.

[0016] In the above technical solution, further, the sum of the weights of the hydrophilic polymer hydrogel material I and the hydrophilic polymer hydrogel material II accounts for 15% to 35% of the total weight of the sustained-release tablet.

[0017] In the above technical solution, further, the disintegrant is cross-linked polyvinyl pyrrolidone (PVPP), the weight proportion of the disintegrant in the drug-containing layer is 5% to 15%, and the weight proportion of the disintegrant in the floating layer is 15% to 25%. Using cross-linked polyvinyl pyrrolidone (PVPP) as a disintegrant can quickly introduce moisture into the tablet while having a small self-expansion coefficient, which is beneficial to maintaining the integrity of the gel layer.

[0018] In the above technical solution, further, the foaming agent is at least one of sodium carbonate, sodium bicarbonate, magnesium carbonate and calcium carbonate, the weight proportion of the foaming agent in the drug-containing layer is 10% to 20%, and the weight proportion of the foaming agent in the floating layer is 10% to 25%.

[0019] In the above technical solution, further, the bleaching agent is at least one of hexadecanol, octadecyl alcohol, stearic acid, polyethylene glycol and acrylic resin, preferably stearic acid. Stearic acid, as a low-density material, can provide appropriate diffusion resistance to prevent water from quickly penetrating and destroying the gel layer to cause it to lose its buoyancy. The weight proportion of the bleaching agent in the floating layer is 20% to 30%.

[0020] In the above technical solution, further, the filler is at least one of glucose, sucrose, microcrystalline cellulose, starch, dextrin, calcium phosphate, maltodextrin and mannitol, and the weight proportion of the filler in the drug-containing layer is 10% to 20%, and the weight proportion of the filler in the floating layer is 15% to 25%. The filler has different selection tendencies according to the release of the drug. If the release is too fast, a blocking filler for this drug is added, and if the release is too slow, a release-promoting filler is added.

[0021] In the above technical solution, further, the anti-adhesive agent is at least one of talc, magnesium stearate, micro-powder silica gel, and stearic acid, and the weight proportion of the anti-adhesive agent in the drug-containing layer is 1% to 2%, and the weight proportion of the anti-adhesive agent in the floating layer is 1% to 2%.

[0022] In the above technical solution, further, the binder is at least one of hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, corn starch, polyvinyl pyrrolidone (also known as povidone, PVP), and polyvinyl alcohol, and the weight proportion of the binder in the drug-containing layer is 1% to 3%, and the weight proportion of the binder in the floating layer is 1% to 3%. The binder is preferably an ethanol solution of PVP K30, such as a 50% povidone K30 ethanol solution, which can also play a wetting role.

[0023] In the above technical scheme, further, in the floating layer, the weight ratio of the hydrophilic polymer gel material II to the bleaching agent is 1:0.7 to 1:1; the weight ratio of the hydrophilic polymer gel material II to the foaming agent is 1:1 to 2:1; in the drug-containing layer, the weight ratio of the hydrophilic polymer gel material I to the foaming agent is 1:1 to 1:2.

[0024] In the above technical solution, further, the weight of the drug-containing layer is 350-450 mg, and the weight of the floating layer is 300-500 mg.

[0025] Another aspect of the present invention provides a method for preparing the above-mentioned sustained-release tablet, the method comprising the following steps:

[0026] (1) Preparation of drug-layered granules:

[0027] Pass the highly water-soluble drug, the hydrophilic polymer gel material I, the disintegrant, the foaming agent, and the filler through a 40-60 mesh sieve, mix them evenly, and perform dry granulation or wet granulation, preferably wet granulation, through a 24-40 mesh sieve to obtain drug-layered granules;

[0028] (2) Preparation of floating layer particles:

[0029] The hydrophilic polymer gel material II, disintegrant, foaming agent, filler and bleaching agent are passed through a 40-60 mesh sieve, mixed evenly, and dry granulated or wet granulated through a 24-40 mesh sieve to obtain floating layer particles;

[0030] (3) Preparation of double-layer sustained-release tablets:

[0031] The drug-containing layer granules were sieved with a 40-mesh sieve, and the anti-adhesive agent was added and mixed evenly. The floating layer granules were sieved with a 40-mesh sieve, and the anti-adhesive agent was added and mixed evenly. Subsequently, the drug-containing layer granules were filled into a die for pre-compression, and then the floating layer granules were filled into the die for tableting to obtain a double-layer sustained-release tablet.

[0032] In the above technical solution, further, the specification of the die is 19*10mm.

[0033] The hardness of the highly water-soluble drug gastric floating double-layer sustained-release tablet involved in the present invention is between 50 and 100N.

[0034] The beneficial effects of the present invention are:

[0035] The double-layer floating sustained-release tablet prepared by the present invention can expand after contacting with gastric juice because the floating layer contains a foaming agent that can produce gas when encountering gastric juice, so that the density of the entire double-layer tablet is lower than the density of the medium, and it can float on the gastric juice. The hydrophilic polymer gel material II of the floating layer can form a gel after contacting with gastric juice to prevent the bubbles from bursting, so that a lasting buoyancy can be generated. The hydrophilic polymer gel material I of the drug-containing layer forms a gel after contacting with water, and controls the release of the drug together with other materials by a combination of dissolution and diffusion. Therefore, the drug carried can be slowly and continuously released during the floating process, and a relatively constant drug concentration is maintained locally in the stomach. DETAILED DESCRIPTION

[0036] The technical solutions in the present invention will be described clearly and completely below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0037] The cumulative release test method is as follows: take a double-layer gastric floating tablet, release medium 0.1mol / L HCl 900ml, speed 100r / min, temperature 37±0.5℃, sample 6ml at 0.5, 1, 2, 4, 6, 8, 10, 12h, and replenish the dissolution medium of the same volume and temperature in time, filter through a 0.45μm microporous filter membrane, discard the initial filtrate, and take 4ml of the subsequent filtrate as the test solution for testing. Accurately weigh an appropriate amount of each drug reference substance, dissolve and dilute it with the dissolution medium to a drug reference solution with a concentration of about 10μg / mL, use the dissolution medium as a blank control, and use the UV-visible spectrophotometry method (General Rules 0401 of the 2020 edition of the Chinese Pharmacopoeia) at the corresponding wavelength to measure the absorbance values ​​of the reference solution and the test solution, and calculate the cumulative release at each time point by the external standard method.

[0038] Determination of floating lag time and total floating time: Use the dissolution determination method II (paddle method) apparatus in the 2020 edition of the "Chinese Pharmacopoeia" at pH 1.2 with 0.1 mol﹒ L -1 Hydrochloric acid solution was used as the release medium, the temperature was 37±0.5℃, and the rotation speed was 100r﹒min -1 , use a stopwatch to record the time. The time T1 (s) from the time the gastric floating tablet is placed in the dissolution cup to the time the tablet floats to the liquid surface is set as the floating lag time. If T1 < 10s, it is called immediate floating; if T1 > 90s, it is unqualified; the time from the start of floating to the sinking of the tablet is set as the total floating time T2 (h). If T2 < 12h, it is unqualified. Three tablets of each prescription were measured and the average value was taken.

[0039] Example 1

[0040] The prescription consists of 1000 tablets. The raw material composition of the drug-containing layer is shown in Table 1, and the raw material composition of the floating layer is shown in Table 2.

[0041] Table 1 Raw material composition of drug-containing layer

[0042] Drug-containing layer Dosage Loxoprofen Sodium 180g HPMC K15M 23g PVPP 35g PVP K30 7g Calcium phosphate 28g Sodium carbonate 70g Magnesium Stearate 3.5g Stearic acid 3.5g

[0043] Table 2 Raw material composition of floating layer

[0044] Floating layer Dosage HPMC K100M 137g Sodium carbonate 125g Calcium phosphate 30.5g PVP K30 10g Magnesium Stearate 2.5g Stearic acid 100g PVPP 95g

[0045] The preparation method of the above-mentioned gastric floating double-layer sustained-release tablet comprises the following steps:

[0046] (1) Weigh 180 g of loxoprofen sodium, 23 g of HPMC K15M, 70 g of sodium carbonate, 35 g of PVPP, and 28 g of calcium phosphate, pass through a 40-60 mesh sieve, and mix uniformly to obtain a first material; weigh 7 g of PVP K30, place it in 100 ml of a 50% ethanol aqueous solution, and fully dissolve it to obtain a binder solution; spray the solution uniformly into the first material, perform wet granulation, pass through a 40 mesh sieve to obtain wet granules, and dry them at 60° C. until the moisture content is below 5% to obtain drug-layered granules;

[0047] (2) Weigh 137 g of HPMC K100M, 95 g of PVPP, 30.5 g of calcium phosphate, 100 g of stearic acid, and 125 g of sodium carbonate, pass through a 40-60 mesh sieve, mix evenly to obtain a second material, weigh 10 g of PVP K30, place it in 200 ml of 50% ethanol aqueous solution, and fully dissolve it into a binder solution, and evenly spray the solution into the second material for wet granulation, pass through a 40 mesh sieve to obtain wet granules, and dry them at 60° C. until the moisture content is below 5%, to obtain floating layer granules;

[0048] (3) After the drug-containing layer particles and the floating layer particles are sized with a 40-mesh sieve, 3.5 g of magnesium stearate and 3.5 g of stearic acid are added to the drug-containing layer particles, and 2.5 g of magnesium stearate is added to the floating layer particles, and the mixture is evenly mixed. The drug-containing layer is then filled into a 19*10 mm special-shaped die for pre-compression, and the floating layer particles are then filled into the die for tableting, so that the hardness is between 50 and 100 N and the thickness is between 6.5 and 7 mm.

[0049] The loxoprofen sodium double-layer gastric floating tablet prepared in Example 1 was placed in simulated artificial gastric fluid for in vitro release test, and the test results are shown in Table 3. The floating lag time test and the total floating time test, the results are shown in Table 4.

[0050] Table 3 In vitro cumulative release of loxoprofen sodium gastric floating double-layer sustained-release tablets obtained in Example 1

[0051] time 0.5 hours 1 hour 2 hours 4 hours 6 hours 8 hours 10 hours 12 hours Example 1 15.86％ 26.46％ 33.26％ 51.30％ 63.93％ 77.10％ 86.73％ 90.99％

[0052] Table 4 Floating lag time and total floating time of loxoprofen sodium gastric floating double-layer sustained-release tablets obtained in Example 1

[0053] serial number Floating lag time Total floating time Example 1 1min More than 12 hours

[0054] It can be seen from Tables 3 and 4 that the sustained release control using PVPP as a disintegrant is good and the floating lag time is short.

[0055] Example 2

[0056] The foaming agent sodium carbonate in step (1) and step (2) of Example 1 was replaced by sodium bicarbonate, and the other parameters were the same as those in Example 1.

[0057] Example 3

[0058] The foaming agent sodium carbonate in step (1) and step (2) of Example 1 was replaced by calcium carbonate, and the other parameters were the same as those in Example 1.

[0059] The loxoprofen sodium double-layer gastric floating tablets prepared in Test Example 1 and Examples 2-3 were placed in simulated artificial gastric fluid for in vitro release investigation, and the results are shown in Table 5. The floating lag time and total floating time were investigated, and the results are shown in Table 6.

[0060] Table 5 In vitro cumulative release of loxoprofen sodium gastric floating double-layer sustained-release tablets obtained in Example 1 and Examples 2-3

[0061] time 0.5 hours 1 hour 2 hours 4 hours 6 hours 8 hours 10 hours 12 hours Example 1 15.86％ 26.46％ 33.26％ 51.30％ 63.93％ 77.10％ 86.73％ 90.99％ Example 2 21.15％ 26.53％ 39.97％ 53.27％ 64.96％ 74.84％ 89.50％ 99.94％ Example 3 12.84％ 21.45％ 36.08％ 46.96％ 53.59％ 67.72％ 73.15％ 88.42％

[0062] Table 6 Floating lag time and total floating time of loxoprofen sodium gastric floating double-layer sustained-release tablets obtained in Example 1 and Example 2-3

[0063] serial number Floating lag time Total floating time Example 1 1min More than 12 hours Example 2 1min 20 s More than 12 hours Example 3 20 s More than 12 hours

[0064] It can be seen from Table 5 that the sustained-release control effect of using sodium carbonate as a foaming agent is higher than that of other foaming agents.

[0065] Example 4

[0066] The filler calcium phosphate in step (1) and step (2) of Example 1 was replaced with microcrystalline cellulose, and the other parameters were the same as those in Example 1.

[0067] The loxoprofen sodium double-layer gastric floating tablets prepared in Test Example 1 and Example 4 were placed in simulated artificial gastric fluid for in vitro release investigation, and the results are shown in Table 7. The floating lag time and total floating time were investigated, and the results are shown in Table 8.

[0068] Table 7 In vitro cumulative release of loxoprofen sodium gastric floating double-layer sustained-release tablets obtained in Example 1 and Example 4

[0069]

[0070]

[0071] Table 8 Floating lag time and total floating time of loxoprofen sodium gastric floating double-layer sustained-release tablets obtained in Example 1 and Example 4

[0072] serial number Floating lag time Total floating time Example 1 1min More than 12 hours Example 4 30 s More than 12 hours

[0073] It can be seen from Table 7 that the sustained-release control effect of using calcium phosphate as a filler is higher than that of other fillers.

[0074] Example 5

[0075] The prescription consists of 1000 tablets. The raw material composition of the drug-containing layer is shown in Table 9, and the raw material composition of the floating layer is shown in Table 10.

[0076] Table 9 Raw material composition of drug-containing layer

[0077] Drug-containing layer Dosage Loxoprofen Sodium 180g HPMC K15M 35g PVPP 35g Calcium phosphate 23g Sodium carbonate 70g Magnesium Stearate 3.5g Stearic acid 3.5g

[0078] Table 10 Raw material composition of floating layer

[0079] Floating layer Dosage HPMC K100M 75g Sodium carbonate 125g Calcium phosphate 102.5g Magnesium Stearate 2.5g Stearic acid 100g PVPP 95g

[0080] The preparation method of the above-mentioned gastric floating double-layer sustained-release tablet comprises the following steps:

[0081] (1) Weigh 180 g of loxoprofen sodium, 35 g of HPMC K15M, 70 g of sodium carbonate, 23 g of calcium phosphate, and 35 g of PVPP, pass through a 40-60 mesh sieve, mix evenly to obtain a first material, spray 100 ml of a 50% ethanol aqueous solution evenly into the first material, perform wet granulation, pass through a 40 mesh sieve to obtain wet granules, and dry at 60° C. until the moisture content is below 5%, to obtain drug-layered granules;

[0082] (2) Weigh 100 g of HPMC K100M, 77.5 g of calcium phosphate, 100 g of stearic acid, 125 g of sodium carbonate, and 95 g of PVPP, pass through a 40-60 mesh sieve, mix evenly to obtain a second material, spray 200 ml of a 50% ethanol aqueous solution evenly into the second material, perform wet granulation, pass through a 40 mesh sieve to obtain wet granules, and dry at 60° C. until the moisture content is below 5%, to obtain floating layer granules;

[0083] (3) After the drug-containing layer particles and the floating layer particles are sized with a 40-mesh sieve, 3.5 g of magnesium stearate and 3.5 g of stearic acid are added to the drug-containing layer particles, and 2.5 g of magnesium stearate is added to the floating layer particles, and the mixture is evenly mixed. The drug-containing layer is then filled into a 19*10 mm special-shaped die for pre-compression, and the floating layer particles are then filled into the die for tableting, so that the hardness is between 50 and 100 N and the thickness is between 6.5 and 7 mm.

[0084] Example 6

[0085] The amount of HPMC K100M in the floating layer in Example 5 was replaced with 125 g, and the amount of calcium phosphate was replaced with 52.5 g. Other parameters were the same as those in Example 5.

[0086] The loxoprofen sodium double-layer gastric floating tablets prepared in Test Examples 5-6 were placed in simulated artificial gastric fluid for in vitro release investigation, and the results are shown in Table 11. The floating lag time and total floating time were investigated, and the results are shown in Table 12.

[0087] Table 11 In vitro cumulative release of loxoprofen sodium gastric floating double-layer sustained-release tablets obtained in Examples 5 to 6

[0088] time 0.5 hours 1 hour 2 hours 4 hours 6 hours 8 hours 10 hours 12 hours Example 5 8.18％ 14.96％ 23.81％ 37.41％ 47.67％ 60.84％ 72.88％ 79.40％ Example 6 9.23％ 16.79％ 23.42％ 36.78％ 50.58％ 63.61％ 74.11％ 84.26％

[0089] Table 12 Floating lag time and total floating time of loxoprofen sodium gastric floating double-layer sustained-release tablets obtained in Examples 5 to 6

[0090] serial number Floating lag time Total floating time Example 5 30s More than 12 hours Example 6 10 s More than 12 hours

[0091] It can be seen from Tables 11 and 12 that when the dosage of HPMC K100M is 125 g and the dosage of calcium phosphate is 52.5 g, the sustained-release effect is the best and the floating lag time is qualified.

[0092] Example 7

[0093] The prescription consists of 1000 tablets. The raw material composition of the drug-containing layer is shown in Table 13, and the raw material composition of the floating layer is shown in Table 14.

[0094] Table 13 Raw material composition of drug-containing layer

[0095] Drug-containing layer Dosage Loxoprofen Sodium 180g HPMC K15M 53g PVPP 35g Calcium phosphate 5g Sodium carbonate 70g Magnesium Stearate 3.5g Stearic acid 3.5g

[0096] Table 14 Raw material composition of floating layer

[0097] Floating layer Dosage HPMC K100M 107g Sodium carbonate 125g Calcium phosphate 70.5g Magnesium Stearate 2.5g Stearic acid 100g PVPP 95g

[0098] The preparation method of the above-mentioned gastric floating double-layer sustained-release tablet comprises the following steps:

[0099] (1) Weigh 180 g of loxoprofen sodium, 35 g of HPMC K15M, 70 g of sodium carbonate, 5 g of calcium phosphate, and 35 g of PVPP, pass through a 40-60 mesh sieve, mix evenly to obtain a first material, spray 100 ml of a 50% ethanol aqueous solution evenly into the first material, perform wet granulation, pass through a 40 mesh sieve to obtain wet granules, and dry at 60° C. until the moisture content is below 5%, to obtain drug-layered granules;

[0100] (2) Weigh 107 g of HPMC K100M, 70.5 g of calcium phosphate, 100 g of stearic acid, 125 g of sodium carbonate, and 95 g of PVPP, pass through a 40-60 mesh sieve, mix evenly to obtain a second material, spray 200 ml of a 50% ethanol aqueous solution evenly into the second material, perform wet granulation, pass through a 40 mesh sieve to obtain wet granules, and dry at 60° C. until the moisture content is below 5%, to obtain floating layer granules;

[0101] (3) After the drug-containing layer particles and the floating layer particles are sized with a 40-mesh sieve, 3.5 g of magnesium stearate and 3.5 g of stearic acid are added to the drug-containing layer particles, and 2.5 g of magnesium stearate is added to the floating layer particles, and the mixture is evenly mixed. The drug-containing layer is then filled into a 19*10 mm special-shaped die for pre-compression, and the floating layer particles are then filled into the die for tableting, so that the hardness is between 50 and 100 N and the thickness is between 6.5 and 7 mm.

[0102] Example 8

[0103] The amount of HPMC K15M in the drug-containing layer in Example 7 was replaced with 32 g, and the amount of calcium phosphate was replaced with 26 g; the amount of HPMC K100M in the floating layer was replaced with 128 g, and the amount of calcium phosphate was replaced with 49.5 g. Other parameters were the same as those in Example 7.

[0104] Example 9

[0105] The amount of HPMC K15M in the drug-containing layer in Example 7 was replaced with 23 g, and the amount of calcium phosphate was replaced with 35 g; the amount of HPMC K100M in the floating layer was replaced with 137 g, and the amount of calcium phosphate was replaced with 40.5 g. Other parameters were the same as those in Example 7.

[0106] The loxoprofen sodium double-layer gastric floating tablets prepared in Test Examples 7 to 9 were placed in simulated artificial gastric fluid for in vitro release investigation, and the results are shown in Table 15. The floating lag time and total floating time were investigated, and the results are shown in Table 16.

[0107] Table 15 In vitro cumulative release of loxoprofen sodium gastric floating double-layer sustained-release tablets obtained in Examples 7 to 9

[0108] time 0.5 hours 1 hour 2 hours 4 hours 6 hours 8 hours 10 hours 12 hours Example 7 8.95％ 16.24％ 23.80％ 39.08％ 48.21％ 58.67％ 69.91％ 82.90％ Example 8 11.31％ 19.94％ 28.89％ 45.80％ 57.72％ 67.15％ 75.51％ 80.75％ Example 9 14.31％ 25.25％ 34.36％ 51.83％ 63.08％ 69.79％ 81.26％ 86.22％

[0109] Table 16 Floating lag time and total floating time of loxoprofen sodium gastric floating double-layer sustained-release tablets obtained in Examples 7 to 9

[0110]

[0111]

[0112] It can be seen from Tables 15-16 that when the dosage of HPMC K15M in the drug-containing layer is replaced with 23 g and the dosage of calcium phosphate is replaced with 35 g; when the dosage of HPMC K100M in the floating layer is replaced with 137 g and the dosage of calcium phosphate is replaced with 40.5 g, the sustained-release effect is the best and the floating lag time is qualified.

[0113] Example 10

[0114] The amount of sodium carbonate in the drug-containing layer in Example 1 was replaced by 52.5 g, and the amount of calcium phosphate was replaced by 45.5 g. Other parameters were the same as in Example 1.

[0115] Embodiment 11

[0116] The amount of sodium carbonate in the drug-containing layer in Example 1 was replaced by 35 g, and the amount of calcium phosphate was replaced by 63 g. Other parameters were the same as in Example 1.

[0117] The loxoprofen sodium double-layer gastric floating tablets prepared in Test Examples 1, 10-11 were placed in simulated artificial gastric fluid for in vitro release investigation, and the results are shown in Table 17. The floating lag time and total floating time were investigated, and the results are shown in Table 18.

[0118] Table 17 In vitro cumulative release of loxoprofen sodium gastric floating double-layer sustained-release tablets obtained in Examples 1, 10-11

[0119] time 0.5 hours 1 hour 2 hours 4 hours 6 hours 8 hours 10 hours 12 hours Embodiment 11 9.77％ 15.69％ 26.79％ 44.88％ 61.14％ 65.91％ 77.83％ 82.95％ Example 10 9.81％ 17.74％ 33.30％ 50.04％ 66.35％ 80.47％ 91.96％ 95.22％ Example 1 15.86％ 26.46％ 33.26％ 51.30％ 63.93％ 77.10％ 86.73％ 90.99％

[0120] Table 18 Floating lag time and total floating time of loxoprofen sodium gastric floating double-layer sustained-release tablets obtained in Examples 1, 10 to 11

[0121] serial number Floating lag time Total floating time Example 1 1min More than 12 hours Example 10 1min More than 12 hours Embodiment 11 1min 20 s More than 12 hours

[0122] It can be seen from Table 17 that when the dosage of sodium carbonate in the drug-containing layer is 70 g and the dosage of calcium phosphate is 28 g, the sustained-release effect is the best and the drug release is more complete.

[0123] Example 12

[0124] The prescription consists of 1000 tablets. The raw material composition of the drug-containing layer is shown in Table 19, and the raw material composition of the floating layer is shown in Table 20.

[0125] Table 19 Raw material composition of drug-containing layer

[0126] Drug-containing layer Dosage Loxoprofen Sodium 180g HPMC K15M 23g PVPP 35g Calcium phosphate 45.5g PVP K30 7g Sodium carbonate 52.5g Magnesium Stearate 3.5g Stearic acid 3.5g

[0127] Table 20 Raw material composition of floating layer

[0128] Floating layer Dosage HPMC K100M 137g Sodium carbonate 75g Calcium phosphate 80.5g Magnesium Stearate 2.5g Stearic acid 100g PVP K30 10g PVPP 95g

[0129] The preparation method of the above-mentioned gastric floating double-layer sustained-release tablet comprises the following steps:

[0130] (1) Weigh 180 g of loxoprofen sodium, 23 g of HPMC K15M, 52.5 g of sodium carbonate, 45.5 g of calcium phosphate, and 35 g of PVPP, pass through a 40-60 mesh sieve, mix evenly to obtain a first material, weigh 7 g of PVP K30, place it in 100 ml of 50% ethanol aqueous solution, and fully dissolve it to obtain a binder solution, and evenly spray the solution into the first material for wet granulation, pass through a 40 mesh sieve to obtain wet granules, and dry them at 60° C. until the moisture content is below 5%, to obtain drug-layered granules;

[0131] (2) Weigh 137 g of HPMC K100M, 95 g of PVPP, 30.5 g of calcium phosphate, 100 g of stearic acid, and 125 g of sodium carbonate, pass through a 40-60 mesh sieve, mix evenly to obtain a second material, weigh 10 g of pvp K30, place it in 200 ml of 50% ethanol aqueous solution, and fully dissolve it into a binder solution, spray the solution evenly into the second material, perform wet granulation, pass through a 40 mesh sieve to obtain wet granules, and dry them at 60° C. until the moisture content is below 5%, to obtain floating layer granules;

[0132] (3) After the drug-containing layer particles and the floating layer particles are sized with a 40-mesh sieve, 3.5 g of magnesium stearate and 3.5 g of stearic acid are added to the drug-containing layer particles, and 2.5 g of magnesium stearate is added to the floating layer particles, and the mixture is evenly mixed. The drug-containing layer is then filled into a 19*10 mm special-shaped die for pre-compression, and the floating layer particles are then filled into the die for tableting, so that the hardness is between 50 and 100 N and the thickness is between 6.5 and 7 mm.

[0133] Example 13

[0134] The prescription composition is the same as that of Example 12.

[0135] (1) Weigh 180 g of loxoprofen sodium, 23 g of HPMC K15M, 52.5 g of sodium carbonate, 45.5 g of calcium phosphate, and 17.5 g of PVPP, pass through a 40-60 mesh sieve, mix evenly to obtain a first material, weigh 7 g of PVP K30, place it in 100 ml of 50% ethanol aqueous solution, and fully dissolve it to obtain a binder solution, and evenly spray the solution into the first material for wet granulation, pass through a 40 mesh sieve to obtain wet granules, and dry them at 60° C. until the moisture content is below 5%, to obtain drug-layered granules;

[0136] (2) Weigh 137 g of HPMC K100M, 47.5 g of PVPP, 30.5 g of calcium phosphate, 100 g of stearic acid, and 125 g of sodium carbonate, pass through a 40-60 mesh sieve, mix evenly to obtain a second material, weigh 10 g of PVP K30, place it in 200 ml of 50% ethanol aqueous solution, and fully dissolve it into a binder solution, and evenly spray the solution into the second material for wet granulation, pass through a 40 mesh sieve to obtain wet granules, and dry them at 60° C. until the moisture content is below 5%, to obtain floating layer granules;

[0137] (3) After the drug-containing layer particles and the floating layer particles are sized with a 40-mesh sieve, 17.5 g PVPP, 3.5 g magnesium stearate and 3.5 g stearic acid are added to the drug-containing layer particles, and 47.5 g PVPP and 2.5 g magnesium stearate are added to the floating layer particles, and mixed evenly. Then, the drug-containing layer is filled into a 19*10 mm special-shaped die for pre-compression, and then the floating layer particles are filled into the die for tableting, so that the hardness is between 50 and 100 N and the thickness is between 6.5 and 7 mm.

[0138] Embodiment 14

[0139] The prescription composition is the same as that of Example 12.

[0140] (1) Weigh 180 g of loxoprofen sodium, 23 g of HPMC K15M, 52.5 g of sodium carbonate, and 45.5 g of calcium phosphate, pass through a 40-60 mesh sieve, mix evenly to obtain a first material, weigh 7 g of PVP K30, place it in 100 ml of a 50% ethanol aqueous solution, and fully dissolve it to obtain a binder solution, and evenly spray the solution into the first material to perform wet granulation, pass through a 40 mesh sieve to obtain wet granules, and dry them at 60° C. until the moisture content is below 5%, to obtain drug-layered granules;

[0141] (2) Weigh 137 g of HPMC K100M, 30.5 g of calcium phosphate, 100 g of stearic acid, and 125 g of sodium carbonate, pass through a 40-60 mesh sieve, mix evenly to obtain a second material, weigh 10 g of PVP K30, place it in 200 ml of 50% ethanol aqueous solution, and fully dissolve it into a binder solution, and evenly spray the solution into the second material for wet granulation, pass through a 40 mesh sieve to obtain wet granules, and dry them at 60° C. until the moisture content is below 5%, to obtain floating layer granules;

[0142] (3) After the drug-containing layer particles and the floating layer particles are sized with a 40-mesh sieve, 35 g of PVPP, 3.5 g of magnesium stearate and 3.5 g of stearic acid are added to the drug-containing layer particles, and 95 g of PVPP and 2.5 g of magnesium stearate are added to the floating layer particles, and mixed evenly. The drug-containing layer is then filled into a 19*10 mm special-shaped die for pre-compression, and the floating layer particles are then filled into the die for tableting, so that the hardness is between 50 and 100 N and the thickness is between 6.5 and 7 mm.

[0143] The loxoprofen sodium double-layer gastric floating tablets prepared in Test Examples 12 to 14 were placed in simulated artificial gastric fluid for in vitro release investigation, and the results are shown in Table 21. The floating lag time and total floating time were investigated, and the results are shown in Table 22.

[0144] Table 21 In vitro cumulative release of loxoprofen sodium gastric floating double-layer sustained-release tablets obtained in Examples 12 to 14

[0145] time 0.5 hours 1 hour 2 hours 4 hours 6 hours 8 hours 10 hours 12 hours Example 12 25.64％ 33.73％ 45.83％ 64.81％ 79.34％ 85.59％ 95.03％ 98.19％ Example 13 16.46％ 26.72％ 40.13％ 59.81％ 74.56％ 90.13％ 93.11％ 97.29％ Embodiment 14 25.62％ 31.85％ 45.62％ 65.11％ 77.34％ 90.67％ 97.03％ 101.71％

[0146] Table 22 Floating lag time and total floating time of loxoprofen sodium gastric floating double-layer sustained-release tablets obtained in Examples 12 to 14

[0147]

[0148]

[0149] It can be seen from Table 21 that when the disintegrant is added in the manner as in Example 13, the sustained release effect is the best and the floating lag time is the shortest.

[0150] Embodiment 15

[0151] The prescription consists of 1000 tablets. The raw material composition of the drug-containing layer is shown in Table 23, and the raw material composition of the floating layer is shown in Table 24.

[0152] Table 23 Raw material composition of drug-containing layer

[0153] Drug-containing layer Dosage Diclofenac Sodium 75g HPMC K15M 128g PVPP 30g Calcium phosphate 60g PVP K30 7g Sodium carbonate 43g Magnesium Stearate 3.5g Stearic acid 3.5g

[0154] Table 24 Raw material composition of floating layer

[0155] Floating layer Dosage HPMC K100M 137g Sodium carbonate 75g Calcium phosphate 80.5g Magnesium Stearate 2.5g Stearic acid 100g PVP K30 10g PVPP 95g

[0156] (1) Weigh 75 g of diclofenac sodium, 128 g of HPMC K15M, 43 g of sodium carbonate, 15 g of PVPP, and 60 g of calcium phosphate, pass through a 40-60 mesh sieve, mix evenly to obtain a first material, weigh 7 g of PVP K30, place it in 100 ml of 50% ethanol aqueous solution, and fully dissolve it to obtain a binder solution, and evenly spray the solution into the first material for wet granulation, pass through a 40 mesh sieve to obtain wet granules, and dry them at 60° C. until the moisture content is below 5%, to obtain drug-layered granules;

[0157] (2) Weigh 137 g of HPMC K100M, 80.5 g of calcium phosphate, 100 g of stearic acid, 47.5 g of PVPP, and 75 g of sodium carbonate, pass through a 40-60 mesh sieve, mix evenly to obtain a second material, weigh 10 g of PVP K30, place it in 200 ml of 50% ethanol aqueous solution, and fully dissolve it to obtain a binder solution, and evenly spray the solution into the second material for wet granulation, pass through a 40 mesh sieve to obtain wet granules, and dry them at 60° C. until the moisture content is below 5%, to obtain floating layer granules;

[0158] (3) After the drug-containing layer particles and the floating layer particles are sized with a 40-mesh sieve, 15 g PVPP, 3.5 g magnesium stearate and 3.5 g stearic acid are added to the drug-containing layer particles, and 47.5 g PVPP and 2.5 g magnesium stearate are added to the floating layer particles, and mixed evenly. Then, the drug-containing layer is filled into a 19*10 mm special-shaped die for pre-compression, and then the floating layer particles are filled into the die for tableting, so that the hardness is between 50 and 100 N and the thickness is between 6.5 and 7 mm.

[0159] Example 16

[0160] The prescription consists of 1000 tablets. The raw material composition of the drug-containing layer is shown in Table 25, and the raw material composition of the floating layer is shown in Table 26.

[0161] Table 25 Raw material composition of drug-containing layer

[0162] Drug-containing layer Dosage Sodium salicylate 250g HPMC K15M 28g PVPP 30g Calcium phosphate 30g PVP K30 7g Sodium carbonate 43g Magnesium Stearate 3.5g Stearic acid 3.5g

[0163] Table 26 Raw material composition of floating layer

[0164] Floating layer Dosage HPMC K100M 92g Sodium carbonate 75g Calcium phosphate 80.5g Magnesium Stearate 2.5g Stearic acid 100g PVP K30 10g PVPP 95g

[0165] (1) Weigh 250 g of sodium salicylate, 28 g of HPMC K15M, 43 g of sodium carbonate, 15 g of PVPP, and 30 g of calcium phosphate, pass through a 40-60 mesh sieve, mix evenly to obtain a first material, weigh 7 g of PVP K30, place it in 100 ml of 50% ethanol aqueous solution, and fully dissolve it to obtain a binder solution, and evenly spray the solution into the first material for wet granulation, pass through a 40 mesh sieve to obtain wet granules, and dry them at 60° C. until the moisture content is below 5%, to obtain drug-containing layer granules;

[0166] (2) Weigh 92 g of HPMC K100M, 80.5 g of calcium phosphate, 100 g of stearic acid, 47.5 g of PVPP, and 75 g of sodium carbonate, pass through a 40-60 mesh sieve, mix evenly to obtain a second material, weigh 10 g of pvp K30, place it in 200 ml of 50% ethanol aqueous solution, and fully dissolve it into a binder solution, and evenly spray the solution into the second material for wet granulation, pass through a 40 mesh sieve to obtain wet granules, and dry them at 60° C. until the moisture content is below 5%, to obtain floating layer granules;

[0167] (3) After the drug-containing layer particles and the floating layer particles are sized with a 40-mesh sieve, 15 g of PVPP, 3.5 g of magnesium stearate and 3.5 g of stearic acid are added to the drug-containing layer particles; 47.5 g of PVPP and 2.5 g of magnesium stearate are added to the floating layer particles, mixed evenly, and then the drug-containing layer is filled into a 19*10 mm special-shaped die for pre-pressing, and then the floating layer particles are filled into the die for tableting, so that the hardness is between 50 and 100 N and the thickness is between 6.5 and 7 mm.

[0168] Embodiment 17

[0169] The prescription consists of 1000 tablets. The raw material composition of the drug-containing layer is shown in Table 27, and the raw material composition of the floating layer is shown in Table 28.

[0170] Table 27 Raw material composition of drug-containing layer

[0171] Drug-containing layer Dosage Sodium valproate 200g HPMC K15M 28g PVPP 30g Calcium phosphate 80g PVP K30 7g Sodium carbonate 43g Magnesium Stearate 3.5g Stearic acid 3.5g

[0172] Table 28 Raw material composition of floating layer

[0173] Floating layer Dosage HPMC K100M 92g Sodium carbonate 75g Calcium phosphate 80.5g Magnesium Stearate 2.5g Stearic acid 100g PVP K30 10g PVPP 95g

[0174] (1) Weigh 200 g of sodium valproate, 28 g of HPMC K15M, 43 g of sodium carbonate, 15 g of PVPP, and 80 g of calcium phosphate, pass through a 40-60 mesh sieve, mix evenly to obtain a first material, weigh 7 g of PVP K30, place it in 100 ml of 50% ethanol aqueous solution, and fully dissolve it to obtain a binder solution. The solution is evenly sprayed into the first material for wet granulation, and passed through a 40 mesh sieve to obtain wet granules, which are dried at 60° C. until the moisture content is below 5%, to obtain drug-layered granules;

[0175] (2) Weigh 92 g of HPMC K100M, 80.5 g of calcium phosphate, 100 g of stearic acid, 47.5 g of PVPP, and 75 g of sodium carbonate, pass through a 40-60 mesh sieve, mix evenly to obtain a second material, weigh 10 g of pvp K30, place it in 200 ml of 50% ethanol aqueous solution, and fully dissolve it into a binder solution, and evenly spray the solution into the second material for wet granulation, pass through a 40 mesh sieve to obtain wet granules, and dry them at 60° C. until the moisture content is below 5%, to obtain floating layer granules;

[0176] (3) After the drug-containing layer particles and the floating layer particles are sized with a 40-mesh sieve, 15 g PVPP, 3.5 g magnesium stearate and 3.5 g stearic acid are added to the drug-containing layer particles, and 47.5 g PVPP and 2.5 g magnesium stearate are added to the floating layer particles, and mixed evenly. Then, the drug-containing layer is filled into a 19*10 mm special-shaped die for pre-compression, and then the floating layer particles are filled into the die for tableting, so that the hardness is between 50 and 100 N and the thickness is between 6.5 and 7 mm.

[0177] Embodiment 18

[0178] The prescription consists of 1000 tablets. The raw material composition of the drug-containing layer is shown in Table 29, and the raw material composition of the floating layer is shown in Table 30.

[0179] Table 29 Raw material composition of drug-containing layer

[0180] Drug-containing layer Dosage Ketoprofen 200g HPMC K15M 28g PVPP 30g Calcium phosphate 80g PVP K30 7g Sodium carbonate 43g Magnesium Stearate 3.5g Stearic acid 3.5g

[0181] Table 30 Raw material composition of floating layer

[0182]

[0183]

[0184] (1) Weigh 200 g of ketoprofen, 28 g of HPMC K15M, 43 g of sodium carbonate, 15 g of PVPP, and 80 g of calcium phosphate, pass through a 40-60 mesh sieve, mix evenly to obtain a first material, weigh 7 g of PVP K30, place it in 100 ml of 50% ethanol aqueous solution, and fully dissolve it to obtain a binder solution, and evenly spray the solution into the first material for wet granulation, pass through a 40 mesh sieve to obtain wet granules, and dry them at 60° C. until the moisture content is below 5%, to obtain drug-layered granules;

[0185] (2) Weigh 92 g of HPMC K100M, 80.5 g of calcium phosphate, 100 g of stearic acid, 47.5 g of PVPP, and 75 g of sodium carbonate, pass through a 40-60 mesh sieve, mix evenly to obtain a second material, weigh 10 g of pvp K30, place it in 200 ml of 50% ethanol aqueous solution, and fully dissolve it into a binder solution, and evenly spray the solution into the second material for wet granulation, pass through a 40 mesh sieve to obtain wet granules, and dry them at 60° C. until the moisture content is below 5%, to obtain floating layer granules;

[0186] (3) After the drug-containing layer particles and the floating layer particles are sized with a 40-mesh sieve, 15 g PVPP, 3.5 g magnesium stearate and 3.5 g stearic acid are added to the drug-containing layer particles, and 47.5 g PVPP and 2.5 g magnesium stearate are added to the floating layer particles, and mixed evenly. Then, the drug-containing layer is filled into a 19*10 mm special-shaped die for pre-compression, and then the floating layer particles are filled into the die for tableting, so that the hardness is between 50 and 100 N and the thickness is between 6.5 and 7 mm.

[0187] The double-layer gastric floating tablets prepared in Test Examples 15 to 18 were placed in simulated artificial gastric fluid for in vitro release investigation, and the results are shown in Table 31. The floating lag time investigation and the total floating time investigation, and the results are shown in Table 32.

[0188] Table 31 In vitro cumulative release of gastric floating double-layer sustained-release tablets obtained in Examples 15 to 18

[0189] time 0.5 hours 1 hour 2 hours 4 hours 6 hours 8 hours 10 hours 12 hours Embodiment 15 17.56％ 29.58％ 40.83％ 60.85％ 75.39％ 91.52％ 95.78％ 99.98％ Example 16 16.46％ 26.72％ 40.13％ 59.81％ 74.56％ 90.13％ 93.11％ 97.29％ Embodiment 17 19.52％ 30.78％ 42.85％ 58.11％ 74.34％ 90.67％ 97.03％ 100.71％ Embodiment 18 17.39％ 25.29％ 41.32％ 56.75％ 73.26％ 89.25％ 92.35％ 96.73％

[0190] Table 32 Floating lag time and total floating time of gastric floating double-layer sustained-release tablets obtained in Examples 15 to 18

[0191]

[0192]

[0193] As can be seen from the above table, the gastric floating double-layer sustained-release tablets of highly water-soluble drugs have good sustained-release effect, long in vitro floating time and short floating start time, which meets the requirements.

[0194] Embodiment 19

[0195] In Example 13, the hydrophilic polymer gel material I of the drug-containing layer in step (1) was replaced with 45 g of SAL (PH172), and the amount of calcium phosphate was replaced with 23.5 g; the hydrophilic polymer gel material II of the floating layer in step (2) was replaced with SAL PH176. All other parameters were the same as in Example 1.

[0196] Embodiment 20

[0197] In Example 13, the hydrophilic polymer gel material I of the drug-containing layer in step (1) was replaced with 20 g of Carbopol 971P NF, and the amount of calcium phosphate was replaced with 43.5 g; the hydrophilic polymer gel material II of the floating layer in step (2) was replaced with Carbopol 974P NF. All other parameters were the same as in Example 1.

[0198] Embodiment 21

[0199] In Example 13, the hydrophilic polymer gel material I of the drug-containing layer in step (1) was replaced with 30.5 g of HEC 250M, and the amount of calcium phosphate was replaced with 33 g; the hydrophilic polymer gel material II of the floating layer in step (2) was replaced with HEC 250H. All other parameters were the same as in Example 1.

[0200] The double-layer gastric floating tablets prepared in Test Examples 13, 19 to 21 were placed in simulated artificial gastric fluid for in vitro release investigation, and the results are shown in Table 33. The floating lag time and total floating time were investigated, and the results are shown in Table 34.

[0201] Table 33 In vitro cumulative release of gastric floating double-layer sustained-release tablets obtained in Examples 13, 19 to 21

[0202] time 0.5 hours 1 hour 2 hours 4 hours 6 hours 8 hours 10 hours 12 hours Example 13 16.46％ 26.72％ 40.13％ 59.81％ 74.56％ 90.13％ 93.11％ 97.29％ Embodiment 19 17.23％ 24.62％ 37.15％ 58.81％ 78.54％ 92.73％ 96.57％ 98.22％ Embodiment 20 19.57％ 29.87％ 42.85％ 57.20％ 72.58％ 88.67％ 87.03％ 95.71％ Embodiment 21 20.36％ 30.29％ 45.39％ 60.68％ 75.62％ 89.52％ 95.87％ 99.25％

[0203] Table 34 Floating lag time and total floating time of gastric floating double-layer sustained-release tablets obtained in Examples 13, 19 to 21

[0204]

[0205]

[0206] It can be seen from the above table that the loxoprofen sodium gastric floating double-layer sustained-release tablets with hydroxypropyl methylcellulose as the sustained-release material have a good sustained-release effect and meet the requirements.

[0207] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A highly water-soluble drug gastric floating double-layer sustained-release tablet, characterized in that: include: Drug-containing layer and floating layer; The drug-containing layer is composed of highly water-soluble drugs, hydrophilic polymer gel material I, disintegrants, foaming agents, adhesives, anti-adhesive agents, and fillers; The floating layer is composed of hydrophilic polymer gel material II, disintegrant, foaming agent, adhesive, anti-adhesive agent, bleaching aid and filler.

2. The highly water-soluble drug gastric floating double-layer sustained-release tablet according to claim 1, characterized in that: The highly water-soluble drug accounts for 15% to 25% of the total weight of the sustained-release tablet.

3. The highly water-soluble drug gastric floating double-layer sustained-release tablet according to claim 1, characterized in that: The highly water-soluble drug includes one of loxoprofen sodium, diclofenac sodium, sodium salicylate, sodium valproate, and ketoprofen.

4. The highly water-soluble drug gastric floating double-layer sustained-release tablet according to claim 1, characterized in that: The hydrophilic polymer gel material I is at least one of HPMC E50, HPMC K4M, HPMC K10M, HPMC K15M, HPC HF, HPC MF, HEC 250L, HEC 250M, PEO WSR Coagulant, Carbopol 974P NF, and SAL PH172, and the weight proportion of the hydrophilic polymer gel material I in the drug-containing layer is 5% to 15%; The hydrophilic polymer gel material II is at least one of HPMC K100M, HPC HXF, HEC 250H, HEC 250HHX, CMC, CMC-Na, PEO WSR-303, Carbopol 974P NF, SAL PH175 and SAL PH176, and the weight proportion of the hydrophilic polymer gel material II in the floating layer is 20% to 35%; The total weight of the hydrophilic polymer hydrogel material I and the hydrophilic polymer hydrogel material II accounts for 15% to 35% of the total weight of the sustained-release tablet.

5. The highly water-soluble drug gastric floating double-layer sustained-release tablet according to claim 1, characterized in that: The disintegrant is cross-linked polyvinyl pyrrolidone, and the weight proportion of the disintegrant in the drug-containing layer is 5% to 15%, and the weight proportion of the disintegrant in the floating layer is 15% to 25%; The foaming agent is at least one of sodium carbonate, sodium bicarbonate, magnesium carbonate and calcium carbonate, the weight proportion of the foaming agent in the drug-containing layer is 10% to 20%, and the weight proportion of the foaming agent in the floating layer is 10% to 25%; The bleaching agent is at least one of hexadecanol, stearyl alcohol, stearic acid, polyethylene glycol and acrylic resin, and the weight proportion of the bleaching agent in the floating layer is 20% to 30%; The filler is at least one of glucose, sucrose, microcrystalline cellulose, starch, dextrin, calcium phosphate, maltodextrin and mannitol, and the weight proportion of the filler in the drug-containing layer is 10% to 20%, and the weight proportion of the filler in the floating layer is 15% to 25%; The binder is at least one of hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, corn starch, polyvinyl pyrrolidone and polyvinyl alcohol, and the weight proportion of the binder in the drug-containing layer is 1% to 3%, and the weight proportion of the binder in the floating layer is 1% to 3%; The anti-adhesive agent is at least one of talc, magnesium stearate, micro-powder silica gel and stearic acid. The weight proportion of the anti-adhesive agent in the drug-containing layer is 1% to 2%, and the weight proportion of the anti-adhesive agent in the floating layer is 1% to 2%.

6. The highly water-soluble drug gastric floating double-layer sustained-release tablet according to claim 1, characterized in that: In the floating layer, the weight ratio of the hydrophilic polymer gel material II to the bleaching agent is 1:0.7 to 1:1; the weight ratio of the hydrophilic polymer gel material II to the foaming agent is 1:1 to 2:1; In the drug-containing layer, the weight ratio of the hydrophilic polymer gel material I to the foaming agent is 1:1 to 1:

2.

7. The highly water-soluble drug gastric floating double-layer sustained-release tablet according to claim 1, characterized in that: The weight of the drug-containing layer is 350-450 mg, and the weight of the floating layer is 300-500 mg.

8. A method for preparing the sustained-release tablet according to any one of claims 1 to 7, characterized in that: The preparation method of the sustained-release tablet is one of the following three methods: Method 1: The method comprises the following steps: (1) Preparation of drug-layered granules: Pass the highly water-soluble drug, hydrophilic polymer gel material I, disintegrant, foaming agent and filler through a 40-60 mesh sieve, mix evenly, add the binder to the material, and perform dry granulation or wet granulation through a 24-40 mesh sieve to obtain drug-layered granules; (2) Preparation of floating layer particles: The hydrophilic polymer gel material II, disintegrant, foaming agent, filler and bleaching agent are passed through a 40-60 mesh sieve and mixed evenly, a binder is added to the material, and dry granulation or wet granulation is performed through a 24-40 mesh sieve to obtain floating layer particles; (3) Preparation of double-layer sustained-release tablets: The drug-containing layer granules were sieved with a 40-mesh sieve, and the anti-adhesive agent was added and mixed evenly. The floating layer granules were sieved with a 40-mesh sieve, and the anti-adhesive agent was added and mixed evenly. Subsequently, the drug-containing layer granules were filled into a die for pre-compression, and then the floating layer granules were filled into the die for tableting to obtain a double-layer sustained-release tablet. Method 2: The method comprises the following steps: (1) Preparation of drug-layered granules: Pass a highly water-soluble drug, a hydrophilic polymer gel material I, 50% of the drug-containing layer prescription amount of a disintegrant, a foaming agent, and a filler through a 40-60 mesh sieve, mix them evenly, add a binder to the materials, and perform dry granulation or wet granulation through a 24-40 mesh sieve to obtain drug-containing layer granules; (2) Preparation of floating layer particles: The hydrophilic polymer gel material II, 50% of the floating layer prescription amount of disintegrant, foaming agent, filler, and bleaching agent are passed through a 40-60 mesh sieve and mixed evenly, a binder is added to the material, and dry granulation or wet granulation is performed through a 24-40 mesh sieve to obtain floating layer particles; (3) Preparation of double-layer sustained-release tablets: The drug-containing layer particles are sieved with a 40-mesh sieve, and an anti-adhesive agent and 50% of the prescribed amount of disintegrant for the drug-containing layer are added and mixed evenly; the floating layer particles are sieved with a 40-mesh sieve, and an anti-adhesive agent and 50% of the prescribed amount of disintegrant for the floating layer are added and mixed evenly; then, the drug-containing layer particles are filled into a die for pre-compression, and then the floating layer particles are filled into the die for tableting to obtain a double-layer sustained-release tablet. Method 3: The method comprises the following steps: (1) Preparation of drug-layered granules: Pass the highly water-soluble drug, hydrophilic polymer gel material I, foaming agent and filler through a 40-60 mesh sieve, mix them evenly, add the binder to the materials, and perform dry granulation or wet granulation through a 24-40 mesh sieve to obtain drug-containing layer granules; (2) Preparation of floating layer particles: The hydrophilic polymer gel material II, the foaming agent, the filler and the bleaching agent are passed through a 40-60 mesh sieve and mixed evenly, the binder is added to the material, and dry granulation or wet granulation is performed through a 24-40 mesh sieve to obtain floating layer particles; (3) Preparation of double-layer sustained-release tablets: The drug-containing layer granules are sieved with a 40-mesh sieve, and the anti-adhesive agent and disintegrant are added and mixed evenly. The floating layer granules are sieved with a 40-mesh sieve, and the anti-adhesive agent and disintegrant are added and mixed evenly. Subsequently, the drug-containing layer granules are filled into a die for pre-compression, and then the floating layer granules are filled into the die for tableting to obtain a double-layer sustained-release tablet.

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