Oral dye solid composition

Abstract

The invention belongs to the field of biological medicine, and particularly relates to an oral dye solid composition and application thereof. The invention provides an oral dye solid composition. The composition comprises a lipophilic matrix, a sustained-release material and other pharmaceutically acceptable auxiliary materials, the lipophilic matrix is glyceryl behenate or carnauba wax. The solid composition provided by the invention has good stability, especially good stability at high temperature. And after long-time storage under a high-temperature condition, the content of the specific impurity azurol B is slowly increased, and the dissolution speed is slightly influenced.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and in particular relates to an oral dye solid composition and application thereof. Background Art

[0002] Endoscopy plays a key role in the diagnosis of gastrointestinal diseases and is an important tool for detecting inflammatory, ulcerative, and neoplastic lesions of the gastrointestinal tract. This technology allows doctors to directly observe the condition of the gastrointestinal mucosa, including its maintenance and development, as well as the presence of abnormalities such as surface irritation, deformation, and ulcers. In recent years, with the continuous advancement of technology, the performance of endoscopic probes has significantly improved. Improved materials have enhanced their illumination and resolution, providing a clearer field of view for disease diagnosis.

[0003] Chromoendoscopy is an important technique developed based on endoscopic examination. By using vital dyes to produce localized contrasting colors, it greatly improves the identification of lesions, particularly in identifying degenerative features in suspicious areas. Commonly used vital dyes such as methylene blue, Congo red, carmine indigo, and toluidine blue play an important role in chromoendoscopy. These dyes are absorbed by the gastrointestinal mucosa, and in conditions such as inflammation and tumors, their absorption by mucosal cells varies. This property makes them useful for determining the severity of inflammation and for differentiating true from false polyps.

[0004] The traditional method of dye application is to insert a catheter or capillary into the endoscope probe cavity after completing the initial endoscopic analysis and cleaning the mucosal tract, and spray a dye-containing solution onto the mucosal surface. However, this method of local spraying of the solution has obvious defects. It cannot achieve precise control of the dye release rate and location, making some tiny or latent lesions difficult to be effectively detected, and there are great limitations in diagnosing the early degeneration process of the digestive system.

[0005] In response to the above technical difficulties, CN102811747A discloses a methylene blue oral preparation based on sustained-release technology, which realizes the slow release and targeted distribution of drugs in the gastrointestinal tract through a multi-matrix collaborative controlled-release design, effectively improving the uniformity of staining and the sensitivity of lesion detection. This dosage form can also simplify the clinical drug administration process, reduce the dependence on complex drug administration equipment, and significantly promote the popularization of dye endoscopy technology. However, studies have found that methylene blue preparations are prone to degradation reactions such as methylene blue demethylation during long-term storage, resulting in a decrease in drug content and a shift in the dissolution curve. Therefore, the development of a new oral dye solid preparation with both excellent stability and precise controlled-release performance remains an important task that needs to be solved urgently. Summary of the Invention

[0006] The purpose of the present invention is to develop an oral solid dye composition that has good stability and can achieve sustained release, so as to ensure that the solid dye composition is evenly distributed in specific areas of the gastrointestinal tract.

[0007] In one aspect, the present invention provides an oral dye solid composition, comprising a lipophilic matrix, a sustained-release material, and other pharmaceutically acceptable excipients; the lipophilic matrix is ​​glyceryl behenate or carnauba wax.

[0008] In a preferred embodiment of the present invention, the lipophilic matrix is ​​glyceryl behenate.

[0009] In a further preferred embodiment of the present invention, the lipophilic matrix is ​​1.5-5.0% by mass; preferably 2.0-4.0%; more preferably 2.5-3.8%.

[0010] In one embodiment of the present invention, the lipophilic matrix is ​​3.1% by mass.

[0011] In a preferred embodiment of the present invention, the dye comprises one or more of methylene blue, Congo red, carmine indigo, and toluidine blue.

[0012] In a further preferred embodiment of the present invention, the dye is methylene blue.

[0013] In a further preferred embodiment of the present invention, the dye is present in an amount of 1.0 to 20.0% by mass; preferably 4.0 to 15.0%; more preferably 5.0 to 10.0% by mass.

[0014] In one embodiment of the present invention, the dye is 7.8% by mass.

[0015] In a preferred embodiment of the present invention, the sustained-release material includes one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, carbomer, sodium alginate, xanthan gum, polyethylene oxide, hydroxyethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose phthalate, and cellulose acetate phthalate.

[0016] In a further preferred embodiment of the present invention, the sustained-release material is hypromellose.

[0017] In a further preferred embodiment of the present invention, the sustained-release material accounts for 15.0-40.0% by mass; preferably 20.0-35.0%; more preferably 25.0-32.0%.

[0018] In one embodiment of the present invention, the sustained-release material accounts for 28.1% by mass.

[0019] In a preferred embodiment of the present invention, the other pharmaceutically acceptable excipients include one or more of an amphiphilic matrix, a filler, a glidant, and a lubricant.

[0020] In a preferred embodiment of the present invention, the amphiphilic matrix comprises one or more of phosphatidylcholine, egg phosphatidylcholine, and sphingosine phosphatidylcholine.

[0021] In a further preferred embodiment of the present invention, the amphiphilic matrix is ​​lecithin.

[0022] In a further preferred embodiment of the present invention, the amphiphilic matrix is ​​present in an amount of 0 to 1.5% by mass; preferably 0.5 to 1.5%; more preferably 0.7 to 1.2% by mass.

[0023] In one embodiment of the present invention, the amphiphilic matrix accounts for 0.9% by mass.

[0024] In a preferred embodiment of the present invention, the filler comprises one or more of microcrystalline cellulose, mannitol, lactose, starch, pregelatinized starch, cyclodextrin, maltodextrin and calcium hydrogen phosphate.

[0025] In a further preferred embodiment of the present invention, the filler is microcrystalline cellulose and mannitol.

[0026] In a further preferred embodiment of the present invention, the mannitol is in an amount of 30.0-45.0% by mass; preferably 35.0-45.0%; more preferably 35.0-40.0%.

[0027] In one embodiment of the present invention, the mannitol is 37.8% by mass.

[0028] In a further preferred embodiment of the present invention, the microcrystalline cellulose is 5.0-35.0% by mass; preferably 10.0-30.0%; more preferably 15.0-25.0%.

[0029] In one embodiment of the present invention, the microcrystalline cellulose is 18.8% by mass.

[0030] In a preferred embodiment of the present invention, the glidant includes one or more of colloidal silicon dioxide and talc.

[0031] In a further preferred embodiment of the present invention, the glidant is colloidal silicon dioxide and talc.

[0032] In a further preferred embodiment of the present invention, the colloidal silicon dioxide is present in an amount of 0 to 2.0% by mass, preferably 1.0 to 2.0% by mass, and more preferably 1.3 to 1.7% by mass.

[0033] In one embodiment of the present invention, the colloidal silicon dioxide is 1.6% by mass.

[0034] In a further preferred embodiment of the present invention, the talc powder is 0-2.0% by mass; preferably 0.5-1.5%; more preferably 0.8-1.1%.

[0035] In one embodiment of the present invention, the talc powder is 0.9% by mass.

[0036] In a preferred embodiment of the present invention, the lubricant includes one or more of magnesium stearate, hard sodium fumarate, and mono- and distearic acid glyceryl.

[0037] In a further preferred embodiment of the present invention, the lubricant is magnesium stearate or hard sodium fumarate.

[0038] In a further preferred embodiment of the present invention, the lubricant is hard sodium fumarate.

[0039] In a further preferred embodiment of the present invention, the lubricant is present in an amount of 0 to 2.0% by mass; preferably 0.5 to 1.5%; more preferably 0.8 to 1.1% by mass.

[0040] In one embodiment of the present invention, the lubricant is 0.9% by mass.

[0041] In one embodiment of the present invention, the composition comprises the following components: a lipophilic matrix, a sustained-release material, an amphiphilic matrix, a filler, a glidant, and a lubricant.

[0042] In one embodiment of the present invention, the composition comprises the following components: a lipophilic matrix, a sustained-release material, an amphiphilic matrix, microcrystalline cellulose, mannitol, colloidal silicon dioxide, talc and a lubricant.

[0043] In one embodiment of the present invention, the dye, lipophilic matrix, amphiphilic matrix and mannitol are added by internal addition.

[0044] In one embodiment of the present invention, the sustained-release material, microcrystalline cellulose, colloidal silicon dioxide, talc and lubricant are added externally.

[0045] In one embodiment of the present invention, the composition comprises the following components:

[0046]

[0047] In one embodiment of the present invention, the composition comprises the following components:

[0048]

[0049] In one embodiment of the present invention, the composition comprises the following components:

[0050]

[0051] In a preferred embodiment of the present invention, the composition further comprises a coating layer, and the coating layer is an enteric coating layer.

[0052] In a preferred embodiment of the present invention, the coating layer comprises a common enteric coating material, and optionally comprises one or more of a plasticizer, an anti-sticking agent, and a light-shielding agent.

[0053] In a preferred embodiment of the present invention, the enteric coating material includes one or more of Eudragit L30D-55, Eudragit L100-55, Eudragit L100, Eudragit S100, Eudragit FS30D, hydropropyl methylcellulose phthalate HP-50, hydropropyl methylcellulose phthalate HP-55, hydropropyl methylcellulose acetate succinate HPMCAS-L, hydropropyl methylcellulose acetate succinate HPMCAS-M, and cellulose acetate phthalate CAP.

[0054] In one embodiment of the present invention, the enteric coating material is Eudragit L100 and Eudragit S100.

[0055] In one embodiment of the present invention, the enteric coating materials are Eudragit L100 and Eudragit S100, and the mass ratio of the two is 1:1.

[0056] In a preferred embodiment of the present invention, the plasticizer includes one or more of triethyl citrate, triacetin, diisopropyl succinate, and glycerol.

[0057] In one embodiment of the present invention, the plasticizer is triethyl citrate.

[0058] In a preferred embodiment of the present invention, the anti-adhesive agent includes one or more of talc, colloidal silicon dioxide, magnesium stearate, and polyethylene glycol derivatives.

[0059] In one embodiment of the present invention, the anti-sticking agent is talc.

[0060] In a preferred embodiment of the present invention, the sunscreen comprises one or more of titanium dioxide, iron oxide pigment, carbon black, and polyvinyl alcohol copolymer.

[0061] In one embodiment of the present invention, the sunscreen is titanium dioxide.

[0062] In one embodiment of the present invention, the coating layer consists of Eudragit L100, Eudragit S100, triethyl citrate, talc and titanium dioxide.

[0063] In one embodiment of the present invention, based on 100% of the coating layer composition, Eudragit L100 accounts for 25.0-28.5%, Eudragit S100 accounts for 25.0-27.0%, triethyl citrate accounts for 10.5-15.5%, talc accounts for 24.0-26.5% and titanium dioxide accounts for 9.0-10.5%.

[0064] In one embodiment of the present invention, based on 100% of the coating layer composition, Eudragit L100 accounts for 26.7%, Eudragit S100 accounts for 26.7%, triethyl citrate accounts for 10.7%, talc accounts for 26.0% and titanium dioxide accounts for 10.0%.

[0065] In one embodiment of the present invention, based on 100% of the coating layer composition, Eudragit L100 accounts for 25.3%, Eudragit S100 accounts for 25.3%, triethyl citrate accounts for 15.2%, talc accounts for 24.7% and titanium dioxide accounts for 9.5%.

[0066] In one embodiment of the present invention, the coating weight gain of the coating layer is 8-12%.

[0067] On the other hand, the present invention also provides a use of an oral dye solid composition in preparing a medicament for endoscopic diagnosis and evaluation.

[0068] In a preferred embodiment of the present invention, the endoscopic diagnostic evaluation is used to detect inflammatory, ulcerative, deformed, polypous or neoplastic lesions of the gastrointestinal tract.

[0069] On the other hand, the present invention also provides a method for preparing an oral dye solid composition, which can be prepared by any conventional preparation method such as wet granulation, fluidized bed granulation, dry granulation, and direct compression of powder mixing.

[0070] In one embodiment of the present invention, the oral dye solid composition can be prepared by dry granulation.

[0071] In one embodiment of the present invention, the method for preparing the oral dye solid composition comprises the following steps:

[0072] 1) Premixing; 2) Dry granulation; 3) Final mixing; 4) Tableting; 5) Coating.

[0073] In one embodiment of the present invention, the method for preparing the oral dye solid composition comprises the following steps:

[0074] 1) Premixing: Mix the dye, a portion of the filler and the lipophilic matrix;

[0075] 2) Dry granulation: dry granulate the mixed materials;

[0076] 3) Total mixing: Blend the granulated material with the sustained-release material, the remaining filler, the glidant and the lubricant together;

[0077] 4) Tableting: Compressing the total mixed material into tablets to obtain plain tablets;

[0078] 5) Coating: Coat the plain tablets and control the coating weight gain within the range of 8-12%.

[0079] The solid composition of the present invention has good stability, especially good stability at high temperature. When stored at high temperature for a long time, the content of the specific impurity Azure B increases slowly and the dissolution rate is less affected.

[0080] The degradation of the preparation produces an impurity, Azure B, which has a structure similar to methylene blue and may interfere with and reduce the therapeutic effect of the drug and increase the risk of adverse reactions. Existing technical studies have found that Azure B is highly toxic and may cause harm to the human body. According to the prediction of protox-II software, Azure B is toxic to the nuclear receptor signaling pathway, affects the mitochondrial membrane potential, can target the aromatic hydrocarbon receptor (AhR), interfere with the nuclear receptor signaling pathway, and may also have mutagenic activity. Lazar toxicity prediction shows that Azure B may be carcinogenic to rats, rodents and mice. Therefore, increasing the stability of the preparation can effectively improve the safety of medication. The structure of Azure B is as follows:

[0081]

[0082] Related definitions

[0083] Unless otherwise specified, the following terms used in the specification and claims have the following meanings:

[0084] w / w: mass percentage.

[0085] In the present invention, the mass percentage of each component is calculated based on the total weight of the uncoated tablet.

[0086] In the present invention, coating weight gain is calculated as the coating weight relative to the total weight of the uncoated tablet.

[0087] In the present invention, the percentage amount has an error, and the error range is ±1.0%; preferably ±0.5%; more preferably ±0.2%. DETAILED DESCRIPTION

[0088] Below in conjunction with specific embodiment, the present invention is further elaborated in detail, but those skilled in the art will understand that the embodiment described below is a part of embodiment of the present invention, rather than all embodiments, is only used to illustrate the present invention, and should not be regarded as limiting the scope of the present invention. Based on the embodiments in the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative work premise fall within the scope of protection of the present invention. The experimental method used in the following examples, unless otherwise specified, the experimental method of the specific conditions not specified in the examples, usually according to conventional conditions, the materials, reagents etc. used in the following examples, unless otherwise specified, can be obtained from commercial sources.

[0089] Example 1

[0090] Table 1

[0091]

[0092] Preparation method:

[0093] 1) Premix:

[0094] Add the charged amount of methylene blue, mannitol, and glyceryl behenate to a wet granulator, set the stirring speed to 200 rpm and the shear speed to 1000 rpm, and mix for 3 minutes to perform premixing I. A 1:5 mixture of soy lecithin and anhydrous ethanol was added over 6-10 minutes at a constant stirring speed of 200 rpm and a shear speed of 1000 rpm. After addition, mix for 2 minutes to perform premixing II. Dry the powder after premixing II at a temperature of 30°C to 35°C for 40 minutes.

[0095] 2) Dry granulation:

[0096] The uniformly mixed material was dry granulated, and the granulation parameters were adjusted: the roller pressure was (3.0-5.0) kN, the roller speed was (6.0-10.0) rpm, so that the flake density was (1.1-1.3) g / mL, and the sieve aperture was 30 mesh (0.6 mm).

[0097] 3) Total mixing:

[0098] The granulated material, hypromellose (K100LV), microcrystalline cellulose (PH102), talc, colloidal silicon dioxide and sodium stearyl fumarate were added to the hopper of the hopper mixer, the mixing speed was set to 10 r / min, and the mixture was mixed for 5 minutes for total mixing.

[0099] 4) Tablet pressing:

[0100] Add the mixed intermediate to the tablet press and calculate the theoretical tablet weight based on the intermediate content. Control the tablet weight variation to ±5% and the hardness to 70N-150N.

[0101] 5) Coating:

[0102] A certain amount of 95% ethanol solution was measured to prepare a coating solution with a solid content of 10% (w / w).

[0103] Solution A: Measure half of the 95% ethanol solution and place it under a high-speed blender. After turning on the blender, slowly add the prescribed amount of Eudragit L100 and S100 and continue stirring for about 40 minutes.

[0104] Solution B: Place the remaining half of the 95% ethanol solution under a high shear machine, add the prescribed amount of triethyl citrate, titanium dioxide and talc, and start high shearing for about 10 minutes.

[0105] After solution A is stirred evenly, slowly add the sheared solution B into solution A and continue stirring for 10 minutes before use. Add the plain tablets into the coating machine, preheat, and start coating when the outlet air temperature reaches 30°C. Set the main machine speed to (8-18) rpm, the inlet air temperature to (30-50)°C, and the inlet air volume to (25-35) m 3 / h, air outlet temperature (25-35)°C; peristaltic pump speed (7-10)%, atomization pressure (0.8-1.2) bar. Control the coating weight gain within the range of (8-12)%. After coating, continue drying at 40°C for 40 minutes before discharging.

[0106] Examples 2 to 14 were prepared by replacing the types or contents of the excipients in the table with those in Example 1. The reference preparation was a commercially available methylene blue sustained-release tablet preparation (batch number DP123).

[0107] Example 2

[0108] Table 2

[0109]

[0110]

[0111] Example 3

[0112] Table 3

[0113]

[0114] Example 4

[0115] Table 4

[0116]

[0117] Example 5

[0118] Table 5

[0119]

[0120] Example 6

[0121] Table 6

[0122]

[0123] Example 7

[0124] Table 7

[0125]

[0126] Example 8

[0127] Table 8

[0128]

[0129] Example 9

[0130] Table 9

[0131]

[0132]

[0133] Example 10

[0134] Table 10

[0135]

[0136] Example 11

[0137] Table 11

[0138]

[0139] Example 12

[0140] Table 12

[0141]

[0142]

[0143] Example 13

[0144] Table 13

[0145]

[0146] Example 14

[0147] Table 14

[0148]

[0149] Experimental Example 1 Dissolution Test

[0150] The dissolution and release rate was determined according to the dissolution and release rate determination method (Method 2, Method 0931, General Rules of Part IV of the Chinese Pharmacopoeia 2020 Edition).

[0151] 1) Dissolution conditions

[0152] Take a sinker basket and use 900 mL of phosphate buffer (pH 7.2) as the dissolution medium at a speed of 100 revolutions per minute. Operate according to the method, take 10 mL of the dissolution solution at each time point, and immediately replenish the dissolution medium of the same temperature and volume.

[0153] 2) Detection method

[0154] Test solution (1): Take the 0.5 hour and 1 hour eluates, filter them through a hydrophilic syringe filter made of PTFE (diameter 25 mm, pore size 0.45 μm), and take the filtrate.

[0155] Test solution (2): Take the 2-hour and 3-hour eluates, filter them through a hydrophilic syringe filter made of PTFE (diameter 25 mm, pore size 0.45 μm), accurately measure 2 mL of the filtrate, place them in 10 mL volumetric flasks, dilute to the mark with phosphate buffer (pH 7.2), and shake well.

[0156] Test solution (3): Take the eluate after 4 hours, 6 hours, 8 hours and 10 hours respectively, filter it with a hydrophilic syringe filter made of PTFE (diameter 25 mm, pore size 0.45 μm), accurately measure 2 mL of the filtrate, place it in a 20 mL volumetric flask, dilute it to the scale with phosphate buffer (pH 7.2), and shake well.

[0157] Reference solution: Take an appropriate amount of methylene blue reference solution, weigh accurately, dissolve in dilute ethanol and quantitatively dilute to make a solution containing approximately methylene blue (C 16 H 18 Accurately measure an appropriate amount of the reference substance stock solution and quantitatively dilute it with phosphate buffer (pH 7.2) to produce a solution containing approximately 22.2 g per 1 mL.

[0158] Determination method: Take the test solution and the reference solution, and measure the absorbance at a wavelength of 663 nm according to the UV-visible spectrophotometry method (General Chapter 0401 of Part IV of the Chinese Pharmacopoeia 2020 Edition), and calculate the dissolution amount of each tablet.

[0159] Table 15

[0160]

[0161] Experimental Example 2 Influencing Factors Test

[0162] 1) Inspection conditions

[0163] Take Example 1, Example 2 and the reference preparation and place them at 40±2℃, 60±2℃, high humidity 92.5±5%RH, light (total illumination not less than 1.2×10 6 Lux·hr, near-ultraviolet energy not less than 200w·hr / m 2 ) for 30 days, and samples were taken on day 0 and day 30 to investigate the appearance, related substances, content and dissolution of the samples.

[0164] 2) Related substance testing

[0165] Determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512).

[0166] Solvent: Mobile phase A-acetonitrile (70:30).

[0167] Test solution: Take a sample, grind it into powder, accurately weigh an appropriate amount of fine powder, accurately weigh it, add about 10% of the volume of the volumetric flask of methanol, shake it to disperse it, then add solvent to about 80% of the volume of the volumetric flask, ultrasonicate it for about 20 minutes to dissolve the methylene blue, let it cool, and quantitatively dilute it with solvent to make about 10% of the volume of the volumetric flask of methanol per 1 mL. 16 H 18 CIN3S) 1 mg solution was centrifuged, the supernatant was filtered, and the filtrate was taken.

[0168] Reference solution (1): Take an appropriate amount of methylene blue reference solution, weigh accurately, add solvent and ultrasonicate to dissolve it, and quantitatively dilute it to make a solution containing about methylene blue (C 16 H 18 CIN3S) 50 μg solution.

[0169] Reference solution (2): Accurately measure an appropriate amount of reference solution (1) and quantitatively dilute it with solvent to make a solution containing approximately 1 μg per 1 mL.

[0170] Chromatographic conditions: Phenyl-bonded silica gel as the filler (Waters XBridge BEH Phenyl, 4.6 mm × 100 mm, 3.5 μm or equivalent performance column); 0.1% trifluoroacetic acid solution as mobile phase A, acetonitrile as mobile phase B, gradient elution according to the table below; flow rate, 1.0 mL / min; column temperature, 30°C; detection wavelength, 246 nm; injection volume, 5 μL.

[0171] Table 16

[0172] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 80 20 5 80 20 25 30 70 32 30 70 32.1 80 20 37 80 20

[0173] Determination method: Accurately measure the test solution and reference solution, inject them into liquid chromatograph respectively, and record the chromatogram.

[0174] 3) Content detection

[0175] Determined by high performance liquid chromatography (General Chapter 0512 of the Chinese Pharmacopoeia 2020 edition).

[0176] Solvent: 0.1% trifluoroacetic acid solution-acetonitrile (70:30).

[0177] Test solution: Take the sample, grind it into powder, accurately weigh an appropriate amount of fine powder, add about 10% of the volume of the volumetric flask with methanol, shake to disperse, add solvent to about 80% of the volume of the volumetric flask, sonicate for about 20 minutes to dissolve the methylene blue, let it cool, and quantitatively dilute with solvent to make a methylene blue (C 16 H 18 CIN3S) 1 mg solution was centrifuged, the supernatant was filtered, and the filtrate was taken.

[0178] Reference solution: Take an appropriate amount of methylene blue reference solution, weigh accurately, add solvent and ultrasonicate to dissolve it and quantitatively dilute it to make a solution containing about methylene blue (C 16 H 18 CIN3S) 1mg solution.

[0179] System suitability solution: Take an appropriate amount of methylene blue system suitability reference substance, dissolve it in solvent and dilute it to make a solution containing approximately 1 mg per 1 mL.

[0180] Chromatographic conditions: Phenyl-bonded silica gel as the filler (Waters XBridge BEH Phenyl, 4.6 mm × 100 mm, 3.5 μm or equivalent performance column); 0.1% trifluoroacetic acid solution as mobile phase A, acetonitrile as mobile phase B, gradient elution according to the table below; flow rate, 1.0 mL / min; column temperature, 30°C; detection wavelength, 246 nm; injection volume, 5 μL.

[0181] Table 17

[0182] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 80 20 5 80 20 15 55 45 15.1 80 20 20 80 20

[0183] Determination method: Accurately measure the test solution and reference solution, inject them into the liquid chromatograph, record the chromatogram, and calculate the peak area according to the external standard method.

[0184] 4) Dissolution conditions and detection methods refer to Experiment 1.

[0185] Table 18

[0186]

[0187] a: Total impurities refer to impurities other than Azure B

[0188] Table 19

[0189]

[0190]

Claims

1. An oral dye solid composition comprising a lipophilic matrix, a sustained-release material and other pharmaceutically acceptable excipients; characterized in that: The lipophilic base is glyceryl behenate or carnauba wax.

2. The solid composition according to claim 1, wherein The lipophilic matrix is ​​glyceryl behenate; Preferably, in terms of mass percentage, the lipophilic matrix is ​​1.5-5.0%; preferably 2.0-4.0%; more preferably 2.5-3.8%.

3. The solid composition according to claim 1, wherein The dye includes one or more of methylene blue, Congo red, carmine indigo, and toluidine blue; preferably, the dye is methylene blue; Preferably, in terms of mass percentage, the dye is 1.0 to 20.0%; preferably 4.0 to 15.0%; more preferably 5.0 to 10.0%.

4. The solid composition according to claim 1, wherein The sustained-release material includes one or more of hypromellose, hydroxypropyl cellulose, carbomer, sodium alginate, xanthan gum, polyethylene oxide, hydroxyethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, and cellulose acetate phthalate; preferably, the sustained-release material is hypromellose; Preferably, in terms of mass percentage, the sustained-release material is 15.0-40.0%; preferably 20.0-35.0%; more preferably 25.0-32.0%.

5. The solid composition according to claim 1, wherein The other pharmaceutically acceptable excipients include one or more of an amphiphilic matrix, a filler, a glidant, and a lubricant.

6. The solid composition according to claim 1, characterized in that The amphiphilic matrix includes one or more of lecithin, egg phosphatidylcholine, and sphingosine phosphatidylcholine; preferably, the amphiphilic matrix is ​​lecithin; preferably, the amphiphilic matrix is ​​0-1.5% by mass; preferably 0.5-1.5%; more preferably 0.7-1.2%; And / or, the filler comprises one or more of microcrystalline cellulose, mannitol, lactose, starch, pregelatinized starch, cyclodextrin, maltodextrin and calcium hydrogen phosphate; preferably, the filler is microcrystalline cellulose and mannitol; preferably, the mannitol is 30.0-45.0% by mass; preferably 35.0-45.0%; more preferably 35.0-40.0%; preferably, the microcrystalline cellulose is 5.0-35.0% by mass; preferably 10.0-30.0%; more preferably 15.0-25.0%; And / or, the glidant includes one or more of colloidal silicon dioxide and talc; preferably, the glidant is colloidal silicon dioxide and talc; preferably, the colloidal silicon dioxide is 0-2.0% by mass; preferably 1.0-2.0%; more preferably 1.3-1.7%; preferably, the talc is 0-2.0% by mass; preferably 0.5-1.5%; more preferably 0.8-1.1%; And / or, the lubricant includes one or more of magnesium stearate, hard sodium fumarate, mono- and distearic glycerol; preferably, the lubricant is magnesium stearate or hard sodium fumarate; more preferably, the lubricant is hard sodium fumarate; further preferably, the lubricant is 0-2.0% by mass; preferably 0.5-1.5%; more preferably 0.8-1.1%.

7. The solid composition according to claim 1, wherein The composition comprises the following components: a lipophilic matrix, a sustained-release material, an amphiphilic matrix, a filler, a glidant and a lubricant; preferably, the composition comprises the following components: a lipophilic matrix, a sustained-release material, an amphiphilic matrix, microcrystalline cellulose, mannitol, colloidal silicon dioxide, talc and a lubricant; preferably, the dye, lipophilic matrix, amphiphilic matrix and mannitol are added internally; preferably, the sustained-release material, microcrystalline cellulose, colloidal silicon dioxide, talc and lubricant are added externally.

8. The solid composition according to claim 1, characterized in that The composition comprises the following components: Preferably, the composition comprises the following components: Preferably, the composition comprises the following components:

9. The solid composition according to claim 1, characterized in that The composition further comprises a coating layer, which is an enteric coating layer.

10. The method for preparing the oral dye solid composition according to any one of claims 1 to 9, comprising the following steps: 1) Premixing: Mix the dye, a portion of the filler and the lipophilic matrix; 2) Dry granulation: dry granulate the mixed materials; 3) Total mixing: Blend the granulated material with the sustained-release material, the remaining filler, the glidant and the lubricant together; 4) Tableting: Compressing the total mixed material into tablets to obtain plain tablets; 5) Coating: Coat the plain tablets and control the coating weight gain within the range of 8-12%.

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