Dissolution method for pharmaceutical compositions containing fluralaner and uses thereof

Abstract

The present application relates to the technical field of pet medicine, in particular to a dissolution method of a pharmaceutical composition containing flucloronide and application thereof. The dissolution method is as follows: when the temperature of the dissolution medium is 37 DEG C + / - 0.5 DEG C, the pharmaceutical composition containing flucloronide is added, stirring is started at a speed of 80 revolutions / minute-150 revolutions / minute and timing, sampling is carried out in 1 hour-24 hours, and the dissolution medium includes 0.1-0.5 mol / L strong base and 2% w / v-4% w / v SDS. The dissolution method can be used to evaluate the in-vitro dissolution behavior of the pharmaceutical composition containing flucloronide, investigate the influence of different prescription compositions, different preparation processes and differences of raw and auxiliary materials on in-vitro dissolution, evaluate the consistency of batch quality, guide the development of generic drugs and accelerate the research and development progress of generic drugs.

Description

Technical Field

[0001] This invention relates to the field of pet medicine technology, and specifically to a dissolution method for a pharmaceutical composition containing freranil and its application. Background Technology

[0002] Fluralaner, chemically named 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4H-1,2-oxazol-3-yl]-2-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)]ethylbenzamide, belongs to the isoxazoline class of compounds. It is a systemic antiparasitic drug that kills *Ctenopharynx canis*, exhibiting rapid onset and long-lasting effects on adult fleas. It also inhibits flea egg-laying, thus disrupting the flea's life cycle. Fluralaner is also effective against *Ixodes ricinus* (larvae, nymphs, and adults), *Ixodes hexagonus*, *Ixodes scapulae*, *Ixodes pectinatus*, *Derma reticulata*, *Derma variegata*, and *Hemiberlesia spp.*

[0003] Fluranar is administered in the form of a pharmaceutical composition, primarily in chewable tablet form for dogs. Currently, the commercially available product is Fluranar chewable tablets (brand name Bevedo) manufactured by Intervet International GmbH in Austria. Fluranar itself is a poorly soluble drug, almost insoluble in water. Pharmaceutical compositions containing Fluranar, such as Fluranar chewable tablets, contain complex, poorly soluble matrices such as pork liver powder, chicken liver powder, corn starch, soy protein powder, and soybean oil, further affecting drug disintegration and dissolution, resulting in Fluranar not completely disintegrating and dissolving in conventional media.

[0004] Drug absorption is a crucial step in the efficacy of orally administered drugs. According to the "Guidelines for the Determination and Comparison of Dissolution Curves of Ordinary Oral Solid Dosage Forms" and the "Technical Guidelines for Dissolution Testing of Ordinary Oral Solid Dosage Forms," ​​after oral administration of solid dosage forms, drug absorption depends on the dissolution or release of the drug from the formulation, its dissolution under physiological conditions, and its penetration into the gastrointestinal tract. Therefore, in vivo dissolution and absorption significantly impact absorption. However, in vivo dissolution and absorption are difficult to evaluate, and in vitro dissolution tests are generally used to predict in vivo behavior. In vitro dissolution tests can also distinguish between different formulation processes and raw material / excipient differences, making them an indispensable part of generic drug research. In vitro dissolution tests typically use dissolution rate and dissolution curves as evaluation indicators. The sample is placed in a certain amount of dissolution medium, and samples are taken at specified times for detection using high-performance liquid chromatography (HPLC) or ultraviolet-visible spectrophotometry (UV-Vis).

[0005] In vitro dissolution tests commonly use water, buffer solutions (such as phosphate or citrate buffers), or water or buffer solutions with 0.01%–1.0% (w / v) surfactant as dissolution media. However, fluranar and its drug compositions are difficult to dissolve in these media. In other words, there is no effective in vitro dissolution method for evaluating the in vitro dissolution behavior of fluranar-containing drug compositions. Therefore, there is an urgent need to develop an effective in vitro dissolution method for evaluating the in vitro dissolution behavior of fluranar drug compositions.

[0006] In view of this, the present invention is hereby proposed. Summary of the Invention

[0007] The first objective of this invention is to provide a dissolution method for a pharmaceutical composition containing fluorellana.

[0008] A second objective of this invention is to provide an application of the above-described dissolution method.

[0009] To achieve the above objectives, the present invention adopts the following technical solution:

[0010] A method for dissolving a pharmaceutical composition containing fluorellana, comprising the following steps:

[0011] When the dissolution medium temperature is 37℃±0.5℃, add the drug composition containing fluorellana, start stirring at 80 rpm-150 rpm and start timing, and take samples at 1 hour-24 hours;

[0012] The leaching medium comprises 0.1-0.5 mol / L strong alkali and 2% w / v-4% w / v sodium dodecyl sulfate (SDS), wherein the strong alkali comprises at least one of NaOH, KOH and LiOH.

[0013] Furthermore, the dissolution medium also includes an organic solvent, which includes dioxane, dimethyl sulfoxide, or ethanol, preferably dioxane or dimethyl sulfoxide, and more preferably dimethyl sulfoxide.

[0014] Furthermore, the organic solvent accounts for 5%-20% of the volume of the leaching medium.

[0015] Furthermore, the concentration of the strong base is 0.15-0.3 mol / L, preferably 0.2 mol / L, and the strong base is preferably NaOH.

[0016] Furthermore, the concentration of SDS was 3% w / v.

[0017] Furthermore, the pharmaceutical compositions containing fluranal are available in strengths of 112.5-250 mg.

[0018] Furthermore, the crystal forms of freranil include crystal form A, crystal form B, crystal form C, crystal form D, crystal form E, or crystal form F.

[0019] Furthermore, the stirring speed is 80 rpm to 125 rpm, preferably 100 rpm to 125 rpm.

[0020] Furthermore, the pharmaceutical composition containing freranil contains at least one of pork liver powder, chicken liver powder, corn starch, soy protein powder, and soybean oil.

[0021] Furthermore, the sampling time is 1 hour to 8 hours.

[0022] The above dissolution method can be applied in any of the following:

[0023] (1) Testing of batch-to-batch or intra-batch quality consistency of pharmaceutical compositions containing fluorellana during production;

[0024] (2) Detection of the effects of different formulation compositions, different formulation processes and differences in raw materials and excipients on in vitro dissolution;

[0025] (3) Consistency testing of quality and efficacy of pharmaceutical compositions containing fluorellana before and after changes in formulation and manufacturing process;

[0026] (4) Development of pharmaceutical compositions containing freranil.

[0027] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0028] This invention provides a dissolution method for pharmaceutical compositions containing flurana. By screening dissolution media, rotation speed, and sampling time points, a discriminative dissolution method has been determined for evaluating the in vitro dissolution behavior of flurana-containing pharmaceutical compositions. This dissolution method solves the problem of difficult disintegration and dissolution of flurana and related pharmaceutical excipients (such as pork liver powder, chicken liver powder, corn starch, soybean protein powder, and soybean oil). It is applicable to various crystal forms of flurana and meets the experimental requirements of the "Guidelines for the Determination and Comparison of Dissolution Curves of Ordinary Oral Solid Dosage Forms" and the "Technical Guidelines for Dissolution Testing of Ordinary Oral Solid Dosage Forms," ​​enabling effective detection of in vitro dissolution of flurana-containing pharmaceutical compositions. This method can be used to investigate the effects of different formulation compositions, different formulation processes, and differences in raw materials and excipients on in vitro dissolution, evaluate intra-batch and inter-batch quality consistency, guide generic drug development, and accelerate the research and development of generic drugs. Attached Figure Description

[0029] Figure 1 This is the X-ray powder diffraction pattern of Freranar's crystal form A according to the present invention;

[0030] Figure 2 This is the X-ray powder diffraction pattern of Freranar sodium crystal form B of the present invention;

[0031] Figure 3 This is the X-ray powder diffraction pattern of the Freranar crystal form D of the present invention;

[0032] Figure 4 This is a schematic diagram of the dissolution curve in Example 4 of the present invention;

[0033] Figure 5 This is a schematic diagram of the dissolution curves of reference formulation 1 at different rotation speeds in Example 4 of the present invention;

[0034] Figure 6 This is a schematic diagram of the dissolution curves of reference preparation 2 at different rotation speeds in Example 4 of the present invention. Detailed Implementation

[0035] The specific embodiments of the present invention will now be described in detail.

[0036] The following explanations are provided for the relevant terms used in this invention:

[0037] The term "in vitro dissolution rate," also known as in vitro dissolution amount, refers to the rate and extent to which an active drug dissolves from ordinary formulations such as tablets, capsules, or granules under specified conditions. In formulations such as sustained-release formulations, controlled-release formulations, enteric-coated formulations, and transdermal patches, it is also called release rate.

[0038] The term "in vitro dissolution profile" refers to the curve showing the relationship between the amount of drug dissolved and time in a drug dissolution test.

[0039] This invention provides a method for dissolving a pharmaceutical composition containing fluorellana, comprising the following steps:

[0040] When the dissolution medium temperature is 37℃±0.5℃, add the drug composition containing fluorellana, start stirring at 80 rpm-150 rpm and start timing, and take samples at 1 hour-24 hours;

[0041] The leaching medium includes 0.1-0.5 mol / L strong alkali and 2% w / v-4% w / v SDS, wherein the strong alkali includes at least one of NaOH, KOH and LiOH.

[0042] It should be noted that the dissolution medium in the dissolution method of this invention is freshly prepared before use. The concentration of the strong alkali can be, but is not limited to, 0.1 mol / L, 0.15 mol / L, 0.2 mol / L, 0.25 mol / L, 0.3 mol / L, 0.35 mol / L, 0.4 mol / L, 0.45 mol / L, or 0.5 mol / L; the concentration of SDS can be, but is not limited to, 2% w / v, 2.5% w / v, 3% w / v, 3.5% w / v, or 4% w / v; the dissolution method employs a paddle method, and the stirring speed can be, but is not limited to, 80 rpm or 81 rpm. / minute, 82 rpm, 83 rpm, 84 rpm, 85 rpm, 86 rpm, 87 rpm, 88 rpm, 89 rpm, 90 rpm, 91 rpm, 92 rpm, 93 rpm, 94 rpm, 95 rpm, 96 rpm, 97 rpm, 98 rpm, 99 rpm, 100 rpm, 101 rpm, 102 rpm, 103 rpm, 104 rpm, 105 rpm, 106 rpm, 107 rpm, 108 rpm, 109 rpm Clock, 110 rpm, 111 rpm, 112 rpm, 113 rpm, 114 rpm, 115 rpm, 116 rpm, 117 rpm, 118 rpm, 119 rpm, 120 rpm, 121 rpm, 122 rpm, 123 rpm, 124 rpm, 125 rpm, 126 rpm, 127 rpm, 128 rpm, 129 rpm, 130 rpm, 131 rpm, 132 rpm, 133 rpm, 134 rpm, 135 rpm / min The sampling speed can be 136 rpm, 137 rpm, 138 rpm, 139 rpm, 140 rpm, 141 rpm, 142 rpm, 143 rpm, 144 rpm, 145 rpm, 146 rpm, 147 rpm, 148 rpm, 149 rpm, or 150 rpm; the sampling time can be, but is not limited to, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, or 24 hours.

[0043] The inventors discovered that pharmaceutical compositions containing fluranarane can be effectively dissolved under alkaline conditions containing SDS. By screening dissolution media, rotation speed, and sampling time points, they determined a discriminative dissolution method that can be used to evaluate the in vitro dissolution behavior of fluranarane-containing pharmaceutical compositions.

[0044] In a preferred embodiment, the dissolution medium further includes an organic solvent, such as dioxane, dimethyl sulfoxide, or ethanol, preferably dioxane or dimethyl sulfoxide, more preferably dimethyl sulfoxide. Furthermore, the organic solvent accounts for 5%-20% of the volume of the dissolution medium, and the content of the organic solvent may be, but is not limited to, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20%.

[0045] In a preferred embodiment, the concentration of the strong base is 0.15-0.3 mol / L, preferably 0.2 mol / L, and the strong base is preferably NaOH.

[0046] In a preferred embodiment, the crystalline form of freranil can be crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, or crystalline form F.

[0047] Fluoranar crystal form A, its X-ray powder diffraction pattern is shown below. Figure 1 The interplanar spacing d, Bragg 2θ angle and relative intensity I (expressed as a percentage relative to the strongest ray) were determined by X-ray powder diffraction. The corresponding results are shown in Table 1.

[0048] Fluoranar crystal form B, its X-ray powder diffraction pattern is shown below. Figure 2 The interplanar spacing d, Bragg 2θ angle and relative intensity I (expressed as a percentage relative to the strongest ray) were determined by X-ray powder diffraction. The corresponding results are shown in Table 1.

[0049] For fluorellana crystal form C, see crystal form II in Chinese CN102149695A.

[0050] Fluoranar crystal form D, its X-ray powder diffraction pattern is shown below. Figure 3 The interplanar spacing d, Bragg 2θ angle and relative intensity I (expressed as a percentage relative to the strongest ray) were determined by X-ray powder diffraction. The corresponding results are shown in Table 1.

[0051] For fluorellana crystal form E, see crystal form I in Chinese CN102149695A.

[0052] For fluorellana crystal form F, see crystal form III in Chinese CN102149695A.

[0053] Table 1. X-ray powder diffraction results of fluorellarana crystal forms A, B, and D.

[0054]

[0055]

[0056] In a preferred embodiment, the pharmaceutical composition containing freranil is in the strength of 112.5-250 mg.

[0057] In one embodiment, when the pharmaceutical composition containing freranil is in the specification of 112.5 mg, the sampling time is 1-6 hours.

[0058] In one embodiment, when the pharmaceutical composition containing fluranal is in the specification of 250 mg, the sampling time is 1-8 hours.

[0059] In a preferred embodiment, the stirring speed is 80 rpm to 125 rpm, preferably 100 rpm to 125 rpm.

[0060] The dissolution method provided by this invention is more suitable for flurana chewable tablets, especially flurana chewable tablets containing at least one poorly soluble matrix selected from pork liver powder, chicken liver powder, corn starch, soy protein powder and soybean oil.

[0061] Based on the above, the dissolution method of the present invention can be used for batch-to-batch or batch-to-batch quality consistency testing of pharmaceutical compositions containing fluoreranar during production; testing the impact of differences in different formulation compositions, different formulation processes, and raw and excipient materials on in vitro dissolution; testing the consistency of quality and efficacy of pharmaceutical compositions containing fluoreranar before and after changes in formulation and process; and related scenarios such as the research and development of pharmaceutical compositions containing fluoreranar.

[0062] Example 1: Sample to be tested

[0063] 1.1 Different Freranar Crystal Forms

[0064] Currently, fluorellana mainly exists in the following crystal forms: fluorellana crystal form A, fluorellana crystal form B, fluorellana crystal form C, fluorellana crystal form D, fluorellana crystal form E, and fluorellana crystal form F. The preparation method for fluorellana crystal form A is as follows: Add 70 ml of isopropanol to 10 g of fluorellana, heat to reflux with stirring, reflux for 30 minutes, filter to remove insoluble matter, remove to room temperature and continue stirring. Crystals will slowly precipitate. Continue stirring for 1 hour, filter, and dry the filter cake at 50°C with forced air to obtain 7.2 g of fluorellana crystal form A. The preparation method for fluorellana crystal form B is as follows: Add 500 ml of isopropanol and 500 ml of n-hexane to 100 g of fluorellana, stir and slurry for 24 hours, filter, and dry the filter cake at 50°C with forced air to obtain 92 g of fluorellana crystal form B. The preparation method of fluorellaranoline crystal form D is as follows: add 500 ml of dioxane to 100 g of fluorellaranoline, heat until completely dissolved, filter, cool to room temperature and stir for 2 h to crystallize, filter by suction, and dry the filter cake at 50 °C for 24 h to obtain fluorellaranoline crystal form D.

[0065] 1.2 Preparation of the test sample

[0066] The test samples (pharmaceutical compositions containing fluranarana) include the following nine types, specifically:

[0067] (1) Flureranolol chewable tablets 1, a commercial product, purchased from Intervet International GmbH, Austria, as reference preparation 1, with a specification of 250 mg.

[0068] (2) Flureranolol chewable tablets 2, a commercial product, purchased from Intervet International GmbH, Austria, as reference preparation 2, with a strength of 112.5 mg.

[0069] (3) Fluoranal chewable tablets 3, the specific formula is shown in Table 2. The crystalline form of the fluoranal contained therein is crystal form A. Fluoranal chewable tablets 3 are prepared according to the preparation method of fluoranal chewable tablets, with a specification of 250mg, as self-made preparation 1.

[0070] Table 2. Formulation composition of Fluranarol chewable tablets (w / w)

[0071] Element formula Freranar 15％ corn starch 15％ Soy protein powder 12.5％ Chicken liver powder 22.5％ Hydroxypropyl cellulose 4.5％ Polyethylene glycol 3350 8.0％ Polyethylene glycol 15-hydroxystearate 2.5％ glycerin 7.5％ soybean oil 12.5％ total 100％

[0072] The preparation method of fluranal chewable tablets includes:

[0073] Step 1) Pulverize the Freranar, control the particle size D90≤35μm, and mix it with corn starch, soybean protein powder, chicken liver powder, hydroxypropyl cellulose and polyethylene glycol 3350 in a wet granulator for 10 minutes to obtain a mixture.

[0074] Step 2) Mix glycerin and polyethylene glycol 15-hydroxystearate evenly and slowly add it to the mixture in Step 1). Stir and shear for 2 minutes to mix evenly, then add soybean oil and stir and shear for 1 minute to mix evenly, to obtain a mild and moist Freranar chewing composition.

[0075] Step 3) Transfer the Freranal chewing composition described in Step 2) into a hydroforming machine and press it into Freranal chewing tablets.

[0076] (4) Fluoranal chewable tablets 4, the specific formula is shown in Table 2. The crystalline form of the fluoranal contained therein is crystal form B. Fluoranal chewable tablets 4 are prepared according to the preparation method of fluoranal chewable tablets. The specification is 250mg, which is used as self-made preparation 2.

[0077] (5) Fluoranal chewable tablets 5, the specific formula is shown in Table 2, the crystal form of fluoranal contained therein is crystal form C (prepared according to the preparation method of crystal form II of Chinese patent CN102149695A) fluoranal chewable tablets 5 are prepared according to the preparation method of fluoranal chewable tablets, the specification is 250mg, as a self-made preparation 3.

[0078] (6) Fluoranal chewable tablets 6, the specific formula is shown in Table 2. The crystal form of the fluoranal contained therein is D. Fluoranal chewable tablets 6 are prepared according to the preparation method of fluoranal chewable tablets. The specification is 250mg, which is used as a self-made preparation 4.

[0079] (7) Fluoranal chewable tablets 7, the specific formula is shown in Table 2. The crystalline form of the fluoranal contained therein is B. Fluoranal chewable tablets 7 are prepared according to the preparation method of fluoranal chewable tablets. The specification is 112.5 mg, which is used as a self-made preparation 5.

[0080] (8) Fluoranal chewable tablets 8, the specific formula is shown in Table 2. The crystal form of the fluoranal contained therein is E. Fluoranal chewable tablets 8 are prepared according to the preparation method of fluoranal chewable tablets, with a specification of 250mg, as a self-made preparation 6.

[0081] (9) Fluoranal chewable tablets 9, the specific formula is shown in Table 2. The crystal form of the fluoranal contained therein is F. Fluoranal chewable tablets 9 are prepared according to the preparation method of fluoranal chewable tablets. The specification is 250mg, which is used as a self-made preparation 7.

[0082] Example 2: Dissolution method of a pharmaceutical composition containing fluranar.

[0083] The dissolution method of the fluranarin-containing pharmaceutical composition of the present invention includes:

[0084] Step (1) Prepare the dissolution medium immediately before use;

[0085] Step (2) Paddle method: Measure 900ml of degassed dissolution medium and pour it into a dry dissolution cup. After the temperature of the dissolution medium is constant at 37℃±0.5℃, put the sample to be tested into each dissolution cup. Control the rotation speed to 80-150 rpm, start running and start timing, and take samples from 1 hour to 24 hours.

[0086] After sampling, the in vitro dissolution rate was determined by high performance liquid chromatography (HPLC), and an in vitro dissolution curve was plotted. The specific procedure was as follows: First, prepare the appropriate solution. Immediately filter 10 ml of the dissolution solution through a 0.45 μm filter membrane, discard the initial filtrate (3 ml), take 1 ml of the subsequent filtrate, place it in a 10 ml volumetric flask, and dilute to the mark with 60% acetonitrile to obtain the test solution. Take an appropriate amount of fluranarane reference standard (99.7% purity), accurately weigh it, dissolve and dilute it with 60% acetonitrile to prepare a solution containing approximately 25 μg per ml, as the reference solution. The sample was then determined using high-performance liquid chromatography (HPLC) with octadecylsilane-bonded silica gel as the stationary phase, acetonitrile-water (60:40, V / V) as the mobile phase, a flow rate of 1.0 mL / min, a column temperature of 30 °C, and a detection wavelength of 265 nm. 10 μL of each of the test solution and the reference solution were injected into the HPLC, and the chromatograms were recorded. The dissolution rate of fluoranar was calculated using the external standard method based on the peak area, and a dissolution curve was plotted based on the dissolution rate at each time point.

[0087] Example 3 Selection of dissolution medium

[0088] 3.1 Preparation of dissolution medium

[0089] Prepare dissolution media 1-14 according to the specific preparation methods in Table 3.

[0090]

[0091]

[0092] 3.2 Screening of dissolution media

[0093] The self-made formulation 2 from Example 1 was subjected to dissolution tests using dissolution media 1-14 according to the dissolution method described in Example 2. The dissolution rate was measured over 24 hours, and the phenomena observed over 24 hours were recorded. The results are shown in Table 4.

[0094] Table 4 Screening results of leaching media

[0095]

[0096]

[0097] As shown in Table 4, fluranar chewable tablets showed good disintegration only in dissolution media 8, 11, 13, and 14, with relatively high in vitro dissolution. In other media, white lumps or turbidity were observed, indicating that the fluranar chewable tablets did not disintegrate or disintegrated incompletely, resulting in lower in vitro dissolution. This suggests that the drug composition containing fluranar can be effectively dissolved in dissolution media containing 3% SDS and alkaline conditions. Further optimization will be carried out based on this.

[0098] 3.3 Selection of the amount of sodium hydroxide in the leaching medium

[0099] First, fix the SDS concentration and dioxane ratio, and investigate the effects of SDS with different concentrations of sodium hydroxide or mixed solutions of SDS and dioxane with different concentrations of sodium hydroxide on tablet disintegration and dissolution. Prepare dissolution media according to the method in Table 5, and take the self-made formulation 2 from Example 1 for dissolution determination according to the method in Example 2. The results are shown in Table 6.

[0100] Table 5 Preparation of dissolution medium

[0101]

[0102]

[0103] Table 6. Screening Results of Dissolution Media

[0104]

[0105] Tables 4 and 6 show that the dissolution rate of flurranar in NaOH solution (containing 3% SDS) is 32.24%-86.62% when the NaOH concentration is 0.1 mol / L-1.0 mol / L, and 85.72%-86.62% when the NaOH concentration is 0.2 mol / L-0.3 mol / L. At a NaOH concentration of 0.2 mol / L (corresponding to dissolution medium number 8A2), the disintegration time is only 4 hours and 20 minutes, and the 24-hour dissolution rate is 86.62%, reaching 85% (meeting the requirements of "Determination and Comparison of Dissolution Curves for Common Oral Solid Dosage Forms"). (Compared to the requirements of the "Guiding Principles"); In a NaOH solution (containing 3% SDS): dioxane (90:10, V / V), the dissolution rate of flurranar is 66.67%-90.66% when the NaOH concentration is 0.1 mol / L-1.0 mol / L, and 86.58%-90.66% when the NaOH concentration is 0.2 mol / L-0.3 mol / L. When the NaOH concentration is 0.2 mol / L (corresponding to dissolution medium number 11A2), the disintegration time is only 5 hours and 20 minutes, and the 24-hour dissolution rate is 90.66%, reaching 85%.

[0106] The organic solvent used was optimized in conjunction with preferred dissolution media 8A2 and 11A2.

[0107] 3.4 Investigation of the types of organic solvents used in the leaching medium

[0108] Based on the selected acid and base types and dosages, 900 ml of aqueous medium was prepared and mixed with different types of organic solvents to investigate the effects of different organic solvents on tablet disintegration and dissolution. Dissolution media were prepared according to the methods in Table 7, and the self-made formulation 2 from Example 1 was subjected to dissolution testing according to the method in Example 2. The results are shown in Table 8.

[0109] Table 7 Preparation of dissolution medium

[0110]

[0111]

[0112] Table 8. Screening Results of Dissolution Media

[0113] serial number Dissolution % Phenomenon 15 39.71 50% disintegration within 24 hours 16 90.32 The flakes stuck to the bottom of the cup and completely disintegrated in 5 hours and 10 minutes. 17 82.61 The flakes stuck to the bottom of the cup and completely disintegrated after 6 hours and 40 minutes.

[0114] As shown in Tables 6 and 8, the dissolution rates of fluranar are 39.71%-90.66% when the organic solvents are dioxane, dimethylformamide, dimethyl sulfoxide, and ethanol. When dioxane is used as the organic solvent (corresponding to dissolution medium number 11A2), the disintegration time is only 5 hours and 20 minutes, and the 24-hour dissolution rate is 90.66%, reaching 85%. When dimethyl sulfoxide is used as the organic solvent (corresponding to dissolution medium number 16), the disintegration time is only 5 hours and 10 minutes, and the 24-hour dissolution rate is 90.32%, reaching 85%. Considering the high toxicity of dioxane, dimethyl sulfoxide (corresponding to dissolution medium number 16) is the most preferred organic solvent.

[0115] 3.5 Further investigation into the amount of organic solvent used in the dissolution medium

[0116] Based on the selected acid and base types and dosages, 900 ml of aqueous medium was prepared and mixed with different types of organic solvents to investigate the effect of different organic solvent dosages on tablet disintegration and dissolution. Dissolution media were prepared according to the methods in Table 9, and the self-made formulations 1, 2, 3, and 4 from Example 1 were subjected to dissolution determination according to the method in Example 2. The results are shown in Table 10.

[0117] Table 9 Preparation of dissolution medium

[0118]

[0119]

[0120] Table 10 Screening Results of Dissolution Media

[0121]

[0122] As shown in Table 10, when the amount of dimethyl sulfoxide in the dissolution medium is 5%-20% (V / V), the dissolution rate of fluranar is 85.12%-92.32% when the volume ratio of NaOH solution (containing 3% SDS) to dimethyl sulfoxide is 80:20-95:5, reaching 85%, which is better than the dissolution effect without organic solvent. When the amount of dimethyl sulfoxide in the dissolution medium is 5% (corresponding to dissolution medium number 18), the dissolution effect can meet the requirements.

[0123] In summary, the dissolution medium is NaOH solution (containing 3% SDS), KOH solution (containing 3% SDS), or LiOH solution (containing 3% SDS); preferably, it is 0.1 mol / L-1 mol / L NaOH solution (containing 3% SDS), more preferably, it is 0.2 mol / L-0.3 mol / L NaOH solution (containing 3% SDS); preferably, it also includes an organic solvent of dioxane, dimethyl sulfoxide, dimethylformamide, or ethanol, preferably dioxane or dimethyl sulfoxide, more preferably dimethyl sulfoxide, wherein the volume ratio of NaOH solution (containing 3% SDS) to dioxane or dimethyl sulfoxide is 80:20-95:5, more preferably, the volume ratio of NaOH solution (containing 3% SDS) to dioxane or dimethyl sulfoxide is 95:5.

[0124] Example 4: Optimization of Step 2 in the Dissolution Method of Fluoranarol Chewable Tablets

[0125] Through multiple experiments, it was found that the rotation speed and sampling time point in step 2 of the dissolution method for fluranar chewable tablets are key factors affecting the dissolution results. The "Guidelines for the Determination and Comparison of Dissolution Curves of Ordinary Oral Solid Dosage Forms" stipulates that: "The selection of the cutoff time point for dissolution curve examination should meet the following requirements: the dissolution amount at two consecutive points should both reach more than 85%, and the difference should be within 5%" and "The relative standard deviation of the dissolution result at the first time point of the dissolution curve should not exceed 20%, and the relative standard deviation of the dissolution result from the second time point to the last time point should not exceed 10%". Therefore, we optimized the two key factors affecting step 2 of the dissolution method, and the specific results are as follows.

[0126] 4.1 Selection of dissolution sampling time point

[0127] The dissolution medium was prepared according to the preparation method of dissolution medium No. 18. Twelve tablets each of reference formulation 1, reference formulation 2, self-made formulation 2, and self-made formulation 5 from Example 1 were taken and dissolution tests were performed according to step (2) of the in vitro dissolution method in Example 2. Samples were taken at 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, and 8 hours to determine the dissolution rate and plot dissolution curves. Dissolution phenomena were observed simultaneously. The results are shown in Table 11. Figure 4 .

[0128] Table 11 Results of Dissolution Sampling Time Points

[0129]

[0130] From Table 11, Figure 4It can be seen that the dissolution rate of reference formulation 1 (specification: 250mg) reached over 85% at 6 hours, and the dissolution rate of self-made formulation 2 (specification: 250mg) reached over 85% at 7 hours. The dissolution rates of both formulations at consecutive points of 7 and 8 hours met the requirements of the guidelines. The preferred sampling time points are 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, and 8 hours. Reference formulation 2 (specification: 112.5mg) reached over 85% at 4 hours, and the dissolution rate of self-made formulation 5 (specification: 112.5mg) reached over 85% at 5 hours. The dissolution rates of both formulations at consecutive points of 5-8 hours met the requirements of the guidelines. The preferred sampling time points are 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, and 6 hours.

[0131] During the experiment, it was found that at a dissolution speed of 150 rpm, some tablets stuck to the bottom of the dissolution vessel, resulting in slower dissolution, while tablets that did not stick to the bottom dissolved faster. This caused the relative standard deviation of all four formulations at the second time point to exceed 10%, which does not comply with the "Guidelines for the Determination and Comparison of Dissolution Curves of Ordinary Oral Solid Dosage Forms". Therefore, the next step is to optimize the dissolution speed.

[0132] 4.2 Selection of dissolution speed

[0133] Prepare the dissolution medium according to the preparation method of dissolution medium number 18. Take 12 tablets each of reference preparation 1 and reference preparation 2 from Example 1 and perform dissolution tests according to step (2) in Example 2. Control the rotation speed to 150 rpm, 125 rpm, 100 rpm, and 80 rpm respectively. Take samples at 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, and 8 hours respectively to measure the dissolution rate and plot the dissolution curve. Observe the dissolution phenomenon at the same time. The results are shown in Tables 12-13. Figure 5-6 .

[0134] Table 12 Results of Dissolution Rotation Rate Investigation

[0135]

[0136] Table 13 Results of Dissolution Rotation Rate Investigation

[0137]

[0138]

[0139] From Table 12-13, Figure 5-6It can be seen that the dissolution rates of 250mg and 112.5mg flurana chewable tablets are slightly slower than those at 150 rpm at 125 rpm, 100 rpm, and 80 rpm. The disintegration time and dissolution amount at each time point of the reference preparation are not significantly different at 125 rpm and 100 rpm, and the relative standard deviations at each time point meet the requirements. The dissolution rate is slowest at 80 rpm, and the relative standard deviations at each time point also meet the requirements.

[0140] In summary, the dissolution rates of the 250mg flurana chewable tablets met the requirements under dissolution rates of 80-150 rpm, with a preferred dissolution rate of 80-125 rpm. Sampling times were taken at 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, and 8 hours. Similarly, the dissolution rates of the 112.5mg flurana chewable tablets also met the requirements under dissolution rates of 80-150 rpm, with a preferred dissolution rate of 80-125 rpm. Sampling times were taken at 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, and 6 hours.

[0141] Example 5: Evaluation of the dissolution effect of different specifications of flurana chewable tablets

[0142] According to the "Guidelines for the Determination and Comparison of Dissolution Curves of Common Oral Solid Dosage Forms", the similarity of dissolution curves is often compared using the similarity factor (f2) method in the non-model-dependent method. This method compares the average dissolution amount of the test sample with the average dissolution amount of the reference sample. Generally, when the similarity factor value of the two dissolution curves is not less than 50, the dissolution curves can be considered similar.

[0143] Prepare the dissolution medium according to the preparation method of dissolution medium number 18. Take 12 tablets each of self-made formulations 2, 5, 6 and 7 from Example 1 and conduct dissolution tests according to step (2) in Example 2. Control the rotation speed to 100 rpm. Samples of self-made formulations 2, 6 and 7 were taken at 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours and 8 hours to determine the dissolution curves. Samples of self-made formulation 5 were taken at 1 hour, 2 hours, 3 hours, 4 hours, 5 hours and 6 hours to determine the dissolution curves. The results are shown in Table 14.

[0144] Table 14 Dissolution Results

[0145]

[0146] The established dissolution method was used to evaluate different specifications of fluranarine chewable tablets. The results showed that the similarity factor between self-made formulation 2 and reference formulation 1 was 78.9, the similarity factor between self-made formulation 6 and reference formulation 1 was 52.9, the similarity factor between self-made formulation 7 and reference formulation 1 was 59.5, and the similarity factor between self-made formulation 5 and reference formulation 2 was 70.1. The similarity factors of self-made formulations 2, 5, 6, and 7 with the reference formulation were all greater than 50, indicating that the dissolution curves of self-made formulations 2, 5, 6, and 7 with the reference formulation were similar. The dissolution of self-made formulation 6 was faster, and the dissolution of self-made formulation 7 was slower. The dissolution similarity between self-made formulations 2 and 5 with the reference formulation was the best. The results indicate that the established dissolution method has good discriminative power.

[0147] In summary, the in vitro dissolution method established in this invention is of great significance for guiding the research and development of drug compositions containing fluranarana, evaluating the consistency of intra-batch and inter-batch quality of drug formulations, and evaluating the consistency of quality and efficacy of drug formulations before and after changes in formulation and process.

[0148] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for dissolving fluranal chewable tablets, characterized in that, Includes the following steps: When the dissolution medium temperature is 37℃±0.5℃, add the flurana chewable tablets, start stirring at 80 rpm-125 rpm and start timing, and take samples at 1 hour-8 hours; The dissolution medium comprises 0.2-0.3 mol / L NaOH and 3% w / v SDS; The crystal forms of freranil include crystal form A, crystal form B, crystal form C, or crystal form D; The formulation of Freranilana chewable tablets consists of: 15 w / w % Freranilana, 15 w / w % corn starch, 12.5 w / w % soy protein powder, 22.5 w / w % chicken liver powder, 4.5 w / w % hydroxypropyl cellulose, 8.0 w / w % polyethylene glycol 3350, 2.5 w / w % polyethylene glycol 15-hydroxystearate, 7.5 w / w % glycerin, and 12.5 w / w % soybean oil; The preparation method of fluranal chewable tablets includes: Step 1) Pulverize the Freranal to control the particle size D90≤35μm, and mix it with corn starch, soybean protein powder, chicken liver powder, hydroxypropyl cellulose and polyethylene glycol 3350 in a wet granulator for 10 minutes to obtain a mixture. Step 2) Mix glycerin and polyethylene glycol 15-hydroxystearate evenly and slowly add it to the mixture in Step 1). Stir and shear for 2 minutes to mix evenly, then add soybean oil and stir and shear for 1 minute to mix evenly, to obtain a mild and moisturizing Freranar chewing composition. Step 3) Transfer the Freranal chewing composition described in Step 2) into a hydroforming machine and press it into Freranal chewing tablets.

2. The dissolution method according to claim 1, characterized in that, The dissolution medium also includes an organic solvent, which is dioxane or dimethyl sulfoxide.

3. The dissolution method according to claim 2, characterized in that, The organic solvent is dimethyl sulfoxide.

4. The dissolution method according to claim 2, characterized in that, The organic solvent accounts for 5%-20% of the volume of the leaching medium.

5. The dissolution method according to any one of claims 1-4, characterized in that, Pharmaceutical compositions containing fluranal are available in strengths of 112.5-250 mg.

6. The dissolution method according to any one of claims 1-4, characterized in that, The stirring speed is 100 rpm - 125 rpm.

7. The application of the dissolution method according to any one of claims 1-6 in any of the following: (1) Testing of batch-to-batch or batch-to-batch quality consistency of pharmaceutical compositions containing freranil during production; (2) Detection of the effects of different formulation compositions, different formulation processes and differences in raw materials and excipients on in vitro dissolution; (3) Consistency test of quality and efficacy of pharmaceutical compositions containing freranil before and after changes in formulation and process.

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