A method for determining the dissolution curve of megestrol acetate suspension with discrimination

Abstract

The invention provides a method for determining a dissolution curve of a megestrol acetate suspension with discrimination. The method comprises: a step of dissolving a surfactant in water to prepare a dissolution medium, wherein the surfactant comprises sodium dodecyl sulfate or polysorbate 80, and when the surfactant is sodium dodecyl sulfate, the mass concentration range of the sodium dodecyl sulfate is 0.35% to 0.45%, and when the surfactant is polysorbate 80, the mass concentration range of the polysorbate 80 is 0.8%-1.0%; taking a megestrol acetate oral suspension to be tested, shaking it thoroughly, and degassing it under reduced pressure to obtain a sample to be tested; adding the sample to be tested into the dissolution medium through an automatic sample adding device, and measuring it according to a dissolution instrument paddle method, sampling at a sampling time point, and measuring the dissolution amount at different time points.

Description

Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a method for determining a dissolution curve of a megestrol acetate suspension with discrimination power. Background Art

[0002] Dissolution: refers to the speed and extent of dissolution of active drugs from common preparations such as tablets, capsules or granules under specified conditions (i.e. the amount of drug released when it reaches a certain time point in the dissolution medium). It mainly examines whether the release of the drug at the specified time point can reach the limit specified in the standard.

[0003] Dissolution Profile: It is a dissolution-time curve drawn by the dissolution obtained at different time points of the preparation. The dissolution profile reflects the in vitro dissolution and dissolution process of the preparation. The quality of generic drugs can be evaluated by comparing the similarity of multiple in vitro dissolution curves of generic preparations and original preparations.

[0004] Since 2012, the National Medical Products Administration (NMPA) has launched the work of generic drug quality consistency evaluation, that is, to make the generic drugs that have been approved for marketing consistent with the original drugs in terms of quality and efficacy. Among them, formulating a scientific and reasonable dissolution curve of solid preparations is an important step to improve the success rate of in vivo bioequivalence tests, and provides a basis for including the characteristic dissolution curve of drugs in the corresponding quality standards, and provides guarantees for the consistency of drug quality between batches and the consistency of drug quality before and after process changes.

[0005] At present, there are few suspensions listed in domestic and foreign pharmacopoeias that require dissolution testing, only the United States Pharmacopoeia (USP) <42> The dissolution test requirements for megestrol acetate oral suspension, felbamate oral suspension, and indomethacin oral suspension are specified in the standard (determined by the second dissolution test method).

[0006] In the current market, the first / second method dissolution apparatus is mainly designed for the determination of the dissolution rate of solid preparations. When the liquid preparation is measured by this instrument, manual sample addition with a syringe is generally adopted. The dissolution curve of the suspension is sensitive to changes in sample state, sample addition position, sample addition speed and sample addition needle aperture, thus affecting the precision of the dissolution results of the parallel test samples.

[0007] Currently available megestrol acetate oral suspension is Specification: 40mg / ml (original preparation). In the prior art, the method for determining the dissolution rate of megestrol acetate oral suspension is included in both the United States Pharmacopoeia and the Korean Pharmacopoeia. The method included in the Korean Pharmacopoeia is a dissolution method using a 5% SDS aqueous solution as the dissolution medium. This method has a too fast dissolution rate and has no ability to distinguish the differences in the prescription process between generic drugs and original drugs, and cannot distinguish the quality of generic drug companies. The United States Pharmacopoeia includes three dissolution determination methods, as shown in the following table:

[0008]

[0009] Commercially available preparations of megestrol acetate suspension When method 1 is used as the dissolution curve method, the dissolution rate of this method is relatively fast (the dissolution rate reaches 85% in 15 minutes), and the obtained dissolution curve cannot effectively distinguish the in vitro release of megestrol acetate suspension and its influence on the in vitro release.

[0010] Commercially available preparations (Specification: 40mg / ml) When completely dissolved under the conditions of Method 2 and Method 3, the solubility of megestrol acetate is 0.444mg / ml. It has been determined that the solubility of megestrol acetate raw material in 0.5% SDS aqueous solution is 0.527mg / ml. The conditions of Method 2 and Method 3 have seriously failed to meet the sink condition. The dissolution curve determination by this method has a slow dissolution rate and the difference between the dissolution curves is not obvious. And it cannot be guaranteed that the dissolution process can reach a dissolution amount of 85% or more. Summary of the invention

[0011] The purpose of the present invention is to overcome the shortcomings of existing pharmacopoeia data, provide a method for determining the in vitro release dissolution curve of megestrol acetate suspension that can effectively distinguish the effects of prescription and process variables, and improve the precision and accuracy of the method, so as to provide a guarantee for the consistency of drug batch quality.

[0012] To achieve the above object, the present invention provides a method for determining the dissolution curve of a megestrol acetate suspension with discrimination, wherein the method comprises the following steps:

[0013] (1) preparing a dissolution medium: comprising the step of dissolving a surfactant in water to prepare a dissolution medium, wherein the surfactant comprises sodium dodecyl sulfate (SDS) or polysorbate 80 (Tween 80), when the surfactant is sodium dodecyl sulfate, the mass concentration range of the sodium dodecyl sulfate is 0.35% to 0.45%, when the surfactant is polysorbate 80, the mass concentration range of the polysorbate 80 is 0.8% to 1.0%;

[0014] (2) Preparation of the sample to be tested: the steps include taking the megestrol acetate oral suspension to be tested, shaking it thoroughly, and degassing it under reduced pressure to obtain the sample to be tested;

[0015] (3) Dissolution amount determination: including adding the sample to be tested into the dissolution medium through an automatic sample adding device, performing the determination according to the dissolution apparatus paddle method, sampling at different sampling time points, and determining the dissolution amount at different time points.

[0016] According to some specific embodiments of the present invention, step (2) comprises vigorously shaking the megestrol acetate suspension to be tested so that the suspension is fully mixed, and then degassing under reduced pressure for 30-60 minutes, with the vacuum degree maintained at -50 to -80 KPa, to obtain a sample to be tested.

[0017] The vigorous shaking is the vigorous shaking generally understood in the art, and according to some specific embodiments of the present invention, the vigorous shaking is shaking the sample bottle up and down at a frequency of at least 80 times per minute.

[0018] According to some specific embodiments of the present invention, step (3) comprises adding the sample to be tested into the dissolution medium using an automatic sample adding device, wherein the automatic sample adding device (such as Fig. 9 As shown in the figure, the syringe 2 is at least composed of a syringe 2, a syringe pump 1, a sample addition needle 4, and a connecting hose 3 (preferably a connecting hose made of silicone).

[0019] Wherein, the injection pump can be a conventional injection pump in the art, and according to some specific embodiments of the present invention, wherein, the injection pump in step (3) includes a single-channel or multi-channel injection pump.

[0020] According to some specific embodiments of the present invention, step (3) includes adding a sample in a volume range of 0.5 ml to 10 ml.

[0021] According to some specific embodiments of the present invention, step (3) includes adding the sample at a position 0.5-1.5 cm below the liquid surface of the dissolution medium, preferably 1 cm.

[0022] According to some specific embodiments of the present invention, step (3) includes using a flat-head needle as the sample adding needle, and the inner diameter of the needle is 0.5 mm to 1.54 mm (corresponding to the international standard specification of 21G to 14G).

[0023] According to some specific embodiments of the present invention, the sample addition time in step (3) is 10-15 s.

[0024] According to some specific embodiments of the present invention, the sampling time points in step (3) include 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, and 60 min.

[0025] According to some specific embodiments of the present invention, step (3) includes a dissolution amount determination method including high performance liquid chromatography or ultraviolet spectrophotometry.

[0026] According to some specific embodiments of the present invention, the chromatographic conditions of the high performance liquid chromatography in step (3) include:

[0027] Detector: UV detector;

[0028] Chromatographic column: ODS-3, 4.6mm×150mm, 5μm;

[0029] Detection wavelength: 292nm;

[0030] Column temperature: 35°C;

[0031] Mobile phase: acetonitrile-water (65:35) was used as the mobile phase;

[0032] Flow rate: 1.2ml / min.

[0033] According to some specific embodiments of the present invention, the ultraviolet spectrophotometry detection wavelength in step (3) is 292 nm.

[0034] According to some specific embodiments of the present invention, the method comprises the following steps:

[0035] (1) Preparation of dissolution medium: comprising dissolving a surfactant, sodium dodecyl sulfate or polysorbate 80, in water, wherein the concentration of sodium dodecyl sulfate is in the range of 0.35% to 0.45%, and the concentration of polysorbate 80 is in the range of 0.8% to 1.0%;

[0036] (2) Preparation of the sample to be tested: taking the megestrol acetate oral suspension to be tested, shaking it thoroughly, and degassing it under reduced pressure for 30-60 minutes to obtain the sample to be tested;

[0037] (3) Dissolution determination: The sample to be tested is added to the dissolution medium through an automatic sample adding device. 5-20 ml of the sample to be tested is measured by a syringe. The syringe and the sample adding needle are connected with a silicone hose. The sample adding needle head is placed 0.5 cm to 1.5 cm below the liquid surface of the dissolution medium. The inner diameter of the sample adding needle is about 1.5 mm. The injection pump sample adding speed is adjusted so that the sample adding time is controlled at 8 to 15 s. The paddle speed of the dissolution apparatus is set to 30 rpm. Samples are taken at 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, and 60 min, respectively. The corresponding dissolution amount is determined by high performance liquid chromatography or ultraviolet spectrophotometry.

[0038] According to some specific embodiments of the present invention, step (1) further includes the step of adjusting the pH value of the dissolution medium using a pH adjuster, wherein the pH adjuster is selected from a mixture of one or more of hydrochloric acid, phosphates, acetates, glacial acetic acid, sodium hydroxide and potassium hydroxide, and the amount of the pH adjuster is such that the pH value of the prepared dissolution medium is adjusted to 1.0 to 7.0.

[0039] It is understood that, in step (1), when preparing the dissolution medium, a pH adjuster may or may not be added.

[0040] According to some specific embodiments of the present invention, step (1) comprises dissolving a surfactant in water, and then adding a suitable pH adjuster to prepare a dissolution medium.

[0041] According to some specific embodiments of the present invention, step (1) comprises dissolving a surfactant in water to prepare a dissolution medium, and further adding a pH adjuster to prepare a dissolution medium after the surfactant is dissolved in water, so as to prepare the dissolution medium with the pH adjuster added in an amount of 0, and adjusting the pH value of the prepared dissolution medium to 1.2, 4.5 and 6.8 respectively, and the pH adjuster is selected from a mixture of one or more of hydrochloric acid, phosphate, acetate, glacial acetic acid, sodium hydroxide and potassium hydroxide.

[0042] It is understood that the dissolution medium in step (1) may include eight types:

[0043] According to some specific embodiments of the present invention, there are four types of dissolution media prepared with sodium dodecyl sulfate, namely: 0.4% sodium dodecyl sulfate aqueous solution (without adding a pH adjuster); sodium dodecyl sulfate mass concentration is 0.4%, and a pH adjuster is added to adjust the pH of the prepared dissolution medium to 1.2; sodium dodecyl sulfate mass concentration is 0.4%, and a pH adjuster is added to adjust the pH of the prepared dissolution medium to 4.5; sodium dodecyl sulfate mass concentration is 0.4%, and a pH adjuster is added to adjust the pH of the prepared dissolution medium to 6.8;

[0044] According to some specific embodiments of the present invention, there are four types of dissolution media prepared with polysorbate 80, namely: 0.9% polysorbate 80 aqueous solution (without adding a pH adjuster); a polysorbate 80 mass concentration of 0.9%, and a pH adjuster is added to adjust the pH of the prepared dissolution medium to 1.2; a polysorbate 80 mass concentration of 0.9%, and a pH adjuster is added to adjust the pH of the prepared dissolution medium to 4.5; a polysorbate 80 mass concentration of 0.9%, and a pH adjuster is added to adjust the pH of the prepared dissolution medium to 6.8.

[0045] According to some specific embodiments of the present invention, the preparation process of the dissolution medium with no pH regulator and a sodium dodecyl sulfate mass concentration of 0.4% (or a polysorbate 80 mass concentration of 0.9%) in step (1) is as follows: 4.0 g of sodium dodecyl sulfate (or 9.0 g of polysorbate 80) is weighed and placed in a volumetric flask, 700-800 ml of water is added to dissolve it, and water is added to dilute it to 1000 ml, mixed, and degassed to obtain the product.

[0046] According to some specific embodiments of the present invention, the preparation process of the dissolution medium in step (1) is as follows: weigh 4.0g of sodium dodecyl sulfate (or 9.0g of polysorbate 80) and place it in a volumetric flask, add 700-800ml of water to dissolve it, add 7.65ml of hydrochloric acid, dilute it with water to 1000ml, mix well, and degas.

[0047] According to some specific embodiments of the present invention, the preparation process of the dissolution medium in step (1) is as follows: weigh 2.99g of sodium acetate and place it in a volumetric bottle, add 14ml of 2mol / L acetic acid solution, and dilute it to 400ml with water; weigh 4.0g of sodium dodecyl sulfate (or 9.0g of polysorbate 80) and place it in another volumetric bottle, add 500ml of water to dissolve it, mix the solutions in the two volumetric bottles, dilute it to 1000ml with water, mix well, and degas.

[0048] According to some specific embodiments of the present invention, the preparation process of the dissolution medium in step (1) with a pH value of 6.8 and a mass concentration of sodium dodecyl sulfate of 0.4% (or a mass concentration of polysorbate 80 of 0.9%) is as follows: 6.0 g of sodium dihydrogen phosphate is weighed and placed in a volumetric bottle, 112 ml of a 0.2 mol / L sodium hydroxide solution is added, and the mixture is diluted to 400 ml with water; 4.0 g of sodium dodecyl sulfate (or 9.0 g of polysorbate 80) is weighed and placed in another volumetric bottle, 500 ml of water is added to dissolve the mixture, the solutions in the two volumetric bottles are mixed, the mixture is diluted to 1000 ml with water, mixed evenly, and degassed to obtain the mixture.

[0049] According to some specific embodiments of the present invention, step (3) further comprises drawing a dissolution curve based on the measured dissolution amount to evaluate the in vitro dissolution characteristics of the sample to be tested.

[0050] According to some specific embodiments of the present invention, the dissolution curve drawn in step (3) is used to evaluate the similarity between different formulations and process preparations and the original preparation using a similarity factor f2.

[0051] According to some specific embodiments of the present invention, the in vitro dissolution curve of the sample to be tested is used to evaluate the impact of product formulation or process changes on the quality of megestrol acetate oral suspension.

[0052] According to some specific embodiments of the present invention, the in vitro dissolution curve of the sample to be tested is used to predict the difference in in vivo bioequivalence of the product.

[0053] According to some specific embodiments of the present invention, the method further comprises the step of preparing a reference solution, and in step (3), the reference solution and the sample to be tested are respectively added into the dissolution medium via an automatic sample adding device, and the samples are respectively measured according to the dissolution apparatus paddle method, and samples are respectively taken at different sampling time points to measure the dissolution amounts at different time points.

[0054] According to some specific embodiments of the present invention, the method further comprises:

[0055] (1) preparing a dissolution medium: comprising the step of dissolving a surfactant in water to prepare a dissolution medium, wherein the surfactant comprises sodium dodecyl sulfate (SDS) or polysorbate 80 (Tween 80), when the surfactant is sodium dodecyl sulfate, the mass concentration range of the sodium dodecyl sulfate is 0.35% to 0.45%, when the surfactant is polysorbate 80, the mass concentration range of the polysorbate 80 is 0.8% to 1.0%;

[0056] (2) Prepare reference solution;

[0057] (3) Preparation of the sample to be tested: the steps include taking the megestrol acetate oral suspension to be tested, shaking it thoroughly, and degassing it under reduced pressure to obtain the sample to be tested;

[0058] (4) Dissolution amount determination: including adding the reference substance and the sample to be tested into the dissolution medium through an automatic sample adding device, respectively, and performing the determination according to the dissolution apparatus paddle method, respectively, sampling at different sampling time points, and determining the dissolution amount at different time points.

[0059] In summary, the present invention provides a method for determining the dissolution curve of megestrol acetate suspension with discrimination. The determination method of the present invention has the following advantages:

[0060] (1) In the present invention, the dissolution medium is set to 0.4% sodium dodecyl sulfate solution or 0.9% polysorbate 80 solution, and the rotation speed is set to 30 rpm. A large number of experiments have shown that the dissolution curve measured under this dissolution condition has better discrimination than the USP method, and can appropriately distinguish the quality of generic drugs and original drugs, and can also scientifically distinguish the differences in the prescriptions and processes of generic drugs. Figure 1 .

[0061] (2) In the present invention, the method for preparing the sample to be tested is as follows: shaking violently to fully mix the suspension, and degassing under reduced pressure for 30-60 minutes. If the suspension is left for a long time, sedimentation and stratification will occur. If the mixing time is short, it cannot be ensured that the state and content of samples at different positions in the bottle are consistent; after vigorous shaking and mixing, a large number of tiny bubbles will appear inside the suspension. At this time, when the dissolution curve is measured, the dissolution amount at the same sampling time point will increase, and the discrimination of the dissolution curve will deteriorate. A large number of experiments have shown that the method for preparing the sample to be tested of the present invention can improve the discrimination of the dissolution curve determination method while ensuring the homogeneity of the test sample.

[0062] (3) In the present invention, the dissolution amount determination sample addition method adopts an automatic sample addition device, which eliminates the interference of different personnel and different time addition speed differences, and significantly improves the precision and accuracy of the dissolution curve method.

[0063] (4) In the present invention, the sample addition position, sample addition speed, and sample addition needle aperture are specified to ensure that the dissolution curve can be reproduced.

[0064] (5) The method for determining the dissolution curve of suspension provided by the method of the present invention is scientific, durable, highly precise, and reproducible, and provides reliable guarantees for the quality consistency evaluation of generic drugs and original drugs, the consistency of drug batch quality, and the consistency of drug quality before and after process changes. BRIEF DESCRIPTION OF THE DRAWINGS

[0065] Figure 1 A schematic diagram of the dissolution curve of the original preparation provided in Example 1 of the present invention using USP method 1, and a schematic diagram of the dissolution curve of the original preparation during the SDS concentration screening in the dissolution medium and the dissolution apparatus speed screening process;

[0066] Figure 2 Schematic diagram of the dissolution curves of the original preparation and the self-developed preparation provided in Example 1 of the present invention measured by different treatment methods;

[0067] Figure 3 This is a schematic diagram of the dissolution curve of the original preparation provided in Example 1 of the present invention measured at different sample addition times;

[0068] Figure 4 This is a schematic diagram of the dissolution curve of the original preparation provided in Example 1 of the present invention measured by adding samples at different sample addition positions;

[0069] Figure 5 This is a schematic diagram of the dissolution curve of the original preparation provided in Example 1 of the present invention when the needles with different apertures are used for sample addition;

[0070] Figure 6 This is a schematic diagram of the dissolution curve of the original preparation provided in Example 1 of the present invention measured by automatic sampling and manual sampling;

[0071] Figure 7 The dissolution curves of the original formulation and megestrol acetate oral suspensions prepared by three different prescriptions and processes are determined by using the method for determining the dissolution curve of megestrol acetate oral suspension with discrimination provided in Example 2;

[0072] Figure 8 The dissolution curves of the original preparation in 4 dissolution media with different pH values ​​were determined by using the method for determining the dissolution curve of megestrol acetate oral suspension with discrimination provided in Example 2;

[0073] Fig. 9 It is the automatic sample adding device adopted by the present invention. DETAILED DESCRIPTION

[0074] The implementation process of the present invention and the beneficial effects produced are described in detail below through specific embodiments, which is intended to help readers better understand the essence and characteristics of the present invention, and is not intended to limit the scope of implementation of the present invention.

[0075] Example 1

[0076] In the prior art, the United States Pharmacopoeia (USP <42> ) contains a method for determining the dissolution rate of megestrol acetate oral suspension. The dissolution curve of the original preparation was determined using USP method 1: 0.5% sodium dodecyl sulfate (SDS) aqueous solution was used as the dissolution medium, 900 ml was added to the dissolution cup, and the speed of the dissolution instrument was set to 25 rpm. When the temperature of the dissolution medium reached 37±5°C, 4 ml of the mixed megestrol acetate oral suspension was drawn with a syringe and injected into the dissolution cup on the surface of the dissolution medium. 5 ml of the solution was taken at 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, and 60 min, respectively, and filtered through a 0.45 μm microporous filter membrane. The filtrate was taken as the test solution and the dissolution amount was determined by high performance liquid chromatography. The chromatographic conditions are as follows:

[0077] Detector: UV detector;

[0078] Chromatographic column: ODS-3, 4.6mm×150mm, 5μm;

[0079] Detection wavelength: 292nm;

[0080] Column temperature: 35°C;

[0081] Mobile phase: acetonitrile-water (65:35) was used as the mobile phase;

[0082] Flow rate: 1.2ml / min.

[0083] The results showed that the dissolution results were too fast using USP Method 1 (see Figure 1 ), the dissolution amount reached 85% in 15 minutes, and this dissolution method has no discriminatory power.

[0084] In order to explore a more suitable method to achieve better discrimination of the dissolution curve of megestrol acetate oral suspension, the effects of changes in SDS concentration, rotation speed, sample processing method and sample addition method on the dissolution curve of megestrol acetate oral suspension were investigated in further research experiments.

[0085] A large number of experiments have shown that when the concentration of the dissolution medium SDS is 0.4% and the rotation speed is 30 rpm, the measured dissolution curve has better discrimination than the USP method, and can appropriately distinguish the quality of generic drugs from original drugs, and can also scientifically distinguish the differences in generic drug prescriptions and processes. Figure 1 .

[0086] Suspensions will settle and stratify after being left for a long time. If the mixing time is short, the state and content of samples at different locations in the bottle cannot be guaranteed to be consistent, thus affecting the precision of the dissolution curve method. If the suspension is shaken violently and mixed, a large number of tiny bubbles will appear inside the suspension. At this time, when the dissolution curve is measured, the dissolution amount at the same sampling time point will increase, and the differentiation of the dissolution curve will become worse. Experiments have shown that after the suspension is shaken violently and mixed, and then degassed under reduced pressure for 30-60 minutes, the dissolution amount at the same sampling point within 30 minutes becomes smaller, and the differentiation of the dissolution curve is better, as shown in Table 1. Figure 2 ;

[0087] Table 1 Differences in dissolution amount of different sample treatment methods

[0088]

[0089] A large number of experiments have shown that when adding suspensions, parameters such as the speed of addition, the location of addition, and the diameter of the needle tip will affect the dissolution curve. Figure 3-Figure 6 The present invention provides for using a sample addition needle with an inner diameter of 1.50 mm, adding the sample at 0.5 cm to 1.5 cm below the liquid surface of the dissolution medium, and completing the addition within 10 to 15 seconds.

[0090] In the present invention, the dissolution sample is Fig. 9 The laboratory syringe pump automatic sample addition device shown eliminates the interference of different sample addition speeds of different personnel at different times, ensures constant sample addition, controls the RSD of the first and second points to be less than 5%, and significantly improves the precision and accuracy of the dissolution curve method (as shown in Table 2).

[0091] Table 2 Dissolution curves and precision results of different sample addition methods

[0092]

[0093] Example 2

[0094] The present embodiment provides a method for determining the dissolution curve of megestrol acetate oral suspension, comprising the following steps:

[0095] Step (1) Preparation of dissolution medium

[0096] The dissolution medium is a 0.4% sodium dodecyl sulfate (or 0.9% polysorbate 80) aqueous solution, and the preparation process is: weigh 4.0g of sodium dodecyl sulfate (or 9.0g of polysorbate 80) and place it in a volumetric bottle, add 700ml of water to dissolve it, dilute it with water to 1000mL, mix well, degas, and obtain it.

[0097] The dissolution medium is a pH 1.2 aqueous solution containing 0.4% sodium dodecyl sulfate (or 0.9% polysorbate 80). The preparation process is as follows: weigh 4.0 g of sodium dodecyl sulfate (or 9.0 g of polysorbate 80) and place it in a volumetric bottle, add 700-800 ml of water to dissolve it, add 7.65 ml of hydrochloric acid, dilute with water to 1000 mL, mix well, degas, and obtain the product.

[0098] The dissolution medium is an aqueous solution of pH 4.5 containing 0.4% sodium dodecyl sulfate (or 0.9% polysorbate 80), and the preparation process is as follows: weigh 2.99g of sodium acetate and place it in a volumetric bottle, add 14ml of 2mol / L acetic acid solution, and dilute it to 400ml with water; weigh 4.0g of sodium dodecyl sulfate (or 9.0g polysorbate 80) and place it in another volumetric bottle, add 500ml of water to dissolve it, mix the solutions in the two volumetric bottles, dilute it to 1000ml with water, mix well, and degas to obtain the product.

[0099] The dissolution medium is an aqueous solution of pH 6.8 containing 0.4% sodium dodecyl sulfate (or 0.9% polysorbate 80), and the preparation process is as follows: weigh 6.0g of sodium dihydrogen phosphate and place it in a volumetric bottle, add 112ml of 0.2mol / L sodium hydroxide solution, and dilute it to 400ml with water; weigh another 4.0g of sodium dodecyl sulfate (or 9.0g polysorbate 80) and place it in another volumetric bottle, add 500ml of water to dissolve it, mix the solutions in the two volumetric bottles, dilute it to 1000ml with water, mix well, and degas to obtain the product.

[0100] When determining the dissolution curve of megestrol acetate oral suspension, due to different pH values, it is necessary to determine the dissolution curve of megestrol acetate oral suspension in each pH dissolution medium.

[0101] Step (2) Preparation of reference solution:

[0102] Accurately weigh about 18 mg of megestrol acetate reference substance into a 100 ml volumetric flask, add about 2.5 ml of methanol to dissolve it, dilute to the mark with the dissolution medium in step 1 to make a solution containing about 180 μg of megestrol acetate per 1 ml, shake well, and use it as the reference substance solution.

[0103] Step (3) Preparation of samples to be tested

[0104] The megestrol acetate suspension to be tested was shaken vigorously to fully mix the suspension, and then degassed under reduced pressure for 30-60 minutes to obtain a sample to be tested.

[0105] Step (4) Preparation of test solution:

[0106] Take the dissolution medium in step (1) and set the speed to 30 rpm according to the second method of dissolution determination (paddle method). Use a disposable syringe to draw about 20 ml of the freshly mixed suspension (sample solution) in step (3) and place it in a laboratory dual-channel syringe pump ( Fig. 9 As shown in the figure, use a silicone connecting hose to connect the syringe and the sampling needle (needle with an inner diameter of 1.5 mm), and fill the silicone connecting hose to the sampling needle with sample solution (without bubbles), fix the position of the sampling needle at 1.0 cm below the surface of the dissolution medium for sampling, and the sampling time is 10 seconds. When the temperature of the dissolution cup reaches 37±5℃, automatically add the sample and start timing. Take 5 ml of the solution at 5min, 10min, 15min, 20min, 30min, 45min, and 60min respectively. Filter the dissolution solution through a 0.45μm microporous filter membrane and take the filtrate as the test solution.

[0107] Step (5) Dissolution determination method:

[0108] The dissolution amount was determined by high performance liquid chromatography or ultraviolet spectrophotometry.

[0109] The chromatographic conditions of HPLC are:

[0110] Detector: UV detector;

[0111] Chromatographic column: ODS-3, 4.6mm×150mm, 5μm;

[0112] Detection wavelength: 292nm;

[0113] Column temperature: 35°C;

[0114] Mobile phase: acetonitrile-water (65:35) was used as the mobile phase;

[0115] Flow rate: 1.2ml / min.

[0116] The detection conditions of the ultraviolet spectrophotometry are: detection wavelength 292nm.

[0117] Step (6) Dissolution curve determination

[0118] Prepare the test solution according to step (3) and step (4), accurately measure 10 μl of the reference solution and the test solution, inject them into the liquid chromatograph, and record the chromatogram. Calculate the cumulative dissolution amount of megestrol acetate of the original preparation at 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, and 60 min by peak area according to the external standard method. Repeat the above steps twice, calculate the average cumulative dissolution amount of the original preparation at 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, and 60 min, and draw the dissolution curve of the original preparation in different pH dissolution media in step (1).

[0119] Step (7) Evaluation:

[0120] The similarity factor method was adopted to calculate the similarity factor f2 using the average cumulative dissolution data of the original preparation and the generic preparation at 5 min, 10 min, 15 min, 20 min, 30 min, 45 min and 60 min. The similarity factor f2 was used to compare the similarity between the dissolution curve of the generic preparation and the dissolution curve of the original preparation. When the value of the similarity factor f2 was used to judge the similarity, when the similarity factor f2 was greater than or equal to 50, the dissolution curves of the generic preparation and the original preparation were similar, and when the similarity factor f2 was less than 50, the dissolution curves of the generic preparation and the original preparation were not similar.

[0121] In further optimization schemes, the dissolution data of generic preparations and original preparations at four time points of 10, 15, 20 and 30 minutes can be preferentially selected to calculate the value of similarity factor f2. This can not only achieve the same effect, but also simplify the calculation process, making it easier to use the value of similarity factor f2 to compare the similarity between the dissolution curve of the generic preparation and the dissolution curve of the original preparation.

[0122] Example 3

[0123] According to a discriminating method for determining the dissolution curve of megestrol acetate suspension provided in Example 2, the dissolution curves of megestrol acetate oral suspension of the original preparation, different prescriptions, different processes and the final prescription process were determined, wherein:

[0124] In step (1), the dissolution medium used is 0.4% sodium dodecyl sulfate aqueous solution;

[0125] In step (5), the dissolution amount is determined by high performance liquid chromatography;

[0126] The dissolution results of the original preparation, different prescription preparations, different process preparations and the final prescription process preparation were obtained through the determination, see Table 3 and Figure 7 .

[0127] Table 3 Comparison of dissolution results of different preparations measured by the method of the present invention

[0128]

[0129] It can be seen from the measurement results that the dissolution curve method provided by the present invention has a good ability to distinguish megestrol acetate oral suspensions with different prescriptions and processes, and can effectively distinguish the differences caused by different batches of prescriptions and processes.

[0130] Example 4

[0131] According to the method for determining the dissolution curve of megestrol acetate suspension with discrimination provided in Example 2, the original preparation was first subjected to dissolution curve determination at different pH values, wherein:

[0132] In step (1), the dissolution media used are: the 0.4% sodium dodecyl sulfate aqueous solution described in Example 2, pH 1.2, containing 0.4% sodium dodecyl sulfate solution, pH 4.5, containing 0.4% sodium dodecyl sulfate solution, pH 6.8, containing 0.4% sodium dodecyl sulfate solution;

[0133] In step (5), the dissolution amount is determined by high performance liquid chromatography;

[0134] Through the determination, the dissolution curves of the original preparation in four dissolution media were obtained, such as Figure 8 As shown, it can be seen that the dissolution curves of the original preparation in the four dissolution media are very similar. The method provided by the present invention can be used as a reference for the dissolution curve of the original preparation to effectively evaluate the similarity and quality consistency of the generic preparation.

[0135] In a further example, according to a discriminating method for determining the dissolution curve of megestrol acetate suspension provided in Example 2, the dissolution curves of the final formulation process preparation in Example 3 in different pH dissolution media were determined, and the similarity of the original formulation and the final formulation process preparation was evaluated by the similarity factor f2. The results are shown in Table 4.

[0136] Table 4 Similarity evaluation between original preparations and self-made preparations

[0137]

[0138] Among them, the original preparation is the commercially available megestrol acetate oral suspension. Specification: 40mg / ml;

[0139] The prescription and proportion of the self-made preparation are the same as those of the original preparation, and the preparation process includes: adding water to megestrol acetate, polyethylene glycol 1450, polysorbate 80, xanthan gum, sucrose, sodium benzoate, citric acid (monohydrate), sodium citrate (dihydrate), lemon essence, etc., and mixing and homogenizing.

[0140] The present invention further replaces the sodium lauryl sulfate in Example 2-4 with polysorbate 80, and achieves substantially the same effect as that of Example 2-4.

[0141] In summary, the dissolution curve method of the present invention not only has good discrimination power, but can also be used to evaluate the effect of product formulation or process changes on the quality of megestrol acetate oral suspension, and predict the difference in in vivo bioequivalence of products, and can provide an in vitro basis for quality control and similarity evaluation of generic preparations.

Claims

1. A method for determining the dissolution curve of megestrol acetate suspension with discrimination, wherein: The method comprises the following steps: (1) Preparation of dissolution medium: comprising the step of dissolving a surfactant in water to prepare a dissolution medium, wherein the surfactant comprises sodium dodecyl sulfate or polysorbate 80, when the surfactant is sodium dodecyl sulfate, the mass concentration range of sodium dodecyl sulfate is 0.40% to 0.45%, when the surfactant is polysorbate 80, the mass concentration range of polysorbate 80 is 0.9% to 1.0%, and the rotation speed is set to 30 rpm; or, the surfactant is sodium dodecyl sulfate, the mass concentration range of sodium dodecyl sulfate is 0.40%, and the rotation speed is set to 35 rpm; (2) Preparation of the sample to be tested: the steps include taking the megestrol acetate oral suspension to be tested, shaking it thoroughly, and degassing it under reduced pressure to obtain the sample to be tested; (3) Dissolution amount determination: including adding the sample to be tested into the dissolution medium through an automatic sample adding device, performing the determination according to the dissolution apparatus paddle method, sampling at different sampling time points, and determining the dissolution amount at different time points; the sample adding position is 0.5-1.5 cm below the liquid surface of the dissolution medium; the inner diameter of the sample adding needle is 0.5 mm to 1.54 mm; the sample adding time is 10-15 s.

2. The method according to claim 1, wherein: Step (2) comprises vigorously shaking the megestrol acetate oral suspension to be tested to make the suspension fully shaken, and then degassing under reduced pressure for 30-60 minutes, with the vacuum degree maintained at -50 to -80 KPa, to obtain a sample to be tested.

3. The method according to claim 1, wherein: Step (3) includes adding the sample to be tested into the dissolution medium using an automatic sample adding device, wherein the automatic sample adding device is composed of at least a syringe, a syringe pump, a sample adding needle and a connecting hose.

4. The method according to claim 1, wherein: The sample volume in step (3) ranges from 0.5 ml to 10 ml.

5. The method according to claim 1, wherein: The sample addition position in step (3) is 1 cm below the liquid surface of the dissolution medium.

6. The method according to claim 1, wherein: The sampling time points of step (3) include 5min, 10min, 15min, 20min, 30min, 45min, and 60min.

7. The method according to claim 1, wherein: The dissolution amount determination method in step (3) includes high performance liquid chromatography or ultraviolet spectrophotometry.

8. The method according to any one of claims 1 to 7, wherein: The method comprises the following steps: (1) Preparation of dissolution medium: comprising dissolving a surfactant, sodium dodecyl sulfate or polysorbate 80, in water, wherein the concentration of sodium dodecyl sulfate is in the range of 0.40% to 0.45%, and the concentration of polysorbate 80 is in the range of 0.9% to 1.0%; (2) Preparation of the sample to be tested: taking the megestrol acetate oral suspension to be tested, shaking it thoroughly, and degassing it under reduced pressure for 30-60 minutes to obtain the sample to be tested; (3) Dissolution determination: The sample to be tested is added to the dissolution medium through an automatic sample adding device. 5-20 ml of the sample to be tested is measured by a syringe. The syringe and the sample adding needle are connected with a silicone connecting hose. The sample adding needle head is placed 0.5 cm to 1.5 cm below the liquid surface of the dissolution medium. The inner diameter of the sample adding needle is about 1.5 mm. The injection pump sample adding speed is adjusted so that the sample adding time is controlled within 10 to 15 s. The paddle speed of the dissolution apparatus is set to 30 rpm. Samples are taken at 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, and 60 min, respectively. The corresponding dissolution amount is determined by high performance liquid chromatography or ultraviolet spectrophotometry.

9. The method according to any one of claims 1 to 7, wherein: Step (1) further comprises the step of adjusting the pH value of the dissolution medium using a pH adjuster, wherein the pH adjuster is selected from a mixture of one or more of hydrochloric acid, phosphate, acetate, glacial acetic acid, sodium hydroxide and potassium hydroxide, and the amount of the pH adjuster is such that the pH value of the prepared dissolution medium is adjusted to 1.0 to 7.

0.

10. The method according to claim 9, wherein: Step (1) comprises dissolving a surfactant in water and then adding an appropriate pH adjuster to prepare a dissolution medium.

11. The method according to any one of claims 1 to 7, wherein: Step (1) comprises dissolving a surfactant in water to prepare a dissolution medium, and dissolving the surfactant in water without adding or further adding a pH adjuster to prepare the dissolution medium, so as to prepare the dissolution medium with a pH adjuster added in an amount of 0 and a pH value of the prepared dissolution medium adjusted to 1.2, 4.5 and 6.8, respectively, wherein the pH adjuster is selected from a mixture of one or more of hydrochloric acid, phosphate, acetate, glacial acetic acid, sodium hydroxide and potassium hydroxide.

12. The method according to any one of claims 1 to 7, wherein: Step (3) also includes drawing a dissolution curve based on the measured dissolution amount to evaluate the in vitro dissolution characteristics of the sample to be tested.

13. The method according to claim 12, wherein the evaluation method is performed using a similarity factor f2.

14. The method according to claim 12, wherein: The in vitro dissolution profile of the test sample is used to evaluate the effect of product formulation or process changes on the quality of megestrol acetate oral suspension.

15. The method according to claim 12, wherein: The in vitro dissolution profiles of the test samples are used to predict differences in the in vivo bioequivalence of the products.

16. The method according to any one of claims 1 to 7, wherein: The method also includes the step of preparing a reference solution, and in step (3), the reference and the sample to be tested are added to the dissolution medium via an automatic sample adding device, and the dissolution is respectively measured according to the dissolution apparatus paddle method, and samples are taken at different sampling time points to measure the dissolution amount at different time points.

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