In vitro release method of semisolid preparation for water-containing matrix

Abstract

The invention discloses an in-vitro release method of a semisolid preparation for a water-containing matrix, and relates to the technical field of in-vitro release, and the in-vitro release method comprises the following steps: S1, assembling an IVRT device which comprises a diffusion instrument, a receiving medium is added into the diffusion instrument, and the receiving medium comprises a salt buffer solution and an organic solvent; s2, controlling experiment conditions; s3, sampling is carried out, and the sampling mode comprises the step that after sampling is carried out each time, a receiving medium with the same volume as the taken sample needs to be added; and S4, analyzing the sample. According to the method, the organic solvent is added into the receiving medium to improve the solubility of the medicine in the in-vitro release test, meanwhile, the sampling mode is improved, the sampling mode in the embodiment comprises the steps that after sampling is conducted every time, the receiving medium with the same volume as the taken-out sample needs to be added, a diffusion pool does not need to be inclined in the sampling process, and the uniformity is improved.

Description

Technical Field

[0001] The invention relates to the technical field of in vitro release, and in particular to an in vitro release method for a semi-solid preparation containing a water matrix. Background Art

[0002] In Vitro Release Testing (IVRT) is an important method used to evaluate the drug release characteristics of semisolid preparations (such as creams, gels and other aqueous matrix drug preparations). This method can simulate the process of drug release from preparations into biological membranes such as skin or mucous membranes without involving organisms. IVRT is important for ensuring drug quality, performance consistency, and evaluating differences in preparations from different sources. IVRT is used to evaluate the drug release behavior of semisolid preparations, and is particularly suitable for those preparations that are difficult to evaluate through traditional in vivo tests. Through IVRT, researchers can compare drug release characteristics between different preparations, verify the "sameness" of preparations or detect differences, and perform prescription screening and optimization.

[0003] According to the guidelines of various countries, the receiving medium of IVRT needs to meet the sink conditions. Usually, the saturated solubility of the active ingredient in the selected receiving medium should be 3 to 10 times of 30% of the total amount of active ingredients in the supply pool. While meeting the sink conditions, in order to ensure the stability of the pH value of the receiving medium during the entire test process, a buffer solution is usually selected, but the active ingredients of conventional semi-solid preparations have low solubility or are almost insoluble in water. The guidelines recommend that organic solvents or surfactants can be added to increase the solubility of the active ingredient without affecting the form of the preparation. The use of organic solvents in IVRT experiments can easily cause reverse osmosis, diluting the semi-solid preparations and changing the state of the preparation. The EMA "Draft guideline on quality and equivalence of topical products" mentions that the reverse diffusion of the receiving medium should be minimized to avoid drug transformation.

[0004] Usually, the active ingredients of topical preparations have low water solubility, and a larger volume of receiving liquid is required to achieve the sink condition. Therefore, it is necessary to use a sampling method that takes out all the receiving liquid and then replenishes it to increase the volume of the receiving liquid. However, the sampling method that takes out all the receiving liquid requires tilting the diffusion cell to take samples, replenish the liquid, and remove bubbles side by side. During the tilting process, the semi-solid preparations with low viscosity in the supply cell will accumulate on one side, causing the dosing area to change and affecting the accuracy of the results. In addition, each time the sampling slot is tilted for sampling and replenishing the liquid, operations such as evacuating bubbles are required, which makes the test operation more cumbersome and complicated. Summary of the invention

[0005] In order to solve the above problems, the present invention provides an in vitro release method for a semi-solid preparation containing an aqueous matrix, which is achieved by the following technical scheme: comprising the following steps:

[0006] S1: assembling an IVRT device, wherein the IVRT device comprises a diffuser, wherein a receiving medium is added to the diffuser, and the receiving medium comprises a salt buffer and an organic solvent;

[0007] Specifically, a receiving medium is added to the diffusion instrument, and the medium includes a salt buffer and an organic solvent. The salt buffer is used to maintain the pH value of the receiving medium stable, while the organic solvent is used to increase the solubility of the active ingredient, thereby ensuring the effective release and detection of the drug. The selected organic solvent should be compatible with the preparation and the drug ingredients to avoid any adverse reactions or drug degradation. The salt buffer is usually composed of strong acid and weak base or weak acid and strong base salts, which can provide stable buffering capacity within a certain pH range, resist the interference of external acids and bases, and is suitable for experiments that need to simulate the in vivo environment.

[0008] S2: control experimental conditions;

[0009] Specifically, such as temperature, stirring speed, etc., to simulate the environment in which the drug is actually used. Usually, the temperature is controlled at 31-38°C to simulate the temperature of the human skin or mucosal surface. The stirring speed needs to be sufficient to maintain the concentration gradient in the receiving medium, but not too high to affect the release characteristics of the drug. In addition, the humidity of the environment needs to be monitored and controlled to ensure the accuracy of the test.

[0010] S3: taking samples;

[0011] At a predetermined time point, a certain volume of sample is taken out from the receiving medium and an equal volume of fresh medium is added. During the sampling process, the diffusion cell does not need to be tilted, thereby ensuring that the semi-solid preparation in the supply cell will not accumulate on one side due to tilting, resulting in a change in the dosing area, thereby improving uniformity.

[0012] Usually the volume of the diffusion cell is 10ml~50ml. In order to meet the detection demand without tilting the diffusion cell, the sampling volume range of the 10ml diffusion cell is 0.01ml~0.5ml, and the sampling volume range of the 50ml diffusion cell is 0.01ml~12.5ml. Therefore, the sampling volume range is 0.02~25% of the total volume of the receiving medium.

[0013] S4: Analyze samples.

[0014] Specifically, the sample taken out needs to be measured for drug concentration by appropriate analytical methods. Common analytical methods include high performance liquid chromatography (HPLC), ultraviolet-visible spectrophotometry (UV-Vis), etc. Through these analytical methods, the cumulative release of the drug can be quantitatively evaluated and a drug release curve can be drawn. These data can be used to evaluate the in vitro release characteristics of the preparation, such as release rate and release extent.

[0015] Preferably, the receiving medium further comprises a surfactant.

[0016] Specifically, the introduction of surfactants is to further improve the solubility and stability of drugs and optimize the release process of drugs from formulations to receiving media. Surfactants can reduce the interfacial tension between drugs and media, help improve the solubility of poorly soluble drugs, and thus ensure that the concentration of drugs throughout the release process can be accurately measured.

[0017] Surfactants, including various anionic surfactants such as (RCOO)nM, RO-SO 3 -M, R-SO 3 -M compounds, etc.; cationic surfactants such as quaternary ammonium compounds, etc.; zwitterionic surfactants such as lecithin, amino acid and betaine surfactants; non-ionic surfactants such as various types of fatty acid glycerides, sucrose fatty acid esters, fatty acid sorbitan, polysorbate, polyoxyethylene fatty acid values, polyoxyethylene fatty alcohol ethers, polyoxyethylene-polyoxypropylene polymers, etc., and various compounds with solubilizing effect.

[0018] Preferably, the concentration of the surfactant is 0 to 30 wt%. The selection of a surfactant concentration below 30 wt% is based on comprehensive considerations such as improving drug solubility, maintaining the stability of the formulation and the receiving medium, optimizing the uniformity of drug release, and considering cost and environmental impact. This concentration range helps to ensure the accuracy and reliability of the IVRT method, while providing effective support for drug development and quality control.

[0019] Preferably, the organic solvent includes various commonly used organic solvents such as aromatic hydrocarbons, aliphatic hydrocarbons, alicyclic hydrocarbons, halogenated hydrocarbons, alcohols, ethers, esters, ketones, glycol derivatives, acetonitrile, pyridine, etc. The concentration of the organic solvent is 10-50wt%. Although the organic solvent can improve the solubility of the drug, too high a concentration may affect the release kinetics of the drug, resulting in excessive release or instability under non-physiological conditions, such as severe reverse osmosis, and too low a concentration will affect the solubility of the drug. This concentration range can further reduce the reverse osmosis phenomenon while improving the solubility of the drug, and can even avoid the reverse osmosis phenomenon when used in conjunction with a surfactant.

[0020] Preferably, the experimental conditions include stirring the receiving medium during the test, and the stirring speed is 200 to 600 rpm. Appropriate stirring can ensure the uniformity of the drug concentration in the receiving medium and prevent the drug from being over-concentrated or diluted in a local area. It helps to maintain the drug concentration gradient from the donor chamber to the receiving medium, thereby ensuring the sustained release of the drug. Stirring helps to increase the solubility and diffusion rate of drug molecules in the receiving medium. By maintaining a certain stirring speed, the transfer of drugs from semi-solid preparations to the receiving medium can be accelerated, thereby improving the release efficiency. Excessively high stirring speeds may cause local overheating of the receiving medium or the generation of bubbles, affecting the stable release of the drug. These adverse effects can be avoided by limiting the stirring speed to a range of 200 to 600 rpm.

[0021] Preferably, in S3, the sampling method includes adding a receiving medium with the same volume as the sample taken out after each sampling. The purpose is to maintain a constant volume of the receiving medium, thereby ensuring the continuity of the drug release test and the accurate determination of the drug concentration. Specifically, by supplementing a receiving medium with the same volume as the sample taken out, a constant gradient of drug concentration in the receiving medium can be maintained. This is crucial for simulating the continuous diffusion process of the drug from the donor chamber to the receiving medium, ensuring that the kinetic properties of drug release can be accurately evaluated. Supplementing the receiving medium helps to avoid the effect of volume changes caused by sampling on the drug release rate, and can ensure that after each sampling, the drug concentration in the receiving medium can accurately reflect the actual release of the drug. Under physiological conditions, the release and absorption of drugs is a dynamic process. By supplementing the receiving medium after each sampling, this dynamic balance can be simulated, so that the results of the in vitro release test are closer to the actual situation in vivo.

[0022] Preferably, the sampling volume each time is 0.02-25% of the total volume of the receiving medium. A larger sampling ratio may require tilting the diffusion cell to remove bubbles, thereby affecting the parallelism of drug release. By using an appropriate sampling ratio, this effect can be minimized to ensure the natural and continuous drug release process.

[0023] Preferably, the diffuser is a vertical diffuser, and the diffusion cell type includes, for example, USP <1724> Various types of diffusion cells mentioned in.

[0024] Preferably, the IVRT device comprises a filter membrane having a receiving medium on one side and a semi-solid formulation on the other side.

[0025] The membrane has a specific pore size and properties, allowing drug molecules to pass through while preventing macromolecules or particulate matter in the semi-solid preparation from entering the receiving medium. This ensures that the receiving medium contains only the released drug without interference from other components. Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0026] (1) The present invention improves the sampling method while adding an organic solvent to the receiving medium to improve the solubility of the drug in the in vitro release test. The sampling method of the embodiment of the present invention includes adding a receiving medium with the same volume as the sample taken out after each sampling. During the sampling process, the diffusion cell does not need to be tilted, thereby improving uniformity.

[0027] (2) Under the premise of the above sampling method, the concentration of the organic solvent is reduced to below 50wt%, which not only ensures the solubility of the drug but also reduces the reverse osmosis phenomenon.

[0028] The present invention sets the receiving medium to include a salt buffer, a surfactant and an organic solvent, and limits the concentration of each within a certain range. The resulting release method not only has high uniformity, but also has no reverse osmosis phenomenon. At the same time, the concentration of the organic solvent can be reduced to the greatest extent, eliminating the reverse osmosis phenomenon while ensuring the solubility of the drug.

[0029] (3) The present invention sets the receiving medium to include salt buffer, surfactant and organic solvent, which increases the solubility of the poorly soluble semi-solid preparation, and can achieve the sink condition in a smaller volume. There is no need to tilt the diffusion cell for complete sampling, rehydration and exhaust operations, and only partial sampling and rehydration are required, making the IVRT test operation simpler. At the same time, under the premise of meeting the uniformity, when the concentration of the surfactant is 0.5-2wt% and the concentration of the organic solvent is 10wt%, the drug can also achieve sufficient solubility and no reverse osmosis phenomenon will occur. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] In order to more clearly illustrate the technical solutions of the exemplary embodiments of the present invention, the following briefly introduces the drawings required for use in the embodiments. It should be understood that the following drawings only illustrate certain embodiments of the present invention and should not be regarded as limiting the scope. For those of ordinary skill in the art, other relevant drawings can be obtained based on these drawings without creative work. In the drawings:

[0031] Figure 1 It is the graph of the change of release rate over time in Comparative Example 1;

[0032] Figure 2 The release rate in Example 1 changes with time;

[0033] Figure 3 The release rate in Example 2 changes with time;

[0034] Figure 4 The release rate in Example 3 changes with time;

[0035] Figure 5The graph showing the change of release rate over time in Example 4;

[0036] Figure 6 The release rate in Example 5 changes with time;

[0037] Figure 7 The graph showing the change of release rate over time in Example 7;

[0038] Figure 8 The release rate in Example 8 changes with time;

[0039] Fig. 9 This is a graph showing the change in release over time in Example 9. DETAILED DESCRIPTION

[0040] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments.

[0041] Therefore, the following detailed description of the embodiments of the present invention provided in the accompanying drawings is not intended to limit the scope of the invention claimed for protection, but merely represents selected embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0042] It should be noted that similar reference numerals and letters denote similar items in the following drawings, and therefore, once an item is defined in one drawing, further definition and explanation thereof is not required in subsequent drawings.

[0043] The present invention provides an in vitro release method for a semi-solid preparation containing an aqueous matrix, comprising the following steps:

[0044] S1: Assemble an IVRT device, wherein the IVRT device comprises a diffuser, a receiving medium is added to the diffuser, the receiving medium comprises a salt buffer, an organic solvent and / or a surfactant, the concentration of the surfactant is 0 to 30 wt%, and the concentration of the organic solvent is 10 to 50 wt%; the diffuser is a vertical diffuser; the IVRT device comprises a filter membrane, one side of the filter membrane is the receiving medium, and the other side is the semi-solid preparation.

[0045] S2: Controlling the experimental conditions, wherein the experimental conditions include a release temperature of 31 to 38° C., and the experimental conditions include stirring the receiving medium during the test, and the stirring speed is 200 to 600 rpm.

[0046] S3: Sampling is performed, wherein the sampling method includes adding a receiving medium with the same volume as the sample after each sampling, and the sampling volume each time is 0.02-25% of the total volume of the receiving medium.

[0047] S4: Analyze samples.

[0048] Among them, according to the guidelines of various countries, the receiving medium of IVRT needs to meet the sink condition. Usually, the saturated solubility of the active ingredient in the selected receiving medium should be 3 to 10 times of 30% of the total amount of active ingredients in the supply pool. While meeting the sink condition, in order to ensure the stability of the pH value of the receiving medium during the entire test process, a buffer solution is usually selected, but the active ingredients of conventional semi-solid preparations have low solubility or are almost insoluble in water. The guidelines recommend that organic solvents or surfactants can be added to increase the solubility of the active ingredient without affecting the form of the preparation. However, the use of organic solvents in IVRT experiments can easily cause reverse osmosis, dilute the semi-solid preparation, and change the state of the preparation. EMA's "Draft guideline on quality and equivalence of topical products" mentions that the reverse diffusion of the receiving medium should be minimized to avoid drug conversion.

[0049] At the same time, the active ingredients of topical preparations usually have low water solubility, while the volume of the receiving pool of the IVRT experiment is small, usually 10 to 50 ml, and it is difficult for the receiving medium to reach the leakage condition. Therefore, it is necessary to use a sampling method of taking out all the receiving liquid and then replenishing the liquid to increase the volume of the receiving liquid. However, the method of taking out all the receiving liquid requires tilting the diffusion pool and then replenishing the liquid to exhaust the bubbles. During the tilting process, the semi-solid preparation with lower viscosity in the supply pool will accumulate on one side, and the dosing area will change, affecting the accuracy of the results. In order to solve the above problems, the embodiments of the present invention will be studied.

[0050] It should be noted that according to the FDA guidelines (In Vitro Release Test Studies for Topical Drug Products Submitted in ANDAs, Guidance for Industry, DRAFT GUIDANCE), the slope of the IVRT curve R 2 ≥0.97, RSD≤15%, R 2 The smaller the two data are, the better the data linearity is and the better the batch uniformity is.

[0051] Comparative Example 1

[0052] Provided is an in vitro release method for a semi-solid preparation containing an aqueous matrix, comprising the following:

[0053] 1) IVRT method parameters:

[0054] Instrument: vertical transdermal diffusion instrument, temperature: 32℃±1℃, stirring speed: 200rpm;

[0055] 2) Receiving medium: ethanol-buffer (50wt%:50wt%), one experiment is usually carried out in parallel with 6 samples.

[0056] 3) Specific operations:

[0057] I. After the diffusion cell is assembled, add about 20 ml of receiving medium, heat to 32℃±1℃, start stirring, and rotate at 200rpm; II. Cut the filter membrane to a suitable size, and use PVDF filter membrane; III. Weigh the sample on the filter membrane; IV. Add the sample to the diffusion cell; V. Add the remaining medium;

[0058] 4) Sampling method: Take out all the liquid in the receiving pool and then add the same volume of receiving liquid. During this process, the diffusion pool needs to be tilted and exhaust needs to be performed after liquid addition;

[0059] The test results are shown in Table 1 and Figure 1 As shown:

[0060] Table 1

[0061] serial number Slope <![CDATA[R 2 ]]> Whether reverse osmosis 1 20.6015 0.9643 yes 2 7.765 0.9888 yes 3 14.4693 0.9613 yes 4 7.0995 0.9197 yes 5 22.5866 0.9284 yes 6 12.3772 0.9941 yes RSD(%) 45.5 / /

[0062] From Table 1 and Figure 1 It can be seen that when the receiving medium is ethanol-buffer (50wt%:50wt%), reverse osmosis will occur. The full-take and full-replenishment method will cause the preparation to tilt to one side, resulting in a change in the dosing area. Therefore, the RSD of the result is much greater than the limit, and the parallelism of the result is poor. 2 It does not meet the requirements, and there are several sets of data R 2 Low (Groups 4 and 5).

[0063] Example 1

[0064] Provided is an in vitro release method for a semi-solid preparation containing an aqueous matrix, comprising the following:

[0065] 1) IVRT method parameters:

[0066] Instrument: vertical transdermal diffusion instrument, temperature: 32℃±1℃, stirring speed: 200rpm;

[0067] 2) Receiving medium: ethanol-buffer (50wt%:50wt%), one experiment is usually carried out in parallel with 6 samples.

[0068] 3) Specific operations:

[0069] I. After the diffusion cell is assembled, add about 20 ml of receiving medium, heat to 32℃±1℃, start stirring, and rotate at 200rpm; II. Cut the filter membrane to a suitable size, and use PVDF filter membrane; III. Weigh the sample on the filter membrane; IV. Add the sample to the diffusion cell; V. Add the remaining medium;

[0070] 4) Sampling method: 1.5 ml of sample is taken each time, and 1.5 ml of liquid is replenished after sampling; there is no need to tilt the diffusion cell during the sampling process.

[0071] The test results are shown in Table 2 and Figure 2 As shown:

[0072] Table 2

[0073] serial number Slope <![CDATA[R 2 ]]> Whether reverse osmosis 1 10.6804 0.9612 yes 2 9.4388 0.9653 yes 3 6.6082 0.9878 yes 4 9.2888 0.9539 yes 5 9.4366 0.9683 yes 6 7.6266 0.9726 yes RSD(%) 16.6 / /

[0074] After changing the sampling method to sampling 1.5ml and replenishing 1.5ml, the uniformity of the results within the batch was significantly improved, and R 2 The data are also more homogeneous, with no significantly lower R 2 value, but still did not improve the reverse osmosis phenomenon.

[0075] Example 2

[0076] Provided is an in vitro release method for a semi-solid preparation containing an aqueous matrix, comprising the following:

[0077] 1) IVRT method parameters:

[0078] Instrument: vertical transdermal diffusion instrument, temperature: 32℃±1℃, stirring speed: 200rpm;

[0079] 2) Receiving medium: ethanol-buffer (50wt%:50wt%), one experiment is usually carried out in parallel with 6 samples.

[0080] 3) Specific operations:

[0081] I. After the diffusion cell is assembled, add about 20 ml of receiving medium, heat to 32℃±1℃, start stirring, and rotate at 200rpm; II. Cut the filter membrane to a suitable size, and use PVDF filter membrane; III. Weigh the sample on the filter membrane; IV. Add the sample to the diffusion cell; V. Add the remaining medium;

[0082] 4) Sampling method: 1 ml of sample is taken each time and 1 ml of liquid is replenished after sampling; there is no need to tilt the diffusion cell during the sampling process.

[0083] The test results are shown in Table 3 and Figure 3 As shown:

[0084] Table 3

[0085]

[0086]

[0087] After changing the sampling method to sampling 1 ml and replenishing 1 ml, the uniformity of the results within the batch was also improved, and the RSD met the requirement of less than or equal to 15%, and R 2 The data all meet the requirement of greater than 0.97, and the data uniformity can meet the requirements of the current guidelines, but reverse osmosis still exists.

[0088] Example 3

[0089] Provided is an in vitro release method for a semi-solid preparation containing an aqueous matrix, comprising the following:

[0090] 1) IVRT method parameters:

[0091] Instrument: vertical transdermal diffusion instrument, temperature: 32℃±1℃, stirring speed: 200rpm;

[0092] 2) Receiving medium: ethanol-buffer (50wt%:50wt%), one experiment is usually carried out in parallel with 4.

[0093] 3) Specific operations:

[0094] I. After the diffusion cell is assembled, add about 20 ml of receiving medium, heat to 32℃±1℃, start stirring, and rotate at 200 rpm; II. Cut the filter membrane to a suitable size, and use a nylon filter membrane; III. Weigh the sample on the filter membrane; IV. Add the sample to the diffusion cell; V. Add the remaining medium;

[0095] 4) Sampling method: 1 ml for each sample and 1 ml for each refill; there is no need to tilt the diffusion cell during the sampling process.

[0096] The test results are shown in Table 4 and Figure 4 As shown:

[0097] Table 4

[0098] serial number Slope <![CDATA[R 2 ]]> Whether reverse osmosis 1 4.4489 0.9855 yes 2 3.3682 0.9900 yes 3 3.791 0.9752 yes 4 3.794 0.9930 yes RSD(%) 11.6 / /

[0099] After replacing the filter membrane with a nylon filter membrane, RSD and R 2 The data all meet the requirements, but reverse osmosis still exists.

[0100] Example 4

[0101] Provided is an in vitro release method for a semi-solid preparation containing an aqueous matrix, comprising the following:

[0102] 1) IVRT method parameters:

[0103] Instrument: vertical transdermal diffusion instrument, temperature: 32℃±1℃, stirring speed: 200rpm;

[0104] 2) Receiving medium: ethanol-buffer (50wt%:50wt%), one experiment is usually carried out in parallel with 4.

[0105] 3) Specific operations:

[0106] I. After the diffusion cell is assembled, add about 20 ml of receiving medium, heat to 32℃±1℃, start stirring, and rotate at 200 rpm; II. Cut the filter membrane to a suitable size, and use PTFE filter membrane; III. Weigh the sample on the filter membrane; IV. Add the sample to the diffusion cell; V. Add the remaining medium;

[0107] 4) Sampling method: 1 ml for each sample and 1 ml for each refill; there is no need to tilt the diffusion cell during the sampling process.

[0108] The test results are shown in Table 5 and Figure 5 As shown:

[0109] Table 5

[0110] serial number Slope <![CDATA[R 2 ]]> Whether reverse osmosis 1 4.9935 0.9943 yes 2 4.731 0.9825 yes 3 5.2943 0.9764 yes 4 5.9209 0.9893 yes RSD(%) 9.8 / /

[0111] After replacing the filter membrane with PTFE filter membrane, RSD and R 2 The data all meet the requirements, but reverse osmosis still exists.

[0112] Example 5

[0113] Provided is an in vitro release method for a semi-solid preparation containing an aqueous matrix, comprising the following:

[0114] 1) IVRT method parameters:

[0115] Instrument: vertical transdermal diffusion instrument, temperature: 32℃±1℃, stirring speed: 200rpm;

[0116] 2) Receiving medium: ethanol-buffer (50wt%:50wt%), one experiment is usually carried out in parallel with 6 samples.

[0117] 3) Specific operations:

[0118] I. After the diffusion cell is assembled, add about 20 ml of receiving medium, heat to 32℃±1℃, start stirring, and rotate at 200 rpm; II. Cut the filter membrane to a suitable size, and use PES filter membrane; III. Weigh the sample on the filter membrane; IV. Add the sample to the diffusion cell; V. Add the remaining medium;

[0119] 4) Sampling method: 1 ml for each sample and 1 ml for each refill; there is no need to tilt the diffusion cell during the sampling process.

[0120] The test results are shown in Table 6 and Figure 6 As shown:

[0121] Table 6

[0122]

[0123]

[0124] After replacing the filter membrane with a PES filter membrane, the RSD data met the requirements, but there was still reverse osmosis. In summary, the use of filter membranes of various materials did not affect the results, indicating that when the receiving medium was only ethanol-buffer (50wt%: 50wt%), replacing the filter membrane could not achieve the purpose of solving the reverse osmosis phenomenon. However, the use of partial sampling can make the diffusion pool unnecessary to tilt, and the dosage area of ​​the preparation does not change, which can significantly improve the problem of poor uniformity within and between batches, and can improve the problem of poor linearity of the curve.

[0125] Example 6

[0126] Provided is an in vitro release method for a semi-solid preparation containing an aqueous matrix, comprising the following:

[0127] 1) IVRT method parameters:

[0128] Instrument: vertical transdermal diffusion instrument, temperature: 32℃±1℃, stirring speed: 200rpm;

[0129] 2) Receiving medium: ethanol-buffered solution. One experiment is usually performed in parallel with 6 samples.

[0130] 3) Specific operations:

[0131] I. After the diffusion cell is assembled, add about 20 ml of receiving medium, heat to 32℃±1℃, start stirring, and rotate at 200 rpm; II. Cut the filter membrane to a suitable size, and use PES filter membrane; III. Weigh the sample on the filter membrane; IV. Add the sample to the diffusion cell; V. Add the remaining medium;

[0132] 4) Sampling method: 1 ml for each sample and 1 ml for each refill; there is no need to tilt the diffusion cell during the sampling process.

[0133] The results are shown in Table 7 below:

[0134] Table 7

[0135] Ethanol ratio (%) Whether reverse osmosis 0 no 10 no 20 no 30 no 40 no 45 no 46 no 48 no 49 no 50 yes

[0136] Conclusion: It was found that reverse osmosis would occur when the proportion of ethanol added reached more than 50%, so it is necessary to reduce the amount of organic solvent added while ensuring solubility.

[0137] The solubility of the receiving medium to the sample will be investigated below, specifically, as shown in Table 8 below:

[0138] Table 8

[0139]

[0140]

[0141] Conclusion: After the receiving medium was adjusted from a high-proportion organic solvent medium to a surfactant + organic solvent + buffer or surfactant + buffer system, the amount of organic solvent added was greatly reduced, and the solubility of the active ingredient was significantly increased, which could meet the sink conditions.

[0142] Example 7

[0143] Provided is an in vitro release method for a semi-solid preparation containing an aqueous matrix, comprising the following:

[0144] 1) IVRT method parameters:

[0145] Instrument: vertical transdermal diffusion instrument, temperature: 32℃±1℃, stirring speed: 200rpm;

[0146] 2) Receiving medium: 10 wt% anhydrous ethanol + 2 wt% Tween 80 + buffer. One experiment is usually conducted in parallel with 4 samples.

[0147] 3) Specific operations:

[0148] I. After the diffusion cell is assembled, add about 20 ml of receiving medium, heat to 32℃±1℃, start stirring, and rotate at 200 rpm; II. Cut the filter membrane to a suitable size, and use PES filter membrane; III. Weigh the sample on the filter membrane; IV. Add the sample to the diffusion cell; V. Add the remaining medium;

[0149] 4) Sampling method: 1 ml for each sample and 1 ml for each refill; there is no need to tilt the diffusion cell during the sampling process.

[0150] The test results are shown in Table 9 and Figure 7 As shown:

[0151] Table 9

[0152] serial number Slope <![CDATA[R 2 ]]> Whether reverse osmosis 1 5.0825 0.9919 no 2 4.1646 0.9777 no 3 4.6129 0.9838 no 4 4.4014 0.9908 no RSD(%) 7.0 / /

[0153] After the receiving medium was adjusted to organic solvent + surfactant + buffer, the reverse osmosis phenomenon was significantly improved. There was no reverse osmosis in each group of diffusion cells, and the RSD and R 2 The results all met the requirements, indicating that the uniformity and linearity were good.

[0154] Example 8

[0155] Provided is an in vitro release method for a semi-solid preparation containing an aqueous matrix, comprising the following:

[0156] 1) IVRT method parameters:

[0157] Instrument: vertical transdermal diffusion instrument, temperature: 32℃±1℃, stirring speed: 200rpm;

[0158] 2) Receiving medium: 10 wt% anhydrous ethanol + 0.5 wt% Tween 80 + buffer. One experiment is usually conducted in parallel with 4 samples.

[0159] 3) Specific operations:

[0160] I. After the diffusion cell is assembled, add about 20 ml of receiving medium, heat to 32℃±1℃, start stirring, and rotate at 200 rpm; II. Cut the filter membrane to a suitable size, and use PES filter membrane; III. Weigh the sample on the filter membrane; IV. Add the sample to the diffusion cell; V. Add the remaining medium;

[0161] 4) Sampling method: 1 ml for each sample and 1 ml for each refill; there is no need to tilt the diffusion cell during the sampling process.

[0162] The test results are shown in Table 9 and Figure 8 As shown:

[0163] Table 9

[0164] serial number Slope <![CDATA[R 2 ]]> Whether reverse osmosis 1 1.4228 0.9929 no 2 1.4137 0.9915 no 3 1.5633 0.9977 no 4 1.5194 0.9987 no RSD(%) 9.6 / /

[0165] When the surfactant addition ratio was adjusted from 2% to 0.5%, there was still no reverse osmosis in the diffusion cells of each group, and the RSD and R 2 The results are in line with the requirements and the methods are in line with the requirements.

[0166] Example 9

[0167] Provided is an in vitro release method for a semi-solid preparation containing an aqueous matrix, comprising the following:

[0168] 1) IVRT method parameters:

[0169] Instrument: vertical transdermal diffusion instrument, temperature: 32℃±1℃, stirring speed: 200rpm;

[0170] 2) Receiving medium: 10 wt% ethanol + 0.5 wt% polyethylene glycol monooleate + buffer. One experiment is usually conducted in parallel with 6 samples.

[0171] 3) Specific operations:

[0172] I. After the diffusion cell is assembled, add about 20 ml of receiving medium, heat to 32℃±1℃, start stirring, and rotate at 200 rpm; II. Cut the filter membrane to a suitable size, and use PES filter membrane; III. Weigh the sample on the filter membrane; IV. Add the sample to the diffusion cell; V. Add the remaining medium;

[0173] 4) Sampling method: 1 ml for each sample and 1 ml for each refill; there is no need to tilt the diffusion cell during the sampling process.

[0174] The test results are shown in Table 10 and Fig. 9 As shown:

[0175] Table 10

[0176]

[0177]

[0178] Changing the surfactant type and replacing Tween with polyethylene glycol monooleate, there was still no reverse osmosis in the diffusion cells of each group, and the RSD and R 2 The results are in line with the requirements and the methods are in line with the requirements.

[0179] The specific implementation methods described above further illustrate the objectives, technical solutions and beneficial effects of the present invention in detail. It should be understood that the above description is only a specific implementation method of the present invention and is not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. An in vitro release method for a semisolid preparation containing an aqueous matrix, characterized in that The following steps are involved: S1: assembling an IVRT device, wherein the IVRT device comprises a diffuser, wherein a receiving medium is added to the diffuser, and the receiving medium comprises a salt buffer and an organic solvent; S2: control experimental conditions; S3: Sampling, wherein the sampling method includes adding a receiving medium with the same volume as the sample taken out after each sampling; S4: Analyze samples.

2. The in vitro release method for a semi-solid preparation containing an aqueous matrix according to claim 1, characterized in that: The concentration of the organic solvent is lower than 50 wt %.

3. The in vitro release method for a semi-solid preparation containing an aqueous matrix according to claim 2, characterized in that: The receptor medium also includes a surfactant.

4. The in vitro release method for a semi-solid preparation containing an aqueous matrix according to claim 2, characterized in that: The concentration of the surfactant is 0-30 wt %.

5. The in vitro release method for a semi-solid preparation containing an aqueous matrix according to claim 1, characterized in that: The concentration of the organic solvent is greater than or equal to 10 wt %.

6. The in vitro release method for a semi-solid preparation containing an aqueous matrix according to claim 5, characterized in that: The experimental conditions described in S2 include a release temperature of 31°C to 38°C.

7. The in vitro release method for a semi-solid preparation containing an aqueous matrix according to claim 1, characterized in that: The experimental conditions include stirring the receiving medium during the test, and the stirring speed is 200-600 rpm.

8. The in vitro release method for a semi-solid preparation containing an aqueous matrix according to claim 7, characterized in that: The sampling volume each time is 0.02-25% of the total volume of the receiving medium.

9. The in vitro release method for a semi-solid preparation containing an aqueous matrix according to claim 1, characterized in that: The diffuser is a vertical diffuser.

10. The in vitro release method for a semi-solid preparation containing an aqueous matrix according to claim 1, characterized in that: The IVRT device includes a filter membrane with a receiving medium on one side and a semi-solid formulation on the other side.

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