CN116338119A - Determination method for in-vitro release degree of letrozole inclusion compound solution - Google Patents
Determination method for in-vitro release degree of letrozole inclusion compound solution Download PDFInfo
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- letrozole
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 91
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 title claims abstract description 86
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
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- G—PHYSICS
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- G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
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Abstract
The method for measuring the in-vitro release rate of the letrozole inclusion compound solution comprises the steps of diluting the letrozole inclusion compound solution with hydroxyethyl starch solution, adding the diluted solution into a dialysis bag, putting the dialysis bag into a release medium, stirring or oscillating by a stirring or oscillating instrument, heating in a water bath, and carrying out an in-vitro release rate test of the letrozole inclusion compound solution; the release medium was withdrawn at various time points, the concentration of letrozole in the withdrawn release medium was determined, and the in vitro release of letrozole inclusion compound solution was calculated. The provided determination method can effectively distinguish the in vitro release degree difference of the letromycin clathrate compound of different cyclodextrin formulations, and can be used for prescription screening and quality evaluation of letromycin.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a method for measuring the in-vitro release rate of a letrozole inclusion compound solution.
Background
Letrozole is a novel non-nucleoside Cytomegalovirus (CMV) inhibitor (3, 4-dihydroquinazoline). Has novel CMV resisting effect, and can inhibit the processing and packaging of virus DNA by inhibiting the activity of cytomegalovirus terminal enzyme complex, thereby exerting antiviral effect. Unlike DNA polymerase inhibitors, letromycin has higher CMV selectivity and obviously improved action intensity. Is also the first and currently only drug approved worldwide for the prevention of cytomegalovirus infection in allogeneic hematopoietic stem cell transplant recipients. Lays a foundation for the preventive treatment mode of cytomegalovirus, and provides a new choice for doctors to solve the related problems of cytomegalovirus in the hematopoietic stem cell transplantation process and improve the overall treatment effect of patients by advancing the prevention and control port of the virus.
Methyl beta-cyclodextrin, hydroxyethyl beta-cyclodextrin, hydroxypropyl beta-cyclodextrin and sulfobutyl beta-cyclodextrin are taken as inclusion compounds to be a cyclic oligosaccharide, are in a truncated cone shape, and can wrap hydrophobic drug molecules with proper molecular size and polarity to different degrees. The inclusion compound can improve the chemical stability, membrane permeability and bioavailability of the medicine. This technology has been demonstrated to improve the solubility and dissolution of a variety of drugs.
The letrozole has low solubility, and the solution of the letrozole inclusion compound is prepared by adopting methyl betacyclodextrin, hydroxyethyl betacyclodextrin, hydroxypropyl betacyclodextrin, sulfobutyl betacyclodextrin and the like, so that the solubility of the letrozole can be improved. Letrepyrr can exert the drug effect in vivo after being released into blood from cyclodextrin inclusion compound molecules. A method that effectively distinguishes between different formulations of letrozole inclusion complex solutions would facilitate development and quality assessment of letrozole formulation products.
Disclosure of Invention
Based on the related technical background and problems, in order to effectively distinguish the difference of the letrozole inclusion compound solutions prepared by different prescription processes, an in-vitro release degree measuring method of the letrozole inclusion compound solution is established, the purposes of rapidly characterizing product characteristics and controlling product quality are achieved, and the application provides a method for measuring the in-vitro release degree of the letrozole inclusion compound solution.
In one aspect, the present application provides a method for determining the in vitro release of a solution of letrozole inclusion complex, comprising the steps of:
1) Diluting the Tetemovir inclusion compound solution with hydroxyethyl starch solution, adding the diluted Tetemovir inclusion compound solution into a dialysis bag, then placing the dialysis bag into a release medium, stirring or oscillating by a stirring or oscillating instrument, heating in water bath, and performing in-vitro release degree test of the Tetemovir inclusion compound solution;
2) Taking out the release medium at a set time point, measuring the concentration of the letrozole in the taken-out release medium, and calculating the in vitro release degree of the letrozole inclusion compound solution.
Compared with the prior art, the beneficial effects of this application are: the release rate of the letromycin inclusion compound solution is creatively tested directly through a dissolution instrument or an oscillation instrument, drug molecules and inclusion components are selectively separated by utilizing a dialysis bag with specific permeability, and meanwhile, a specific diluent (containing 3% -8% of hydroxyethyl starch solution (W/V)) is matched, so that the release rate is regulated, and the purposes of rapidly distinguishing the differences among different formulation letromycin inclusion compounds, guiding the development of preparation products and controlling the quality of the products are realized.
Additional features and advantages of the application will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the application. Other advantages of the present application may be realized and attained by the structure particularly pointed out in the written description and drawings.
Drawings
The accompanying drawings are included to provide an understanding of the technical aspects of the present application, and are incorporated in and constitute a part of this specification, illustrate the technical aspects of the present application and together with the examples of the present application, and not constitute a limitation of the technical aspects of the present application.
Figure 1 is an in vitro release profile of a letrozole inclusion complex solution of example 1 of the present application.
Figure 2 is an in vitro release profile of the letrozole inclusion complex solution of example 2 herein.
Figure 3 is an in vitro release profile of the letrozole inclusion complex solution of example 3 herein.
Figure 4 is an in vitro release profile of the letrozole inclusion complex solution of example 4 of the present application.
Figure 5 is an in vitro release profile of the letrozole inclusion complex solution of example 5 of the present application.
Figure 6 is an in vitro release profile of the letrozole inclusion complex solution of example 6 of the present application.
Detailed Description
General terms and definitions
Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. When an amount, concentration, or other value or parameter is expressed as a range, a preferred range, or an upper preferable range value, and a lower preferable range value, this is to be understood as equivalent to any range specifically disclosed by combining any pair of upper range values or preferred range values with any lower range value or preferred range value, regardless of whether the range is specifically disclosed. Unless otherwise indicated, the numerical ranges set forth herein are intended to include the endpoints of the ranges and all integers and fractions (fractions) within the range.
The terms "about", "about" when used in conjunction with a numerical variable generally refer to the value of the variable and all values of the variable being within experimental error (e.g., within a confidence interval of 95% for the average) or within + -10% of the specified value, or more broadly.
The term "metering ratio" is to mix various substances according to a certain weight.
The expression "comprising" or similar expressions "including", "containing" and "having" etc. synonymously therewith are open ended and do not exclude additional unrecited elements, steps or components. The expression "consisting of …" excludes any element, step or ingredient not specified. The expression "consisting essentially of …" means that the scope is limited to the specified elements, steps, or components, plus any elements, steps, or components that are optionally present that do not materially affect the basic and novel characteristics of the claimed subject matter. It should be understood that the expression "comprising" encompasses the expressions "consisting essentially of …" and "consisting of …".
The expression "at least one" or "one (or more)" means 1, 2, 3,4, 5, 6, 7, 8, 9 (or more(s).
The term "clathrate" as used herein refers to a complex in which the molecular structure of one drug is wholly or partially entrapped in the molecular cavity of another substance to form a unique form. Clathrate compounds are active in the field of pharmaceutical formulation research, and in the 50 s of the 20 th century researchers have recognized that clathrate compounds have an effect on the properties of drugs, such as increasing the solubility and stability of drugs, affecting the absorption, distribution and onset time of drugs in vivo, etc.
As used herein, the unit "W/V" refers to g/mL.
The term "inclusion component" as used herein refers to a substance that encapsulates all or part of the structure of a drug molecule into its molecular cavity, such as methyl betacyclodextrin, hydroxyethyl betacyclodextrin, hydroxypropyl betacyclodextrin, sulfobutyl betacyclodextrin as described herein.
The term "dissolution rate" as used herein refers to the rate at which a drug is dissolved from a solid formulation in a prescribed solvent. The term "dissolution" refers to the rate and extent of dissolution of a drug from a solid formulation in a defined solvent.
The term "release profile" as used herein refers to the rate and extent of release of an oral drug from a sustained release formulation, a controlled release formulation or an enteric formulation in a defined solvent. In vitro release test is to measure the drug release rate of the preparation under the condition of simulating the digestive tract in vivo (such as temperature, pH value of medium, stirring rate, etc.), and finally to make reasonable in vitro drug release standard so as to monitor the production process of the product and control the quality of the product. In-vivo and in-vitro correlation studies are combined, and the release degree can predict in-vivo behaviors of the product to a certain extent.
The term "release medium" as used herein refers to a liquid medium into which the active substance is released. Examples of release media may be water, simulated intestinal fluid, simulated gastric fluid, simulated saliva, or true physiological forms of these fluids, water, and various buffer solutions.
The term "release profile" as used herein refers to the change in concentration of a substance to be measured over time.
The term "molecular weight cut-off (MWCO: molecular weight cutoff)" as used herein is the retention property of an ultrafiltration membrane expressed in terms of molecular weight, also known as cut-off molecular weight, in Dalton (D). Since it is quite difficult to directly measure the pore size of an ultrafiltration membrane, measurement is performed using spherical substances of known molecular weight. When the rejection rate of the membrane to the trapped substance is greater than 90%, the molecular weight of the trapped substance is used to represent the rejection performance of the membrane, which is called the rejection molecular weight of the membrane.
In order to determine the in vitro release degree of the letromycin inclusion compound solution, the inclusion compound solution is directly placed in a dialysis bag for release degree test, so that the release is very slow, the time consumption is too long, the efficiency is low, and the release is incomplete; and the inclusion compound solution is diluted by a release medium and then is placed in a dialysis bag for testing, so that the release is too fast and no force is distinguished. The method adopts the hydroxyethyl starch solution (W/V) with the concentration of about 3-8% to dilute the letrozole inclusion compound, so that the release speed of the letrozole inclusion compound can be well regulated, the test efficiency is improved, and the difference of the letrozole inclusion compound with different prescriptions can be effectively distinguished.
In one aspect, the present application provides a method for determining the in vitro release of a solution of letrozole inclusion complex, comprising the steps of:
1) Diluting the TeMo inclusion compound solution with hydroxyethyl starch solution, adding into a dialysis bag, then placing the dialysis bag into a release medium, stirring or oscillating with a stirring or oscillating instrument, heating in water bath, and performing in vitro release degree test of the TeMo inclusion compound solution;
2) The release medium was withdrawn at various time points, the concentration of letrozole in the withdrawn release medium was determined, and the in vitro release of letrozole inclusion compound solution was calculated.
In some embodiments, in step 1), the concentration of the hydroxyethyl starch solution is about 3% -8% (W/V); optionally the concentration of the hydroxyethyl starch solution is about 6% (W/V). The 6% hydroxyethyl starch solution can simulate the plasma environment and can also keep the release of the letromycin in the letromycin clathrate compound at a certain speed.
In some embodiments, in step 1), the concentration of letrozole in the clathrate solution diluted with the hydroxyethylstarch solution is about 2-4mg/mL and the volume of the clathrate solution diluted is about 1-2mL.
In some embodiments, in step 1), the release medium is a buffer solution having a pH of about 6-8 in a volume of about 500-1000mL; the release medium is optionally a buffer solution having a pH of about 7.4 and a volume of about 500-1000mL; the release medium is optionally phosphate buffer at a pH of about 7.4 in a volume of about 500-1000mL. In some embodiments, in step 1), the volume of the release medium may be adjusted to scale up or down according to the volume of solution in the dialysis bag or the concentration of letrozole.
In some embodiments, in step 1), the dialysis bag has a molecular weight cut-off of about 1000 to 5000D, alternatively the dialysis bag has a molecular weight cut-off of about 1000 to 3500D. In some embodiments, in step 1), the dialysis bag has a molecular weight cut-off of about 1000D, 1500D, 2000D, 2500D, 3000D, 3500D, 4000D, 4500D, or 5000D.
In some embodiments, in step 1), the flattened width of the dialysis bag is about 12-54mm, the diameter is about 7.5-34mm, and the volume is about 0.45-9.3mL/cm.
In some embodiments, in step (1), the dialysis bag is rinsed three or more times with purified water after being soaked in purified water for about 10-30 minutes, and then rinsed three or more times with a release medium.
In some embodiments, in step 1), the inclusion component in the letrozole inclusion compound solution is selected from one or more of methyl betacyclodextrin, hydroxyethyl betacyclodextrin, hydroxypropyl betacyclodextrin, and sulfobutyl betacyclodextrin.
In some embodiments, in step 1), the stirring or shaking apparatus is a shaker or a dissolution apparatus, the rate of stirring or shaking being about 50-200rpm; optionally with stirring or shaking at a rate of about 100-150rpm. In some embodiments, in step 1), the rate of stirring or shaking is about 50rpm, 75rpm, 100rpm, 125rpm, 150rpm, 175rpm, or 200rpm. In some embodiments, other types of apparatus for dispersing or mixing the solution may also be selected.
In some embodiments, in step 1), the temperature of the water bath heating is about 25 ℃ -50 ℃, optionally the temperature of the water bath heating is about 37 ℃ ± 5 ℃.
In some embodiments, in step 2), a small amount of release medium (e.g., 1 mL) can be removed at a set point in time (e.g., 0.5h, 1h, 2h, 4h, 6h, 12h, 18h, 24h, and 48 h) and assayed with Yu Laite mowei concentration.
In some embodiments, in step 2), the method of determining the concentration of letrozole in the removed delivery medium is selected from one or both of HPLC and UV. In some embodiments, in step 2), other methods for determining the concentration of the compound may also be employed.
The present application describes a number of embodiments, but the description is illustrative and not limiting and it will be apparent to those of ordinary skill in the art that many more embodiments and implementations are possible within the scope of the embodiments described herein. Although many possible combinations of features are shown in the drawings and discussed in the detailed description, many other combinations of the disclosed features are possible. Any feature of any embodiment may be used in combination with, or in place of, any other feature of any other embodiment, unless expressly limited otherwise.
The present application includes and contemplates combinations of features known to those of ordinary skill in the art. The embodiments and features disclosed in this application may also be combined with any conventional features to form a unique inventive arrangement as defined in the claims. Any feature of any embodiment may also be combined with features from other inventive arrangements to form another unique inventive arrangement as defined in the claims. Thus, it should be understood that any of the features shown and/or discussed in this application may be implemented alone or in any suitable combination. Accordingly, the embodiments are not to be restricted except in light of the attached claims and their equivalents. Further, various modifications and changes may be made within the scope of the appended claims.
Furthermore, in describing representative embodiments, the specification may have presented the method and/or process as a particular sequence of steps. However, to the extent that the method or process does not rely on the particular order of steps set forth herein, the method or process should not be limited to the particular sequence of steps described. Other sequences of steps are possible as will be appreciated by those of ordinary skill in the art. Accordingly, the particular order of the steps set forth in the specification should not be construed as limitations on the claims. Furthermore, the claims directed to the method and/or process should not be limited to the performance of their steps in the order written, and one skilled in the art can readily appreciate that the sequences may be varied and still remain within the spirit and scope of the embodiments of the present application.
The experimental procedures, which are not specified in the following examples, are generally determined according to national standards. The experimental materials not shown in the examples below are all commercially available. The equipment used in each step in the following examples is conventional equipment. If the corresponding national standard does not exist, the method is carried out according to the general international standard, the conventional condition or the condition recommended by the manufacturer. Unless defined or otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition, any method and material similar or equivalent to those described herein can be used in the methods of the present application.
The relevant materials used in the examples are as follows:
1. medicament
The inclusion compound of letrozole (hydroxypropyl betacyclodextrin accounts for 10% (W/V)), the inclusion compound of letrozole (hydroxypropyl betacyclodextrin accounts for 15% (W/V)), the inclusion compound of letrozole (hydroxypropyl betacyclodextrin accounts for 20% (W/V)), the inclusion compound of letrozole (sulfobutylbetacyclodextrin accounts for 20% (W/V)), and the control of letrozole.
2. Reagents, materials
Potassium dihydrogen phosphate (Aladin), sodium hydroxide (national medicine group), polysorbate 80 (Chengdu Colon), and hydroxyethyl starch (Michelin)
Dialysis bag (Ruida Henghui).
3. Instrument for measuring and controlling the intensity of light
Dissolution instrument (Sotax), constant temperature vibration instrument (He Tian Kexue), high performance liquid chromatograph (Agilent), ultraviolet-visible spectrophotometer (Agilent)
Example 1
The embodiment is a method for measuring the in-vitro release rate of a letrozole inclusion compound solution, which comprises the following steps:
(1) Dialysis bag and sample handling: respectively taking dialysis bags (flattening width is 18mm, diameter is 11.5mm, and volume is 1.0 ml/cm) with a molecular weight cut-off of 1000D RC membrane, 3500D RC membrane and 8000D RC membrane, soaking in purified water for 30min, and washing with purified water for three times for use; respectively adding 2mL of letrozole inclusion compound solution (the hydroxypropyl betacyclodextrin accounts for 15% (W/V) in a sample prescription, and the concentration of letrozole is 20 mg/mL) into the treated dialysis bag, and clamping the dialysis bag for later use;
(2) Release conditions: 1000mL of phosphate buffer solution with pH of 7.4 is used as a release medium, the revolution is 100 revolutions per minute, and the dissolution and release degree are detected by a dissolution and release degree measuring method (the second method of the fourth rule 0931 of the Chinese pharmacopoeia 2020 edition);
(3) Taking a dialysis bag containing the letromycin inclusion compound solution in the step (1), fixing the dialysis bag on a paddle, detecting the in-vitro release degree in the method in the step (2), and taking 1mL of dissolution liquid as a sample solution after 0.5, 1, 2, 4, 6, 12, 18, 24 and 48 hours; preparing a proper amount of a Leitemized reference substance into a solution with a certain concentration as a reference substance solution; taking reference substance solution and test substance solution, measuring by high performance liquid chromatography (China Pharmacopeia 2020 edition four division rule 0512) or ultraviolet-visible spectrophotometry (China Pharmacopeia 2020 edition four division rule 0401), and calculating the in vitro release degree of the letrozole inclusion compound solution.
The calculation formula of the release amount of the letrozole inclusion compound solution is shown as follows,
wherein:
f is the ratio of the concentration of the reference substance to the peak area or absorption coefficient;
A feed device Peak area or absorption coefficient of the sample solution;
V medium (C) To a volume of release medium;
C bag(s) Is the concentration of the clathrate solution in the dialysis bag;
V bag(s) Is the volume of clathrate solution in the dialysis bag.
(4) The results of the in vitro release of the letrozole inclusion compound solution of example 1 are shown in Table 1.
TABLE 1 determination of in vitro Release of Letermorvir clathrate solution of EXAMPLE 1
Note that: 8000D RC films were completely released by 12h, and no more testing was performed at the subsequent time points.
As can be seen from Table 1, when a 8000D RC membrane dialysis bag was used, the release rate of the letromycin clathrate solution in pH7.4 phosphate buffer solution for 2 hours reached 90% or more, and the release rate was high, and the distinction between different prescription products was poor. The 1000D RC membrane and 3500D RC membrane distinguish better between release of letromycin clathrate.
Example 2
The embodiment is a method for measuring the in-vitro release rate of a letrozole inclusion compound solution, which comprises the following steps:
(1) Dialysis bag and sample handling: taking a dialysis bag (with flattening width of 18mm, diameter of 11.5mm and volume of 1.0 ml/cm) with a molecular weight cutoff of 3500D RC membrane of 8cm, soaking in purified water for 30min, washing with purified water for three times, and washing with release medium for three times; taking the inclusion compound solutions of the two prescriptions (the hydroxypropyl betacyclodextrin accounts for 10 percent (W/V) in the prescription of the sample of the batch 1, the hydroxypropyl betacyclodextrin accounts for 15 percent (W/V) in the prescription of the sample of the batch 2, and the concentration of the letrovir is 20 mg/mL), respectively diluting the samples of the two prescriptions into inclusion compound solutions containing letromycin Mo Weiyao mg/mL by using a pH7.4 phosphate buffer solution, a 0.6 percent polysorbate 80 solution (W/V) and a 6 percent hydroxyethyl starch solution (W/V), and adding 2mL of diluted letrovir solution into a treated dialysis bag to clamp the dialysis bag;
(2) The release method comprises the following steps: 1000mL of phosphate buffer solution with pH of 7.4 is used as a release medium, the revolution is 100 revolutions per minute, and the dissolution and release degree are detected by a dissolution and release degree measuring method (the second method of the fourth rule 0931 of the Chinese pharmacopoeia 2020 edition);
(3) Taking the dialysis bag containing the letromycin clathrate compound solution in the step (1), fixing the dialysis bag on a paddle, detecting the in-vitro release degree in the method in the step (2), and measuring 1mL of the dissolution liquid after 0.5, 1, 2, 4, 6, 8 and 12 hours, wherein the measuring method is the same as that in the example 1, and calculating the in-vitro release degree of the letromycin clathrate compound solution.
The formulation for the release amount of the letrozole inclusion compound solution was the same as in example 1.
(4) The results of the in vitro release of the letrozole inclusion compound solution of example 2 are shown in Table 2.
TABLE 2 determination of in vitro Release of Letermorvir clathrate solution of EXAMPLE 2
Note 1: after 4 hours, the release was complete and no further test was performed at a later time point.
And (2) injection: the proportion of hydroxypropyl betacyclodextrin in the batch 1 sample prescription is 10 percent, and the proportion of hydroxypropyl betacyclodextrin in the batch 2 sample prescription is 15 percent; the concentration of letrozole was 20mg/mL.
As is clear from Table 2, the inclusion compound solution of letrozole was diluted with a diluent and contained 2mg/ml letrozole at a faster rate than when not diluted. Phosphate buffer solution with pH7.4 is used as a diluent, the release is basically complete within 2 hours to 80 percent; using 0.6% polysorbate 80 solution as diluent, and releasing completely in 2 hr for 1 hr to 80%; these two diluents have no significant difference in force for different prescription products. The 6% hydroxyethyl starch solution is used as a diluent, the release is basically complete in 8 hours, and the composition has obvious distinguishing effect on different prescriptions, and can be used for prescription screening and quality control.
Example 3
The embodiment is a method for measuring the in-vitro release rate of a letrozole inclusion compound solution, which comprises the following steps:
(1) Dialysis bag and sample handling: taking a dialysis bag (with flattening width of 18mm, diameter of 11.5mm and volume of 1.0 ml/cm) with a molecular weight cutoff of 3500D RC membrane of 8cm, soaking in purified water for 30min, washing with purified water for three times, and washing with release medium for three times; a proper amount of letrozole inclusion compound solution (the hydroxypropyl betacyclodextrin accounts for 15 percent (W/V) in the sample prescription, the concentration of letrozole is 20 mg/mL) is taken, and the letrozole inclusion compound solution is diluted into inclusion compound solutions respectively containing 10mg/mL, 4mg/mL and 2mg/mL of letrozole by 6 percent of hydroxyethyl starch solution (W/V). Adding 2ml of diluted letromycin inclusion compound solution into the treated dialysis bag, and clamping the dialysis bag;
(2) Release conditions: 1000mL of phosphate buffer solution with pH of 7.4 is used as a release medium, the revolution is 100 revolutions per minute, and the dissolution and release degree are detected by a dissolution and release degree measuring method (the second method of the fourth rule 0931 of the Chinese pharmacopoeia 2020 edition);
(3) Taking the dialysis bag containing the letromycin clathrate compound solution in the step (1), fixing the dialysis bag on a paddle, detecting the in-vitro release degree in the method in the step (2), and measuring 1mL of the dissolution liquid after 0.5, 1, 2, 4, 6, 8 and 12 hours, wherein the measuring method is the same as that in the example 1, and calculating the in-vitro release degree of the letromycin clathrate compound solution.
The formulation for the release amount of the letrozole inclusion compound solution was the same as in example 1.
(4) The results of the in vitro release of the letrozole inclusion compound solution of example 3 are shown in Table 3.
TABLE 3 determination of in vitro Release of Letermorvir clathrate solution of EXAMPLE 3
As is clear from Table 3, the release rate of the letromycin clathrate solution (containing letromycin at 10 mg/mL) diluted with the 6% hydroxyethyl starch solution was slow at 10mg/mL, and the release rate was incomplete at 12 hours, and the release rates at 4mg/mL and 2mg/mL were moderate with a certain difference.
Example 4
The embodiment is a method for measuring the in-vitro release rate of a letrozole inclusion compound solution, which comprises the following steps:
(1) Taking a dialysis bag (with flattening width of 45mm, diameter of 29mm and volume of 6.4 ml/cm) with a molecular weight cutoff of 3500D RC membrane of 8cm, soaking in purified water for 30min, washing with purified water for three times, and washing with release medium for three times; the inclusion compound solution of letrozole (the concentration of letrozole is 20 mg/mL) was diluted with 1%, 3%, 6% and 8% hydroxyethyl starch solutions (W/V) to form inclusion compound solutions containing letrozole Mo Weiyao mg/mL, respectively, with a hydroxypropyl betacyclodextrin ratio of 15% (W/V) in the sample recipe. Adding 2ml of diluted letromycin solution into the treated dialysis bag, and clamping the dialysis bag;
(2) Release conditions: 1000mL of phosphate buffer solution with pH of 7.4 is used as a release medium, the revolution is 100 revolutions per minute, and the dissolution and release degree are detected by a dissolution and release degree measuring method (the second method of the fourth rule 0931 of the Chinese pharmacopoeia 2020 edition);
(3) Taking the dialysis bag containing the letromycin clathrate compound solution in the step (1), fixing the dialysis bag on a paddle, detecting the in-vitro release degree in the method in the step (2), and measuring 1mL of the dissolution liquid after 0.5, 1, 2, 4, 6, 8 and 12 hours, wherein the measuring method is the same as that in the example 1, and calculating the in-vitro release degree of the letromycin clathrate compound solution.
The formulation for the release amount of the letrozole inclusion compound solution was the same as in example 1.
(4) The results of the in vitro release of the letrozole inclusion compound solution of example 4 are shown in Table 4.
TABLE 4 determination of in vitro Release of Letermorvir clathrate solution of EXAMPLE 4
As is clear from Table 4, the release rate of the letrozole inclusion compound solution (containing letrozole 2 mg/ml) diluted with 1% hydroxyethyl starch solution was slow, and the release was not completed for 12 hours; 3% -8%, more than 90% in 12 hours, and complete release, so that the concentration of the selected hydroxyethyl starch solution is 3% -8%; more preferably, the concentration of the hydroxyethyl starch solution is selected to be 6%.
Example 5
The embodiment is a method for measuring the in-vitro release rate of a letrozole inclusion compound solution, which comprises the following steps:
(1) Taking a dialysis bag (with flattening width of 18mm, diameter of 11.5mm and volume of 1.0 ml/cm) with a molecular weight cutoff of 3500D RC membrane of 8cm, soaking in purified water for 30min, washing with purified water for three times, and washing with release medium for three times; the inclusion compound solution of letrozole (the concentration of letrozole in the sample prescription is 20 mg/mL) is diluted into inclusion compound solution containing letrozole Mo Weiyao mg/mL by 6% of hydroxyethyl starch solution (W/V). Adding 2ml of diluted letromycin solution into the treated dialysis bag, and clamping the dialysis bag;
(2) The release method comprises the following steps: 500mL of phosphate buffer solution with pH of 7.4 is taken as a release medium, added into a beaker, and placed into a constant-temperature oscillator with the temperature of 37+/-5 ℃ for constant temperature; the shaking rate was 200rpm per minute
(3) Taking the dialysis bag containing the letromycin inclusion compound solution in the step (1), putting the dialysis bag into the beaker in the step (2), shaking the dialysis bag, and respectively taking out 1mL of dissolved solution after 0.5, 1, 2, 4, 6, 8 and 12 hours, and calculating the in vitro release degree of the letromycin inclusion compound solution by the same method as in the example 1.
The formulation for the release amount of the letrozole inclusion compound solution was the same as in example 1.
(4) The results of the in vitro release of the letrozole inclusion compound solution of example 5 are shown in Table 5.
TABLE 5 determination of in vitro Release of Letermorvir clathrate solution of EXAMPLE 5
| Time (hours) | Release amount (%) |
| 0 | 0 |
| 0.5 | 11 |
| 1 | 28 |
| 2 | 46 |
| 4 | 66 |
| 6 | 78 |
| 8 | 87 |
| 12 | 95 |
As is clear from Table 5, the release profile of the inclusion compound solution of letrozole (containing letrozole 2 mg/ml) diluted with a 6% hydroxyethyl starch solution was measured by a shaker in pH7.4 phosphate buffer and was substantially identical to that obtained by a paddle method using the dissolution and release profile measurement method (second method of the fourth edition of Chinese pharmacopoeia 2020, rule 0931) under the same conditions of diluent and release medium.
Example 6
The embodiment is a method for measuring the in-vitro release rate of a letrozole inclusion compound solution, which comprises the following steps:
(1) Taking a dialysis bag (with flattening width of 45mm, diameter of 29mm and volume of 6.4 ml/cm) with a molecular weight cutoff of 3500D RC membrane of 8cm, soaking in purified water for 30min, washing with purified water for three times, and washing with release medium for three times; four different formulations of letromycin clathrate solution (10% hydroxypropyl betacyclodextrin in the formulation of batch 1-sample, 15% hydroxypropyl betacyclodextrin in the formulation of batch 2-sample, 20% hydroxypropyl betacyclodextrin in the formulation of batch 3-sample, 20% sulfobutyl betacyclodextrin in the formulation of batch 4-sample, and 2mg/mL of letromycin clathrate solution is released by 6% hydroxyethyl starch solution;
(2) Release conditions: 1000mL of phosphate buffer solution with pH of 7.4 is used as a release medium, the revolution is 100 revolutions per minute, and the dissolution and release degree are detected by a dissolution and release degree measuring method (the second method of the fourth rule 0931 of the Chinese pharmacopoeia 2020 edition);
(3) Taking the dialysis bag containing the letromycin clathrate compound solution in the step (1), fixing the dialysis bag on a paddle, detecting the in-vitro release degree in the method in the step (2), and measuring 1mL of the dissolution liquid after 0.5, 1, 2, 4, 6, 8 and 12 hours, wherein the measuring method is the same as that in the example 1, and calculating the in-vitro release degree of the letromycin clathrate compound solution.
The formulation for the release amount of the letrozole inclusion compound solution was the same as in example 1.
(4) The results of the in vitro release of the letrozole inclusion compound solution of example 6 are shown in Table 6.
TABLE 6 determination of in vitro Release of Letermorvir clathrate solution of EXAMPLE 6
Note that: batch 1-hydroxypropyl betacyclodextrin 10% (W/V) in the recipe; batch 2-hydroxypropyl betacyclodextrin 15% (W/V) in the recipe; batch 3-hydroxypropyl betacyclodextrin 20% (W/V); batch 4-sulfobutyl betacyclodextrin was 20% (W/V) in the formulation.
As can be seen from Table 6, the release rate test was performed after diluting the different formulation of letrozole inclusion compound solutions to 2mg/ml with 6% hydroxyethyl starch solution, and the formulation difference was well differentiated by the release rate measurement method.
The release degree test is carried out by adopting the release degree test method provided by the application, such as a proper dialysis bag (1000-3500D), and a proper diluent (6% hydroxyethyl starch solution) is used for diluting to a proper concentration (containing Lepidotimod 2-4 mg/mL), so that the Lepidotimod inclusion compound solution has good prescription differentiation, and can be used for prescription screening and quality control.
Claims (11)
1. The method for measuring the in-vitro release degree of the letrozole inclusion compound solution comprises the following steps:
1) Diluting the TeMo inclusion compound solution with hydroxyethyl starch solution, adding the diluted TeMo inclusion compound solution into a dialysis bag, then placing the dialysis bag into a release medium, stirring or vibrating, heating in a water bath, and performing in-vitro release degree test of the TeMo inclusion compound solution;
2) And taking out the release medium at a set time point, measuring the concentration of the letrozole in the taken-out release medium, and calculating the in-vitro release degree of the letrozole inclusion compound solution.
2. The assay of claim 1, wherein in step 1), the concentration of the hydroxyethyl starch solution is about 3% -8%; preferably about 6%.
3. The assay of claim 2, wherein in step 1), the concentration of letrozole in the clathrate solution diluted with the hydroxyethyl starch solution is about 2-4mg/mL and the volume of the clathrate solution diluted is about 1-2mL.
4. The assay of claim 3 wherein, in step 1), the release medium is a buffer solution having a pH of about 6-8; preferably the release medium is a buffer solution having a pH of about 7.4; more preferably the release medium is phosphate buffer at a pH of about 7.4.
5. The assay of claim 1, wherein, in step 1), the dialysis bag has a molecular weight cut-off of about 1000-5000D; preferably the dialysis bag has a molecular weight cut-off of about 1000-3500D.
6. The assay of claim 5, wherein in step 1) the flattened width of the dialysis bag is about 12-54mm, the diameter is about 7.5-34mm, and the volume is about 0.45-9.3mL/cm.
7. The assay according to any one of claims 1-6, wherein in step 1) stirring or shaking is performed with a dissolution apparatus or a shaking apparatus, the stirring or shaking being at a rate of about 50-200rpm; preferably the stirring or shaking is at a rate of about 100-150rpm.
8. The assay of any one of claims 1-6, wherein, in step 1), the water bath heating is at a temperature of about 25 ℃ to 50 ℃; preferably the water bath is heated to a temperature of about 37 ℃ ± 5 ℃.
9. The assay of any one of claims 1-6 wherein in step 2) the concentration of letrozole in the removed delivery medium is determined by a method selected from one or both of HPLC and UV.
10. The assay method according to any one of claims 1-6, wherein in step 2) the set point in time is selected from one or more of 0.5h, 1h, 2h, 4h, 6h, 12h, 18h, 24h, 48 h.
11. The assay of any one of claims 1-6, wherein in step 1) the inclusion component in the letrozole inclusion compound solution is selected from one or more of methyl betacyclodextrin, hydroxyethyl betacyclodextrin, hydroxypropyl betacyclodextrin, and sulfobutyl betacyclodextrin.
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