CN110954491B - Method for measuring in-vitro dissolution rate of goserelin acetate sustained-release implant - Google Patents
Method for measuring in-vitro dissolution rate of goserelin acetate sustained-release implant Download PDFInfo
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- 108010069236 Goserelin Proteins 0.000 title claims abstract description 83
- 239000007943 implant Substances 0.000 title claims abstract description 77
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- 238000013268 sustained release Methods 0.000 title claims abstract description 59
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- 238000004090 dissolution Methods 0.000 title claims abstract description 52
- 238000000034 method Methods 0.000 title claims abstract description 38
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims abstract description 33
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- 238000002835 absorbance Methods 0.000 claims description 20
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- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 9
- 229920000053 polysorbate 80 Polymers 0.000 claims description 9
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- XXBDWLFCJWSEKW-UHFFFAOYSA-N dimethylbenzylamine Chemical compound CN(C)CC1=CC=CC=C1 XXBDWLFCJWSEKW-UHFFFAOYSA-N 0.000 description 5
- 238000004321 preservation Methods 0.000 description 5
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- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 4
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- 229910019142 PO4 Inorganic materials 0.000 description 3
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- 239000010452 phosphate Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
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- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
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- 241000282472 Canis lupus familiaris Species 0.000 description 1
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- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 1
- 206010071119 Hormone-dependent prostate cancer Diseases 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
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- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
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- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
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- 230000008520 organization Effects 0.000 description 1
- 238000005220 pharmaceutical analysis Methods 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 238000013441 quality evaluation Methods 0.000 description 1
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- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
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Images
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
- G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N1/00—Sampling; Preparing specimens for investigation
- G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
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- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Spectroscopy & Molecular Physics (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a method for measuring the in-vitro dissolution rate of a goserelin acetate sustained-release implant, which comprises the step of contacting the goserelin acetate sustained-release implant with a release medium, wherein the release medium comprises a buffer solution, and a release promoting agent and citric acid which are dissolved in the buffer solution. The method can greatly shorten the drug release evaluation time of the goserelin acetate sustained-release implant, further shorten the period of drug development and release of production quality, and reduce the cost input in the aspect of personnel. In addition, the method of the invention also helps the preparation workers to evaluate the quality of the drug release characteristic more quickly, efficiently and accurately.
Description
Technical Field
The invention relates to the field of pharmaceutical analysis, in particular to a method for measuring in-vitro dissolution rate of a goserelin acetate sustained-release implant.
Background
Goserelin (goserelin) is an artificially synthesized decapeptide, is an analogue of gonadotropin-releasing hormone (GnRH), and is also an endocrine treatment drug with high efficiency and small toxic and side effects.
The administration cycle of the goserelin sustained release implant (such as norledin) is 28 days, the active ingredient of the goserelin sustained release implant is goserelin acetate, and the auxiliary materials comprise glycolide-lactide copolymer and acetic acid. Is used for treating hormone-dependent prostate cancer, breast cancer of premenopausal and perimenopausal women and endometriosis. The medicine is developed and produced by Aslicon British company, and is a sustained-release implant which can be gradually biodegraded in vivo. It was first marketed globally in 1990 and in china in 1996, and is currently sold in markets in more than 100 countries of the world, including china.
The release evaluation method of the goserelin acetate sustained release preparation disclosed in the literature and quality standards at present comprises a constant-speed in vitro experiment and an animal in vivo experiment (rats, rabbits and dogs). Wherein, the evaluation period of the constant-speed in-vitro release rate method is 28 days, the experimental period in the animal body is not shortened, and the experiment in the animal body needs early-stage preparation work. For example, the entrustment organization reviews the evaluation, signs the contract, purchases qualified laboratory animals, raises, and has certain difficulties in administration and blood sampling operations.
In summary, no document related to accelerated release rate of the goserelin acetate sustained-release implant is reported at present. Therefore, it is highly desirable to establish an in vitro accelerated release assay that has good correlation to in vitro long-term release assays for rapid screening of recipes and acquisition of relevant process parameters.
Disclosure of Invention
Aiming at the problems in the prior art, the invention carries out intensive research and establishes an accelerated experimental method for measuring the in-vitro release of the goserelin acetate sustained-release implant. Specifically, the present invention includes the following.
The invention provides a method for measuring the in vitro dissolution rate of a goserelin acetate sustained-release implant, which comprises the step of contacting the goserelin acetate sustained-release implant with a release medium, wherein the release medium comprises a buffer solution, and a release promoter and citric acid which are dissolved in the buffer solution.
According to the method for measuring the in vitro dissolution rate of the goserelin acetate sustained release implant of the invention, preferably, the buffer is a phosphate buffer and the pH of the release medium is between 6.8 and 7.4.
According to the method for measuring the in vitro dissolution rate of the goserelin acetate sustained-release implant, preferably, the release promoter comprises chloroxyldimethylbenzylamine and polysorbate, and the weight ratio of the chloroxyldimethylbenzylamine to the polysorbate is 0.15-0.3.
According to the method for measuring the in vitro dissolution rate of the goserelin acetate sustained release implant of the invention, preferably, the concentration of the release promoting agent in the release medium is 1.0 to 2.5g/L.
According to the method for measuring the in vitro dissolution rate of the goserelin acetate sustained-release implant, preferably, the goserelin acetate sustained-release implant is kept at a constant temperature of 40-55 ℃ when being contacted with the release medium.
According to the method for measuring the in vitro dissolution rate of the goserelin acetate sustained release implant, the oscillation is preferably kept during the contact.
According to the method for measuring the in vitro dissolution rate of the goserelin acetate sustained-release implant, the contact time of the goserelin acetate sustained-release implant and the release medium is preferably 5-7.
The method for measuring the in vitro dissolution rate of the goserelin acetate sustained release implant according to the present invention preferably further comprises the steps of sampling at a plurality of time points and detecting the dissolution rate of the goserelin acetate sustained release implant in each sample.
According to the method for measuring the in vitro dissolution rate of the goserelin acetate sustained release implant according to the present invention, preferably, the plurality of time points includes at least a first time point 0.5 to 2 hours after the start of the contact, a second time point 80 to 90 hours after the start of the contact, and a third time point 144 to 168 hours after the start of the contact.
According to the method for measuring the in vitro dissolution rate of the goserelin acetate sustained-release implant, preferably, the detection comprises measuring the absorbance at intervals of 2nm in the interval 275nm to 285nm respectively, obtaining the absorbance at six wavelengths, calculating the average value of the absorbance, and calculating the release amount at each time point based on the average value.
The method is an in vitro accelerated experiment method, can greatly shorten the drug release evaluation time of the goserelin acetate sustained-release implant, further can shorten the period of drug development and release of production quality, and reduces the cost input in the aspect of personnel. The rapid evaluation of the drug release property of the goserelin acetate sustained-release implant is also helpful for the preparation worker to perform the quality evaluation of the drug release characteristic more rapidly, efficiently and accurately. The accelerated test of the invention predicts the release speed of the sustained release implant and has practical significance for the sustained release implant.
Drawings
FIG. 1 is a graph showing the release rate of an implant according to the release method under the entry criteria of the drug import registration.
FIG. 2 is a graph showing the release profile of a release medium at pH 7.0, with Tween 80 and chlorocarbon dimethylbenzylamine added to the release medium in a 50 ℃ water bath shaker.
FIG. 3 is a graph showing the release profile of a release medium at pH7.4, with Tween 80 and chlorocarbon dimethylbenzylamine added to the release medium in a 50 ℃ water bath shaker.
FIG. 4 is a graph of release curve fit of an exemplary embodiment of the present invention to an import quality standard.
FIG. 5 is a graph of curve fit of another exemplary embodiment of the present invention to release of an import quality standard.
Detailed Description
Reference will now be made in detail to various exemplary embodiments of the invention, the detailed description should not be construed as limiting the invention but as a more detailed description of certain aspects, features and embodiments of the invention.
It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. Further, for numerical ranges in this disclosure, it is understood that the upper and lower limits of the range, and each intervening value therebetween, is specifically disclosed. Every smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in a stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range.
Unless defined otherwise, 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. Although only preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All documents mentioned in this specification are incorporated by reference herein for the purpose of disclosing and describing the methods and/or materials associated with the documents. In case of conflict with any incorporated document, the present specification will control.
In the present invention, the "goserelin acetate sustained-release implant" refers to a drug which is implanted into the body by injection (e.g., subcutaneous injection) or the like, and comprises goserelin acetate as an active ingredient and a high-molecular polymer, such as a glycolide-lactide polymer, as an auxiliary material. After entering the body, the goserelin acetate is gradually released from the high polymer material to the outside.
The invention provides a method for measuring the in-vitro dissolution rate of a goserelin acetate sustained-release implant, which is sometimes abbreviated as the method of the invention, and is an accelerated release model, which is completely different from the existing in-vitro constant-speed release period of 28 days, and the method can effectively evaluate the release property of the goserelin acetate sustained-release implant within a short time, such as 7 days.
The method for measuring the in-vitro dissolution rate of the goserelin acetate sustained-release implant comprises the step of contacting the goserelin acetate sustained-release implant with a release medium, wherein the release medium comprises a buffer solution, a release promoting agent dissolved in the buffer solution and citric acid. As described in detail below.
[ buffer solution ]
In the present invention, the buffer may use any buffer known in the art, and is not particularly limited thereto, and examples thereof include, but are not limited to, citrate buffer, phosphate buffer, and acetate buffer. In the present invention, one of the above-mentioned buffers may be used, or a mixture of two or more thereof may be used.
In the present invention, the buffer solution should have a specific pH range, and in general, the pH should be between 6.8 and 7.5, preferably between 6.9 and 7.4, and more preferably between 7.0 and 7.4. In order to enable the pH of the buffer to be within the above range, the pH of the buffer may optionally be adjusted. For example, the desired pH range can be adjusted by adding a modifier (e.g., disodium phosphate or citric acid) to the buffer.
In certain embodiments, the buffer of the invention is a phosphate buffer. Here, the phosphate is any type of salt, and examples thereof include, but are not limited to, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and the like. The present invention may use one or a combination of two or more of the above substances. The concentration of phosphate is not particularly limited as long as the desired pH range can be achieved. In general, the concentration of phosphate is from 20 to 30g/L, preferably from 22 to 28g/L, more preferably from 24 to 26g/L.
[ Release promoting Agents ]
The present invention uses release promoters to facilitate the sustained release of goserelin acetate from, for example, an adjuvant. Unlike the substances which generally promote the release of the drugs, the release-promoting agent of the invention not only has higher speed of promoting the release of the drugs, but also has a release curve which is basically consistent with the conventional release curve.
The release promoter comprises chlorocarbon dimethyl benzene methylamine and polysorbate. Alternatively, the release enhancer of the invention consists of both chloroxyldimethylbenzylamine and polysorbate. The invention discovers that the chlorohydrocarbonyl dimethyl benzene methylamine in the buffer solution is beneficial to the release of the goserelin acetate from the auxiliary material, and further discovers that the combination of the chlorohydrocarbonyl dimethyl benzene methylamine and the polysorbate has a synergistic promotion effect on the release of the medicine. In the present invention, the weight ratio of chloroxyldimethylbenzylamine to polysorbate is not particularly limited, and is generally 0.15 to 0.3, preferably 0.16 to 0.28, and more preferably 0.18 to 0.25.
In the present invention, the concentration of chloroxyldimethylbenzylamine in the release medium is advantageously controlled to be generally 0.1g/L or more, preferably 0.2g/L or more. On the other hand, the concentration of chloroxyldimethylbenzylamine is generally controlled to be 0.3g/L or less, preferably 0.25g/L or less. If the concentration of chloroxyldimethylbenzylamine is too high, the release medium tends to foam, which is detrimental to the experimental operation. If the concentration is too low, the desired release rate is not achieved.
The polysorbate is a substance, but not a specific substance. The type of polysorbate is not particularly limited, and any type of polysorbate may be used, examples of which include, but are not limited to, tween 20, tween 40, tween 60, and tween 80, preferably tween 80. In the present invention, one of the above-mentioned substances may be used, or a combination of two or more of them may be used. The concentration of polysorbate in the release medium is generally from 0.5g/L to 5g/L, preferably from 1g/L to 3g/L, more preferably from 1g/L to 2g/L.
[ citric acid ]
The release medium of the present invention also comprises citric acid. Citric acid is advantageous in maintaining the release medium to the desired pH range. In the present invention, the concentration of citric acid is generally 1.5 to 2.5g/L, preferably 1.6 to 2.4g/L, more preferably 1.7 to 2.0g/L.
[ temperature ]
In the present invention, in order to promote the release, it is necessary to increase the temperature at which the goserelin acetate sustained-release implant is contacted with the release medium. One skilled in the art will readily appreciate that the effect of temperature on drug release is complex, with higher temperatures generally favoring drug release, but high temperatures will also affect the release profile. For example, at some point or points in time the release rate is too fast, triggering a burst release and thereby changing the profile. The present inventors have found, after intensive studies, that accelerated release of a drug can be well achieved without substantially affecting the change in the release profile when the temperature is maintained at a constant temperature between 40 ℃ and 55 ℃, preferably between 42 ℃ and 54 ℃, and more preferably between 45 ℃ and 50 ℃. The release profile changes when the temperature is too high, for example above 55 ℃. The reason for this may be that the stability of the implant itself is affected. On the other hand, if the temperature is too low, the increase of the release rate of the drug is not facilitated, and the purpose of simulating the in vivo drug release profile cannot be well achieved in an accelerated manner.
[ oscillation ]
In the present invention, in order to promote the release, agitation may be promoted by means such as stirring to maintain the fluidity of the release medium, thereby further promoting the release. The present invention has found that by controlling the oscillation of the release medium, the release can be accelerated without substantially altering the release profile. The conditions for the oscillation are not particularly limited as long as the fluidity is maintained uniformly or stably during the contact of the goserelin acetate sustained-release implant with the release medium.
[ detection Point ]
In the present invention, in order to obtain the release properties, particularly the release profile, of the goserelin acetate sustained-release implant, it is necessary to measure the release rate or dissolution rate at a plurality of time points during the contact of the goserelin acetate sustained-release implant with the release medium. The detection points of the invention at least comprise a time point for investigating whether the medicament is released suddenly; time points for determining drug release characteristics; and a time point for examining whether drug release is complete. It will be readily appreciated by those skilled in the art that the more time points are set, the more advantageous it is to know or monitor the release characteristics of the drug. Preferably, the number of time points is 3-30, more preferably 3-15, even more preferably 3-10. In certain embodiments, the time points of the invention include at least a first time point 0.5 to 2 hours after the start of the contacting, a second time point 80 to 90 hours after the start of the contacting, and a third time point 144 to 168 hours after the start of the contacting.
[ dissolution measurement ]
The method of the invention comprises measuring the dissolution rate of samples taken at a plurality of time points. Dissolution may be measured in any manner known in the art. Measurements may be made using known correlation standards for purposes of unification or standardization. For example, the measurement method described in the general rules 0401 in the four parts of the chinese pharmacopoeia 2015 year edition. Specifically, it comprises measuring absorbance at intervals of 2nm in an interval of 275nm to 285nm, respectively; the F value was calculated as the average of the absorbance at six wavelengths, and the fluctuation range of the F value measured for the control solution at each sampling time point was within ± 2% of the initial F value, and the released amount at each time point was calculated.
Reference example
The test detects the release rate of the implant according to the release method under the registration standard item of the imported drugs.
Dissolving 25.8g of anhydrous disodium hydrogen phosphate, 1.92g of citric acid and 0.2g of sodium azide in water to 1000ml, adjusting the pH value to 7.4 +/-0.05 by using the anhydrous disodium hydrogen phosphate or the citric acid if necessary, and filtering by using a 0.22-micron microporous filter membrane to obtain a phosphate buffer solution.
Taking 5 goserelin acetate slow-release implants, placing the 5 goserelin acetate slow-release implants in a special dissolution cup in triplicate, taking 50ml of phosphate buffer solution as a release medium, covering the release medium, placing the release medium in a thermostat with the temperature of 39 +/-0.5 ℃, preserving the heat in 168 hours (7 days), 336 hours (14 days), 408 hours (17 days), 504 hours (21 days) and 672 hours (28 days), respectively sampling, precisely measuring 5ml of supernate, placing the supernate in a 10ml measuring flask, diluting the supernate to a scale by using the phosphate buffer solution (pH7.4), and shaking up to be used as a test solution; after sampling, 5ml of phosphate buffer (pH7.4) was immediately added to each dissolution cup, mixed by gentle vortex, covered, and immediately placed in a 39 + -0.5 ℃ incubator to continue incubation.
And taking a proper amount of goserelin acetate reference substance, precisely weighing, adding phosphate buffer solution (pH7.4) to dissolve, and quantitatively diluting to prepare a solution containing about 0.1mg of goserelin in each 1ml, wherein the solution is used as the reference substance solution. Respectively taking the test solution and the reference solution, and respectively measuring absorbance at intervals of 2nm in the interval of 275nm to 285nm by ultraviolet-visible spectrophotometry (the general rule 0401 in the fourth part of the pharmacopoeia 2015 of China); the amount released was calculated at each time point. The results of the release test are shown in table 1. The release profile is shown in figure 1.
TABLE 1
| Release conditions (% Release) | 7d | 14d | 17d | 21d | 28d |
| 39℃ | 9 | 45 | 58 | 80 | 105 |
Examples
1. Effect of chlorocarbon-based Dimethylbenzylamine on the Release degree
This experiment was conducted to examine the effect of chloroxyldimethylbenzylamine as the first component of the release-promoting agent on the degree of release.
1. Lofting:
taking 5 goserelin acetate sustained-release implants (about equivalent to 18mg of goserelin), placing the implants into a 120ml special dissolution cup in triplicate, taking 50ml of phosphate buffer (pH 7.4) as a release medium, covering the cup, and placing the cup in an incubator at 39 +/-0.5 ℃. The phosphate buffer was prepared as follows:
2. sampling and preparing a test solution:
samples were taken at 168 hours (7 days), 336 hours (14 days), 408 hours (17 days), 504 hours (21 days) and 672 hours (28 days), respectively; taking out the dissolution cups from the incubator, cooling, slightly whirling and mixing uniformly, precisely measuring 5ml of supernatant, placing the supernatant in a 10ml measuring flask, diluting the supernatant to a scale by using a phosphate buffer solution (pH7.4), shaking uniformly to serve as a test solution, immediately supplementing 5ml of phosphate buffer solution (pH7.4) into each dissolution cup after sampling, slightly whirling and mixing uniformly, covering, and immediately placing in an incubator at 39 +/-0.5 ℃ for continuous heat preservation.
3. Preparing a reference solution:
taking a proper amount of goserelin acetate reference substance, precisely weighing, adding phosphate buffer solutions (pH7.4) with various numbers for dissolving, and quantitatively diluting to prepare a solution containing about 0.1mg of goserelin in each 1ml, wherein the solution is used as a reference substance solution. Each medium was run in duplicate.
4. And (3) detecting the release degree of the sample:
respectively taking a test solution and a reference solution, and respectively measuring absorbance at intervals of 2nm within the interval of 275nm to 285nm by ultraviolet-visible spectrophotometry (0401 in the fourth part of the pharmacopoeia 2015, china); the F value was calculated as the average of the absorbance at six wavelengths, and the fluctuation range of the F value measured for the control solution at each sampling time point was within ± 2% of the initial F value, and the released amount at each time point was calculated. The results are shown in Table 2.
TABLE 2 Release test results
| Release media numbering | 7 days | 14 days | 17 days | 21 days | 28 days | 35 days |
| Number 1 | 34 | 98 | 103 | 105 | - | - |
| Number 2 | 14 | 64 | 87 | 104 | - | - |
| No. 3 | 10 | 53 | 74 | 100 | 104 | - |
| Number 4 | 8 | 36 | 49 | 82 | 102 | 106 |
As can be seen from table 2: the release speed is accelerated along with the increase of the concentration of the chlorohydrocarbonyl dimethyl benzene methylamine in the release medium, and when the concentration of the chlorohydrocarbonyl dimethyl benzene methylamine in the release medium is 0.001 percent, the obtained release data is basically consistent with the result of the reference example; at a concentration of 0.02%, the release rate was accelerated to 14 days. In addition, in the experimental process, it is also found that as the concentration of the chlorocarbon-based dimethylbenzylamine increases, a large amount of foam is generated after shaking in the release medium, which is not beneficial to the operation of an analysis experiment. Therefore, the maximum concentration should be controlled below 0.03%.
2. Effect of Release enhancer second component in Release media on Release Rate
This experiment examined the effect of the type of second component acting as a release promoter in a release medium at 60 ℃ on the release rate of the implant
1. Lofting:
taking 5 goserelin acetate sustained-release implants (about equal to 18mg of goserelin), placing the goserelin acetate sustained-release implants into a 120ml special dissolution cup in triplicate, taking 50ml of phosphate buffer (pH 7.40) as a release medium, covering the dissolution cup, and placing the dissolution cup in a water bath kettle at 60 +/-0.5 ℃ for heat preservation. The phosphate buffer was prepared as follows:
2. sampling and preparing a test solution:
samples were taken at 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours (1 day), 36 hours, 48 hours (2 days), 72 hours (3 days), 144 hours (7 days), respectively; taking out the dissolution cups from the water bath, cooling, slightly whirling and mixing uniformly, precisely measuring 5ml of supernatant, putting the supernatant into a 10ml measuring flask, diluting the supernatant to a scale by using respective phosphate buffer solution, shaking uniformly to be used as a test solution, immediately supplementing 5ml of phosphate buffer solution into each dissolution cup after sampling, slightly whirling and mixing uniformly, covering, and immediately putting the dissolution cups in a water bath kettle at 60 +/-0.5 ℃ for continuous heat preservation.
3. Preparing a reference substance solution:
taking a proper amount of goserelin acetate reference substance, precisely weighing, adding phosphate buffer solutions with various numbers, dissolving and quantitatively diluting to prepare a solution containing about 0.1mg of goserelin in each 1ml, and taking the solution as a reference substance solution. Each medium was run in duplicate.
4. And (3) detecting the release degree of the sample:
respectively taking a test solution and a reference solution, and respectively measuring absorbance at intervals of 2nm within the interval of 275nm to 285nm by ultraviolet-visible spectrophotometry (0401 in the fourth part of the pharmacopoeia 2015, china); the F value was calculated as the average of the absorbance at six wavelengths, and the fluctuation range of the F value measured for the control solution at each sampling time point should be within ± 2% of the initial F value, and the released amount at each time point was calculated. The results are shown in Table 3.
TABLE 3 Release test results
As shown in Table 3, the release of the implant is accelerated by adding polysorbate substances into the release medium under the condition of 60 ℃, and the SDS inhibits the release of the implant. In addition, in the experiment, the condition that the shape of the implant is obviously changed due to overhigh temperature can cause the damage of the slow release mechanism of the implant.
3. Effect of Polysorbate on Release
This experiment examined the effect of adding tween 80 as a polysorbate in a release medium at 50 ℃ on the release rate of the implant.
1. Lofting:
taking 5 goserelin acetate sustained-release implants (about equivalent to 18mg of goserelin), placing the implants into a 120ml special dissolution cup in triplicate, taking 50ml of phosphate buffer (pH 7.40) as a release medium, covering the cup, and placing the cup in a water bath kettle at 50 +/-0.5 ℃ for release. The phosphate buffer was prepared as follows:
2. sampling and preparing a test solution:
samples were taken at 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours (1 day) and 3 days, 5 days, 7 days, 10 days and 14 days, respectively; taking out the dissolution cups from the water bath, cooling, slightly whirling and mixing uniformly, precisely measuring 5ml of supernatant, putting the supernatant into a 10ml measuring flask, diluting the supernatant to a scale by using respective phosphate buffer solution, shaking uniformly to be used as a test solution, immediately supplementing 5ml of phosphate buffer solution into each dissolution cup after sampling, slightly whirling and mixing uniformly, covering, and immediately putting the dissolution cups in a water bath kettle at 50 +/-0.5 ℃ for continuous release.
3. Preparing a reference solution:
taking a proper amount of goserelin acetate reference substance, precisely weighing, adding phosphate buffer solutions with various numbers, dissolving and quantitatively diluting to prepare a solution containing about 0.1mg of goserelin in every 1ml, and using the solution as a reference substance solution. Each medium was run in duplicate.
4. And (3) detecting the release degree of the sample:
respectively taking a test solution and a reference solution, and respectively measuring absorbance at intervals of 2nm within the interval of 275nm to 285nm by ultraviolet-visible spectrophotometry (0401 in the fourth part of the pharmacopoeia 2015, china); the F value was calculated as the average of the absorbance at six wavelengths, and the fluctuation range of the F value measured for the control solution at each sampling time point should be within ± 2% of the initial F value, and the released amount at each time point was calculated. The results are shown in Table 4.
TABLE 4 Release test results
As shown in Table 4, tween 80 was added to the release medium under the release condition of 50 ℃ to increase the release rate but not to be obvious.
4. Effect of pH of Release Medium on Release Rate
The experiment investigates the influence of the pH value on the release degree of the implant.
1. Lofting: taking 5 goserelin acetate sustained-release implants (about equivalent to 18mg of goserelin), placing the implants in a 120ml special dissolution cup in triplicate, taking 50ml of phosphate buffer (pH1.2/4.0/6.8) as a release medium, covering the cup, and placing the cup in an incubator at 39 +/-0.5 ℃ for heat preservation. The phosphate buffer was prepared as follows:
| release Medium numbering | pH value | Ingredients (1000 ml in medium) |
| Number 1 | 1.2 | Hydrochloric acid 7.65ml |
| Number 2 | 4.0 | 20.5ml of 2mol/L acetic acid solution; sodium acetate 1.22g |
| No. 3 | 6.8 | 250ml of 0.2mol/L potassium dihydrogen phosphate solution; 112ml of 0.2mol/L sodium hydroxide solution |
2. Sampling and preparing a test solution:
samples were taken at 1 hour, 2 hours, 4 hours, 7 hours, 24 hours, 72 hours (3 days) and 168 hours (7 days), respectively; taking out the dissolution cups from the incubator, cooling, slightly whirling and mixing uniformly, precisely measuring 5ml of supernatant, putting the supernatant into a 10ml measuring flask, diluting the supernatant to a scale by using respective phosphate buffer solution, shaking uniformly to serve as a test solution, immediately supplementing 5ml of phosphate buffer solution into each dissolution cup after sampling, slightly whirling and mixing uniformly, covering, and immediately putting the dissolution cups in an incubator at 39 +/-0.5 ℃ for continuous heat preservation.
3. Preparing a reference substance solution:
taking a proper amount of goserelin acetate reference substance, precisely weighing, adding phosphate buffer solutions with various numbers, dissolving and quantitatively diluting to prepare a solution containing about 0.1mg of goserelin in every 1ml, and using the solution as a reference substance solution. Each medium was run in duplicate.
4. And (3) detecting the release degree of the sample:
respectively taking the test solution and the reference solution, and respectively measuring absorbance at intervals of 2nm in the interval of 275nm to 285nm by ultraviolet-visible spectrophotometry (the general rule 0401 in the fourth part of the pharmacopoeia 2015 of China); the F value was calculated as the average of the absorbance at six wavelengths, and the fluctuation range of the F value measured for the control solution at each sampling time point should be within ± 2% of the initial F value, and the released amount at each time point was calculated. The results are shown in Table 5.
TABLE 5 Release test results
As shown in Table 5, under the release condition of 39 ℃, the release is inhibited and hardly released in the early stage of release as the pH value of the release medium is decreased; in the release medium with the pH value of about 7, the release speed is higher.
Example 1
The release conditions of this example are that tween 80 and chlorocarbon dimethylbenzylamine are added to the release medium in a 50 ℃ water bath oscillator, and the pH of the release medium is adjusted to 7.0.
Taking 5 goserelin acetate sustained-release implants, placing the implants in a 120ml special dissolution cup in six copies, taking 50ml of phosphate buffer as a release medium, covering the cup, and placing the cup in a 50 ℃ water bath oscillator (amplitude: 4cm; oscillation speed: 125 rpm/min) for release. The phosphate buffer was prepared as follows:
samples were taken at 9 hours, 48 hours (2 days), 3 days, 4 days, 5 days, and 6 days, respectively; taking out the dissolution cups from the water bath oscillator, cooling, slightly whirling and mixing, precisely measuring 5ml of supernatant, putting the supernatant into a 10ml measuring flask, diluting the supernatant to a scale by using respective phosphate buffer solution, shaking the supernatant uniformly to serve as a test solution, immediately supplementing 5ml of phosphate buffer solution into each dissolution cup after sampling, slightly whirling and mixing the supernatant, covering the cups, and immediately putting the cups into respective water bath oscillators for continuous release.
Taking a proper amount of goserelin acetate reference substance, precisely weighing, adding phosphate buffer solutions with various numbers, dissolving and quantitatively diluting to prepare a solution containing about 0.1mg of goserelin in each 1ml, and taking the solution as a reference substance solution. Each medium was run in duplicate. Respectively taking the test solution and the reference solution, and respectively measuring absorbance at intervals of 2nm in the interval of 275nm to 285nm by ultraviolet-visible spectrophotometry (the general rule 0401 in the fourth part of the pharmacopoeia 2015 of China); the F value was calculated as the average of the absorbance at six wavelengths, and the fluctuation range of the F value measured for the control solution at each sampling time point should be within ± 2% of the initial F value, and the released amount at each time point was calculated. The results of the release test are shown in table 6. The release profile is shown in figure 2.
TABLE 6
The experimental result shows that the release curve after the release acceleration of the implant in the release medium is basically consistent with the constant-speed curve under the condition of 50 ℃ release, and the release acceleration experimental condition can be used as the release acceleration experimental condition of the goserelin acetate sustained-release implant.
Example 2
The release conditions of this example were to add tween 80 and chloroxylyldimethylbenzylamine to the release medium in a 50 ℃ water bath shaker and adjust the pH of the release medium to 7.4.
Taking 5 goserelin acetate sustained-release implants, placing the implants in a special 120ml dissolution cup in six copies, taking 50ml of phosphate buffer as a release medium, covering the cup, and placing the cup in a 50 ℃ water bath oscillator (amplitude: 4cm; oscillation speed: 125 rpm/min) for release. The phosphate buffer was prepared as follows:
sampling at 9 hours, 48 hours (2 days), 3 days, 4 days and 5 days; taking out the dissolving cups from the water bath oscillator, cooling, slightly whirling and mixing uniformly, precisely measuring 5ml of supernatant, putting the supernatant into a 10ml measuring flask, diluting the supernatant to a scale by using respective phosphate buffer solution, shaking uniformly to be used as a test solution, immediately supplementing 5ml of phosphate buffer solution into each dissolving cup after sampling, slightly whirling and mixing uniformly, covering, and immediately putting into respective water bath oscillator for continuous release. Taking a proper amount of goserelin acetate reference substance, precisely weighing, adding phosphate buffer solutions with various numbers, dissolving and quantitatively diluting to prepare a solution containing about 0.1mg of goserelin in each 1ml, and taking the solution as a reference substance solution. Each medium was run in duplicate. Respectively taking a test solution and a reference solution, and respectively measuring absorbance at intervals of 2nm within the interval of 275nm to 285nm by ultraviolet-visible spectrophotometry (0401 in the fourth part of the pharmacopoeia 2015, china); the F value was calculated as the average of the absorbance at six wavelengths, and the fluctuation range of the F value measured for the control solution at each sampling time point should be within ± 2% of the initial F value, and the released amount at each time point was calculated. The results of the release test are shown in table 7. The release profile is shown in figure 3.
TABLE 7
| Release time point/h | 9 | 48 | 72 | 96 | 120 |
| Cumulative degree of release/%) | 5 | 30 | 60 | 78 | 105 |
The experimental result shows that the release curve after the release acceleration of the implant in the release medium is basically consistent with the constant-speed curve under the condition of 50 ℃ release, and the release acceleration experimental condition can be used as the release acceleration experimental condition of the goserelin acetate sustained-release implant.
From the results of the release experiments of examples 1 and 2, a linear fit analysis was performed with the release results of the reference example, wherein the origin software linear fit equation was as follows:
this results in a fitted curve, see fig. 4 and 5. The R values of the linear equations of the two fitting curves are 0.98964 and 0.99395 respectively, and the linear relation is good. The fitting degree is higher.
While the present invention has been described with reference to exemplary embodiments, it is to be understood that the invention is not limited to the disclosed exemplary embodiments. Many modifications and variations may be made to the exemplary embodiments of the present description without departing from the scope or spirit of the present invention. The scope of the claims is to be accorded the broadest interpretation so as to encompass all modifications and equivalent structures and functions.
Claims (7)
1. A method for measuring the in vitro dissolution rate of a goserelin acetate sustained release implant, comprising the step of contacting the goserelin acetate sustained release implant with a release medium, wherein the release medium comprises a buffer and a release promoting agent and citric acid dissolved in the buffer, the buffer is a phosphate buffer, and the pH of the release medium is between 6.8 and 7.5; the release promoter comprises chloroxyldimethylbenzylamine and polysorbate, the weight ratio of the chloroxyldimethylbenzylamine to the polysorbate is 0.15-0.3, the concentration of the chloroxyldimethylbenzylamine in a release medium is controlled to be more than 0.1g/L and less than 0.3g/L, wherein the polysorbate is Tween 80, and the concentration of the polysorbate in the release medium is 1-2g/L.
2. The method for measuring the in vitro dissolution rate of a goserelin acetate sustained release implant according to claim 1, wherein the goserelin acetate sustained release implant is maintained at a constant temperature of 40 ℃ to 55 ℃ when in contact with the release medium.
3. The method for measuring the in vitro dissolution rate of a goserelin acetate sustained release implant according to claim 1, wherein the agitation is maintained during the contacting.
4. The method for measuring the in vitro dissolution rate of a goserelin acetate sustained release implant according to claim 1, wherein the contact time of the goserelin acetate sustained release implant with the release medium is 5 to 7 days.
5. The method for measuring the in vitro dissolution rate of a goserelin acetate sustained release implant according to claim 4, further comprising the step of sampling at a plurality of time points and detecting the dissolution rate of the goserelin acetate sustained release implant in each sample.
6. The method for measuring the in vitro dissolution rate of a goserelin acetate sustained release implant according to claim 5, wherein the plurality of time points comprises at least a first time point 0.5 to 2 hours after the start of the contacting, a second time point 80 to 90 hours after the start of the contacting, and a third time point 144 to 168 hours after the start of the contacting.
7. The method for measuring the in vitro dissolution rate of a goserelin acetate sustained release implant according to claim 5, wherein the measuring comprises measuring absorbance at intervals of 2nm in the interval 275nm to 285nm, obtaining absorbance at six wavelengths, calculating the average value thereof, and calculating the released amount at each time point based on the average value.
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