WO2022001976A1 - 一种肠溶片耐酸力的快速检测方法 - Google Patents
一种肠溶片耐酸力的快速检测方法 Download PDFInfo
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- WO2022001976A1 WO2022001976A1 PCT/CN2021/102819 CN2021102819W WO2022001976A1 WO 2022001976 A1 WO2022001976 A1 WO 2022001976A1 CN 2021102819 W CN2021102819 W CN 2021102819W WO 2022001976 A1 WO2022001976 A1 WO 2022001976A1
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- enteric
- acid
- coated tablet
- gastric juice
- artificial gastric
- Prior art date
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- 239000002662 enteric coated tablet Substances 0.000 title claims abstract description 142
- 239000002253 acid Substances 0.000 title claims abstract description 130
- 238000000034 method Methods 0.000 title abstract description 37
- 238000001514 detection method Methods 0.000 claims abstract description 80
- 238000003756 stirring Methods 0.000 claims abstract description 20
- 210000004051 gastric juice Anatomy 0.000 claims description 71
- 239000000243 solution Substances 0.000 claims description 63
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 60
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 26
- 238000009210 therapy by ultrasound Methods 0.000 claims description 20
- 239000003826 tablet Substances 0.000 claims description 16
- 102000057297 Pepsin A Human genes 0.000 claims description 13
- 108090000284 Pepsin A Proteins 0.000 claims description 13
- 229940111202 pepsin Drugs 0.000 claims description 13
- 239000011780 sodium chloride Substances 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000011259 mixed solution Substances 0.000 claims description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- 238000000527 sonication Methods 0.000 claims 2
- 239000012530 fluid Substances 0.000 abstract description 3
- 230000002496 gastric effect Effects 0.000 abstract 2
- 238000012360 testing method Methods 0.000 description 25
- 239000000463 material Substances 0.000 description 12
- 238000012545 processing Methods 0.000 description 12
- 239000004925 Acrylic resin Substances 0.000 description 8
- 229920000178 Acrylic resin Polymers 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 8
- 238000007689 inspection Methods 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 238000010306 acid treatment Methods 0.000 description 5
- 229920002301 cellulose acetate Polymers 0.000 description 5
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 229920003138 Eudragit® L 30 D-55 Polymers 0.000 description 4
- 239000002702 enteric coating Substances 0.000 description 4
- 238000009505 enteric coating Methods 0.000 description 4
- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 4
- 229960003943 hypromellose Drugs 0.000 description 4
- 125000005591 trimellitate group Chemical group 0.000 description 4
- 238000000576 coating method Methods 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 2
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical class [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- WTHBRXCDDPKUOT-UHFFFAOYSA-N C(=O)O.C(=O)O.C(C)(=O)O Chemical compound C(=O)O.C(=O)O.C(C)(=O)O WTHBRXCDDPKUOT-UHFFFAOYSA-N 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 241000190070 Sarracenia purpurea Species 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WZNRVWBKYDHTKI-UHFFFAOYSA-N cellulose, acetate 1,2,4-benzenetricarboxylate Chemical compound OC1C(O)C(O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O.OC1C(O)C(O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O.CC(=O)OCC1OC(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(COC(C)=O)O1.CC(=O)OCC1OC(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(COC(C)=O)O1.OC(=O)C1=CC(C(=O)O)=CC=C1C(=O)OCC1C(OC2C(C(OC(=O)C=3C(=CC(=CC=3)C(O)=O)C(O)=O)C(OC(=O)C=3C(=CC(=CC=3)C(O)=O)C(O)=O)C(COC(=O)C=3C(=CC(=CC=3)C(O)=O)C(O)=O)O2)OC(=O)C=2C(=CC(=CC=2)C(O)=O)C(O)=O)C(OC(=O)C=2C(=CC(=CC=2)C(O)=O)C(O)=O)C(OC(=O)C=2C(=CC(=CC=2)C(O)=O)C(O)=O)C(OC(=O)C=2C(=CC(=CC=2)C(O)=O)C(O)=O)O1 WZNRVWBKYDHTKI-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000007923 drug release testing Methods 0.000 description 1
- LUJQXGBDWAGQHS-UHFFFAOYSA-N ethenyl acetate;phthalic acid Chemical compound CC(=O)OC=C.OC(=O)C1=CC=CC=C1C(O)=O LUJQXGBDWAGQHS-UHFFFAOYSA-N 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 229920002744 polyvinyl acetate phthalate Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- 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
- G01N33/15—Medicinal preparations ; Physical properties thereof, e.g. dissolubility
Definitions
- the invention relates to the detection of acid resistance of enteric-coated tablets, in particular to a rapid detection method of acid resistance of enteric-coated tablets.
- enteric-coated tablets are enteric-coated tablets.
- a commonly used enteric-coated tablet is a tablet that does not disintegrate in gastric juice, but can be disintegrated and absorbed in intestinal juice.
- the drug is made into enteric-coated tablets mainly to meet the needs of drug properties and treatment. Because many drugs are unstable under the acidic conditions of gastric juice, they are easily decomposed and fail or are irritating to the gastric mucosa; some drugs can only be better absorbed in the intestinal tract. In order to give full play to the therapeutic effect of drugs, these drugs are coated with a substance that can only be dissolved in alkaline intestinal fluid - enteric coating.
- enteric coating materials are acrylic resin No. I, No. II, No.
- enteric coating materials have a common feature, that is, they are insoluble below pH 5 and can meet the requirement of not disintegrating in human gastric juice.
- the enteric coating material is required to evenly wrap the tablet core containing the active ingredient so that it does not disintegrate in gastric juice, which corresponds to the in vitro acid resistance test.
- the traditional acid resistance testing method needs to be carried out in a professional analytical laboratory using a professional dissolution apparatus, which requires a high test site and takes a long time to test.
- the embodiment of the present invention provides a method for rapid detection of acid resistance of enteric-coated tablets, which can easily and quickly realize the detection of acid resistance of enteric-coated tablets.
- a rapid detection method for acid resistance of enteric-coated tablets comprising:
- the above-mentioned rapid detection method further includes the steps of taking out the enteric-coated tablet treated with artificial gastric juice and observing it, so as to judge the acid resistance of the enteric-coated tablet.
- the observation mainly refers to the visual observation. If there is no crack, disintegration or softening in each enteric-coated tablet, it is judged to be qualified for acid resistance; otherwise, it is judged to be unqualified for acid resistance.
- one enteric-coated tablet is softened, it is judged that the acid resistance is unqualified.
- each enteric-coated tablet has no cracks, disintegration and softening, it is judged that the acid resistance is qualified.
- the acid solution has a pH value of 1-3, such as a pH value of 1.2-2, for example, a pH value of 1, 1.2, 1.4, 1.8, 2 or 3.
- the acid solution can be selected from a hydrochloric acid solution, a sulfuric acid solution or a nitric acid solution; it can also be selected from a mixed solution of hydrochloric acid and acetic acid, or a mixed solution of hydrochloric acid and carbonic acid; a hydrochloric acid solution is preferred.
- an appropriate amount of acid eg, hydrochloric acid
- an acid solution such as an acid solution with a pH value of 1-3 or a pH value of 1.2-2.
- the temperature of the acid solution is 10-60°C, such as 10°C, 20°C, 30°C, 40°C, 50°C or 60°C.
- the inventor found in practice that if the temperature of the acid solution is lower than 10°C, the discrimination power is not strong; if the temperature is higher than 60°C, the error of the detection result increases. Controlling the temperature of the acid solution in the range of 10-60°C can not only improve the detection accuracy, but also shorten the detection time, so as to achieve the purpose of rapid detection.
- the temperature of the acid solution is 30-50°C.
- the power of the ultrasonic treatment in step 1) is 100-1500w, such as 100w, 400w, 800w or 1500w.
- the inventor found in practice that if the ultrasonic power is lower than 100w, the acid solution around the enteric-coated tablet cannot be kept uniform, so that the samples whose acid resistance does not meet the requirements cannot be effectively detected; if the ultrasonic power is higher than 1500w, the enteric-coated tablet It is easy to be crushed by ultrasonic in acid solution, resulting in large error in test results.
- the power of the ultrasonic treatment in step 1) is 400-800w.
- the time of the ultrasonic treatment in step 1) is 1-10 min, such as 1 min, 2 min, 5 min, 6 min, 8 min or 10 min.
- the time of the ultrasonic treatment in step 1) is 2-6 min.
- 1-150 enteric-coated tablets such as 1, 10, 100, 120 or 150 tablets, are placed in each 1000 mL of the acid solution. In this way, the volume of acid consumed during the acid treatment of the enteric-coated tablet is less, and the detection result will not be affected by the interaction between the enteric-coated tablets, thereby ensuring the detection accuracy.
- 100-120 enteric-coated tablets are placed in every 1000 mL of the acid solution in step 1). Another advantage of this is that the detection sample base is large and the detection result is highly accurate.
- the artificial gastric juice is a solution containing sodium chloride, pepsin, and acid.
- the artificial gastric juice has a pH value of 1-3, such as a pH value of 1.2-2, for example, a pH value of 1, 1.2, 2 or 3.
- the pH of the artificial gastric juice can be adjusted with hydrochloric acid, sulfuric acid or nitric acid, or with hydrochloric acid and acetic acid, or with hydrochloric acid and carbonic acid, preferably using hydrochloric acid.
- each 1000 mL of the artificial gastric juice contains 1-3 g of sodium chloride, 2-4 g of pepsin and an appropriate amount of acid, wherein the amount of the acid is to adjust the pH of the artificial gastric juice to 1-3, such as pH The value is 1.2-2.
- each 1000 mL of the artificial gastric juice contains 2 g of sodium chloride, 3.2 g of pepsin and an appropriate amount of acid, wherein the acid dosage is to adjust the pH of the artificial gastric juice to 1-3, for example, the pH is 1.2- 2.
- the artificial gastric juice preparation take 1-3 g of sodium chloride and 2-4 g of pepsin into a purified water cup containing an appropriate amount of acid, make a solution with a pH value of 1-3 and a volume of 1000 mL, and stir After homogenization, it becomes artificial gastric juice.
- the temperature of the hot artificial gastric juice is 34-40°C, eg, 34°C, 35°C, 39°C or 40°C.
- the artificial gastric juice can be heated by conventional methods. The study found that if the temperature of the artificial gastric juice is lower than 34 °C, the acid resistance of the enteric-coated tablets cannot be effectively detected; if the temperature of the artificial gastric juice is higher than 40 °C, the error of the test results will increase. Controlling the temperature of the artificial gastric juice within the range of 34-40°C can not only improve the detection accuracy, but also shorten the detection time and achieve the purpose of rapid detection.
- the temperature of the hot artificial gastric juice is 35-39°C.
- the power of the ultrasonic treatment in step 2) is 100-1500w, such as 100w, 400w, 800w or 1500w.
- the power of the ultrasonic treatment in step 2) is 400-800w.
- the processing time of step 2) is 1-10 min, such as 1 min, 2 min, 5 min, 6 min, 8 min or 10 min.
- the processing time of step 2) is 2-6 min.
- step 2) 1-150 enteric-coated tablets, such as 1, 10, 100, 120 or 150 tablets, are placed in each 1000 mL of the artificial gastric juice. In this way, less volume is consumed during the artificial gastric juice processing the enteric-coated tablet, and the detection result will not be affected by the interaction between the enteric-coated tablets, thereby ensuring the detection accuracy.
- 100-120 enteric-coated tablets are placed in each 1000 mL of the artificial gastric juice in step 1). Another advantage of this is that the detection sample base is large and the detection result is highly accurate.
- the rotational speed of the stirring in step 1) is 80-120 rpm, such as 80 rpm, 90 rpm, 100 rpm or 120 rpm.
- the inventor found in practice that if the stirring speed is lower than 80 rpm, the acid solution around the enteric-coated tablet cannot be kept uniform, so that samples whose acid resistance does not meet the requirements cannot be effectively detected; if the stirring speed is higher than 120 rpm, then the enteric-coated tablet It is easy to rotate and collide with each other in the acid solution, resulting in a large error in the detection result.
- the stirring methods that can be adopted include glass rod stirring, magnetic stirring and mechanical stirring.
- the rapid detection method for acid resistance of the enteric-coated tablet comprises the following steps:
- an acid solution preferably a hydrochloric acid solution
- a pH value of 1-3 and a temperature of 10-60°C place the enteric-coated tablet to be tested in the acid solution, and stir for 1-10min or at a power of 100-1500w Ultrasonic treatment under the condition for 1-10min; wherein, preferably 100-120 enteric-coated tablets are put into every 1000mL of the acid solution;
- each 1000mL of the artificial gastric juice contains 1-3g of sodium chloride and 2-4g of pepsin; preferably, 100-120 enteric-coated tablets are placed in each 1000mL of the artificial gastric juice;
- the method of the invention can quickly detect the enteric-coated tablets whose acid resistance does not meet the requirements.
- the method of the present invention is applicable to various enteric-coated tablets.
- the enteric-coated materials used in the enteric-coated tablets include Eudragit L30D-55, hypromellose phthalate, cellulose acetate trimellitate, acrylic resin No. 1, No. II, No. III, phthalate Cellulose acetate diformate, polyvinyl alcohol titanate, acrylic resin EuS100, Eu1100, etc.
- the quick acid resistance detection method of the enteric-coated tablet of the invention is close to the results of the traditional detection method, the detection time is shorter, and the method is more convenient.
- the quick detection method for acid resistance of enteric-coated tablets of the invention can be preferably applied to acid resistance testing in the coating process of enteric-coated tablets, and provides a basis for adjustment of coating parameters in the research process.
- the instruments and reagents used in the method of the invention are simple and easy to obtain, and there are no special requirements for the test site, which is convenient for research units and production workshops to carry out the test.
- the method of the invention solves the problem that the existing test method needs to be tested in a specific test site due to the special equipment required, and the detection takes a long time, so it cannot be applied to the test of the production research process, and provides the coating parameters for the production and research of enteric-coated tablets. Effective and immediate detection method.
- the rapid detection method of acid resistance of enteric-coated tablets includes the following steps:
- Acid treatment of enteric-coated tablets 1000 mL of a hydrochloric acid solution with a pH value of 3 was heated to 60° C., and 100 enteric-coated tablets were put into it, and the ultrasonic treatment time was 2min under the condition of power 800w;
- every 1000mL of the artificial gastric juice contains 2g of sodium chloride, 3.2g of pepsin and hydrochloric acid, wherein the amount of hydrochloric acid is to adjust the pH value of the artificial gastric juice to 1.2;
- the method of this embodiment is especially suitable for detecting enteric-coated tablets whose enteric-coated material is Eudragit L30D-55.
- the rapid detection method of acid resistance of enteric-coated tablets includes the following steps:
- Acid treatment of enteric-coated tablets control the temperature of 1000 mL of a hydrochloric acid solution with a pH value of 1 to 10 °C, take 100 enteric-coated tablets and put them in, and ultrasonically treat them for 1 min under the condition of a power of 1500 w;
- every 1000mL of the artificial gastric juice contains 2g of sodium chloride, 3.2g of pepsin and hydrochloric acid, wherein the amount of hydrochloric acid is to adjust the pH value of the artificial gastric juice to 2;
- the method of this embodiment is especially suitable for detecting enteric-coated tablets whose enteric-coated material is hypromellose phthalate.
- the rapid detection method of acid resistance of enteric-coated tablets includes the following steps:
- Acid treatment of enteric-coated tablets 1000 mL of hydrochloric acid solution with a pH value of 1.4 was heated to 40°C, 100 enteric-coated tablets were taken and placed, and the ultrasonic treatment time was 6 min under the condition of power 100w;
- every 1000mL of the artificial gastric juice contains 2g of sodium chloride, 3.2g of pepsin and hydrochloric acid, wherein the amount of hydrochloric acid is to adjust the pH value of the artificial gastric juice to 1.2;
- the method of this embodiment is especially suitable for detecting enteric-coated tablets whose enteric-coated material is cellulose acetate trimellitate.
- the rapid detection method of acid resistance of enteric-coated tablets includes the following steps:
- every 1000mL of the artificial gastric juice contains 2g of sodium chloride, 3.2g of pepsin and hydrochloric acid, wherein the amount of hydrochloric acid is to adjust the pH value of the artificial gastric juice to 1.2;
- the method of this embodiment is especially suitable for detecting enteric-coated tablets whose enteric-coated materials are acrylic resin No. II and acrylic resin No. III.
- the detection method for acid resistance of enteric-coated tablets includes the following steps:
- Acid solution preparation take 9 mL of hydrochloric acid and add purified water to make a solution with a volume of 1000 mL, and use a glass rod to stir evenly to become an acid solution;
- Acid resistance test of enteric-coated tablets Take 100 enteric-coated tablets, and put the enteric-coated tablets into 1000ml of acid solution at 37°C according to the dissolution and release testing method of the 2020 edition of the Chinese Pharmacopoeia, using an intelligent dissolution apparatus. In the dissolution vessel, the stirring speed is 100rpm, and the processing time is 120min;
- the enteric-coated material is the enteric-coated tablet No. 1 of Eudragit L30D-55;
- the enteric-coated material is No. 2 enteric-coated tablet of hypromellose phthalate;
- the enteric-coated material is No. 3 enteric-coated tablets of cellulose acetate trimellitate;
- the enteric-coated material is the enteric-coated tablet No. 4 of acrylic resin No. II and acrylic resin No. III.
- enteric-coated tablets used in the rapid detection method and traditional detection method of the same variety in Table 1 are of the same batch.
- enteric-coated tablets used in the rapid detection method and traditional detection method of the same variety in Table 2 are of the same batch.
- the detection results show that the rapid acid resistance detection method of the enteric-coated tablet of the present invention is close to the detection results of the traditional method. Compared with the traditional method, the rapid acid resistance detection method of the enteric-coated tablet of the present invention has shorter detection time, and the method is more convenient and does not require a special instrument.
- Acid treatment of enteric-coated tablets 1000 mL of a hydrochloric acid solution with a pH value of 3 was heated to 60° C., and 100 enteric-coated tablets were put into it, and the ultrasonic treatment time was 2min under the condition of power 800w;
- every 1000mL of the artificial gastric juice contains 2g of sodium chloride, 3.2g of pepsin and hydrochloric acid, wherein the amount of hydrochloric acid is to adjust the pH value of the artificial gastric juice to 1.2;
- step S1 The temperature of the acid solution in step S1 was adjusted to 5°C, 10°C, 40°C, 50°C, 60°C, and 65°C, respectively, for detection, and compared with the method of Comparative Example 1. The results are shown in Tables 3 and 4 below.
- the invention provides a rapid detection method for acid resistance of enteric-coated tablets.
- the method for rapid detection of acid resistance of enteric-coated tablets provided by the present invention includes: 1) providing acid solution, placing the enteric-coated tablet to be detected in the acid solution, and ultrasonically or stirring for 1-10 minutes; 2) providing hot artificial gastric juice , placing the enteric-coated tablet treated in the acid solution in the hot artificial gastric juice, and ultrasonically or stirring the treatment for 1-10 min.
- the method of the invention can simply and quickly realize the detection of the acid resistance of the enteric-coated tablet.
- the quick acid resistance detection method of the enteric-coated tablet of the invention is close to the results of the traditional method, the detection time is shorter, the method is more convenient, and has better economic value and application prospect.
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Abstract
本发明涉及一种肠溶片耐酸力的快速检测方法。本发明提供的肠溶片耐酸力的快速检测方法包括：1)提供酸液，将待检测的肠溶片置于该酸液中，超声或搅拌处理1-10min；2)提供热的人工胃液，将在所述酸液中处理后的肠溶片置于该热的人工胃液中，超声或搅拌处理1-10min。本发明方法可以简便快速地实现肠溶片耐酸力的检测。本发明的肠溶片快速耐酸力检测方法与传统方法结果接近，检测时间更短，方法更为方便。
Description
交叉引用
本申请要求2020年6月30日提交的专利名称为“一种肠溶片耐酸力的快速检测方法”的第202010619094.6号中国专利申请的优先权，其全部公开内容通过引用整体并入本文。
本发明涉及肠溶片耐酸力检测，具体涉及一种肠溶片耐酸力的快速检测方法。
在药物的各种剂型中，有些是肠溶片。常用的肠溶片剂是一种在胃液中不崩解，而在肠液中能够崩解、吸收的一种片剂。将药物制成肠溶片主要是为了满足药物性质及治疗的需要。因为许多药物在胃液酸性条件下不稳定，易分解失效或对胃黏膜有刺激性；还有的药品只有在肠道中才能够更好地吸收。为了充分发挥药物的治疗作用，就在这些药物的外面包上一层只能在碱性肠液中溶解的物质—肠溶衣。目前常用的肠溶衣材料有丙烯酸树脂Ⅰ号、Ⅱ号、III号，邻苯二甲酸醋酸纤维素(CAP)，羟丙甲纤维素邻苯二甲酸酯(HPMCP)，聚乙烯醇钛酸酯(PVAP)，醋酸纤维素苯三酸酯(CAT)，丙烯酸树脂EuS100、Eu1100,尤特奇L30D-55等。这些肠溶衣材料都有一个共性，那就是在pH5以下不溶解，能够满足在人体胃液中不崩解的要求。在肠溶片的应用中要求肠溶衣材料将含活性成分的片芯均匀包裹，才能使之在胃液中不崩解，与之对应的就是体外的耐酸力检测。
传统耐酸力检测方法需在专业的分析实验室，使用专业的溶出仪进行，对试验场地要求较高，且检测时间耗时较长。
针对目前肠溶片耐酸力即时检测的问题，急需提供一种新的肠溶片耐酸力快速检测方法以解决或部分解决现有技术中的问题。
发明内容
本发明实施例提供一种肠溶片耐酸力的快速检测方法，该方法可以简便快速地实现肠溶片耐酸力的检测。
一种肠溶片耐酸力的快速检测方法，包括：
1)提供10-60℃的酸液，将待检测的肠溶片置于该酸液中，搅拌处理或超声处理1-10min；
2)提供热的人工胃液，将在所述酸液中处理后的肠溶片置于该热的人工胃液中，搅拌处理或超声处理1-10min。
进一步地，上述快速检测方法还包括将人工胃液处理后的肠溶片取出以及对其进行观察，以对该肠溶片的耐酸力进行判断的步骤。其中，所述的观察主要是指目测。若每片肠溶片均未出现裂缝、崩解或软化现象，即判为耐酸力合格；否则即判为耐酸力不合格。
在一些实施例中，若有一片肠溶片有裂缝，即判为耐酸力不合格。
在一些实施例中，若有一片肠溶片有崩解，即判为耐酸力不合格。
在一些实施例中，若有一片肠溶片有软化，即判为耐酸力不合格。
在一些实施例中，若每片肠溶片均无裂缝、崩解和软化，即判为耐酸力合格。
在一些实施例中，所述酸液的pH值为1-3，例如pH值为1.2-2，具体例如pH值为1、1.2、1.4、1.8、2或3。
在一些实施例中，所述酸液可选自盐酸溶液、硫酸溶液或硝酸溶液；也可选自盐酸与醋酸的混合溶液，或者盐酸与碳酸的混合溶液；其中较佳的是盐酸溶液。
在一些实施例中，是取适量酸(如盐酸)加入纯化水，制成酸液，例如pH值1-3或pH值为1.2-2的酸液。
在一些实施例中，所述酸液的温度为10-60℃，例如10℃、20℃、30℃、40℃、50℃或60℃。发明人在实践中发现，若酸液的温度低于10℃，则区分力不强；若温度高于60℃，则检测结果误差增大。将酸液的温度控 制在10-60℃范围内既可以提高检测准确率，还可以缩短检测时间，达到快速检测的目的。
在一些实施例中，所述酸液的温度为30-50℃。
在一些实施例中，步骤1)所述超声处理的功率为100-1500w，例如100w、400w、800w或1500w。发明人在实践中发现，若超声功率低于100w，则肠溶片周围的酸液无法保持均匀，从而不能有效检出耐酸力不符合要求的样品；若超声功率高于1500w，则肠溶片易在酸液中被超声击碎，导致检测结果误差大。
在一些实施例中，步骤1)所述超声处理的功率为400-800w。
在一些实施例中，步骤1)所述超声处理的时间为1-10min，例如1min、2min、5min、6min、8min或10min。研究发现，若处理时间低于1min，则检出能力不足；若处理时间高于10min，则检测结果误差大。
在一些实施例中，步骤1)所述超声处理的时间为2-6min。
在一些实施例中，步骤1)中每1000mL所述酸液中放入1-150片肠溶片，例如1片、10片、100片、120片或150片。这样在酸液处理肠溶片过程中所消耗的酸液体积较少，而且也不会因肠溶片之间的相互作用而影响检测结果，从而能够保证检测准确率。在一些实施例中，步骤1)中每1000mL所述酸液中放入100-120片肠溶片，这样另一优点是检测样本基数较大，检测结果准确度高。
在一些实施例中，所述人工胃液为含有氯化钠、胃蛋白酶和酸的溶液。
在一些实施例中，所述人工胃液的pH值为1-3，例如pH值为1.2-2，具体例如pH值为1、1.2、2或3。
在一些实施例中，可用盐酸、硫酸或硝酸，或用盐酸与醋酸，或用盐酸与碳酸调节所述人工胃液的pH值，优选使用盐酸。
在一些实施例中，每1000mL所述人工胃液中含有氯化钠1-3g，胃蛋白酶2-4g和酸适量，其中所述酸的用量为调节该人工胃液pH值至1-3，例如pH值为1.2-2。
在一些实施例中，每1000mL所述人工胃液中含有氯化钠2g，胃蛋白酶3.2g和酸适量，其中所述的酸用量为调节人工胃液pH值至1-3，例如pH值为1.2-2。
在一些实施例中，所述人工胃液配制：取氯化钠1-3g和胃蛋白酶2-4g放入含有酸适量的纯化水杯内，制成pH值为1-3、体积为1000mL溶液，搅拌均匀后成为人工胃液。
在一些实施例中，所述热的人工胃液的温度为34-40℃，例如34℃、35℃、39℃或40℃。可采用常规方法对人工胃液进行加热。研究发现，若人工胃液的温度低于34℃，则无法有效检测耐酸力不合格肠溶片；若人工胃液的温度高于40℃，则检测结果误差增大。将人工胃液的温度控制在34-40℃范围内既可以提高检测准确率，还可以缩短检测时间，达到快速检测的目的。
在一些实施例中，所述热的人工胃液的温度为35-39℃。
在一些实施例中，步骤2)所述超声处理的功率为100-1500w，例如100w、400w、800w或1500w。发明人在实践中发现，若超声功率低于100w，则肠溶片周围的人工胃液无法保持均匀，从而不能保证检测结果的准确率；若超声功率高于1500w，则肠溶片易在人工胃液中被超声击碎，导致检测结果误差大。
在一些实施例中，步骤2)所述超声处理的功率为400-800w。
在一些实施例中，步骤2)所述处理时间为1-10min，例如1min、2min、5min、6min、8min或10min。研究发现，若处理时间低于1min，则检出能力不足；若处理时间高于10min，则检测结果误差大。
在一些实施例中，步骤2)所述处理时间为2-6min。
在一些实施例中，步骤2)中每1000mL所述人工胃液中放入1-150片肠溶片，例如1片、10片、100片、120片或150片。这样在人工胃液处理肠溶片过程中所消耗的体积较少，而且也不会因肠溶片之间的相互作用而影响检测结果，从而能够保证检测准确率。在一些实施例中，步骤1) 中每1000mL所述人工胃液中放入100-120片肠溶片，这样另一优点是检测样本基数较大，检测结果准确度高。
在一些实施例中，步骤1)所述搅拌的转速为80-120rpm，例如80rpm、90rpm、100rpm或120rpm。发明人在实践中发现，若搅拌转速低于80rpm，则肠溶片周围的酸液无法保持均匀，从而不能有效检出耐酸力不符合要求的样品；若搅拌转速高于120rpm，则肠溶片易在酸液中旋转互相撞击，导致检测结果误差大。
在本发明实施例中，可以采用的搅拌方式包括玻璃棒搅拌、磁力搅拌和机械搅拌。
在本发明一些实施例中，所述肠溶片耐酸力的快速检测方法，包括如下步骤：
1)提供pH值为1-3、温度为10-60℃的酸溶液(优选盐酸溶液)，将待检测的肠溶片置于该酸溶液中，搅拌处理1-10min或在功率100-1500w条件下超声处理1-10min；其中，优选每1000mL所述酸液中放入100-120片肠溶片；
2)提供pH值为1-3、温度34-40℃的人工胃液，将在所述酸溶液中处理后的肠溶片置于该人工胃液中，搅拌处理1-10min或在功率100-1500w条件下超声处理1-10min；
其中，优选每1000mL所述人工胃液中含有氯化钠1-3g、胃蛋白酶2-4g；优选每1000mL所述人工胃液中放入100-120片肠溶片；
3)将人工胃液处理后的肠溶片取出，进行观察，判断是否合格。
本发明方法可快速检测出耐酸力不符合要求的肠溶片。
本发明方法适用于各种肠溶片。其中肠溶片所用的肠溶材料包括尤特奇L30D-55，羟丙甲纤维素邻苯二甲酸酯，醋酸纤维素苯三酸酯，丙烯酸树脂Ⅰ号、Ⅱ号、III号，邻苯二甲酸醋酸纤维素，聚乙烯醇钛酸酯，丙烯酸树脂EuS100、Eu1100等。
本发明肠溶片快速耐酸力检测方法与传统检测方法结果接近，，且检测时间更短，方法更为方便。本发明肠溶片耐酸力快速检测方法可较好的应用于肠溶片包衣过程中耐酸力测试，为研究过程包衣参数调整提供依据。本发明方法所用的仪器和试剂均简单易得，测试场地无特殊要求，便于研究单位和生产车间实施测试。本发明方法解决了现有测试方法因所需仪器特殊，需在特定试验场地进行测试，且检测耗时长，无法应用于生产研究过程测试的问题，为生产和研究肠溶片包衣参数提供了有效即时的检测方法。
下面结合具体实施例对本方案作进一步的详细描述，以便本领域技术人员理解。
实施例1
肠溶片耐酸力的快速检测方法，包括如下步骤：
S1、肠溶片酸液处理：将1000mL的pH值为3的盐酸溶液升温至60℃，取肠溶片100片放入，在功率800w条件下超声处理时间2min；
S2、肠溶片人工胃液处理：取酸液处理过的肠溶片100片放入40℃的1000mL人工胃液中，在功率800w条件下超声处理时间1min；
其中，每1000mL所述人工胃液中含有氯化钠2g、胃蛋白酶3.2g和盐酸，其中盐酸用量为调节人工胃液pH值至1.2；
S3、结果判定：将人工胃液处理后的肠溶片取出，每片应不得有裂缝、崩解或软化现象，即判为合格，否则判为不合格。
本实施例方法尤其适用于检测肠溶材料为尤特奇L30D-55的肠溶片。
实施例2
肠溶片耐酸力的快速检测方法，包括如下步骤：
S1、肠溶片酸液处理：将1000mL的pH值为1的盐酸溶液控温至10℃，取肠溶片100片放入，在功率1500w条件下超声处理时间1min；
S2、肠溶片人工胃液处理：取酸液处理过的肠溶片100片放入39℃ 的1000mL人工胃液中，在功率100w条件下超声处理时间10min；
其中，每1000mL所述人工胃液中含有氯化钠2g、胃蛋白酶3.2g和盐酸，其中盐酸用量为调节人工胃液pH值至2；
S3、结果判定：将人工胃液处理后的肠溶片取出，每片应不得有裂缝、崩解或软化现象，即判为合格，否则判为不合格。
本实施例方法尤其适用于检测肠溶材料为羟丙甲纤维素邻苯二甲酸酯的肠溶片。
实施例3
肠溶片耐酸力的快速检测方法，包括如下步骤：
S1、肠溶片酸液处理：将1000mL的pH值为1.4的盐酸溶液升温至40℃，取肠溶片100片放入，在功率100w条件下超声处理时间6min；
S2、肠溶片人工胃液处理：取酸液处理过的肠溶片100片放入34℃的1000mL人工胃液中，在功率1500w条件下超声处理时间6min；
其中，每1000mL所述人工胃液中含有氯化钠2g、胃蛋白酶3.2g和盐酸，其中盐酸用量为调节人工胃液pH值至1.2；
S3、结果判定：将人工胃液处理后的肠溶片取出，每片应不得有裂缝、崩解或软化现象，即判为合格，否则判为不合格。
本实施例方法尤其适用于检测肠溶材料为醋酸纤维素苯三酸酯的肠溶片。
实施例4
肠溶片耐酸力的快速检测方法，包括如下步骤：
S1、肠溶片酸液处理：将1000mL的pH值为1.8的盐酸溶液升温至50℃，取肠溶片100片放入，在功率400w条件下超声处理时间10min；
S2、肠溶片人工胃液处理：取酸液处理过的肠溶片100片放入35℃的1000mL人工胃液中，在功率400w条件下超声处理时间2min；
其中，每1000mL所述人工胃液中含有氯化钠2g、胃蛋白酶3.2g和盐酸，其中盐酸用量为调节人工胃液pH值至1.2；
S3、结果判定：将人工胃液处理后的肠溶片取出，每片应不得有裂缝、崩解或软化现象，即判为合格，否则判为不合格。
本实施例方法尤其适用于检测肠溶材料为丙烯酸树脂Ⅱ号和丙烯酸树脂Ⅲ号的肠溶片。
对比例1
肠溶片耐酸力的检测方法，包括如下步骤：
S1、酸液配制：取盐酸9mL加入纯化水，制成体积为1000mL溶液，使用玻璃棒搅拌均匀后成为酸液；
S2、肠溶片耐酸力检查：取肠溶片100片，按照《中国药典》2020年版溶出度与释放度检测方法，使用智能溶出仪，将肠溶片放入盛有37℃的1000ml酸液的溶出杯中，搅拌转速100rpm，处理时间120min；
S3、结果判定：将耐酸力检查后的肠溶片取出，每片应不得有裂缝、崩解或软化现象，即判为合格，否则判为不合格。
实验例1
实验样品：
肠溶材料为尤特奇L30D-55的肠溶片1号；
肠溶材料为羟丙甲纤维素邻苯二甲酸酯的肠溶片2号；
肠溶材料为醋酸纤维素苯三酸酯的肠溶片3号；
肠溶材料为丙烯酸树脂Ⅱ号和丙烯酸树脂Ⅲ号的肠溶片4号。
分别选取同批次经检测为耐酸力不合格及合格的以上样品，分别采用实施例1-4及对比例1方法进行检测。其中，以上肠溶片1-4号分别采用实施例1-4方法进行检测，并对这四种肠溶片分别采用对比例1方法进行检测。结果见下表1和表2。
表1耐酸力检查结果统计
注：表1同一品种快速检测方法和传统检测方法使用的肠溶片为同批次。
表2耐酸力检查结果统计
注：表2同一品种快速检测方法和传统检测方法使用的肠溶片为同批次。
检测结果表明，本发明的肠溶片快速耐酸力检测方法与传统方法检测结果接近。本发明的肠溶片快速耐酸力检测方法与传统方法相比，检测时间更短，且方法更为方便，不需要专用仪器。
实验例2 研究实验
采用以下基本方法，分别改变其中的关键条件进行肠溶片耐酸力的快速检测：
S1、肠溶片酸液处理：将1000mL的pH值为3的盐酸溶液升温至60℃，取肠溶片100片放入，在功率800w条件下超声处理时间2min；
S2、肠溶片人工胃液处理：取酸液处理过的肠溶片100片放入40℃的1000mL人工胃液中，在功率800w条件下超声处理时间1min；
其中，每1000mL所述人工胃液中含有氯化钠2g、胃蛋白酶3.2g和盐酸，其中盐酸用量为调节人工胃液pH值至1.2；
S3、结果判定：将人工胃液处理后的肠溶片取出，每片应不得有裂缝、崩解或软化现象，即判为合格，否则判为不合格。
以下实验所用样品为肠溶片1号，同实验例1。
1.酸液的温度对于检测结果的影响
将步骤S1中酸液的温度分别调整为5℃、10℃、40℃、50℃、60℃、65℃，进行检测，并与对比例1方法进行对比。结果见下表3和表4。
表3耐酸力检查结果统计
注：表3各肠溶片为同批次。
表4耐酸力检查结果统计
注：表4各肠溶片为同批次。
以上结果表明，若酸液的温度为5℃，则区分力不强；若温度为65℃，则检测结果误差增大。将酸液的温度控制在10-60℃范围内既可以提高检测准确率，还可以缩短检测时间，达到快速检测的目的。
2.超声处理的功率对于检测结果的影响
2.1将步骤S1中超声处理的功率分别调整为80w、100w、400w、800w、1500w、1600w，进行检测，并与对比例1方法进行对比。结果见下表5和表6。
表5耐酸力检查结果统计
注：表5各肠溶片为同批次。
表6耐酸力检查结果统计
注：表6各肠溶片为同批次。
2.2将步骤S2中超声处理的功率分别调整为80w、100w、400w、800w、1500w、1600w，进行检测，并与对比例1方法进行对比。结果见下表7和表8。
表7耐酸力检查结果统计
注：表7各肠溶片为同批次。
表8耐酸力检查结果统计
注：表8各肠溶片为同批次。
以上结果表明，若超声功率为80w，则肠溶片周围的酸液、人工胃液无法保持均匀，从而不能有效检出耐酸力不符合要求的样品；若超声功率为1600w，则肠溶片易在酸液中被超声击碎，导致检测结果误差大。
3.超声处理的时间对于检测结果的影响
3.1将步骤S1中超声处理的时间分别调整为30s、1min、2min、6min、10min、12min，进行检测，并与对比例1方法进行对比。结果见下表9和表10。
表9耐酸力检查结果统计
注：表9各肠溶片为同批次。
表10耐酸力检查结果统计
注：表10各肠溶片为同批次。
3.2将步骤S2中超声处理的时间分别调整为30s、1min、2min、6min、10min、12min，进行检测，并与对比例1方法进行对比。结果见下表11和表12
表11耐酸力检查结果统计
注：表11各肠溶片为同批次。
表12耐酸力检查结果统计
注：表12各肠溶片为同批次。
以上结果表明，若处理时间为30s，则检出能力不足；若处理时间为12min，则检测结果误差大。
虽然，上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述，但在本发明基础上，可以对之作一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。
本发明提供一种肠溶片耐酸力的快速检测方法。本发明提供的肠溶片耐酸力的快速检测方法包括：1)提供酸液，将待检测的肠溶片置于该酸液中，超声或搅拌处理1-10min；2)提供热的人工胃液，将在所述酸液中处理后的肠溶片置于该热的人工胃液中，超声或搅拌处理1-10min。本发明方法可以简便快速地实现肠溶片耐酸力的检测。本发明的肠溶片快速耐酸力检测方法与传统方法结果接近，检测时间更短，方法更为方便，具有较好的经济价值和应用前景。
Claims (10)
- 一种肠溶片耐酸力的快速检测方法，其包括：1)提供10-60℃的酸液，将待检测的肠溶片置于该酸液中，搅拌处理或超声处理1-10min；2)提供热的人工胃液，将在所述酸液中处理后的肠溶片置于该热的人工胃液中，搅拌处理或超声处理1-10min；或者还进一步包括：将人工胃液处理后的肠溶片取出以及对其进行观察，以对该肠溶片的耐酸力进行判断的步骤。
- 根据权利要求1所述肠溶片耐酸力的快速检测方法，其中，所述酸液的pH值为1-3，优选为1.2-2；和/或，所述酸液的温度为30-50℃。
- 根据权利要求1或2所述肠溶片耐酸力的快速检测方法，其中，所述酸液选自盐酸溶液，硫酸溶液，硝酸溶液，盐酸与醋酸的混合溶液，盐酸与碳酸的混合溶液；优选为盐酸溶液。
- 根据权利要求1-3任一项所述肠溶片耐酸力的快速检测方法，其中，步骤1)所述超声处理的功率为100-1500w，优选为400-800w；和/或，步骤1)所述超声处理的时间为2-6min。
- 根据权利要求1-4任一项所述肠溶片耐酸力的快速检测方法，其中，步骤1)中每1000mL所述酸液中放入1-150片肠溶片，例如1片、10片、100片、120片或150片。
- 根据权利要求1-5任一项所述肠溶片耐酸力的快速检测方法，其中，所述人工胃液为含有氯化钠、胃蛋白酶和酸的溶液；优选，所述人工胃液pH值为1-3，更优选为1.2-2；进一步优选，每1000mL所述人工胃液中含有氯化钠1-3g，胃蛋白酶2-4g。
- 根据权利要求1-6任一项所述肠溶片耐酸力的快速检测方法，其中，所述热的人工胃液的温度为34-40℃，优选为35-39℃。
- 根据权利要求1-7任一项所述肠溶片耐酸力的快速检测方法，其 中，步骤2)所述超声处理的功率为100-1500w，优选为400-800w；和/或，步骤2)所述超声处理的时间为2-6min。
- 根据权利要求1-8任一项所述肠溶片耐酸力的快速检测方法，其中，步骤2)中每1000mL所述人工胃液中放入1-150片肠溶片，例如1片、10片、100片、120片或150片。
- 根据权利要求1-9任一项所述肠溶片耐酸力的快速检测方法，包括如下步骤：1)提供pH值为1-3、温度为10-60℃的酸溶液，将待检测的肠溶片置于该酸溶液中，搅拌处理1-10min或在功率100-1500w条件下超声处理1-10min；2)提供pH值为1-3、温度为34-40℃的人工胃液，将在所述酸溶液中处理后的肠溶片置于该人工胃液中，搅拌处理1-10min或在功率100-1500w条件下超声处理1-10min；其中，优选每1000mL所述人工胃液中含有氯化钠1-3g、胃蛋白酶2-4g；3)将人工胃液处理后的肠溶片取出，进行观察，判断是否合格。
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