CN117442615A - H (H) 2 Receptor antagonist pharmaceutical composition and preparation method thereof - Google Patents
H (H) 2 Receptor antagonist pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN117442615A CN117442615A CN202311572886.2A CN202311572886A CN117442615A CN 117442615 A CN117442615 A CN 117442615A CN 202311572886 A CN202311572886 A CN 202311572886A CN 117442615 A CN117442615 A CN 117442615A
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- famotidine
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- phosphoric acid
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 19
- 229940044551 receptor antagonist Drugs 0.000 title claims abstract description 11
- 239000002464 receptor antagonist Substances 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 81
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 36
- XUFQPHANEAPEMJ-UHFFFAOYSA-N famotidine Chemical compound NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 XUFQPHANEAPEMJ-UHFFFAOYSA-N 0.000 claims abstract description 31
- 229960001596 famotidine Drugs 0.000 claims abstract description 30
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims abstract description 29
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims abstract description 20
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 15
- 229960003966 nicotinamide Drugs 0.000 claims abstract description 15
- 235000005152 nicotinamide Nutrition 0.000 claims abstract description 15
- 239000011570 nicotinamide Substances 0.000 claims abstract description 15
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229960000281 trometamol Drugs 0.000 claims abstract description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000008215 water for injection Substances 0.000 claims abstract description 11
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229930003268 Vitamin C Natural products 0.000 claims abstract description 10
- 235000019154 vitamin C Nutrition 0.000 claims abstract description 10
- 239000011718 vitamin C Substances 0.000 claims abstract description 10
- 229960004838 phosphoric acid Drugs 0.000 claims abstract description 3
- 235000011007 phosphoric acid Nutrition 0.000 claims abstract description 3
- 229940083608 sodium hydroxide Drugs 0.000 claims abstract description 3
- 239000000243 solution Substances 0.000 claims description 37
- 229940005526 famotidine injection Drugs 0.000 claims description 16
- 229940090044 injection Drugs 0.000 claims description 14
- 239000007924 injection Substances 0.000 claims description 14
- 238000002347 injection Methods 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 6
- 230000001954 sterilising effect Effects 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 5
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 claims description 4
- 239000012528 membrane Substances 0.000 claims description 4
- 239000003708 ampul Substances 0.000 claims description 3
- 238000011049 filling Methods 0.000 claims description 3
- 238000007789 sealing Methods 0.000 claims description 3
- 238000004659 sterilization and disinfection Methods 0.000 claims description 3
- 229940083645 famotidine 10 mg/ml Drugs 0.000 claims 1
- 229930003231 vitamin Natural products 0.000 claims 1
- 235000013343 vitamin Nutrition 0.000 claims 1
- 239000011782 vitamin Substances 0.000 claims 1
- 229940088594 vitamin Drugs 0.000 claims 1
- 150000003722 vitamin derivatives Chemical class 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 18
- 238000001556 precipitation Methods 0.000 abstract description 6
- 230000008569 process Effects 0.000 abstract description 5
- 239000003513 alkali Substances 0.000 abstract description 2
- 239000004480 active ingredient Substances 0.000 abstract 1
- 239000011259 mixed solution Substances 0.000 abstract 1
- 230000000052 comparative effect Effects 0.000 description 54
- 238000012360 testing method Methods 0.000 description 18
- 238000009472 formulation Methods 0.000 description 14
- 239000012535 impurity Substances 0.000 description 10
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 10
- 230000007774 longterm Effects 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 7
- 230000007794 irritation Effects 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 230000002378 acidificating effect Effects 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 5
- 229930195725 Mannitol Natural products 0.000 description 5
- 241000283973 Oryctolagus cuniculus Species 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000004310 lactic acid Substances 0.000 description 5
- 235000014655 lactic acid Nutrition 0.000 description 5
- 235000010355 mannitol Nutrition 0.000 description 5
- 239000000594 mannitol Substances 0.000 description 5
- 230000002792 vascular Effects 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 238000011835 investigation Methods 0.000 description 3
- 230000003204 osmotic effect Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003485 histamine H2 receptor antagonist Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229920000747 poly(lactic acid) Polymers 0.000 description 2
- 239000004626 polylactic acid Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 206010034344 Peptic ulcer haemorrhage Diseases 0.000 description 1
- 206010046274 Upper gastrointestinal haemorrhage Diseases 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229960001380 cimetidine Drugs 0.000 description 1
- CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229940083646 famotidine 20 mg Drugs 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 230000007056 liver toxicity Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- VMXUWOKSQNHOCA-LCYFTJDESA-N ranitidine Chemical compound [O-][N+](=O)/C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-LCYFTJDESA-N 0.000 description 1
- 229960000620 ranitidine Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 229940097346 sulfobutylether-beta-cyclodextrin Drugs 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Abstract
The invention discloses an H 2 A receptor antagonist pharmaceutical composition comprising the active ingredients famotidine, vitamin C, niacinamide, phosphoric acid, tromethamine, sodium hydroxide and water for injection. The composition is prepared by using FamoIn the mixed solution of the tidine, the vitamin C, the nicotinamide and the phosphoric acid, the pH value is adjusted to 6.0-6.2 by using the organic alkali tromethamine, the pH value is further adjusted to 6.5-8.0 by using sodium hydroxide, and finally the volume is fixed. The invention solves the problems of poor stability and easy precipitation at low temperature of famotidine in the composition. H disclosed in the invention 2 The receptor antagonist pharmaceutical composition has the advantages of good stability, high safety, simple process, controllable quality and the like.
Description
Technical Field
The invention belongs to the field of chemical pharmaceutical preparations, and in particular relates to H 2 Receptor antagonist pharmaceutical compositions and methods of making the same.
Background
H of the invention 2 The receptor antagonist is famotidine, and the molecular formula is: c (C) 8 H 15 N 7 O 2 S 3 Molecular weight: 337.45, chemical name: 3- [ [ [2- [ (diaminomethylene) amino ] amino group]-4-thiazolyl]Methyl group]Thio-]-N-sulfamoyl propionamidine. Famotidine is an effective histamine H 2 Receptor antagonists are widely used in the treatment and prevention of peptic ulcers. As third generation H 2 Receptor antagonists which inhibit gastric acid secretion 2 The receptor antagonist is 7 to 40 times higher, and the effect of treating peptic ulcer and upper gastrointestinal hemorrhage is better than that of ranitidine and cimetidine.
A large amount of literature data report that famotidine is a compound with an extremely unstable chemical structure, is extremely unstable under the conditions of acid, oxidation, high temperature and the like, is extremely easy to degrade, and cannot be prepared into injection by adopting a high-temperature sterilization process. In addition, famotidine has a remarkable characteristic that it is easily dissolved in an acidic aqueous solution but is unstable in an acidic aqueous solution, and is relatively stable in an alkaline aqueous solution but is poor in solubility.
Therefore, famotidine injection is prepared by adding vitamin C as antioxidant to famotidine injection, and adding lactic acid to provide acidic environment for famotidine dissolution, and adding large amount of nicotinamide as cosolvent. However, since famotidine is very unstable under acidic conditions, it is relatively stable in alkaline aqueous solutions but has poor solubility. Therefore, if the pH of the solution is adjusted to be about 6.0 in a weak acid environment by adding sodium hydroxide in the prescription, the famotidine is easy to precipitate out in the range of 15-25 ℃ if the pH is continuously increased, so that the stability can not be continuously increased by increasing the pH.
Aiming at the original ground judicial motidine injection, several problems need to be solved, firstly, the impurity is obviously increased when placed under the condition of normal temperature (10-30 ℃), namely, the stability under the normal condition is not solved; secondly, in order to improve the stability as much as possible, the weak acid environment with the pH value adjusted to about 6.0 causes the famotidine to be precipitated after the solubility of the famotidine is reduced below 15 ℃, so that the famotidine cannot be preserved at a lower temperature (such as 2-8 ℃ or 10-15 ℃) to further improve the stability; thirdly, the addition of lactic acid to the prescription provides an acidic environment, but the lactic acid contains a large proportion of polylactic acid, so that the polylactic acid is easy to hydrolyze into lactic acid in the placing process, the pH is reduced along with the prolonging of the placing time, and the stability is poorer. Fourthly, a large amount of nicotinamide (50 mg/ml) is added into the prescription, and the high dose of nicotinamide can cause the increase of liver toxicity of human bodies, so that certain potential safety hazard exists.
Accordingly, the prior art has been studied around the above problems, and it is desired to develop a method for solving the above problems of the famotidine injection.
Patent CN113143859a discloses a famotidine injection and a preparation method thereof, the famotidine injection comprises famotidine, ethanol, glycerin, acid and mannitol, and a compound system formed by ethanol-glycerin-acid is adopted to synergistically increase the solubility, the tolerance and the stability of the famotidine to pH, thereby improving the safety of the preparation. However, the product is stored for 6 months at 25+/-2 ℃, the total impurities still reach 1.2-2.3%, and the problem of the stability of the famotidine injection is not solved yet.
Patent CN102225050B discloses a method for preparing famotidine sodium chloride injection by an inclusion method and a product thereof, wherein sulfobutyl ether-beta-cyclodextrin is adopted to include the liquid medicine and then the liquid medicine is dissolved in water, so that the solubility and the stability of the famotidine are improved. The patent method has complex process, and researches show that the product still has the problems of poor stability and easy precipitation in storage.
Therefore, the famotidine injection prepared by the prior art still has the problems of poor stability, easy precipitation during low-temperature storage, higher impurity content and the like, and therefore, a new famotidine injection is needed to solve the technical problems.
The inventor surprisingly found in the long-term famotidine injection research that famotidine can not be precipitated and is abnormally stable under the condition that the pH value of a solution system is close to neutral (less in irritation) of 6.5-8 by adopting tromethamine and sodium hydroxide, and the consumption of nicotinamide is greatly reduced, thereby completing the invention.
Disclosure of Invention
In order to overcome the defects in the prior art, the main purpose of the invention is to provide a famotidine injection and a preparation method thereof, wherein the famotidine injection has the advantages of simple composition, good product stability, difficult precipitation in low-temperature storage and high safety.
The technical scheme of the invention is as follows:
h (H) 2 A receptor antagonist pharmaceutical composition comprising famotidine, vitamin C, nicotinamide, phosphoric acid, tromethamine, sodium hydroxide, and water for injection.
Specifically, H is calculated according to the mass-volume ratio 2 The receptor antagonist pharmaceutical composition comprises 10mg/ml of famotidine, 1.2mg/ml of vitamin C, 5mg/ml of nicotinamide, 2mg/ml of phosphoric acid, a proper amount of tromethamine, a proper amount of sodium hydroxide and the balance of water for injection.
Further, phosphoric acid was added in the form of a 10% (w/w) phosphoric acid solution.
Further, sodium hydroxide was added as a 0.1M sodium hydroxide solution.
Further, the pH of the pharmaceutical composition is 6.5-8.0, preferably the pH of the pharmaceutical composition is 7.0-8.0.
The invention also provides an H 2 A process for preparing a receptor antagonist pharmaceutical composition comprising the steps of:
step 1: taking injection water with the prescription amount of 80%, adding vitamin C and nicotinamide with the prescription amount, and uniformly stirring;
step 2: adding 10% (w/w) phosphoric acid solution with a prescription amount to reduce the pH of the solution, adding famotidine with a prescription amount, and stirring to dissolve completely;
step 3: firstly adding a proper amount of tromethamine to adjust the pH to 6.0-6.2, and then adding 0.1M sodium hydroxide solution to adjust the pH to 6.5-8;
step 4: and quantifying the rest water for injection to a full amount, sterilizing and filtering the liquid medicine by a filter membrane, and filling and sealing the ampoule to obtain the famotidine injection.
Further, the water temperature for injection in step 1 was 40 ℃.
Further, in step 2, a prescribed amount of 10% (w/w) phosphoric acid solution was added to lower the pH of the solution to 3-4.
Further, the sterilization filtration in the step 4 adopts a 0.22 μm filter membrane.
Compared with the prior art, the beneficial effect of this application lies in:
(1) During the research process, the application finds that when the pH value of the pharmaceutical composition containing the famotidine is adjusted, firstly, the pharmaceutically and medically acceptable organic alkali tromethamine is added to adjust the pH value to 6.0-6.2, then the pH value is further adjusted to 6.5-8.0 by using sodium hydroxide, and the surprising finding that the famotidine is not separated out due to the continuous increase of the pH value is carried out, and meanwhile, the problems of poor stability and easy separation of the famotidine at low temperature are solved. And the dosage of nicotinamide in the prescription is greatly reduced, and the safety guarantee is improved.
(2) The application also adopts phosphoric acid as a solvent for promoting the dissolution of famotidine, can form phosphate buffer salt with sodium hydroxide, and can replace mannitol used for regulating the osmotic pressure of injection in the original ground product so as to reduce vascular irritation during injection. Meanwhile, prescription components are simplified, and the safety of the product is further improved.
Detailed Description
The present application is further illustrated by the following specific examples. It should be understood that: the examples of the present application are merely illustrative of the present application and are not limiting of the present application. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. The raw materials of specific origin are not noted in the following examples, and are generally commercially available conventional products. The technical scheme obtained by simply improving the application or adopting conventional means or components to perform equivalent substitution on the basis of the technical scheme belongs to the protection scope of the application.
Example 1
Prescription:
the preparation method comprises the following steps:
step 1: taking 800mL of water for injection (40 ℃), adding 1.2g of vitamin C and 5g of nicotinamide, and uniformly stirring;
step 2: adding 20g of 10% (w/w) phosphoric acid solution to reduce the pH of the solution to 3.5, adding 10g of famotidine, and stirring for complete dissolution;
step 3: firstly adding 3.6g of tromethamine, adjusting the pH to 6.0, and then adding a proper amount of 0.1M sodium hydroxide solution to adjust the pH to 7.5;
step 4: and quantifying the rest water for injection to a full amount, sterilizing and filtering the liquid medicine by a 0.22 mu m filter membrane, and filling and sealing the ampoule to obtain the famotidine injection.
Example 2
This example is essentially the same as example 1, except that the formulation is formulated with an appropriate amount of 0.1M sodium hydroxide solution, and the pH is adjusted to 6.5 in step 3.
Example 3
The examples are essentially the same as example 1, except that the formulation is adjusted to a pH of 7.0 in step 3 with an appropriate amount of 0.1M sodium hydroxide solution.
Example 4
The examples are essentially the same as example 1, except that the formulation is adjusted to a pH of 8.0 in step 3 with an appropriate amount of 0.1M sodium hydroxide solution.
Comparative example 1
This comparative example is essentially the same as example 1, except that the formulation is formulated with an appropriate amount of 0.1M sodium hydroxide solution, and the pH is adjusted to 6.1 in step 3.
Comparative example 2
This comparative example is essentially the same as example 1, except that the formulation is formulated with an appropriate amount of 0.1M sodium hydroxide solution, and the pH is adjusted to 8.3 in step 3.
Comparative example 3
This comparative example is essentially the same as example 1 except that 0.1M sodium hydroxide solution is used in the formulation and the pH is adjusted to 7.5 in step 3 using tromethamine alone.
Comparative example 4
This comparative example is essentially the same as example 1, except that the formulation has 0g of tromethamine and the pH is adjusted to 7.5 in step 3 using only a suitable amount of 0.1M sodium hydroxide solution.
Comparative example 5
This comparative example is essentially the same as example 1, except that in step 3, the pH is adjusted to 5.5 with a suitable amount of tromethamine and then to 7.5 with a suitable amount of 0.1M sodium hydroxide solution.
Comparative example 6
This comparative example is essentially the same as example 1, except that in step 3, the pH is adjusted to 6.5 with an appropriate amount of tromethamine and then to 7.5 with 0.1M sodium hydroxide.
Comparative example 7
This comparative example is essentially the same as example 1 except that the formulation is replaced with a 1M hydrochloric acid solution of 20g of 10% (w/w) phosphoric acid solution, and the pH of the solution is lowered to 3.5 using 1M hydrochloric acid in step 2.
Comparative example 8
This comparative example is essentially the same as example 1 except that the formulation is replaced with a 1M acetic acid solution of 20g of 10% (w/w) phosphoric acid solution, and the pH of the solution is lowered to 3.5 using 1M acetic acid in step 2.
Comparative example 9
The information of the original preparation (trade name Gaster Injection 20mg; company-holder LTL film Co., ltd.) is shown in Table 1, using the original preparation as comparative example 9.
TABLE 1 information on the original developer
| Prescription composition | Prescription dosage |
| Famotidine | 20mg |
| Nicotinamide | 100mg |
| Lactic acid | 9.8mg |
| Mannitol (mannitol) | 40mg |
| Vitamin C | 2mg |
| Sodium hydroxide | Proper amount of |
| Water for injection | 2ml |
| pH | 5.8-6.2 |
Comparative example 10
This comparative example is substantially identical to comparative example 9 (as-ground formulation) except that the nicotinamide content in the formulation is reduced from 100mg to 10mg, i.e., the nicotinamide concentration is reduced from 50mg/ml to 5mg/ml.
Comparative example 11
The sample prepared by the recipe and preparation method of example 1 in CN113143859a was comparative example 11.
Comparative example 12
The sample prepared by the recipe and preparation method of example 1 in CN102225050B is comparative example 12.
Test example 1: examine the influence of different pH values on the quality and stability of the product
Since famotidine is easily hydrolyzed and unstable in a lower pH solution, the famotidine is better in stability but easy to separate out in a higher pH solution. The stability of the injection samples prepared by comparing examples 1-4, comparative examples 1-2 and comparative examples 9-10 is tested, wherein the low temperature test method is that the injection samples are placed at 2-8 ℃ for 2 days, then placed at 40 ℃ for 2 days, and circulated for 3 times. The results are shown in Table 2.
Table 2 test example 1 product quality and stability results
As can be seen from the results of Table 2, the total impurity content of examples 1 to 4 was relatively low, wherein the impurity of comparative example 1 was significantly higher than that of examples 1 to 4, the impurity of comparative example 2 was slightly lower than that of example 2, but higher than that of examples 1, 3 and 4, and the impurity of comparative examples 9 to 10 was significantly higher than that of examples 1 to 4 and examples 1 to 2. It is thus obtained that not the higher the pH, the more stable the product. Regarding the problem of low temperature precipitation of crystals, neither examples 1 to 4 nor comparative example 1 had crystals precipitated under low temperature conditions, but comparative example 2 and comparative examples 9 to 10 had crystals precipitated. Comparative example 10 shows that the sample is more prone to precipitate crystals at low temperature by reducing the nicotinamide concentration from 50mg/ml to 5mg/ml compared to comparative example 9. The prescription of the invention has slow growth of related substances within the pH range of 6.5-8.0, and the low-temperature experimental liquid medicine still has no crystal precipitation under the condition of reducing the content of nicotinamide (5 mg/ml).
Test example 2: examine the influence of different pH regulator on the quality and stability of the product
The quality and stability of the prepared injection products are tested by comparing the preparation method with the preparation method of the example 1 and the comparison examples 3-6, wherein the low-temperature experiment method is that the injection products are placed at the temperature of 2-8 ℃ for 2 days, then placed at the temperature of 40 ℃ for 2 days, and circulated for 3 times. The results are shown in Table 3.
TABLE 3 test example 2 product quality and stability results
As is clear from Table 3, in example 1, the crystals were precipitated in comparison with comparative examples 4 to 5 under conditions of low temperature in comparative examples 4 to 5, which were adjusted to the same final pH of 7.5; example 1 was compared with comparative example 3 and comparative example 6, and comparative example 3 and comparative example 6 were higher in impurity than example 1.
Test example 3: investigation of the influence of different buffer systems on vascular irritation
The original formulation (comparative example 9) was prepared by adding mannitol as an osmotic pressure regulator to reduce irritation to blood vessels upon injection. In the preparation process of the famotidine injection, an acidic substance is required to be added first to reduce the pH value so as to promote the dissolution of the famotidine, and an alkaline substance is required to be added later to adjust the pH value to keep the product stable. Based on the thought that an acid-base buffer system can be formed and the osmotic pressure can be regulated, different buffer systems are examined, and vascular irritation tests are carried out on the products of examples 1-4 and comparative examples 7-8, and the results are shown in Table 4.
Vascular stimulation experiments: the rabbits were randomly divided into 6 groups of 36 rabbits, each group having a male and female half. Test group: the medicines of examples 1-4 are respectively injected into the vein of the left auricle of the rabbit; control group: the medicines of comparative examples 7-8 are injected intravenously at the left auricle of rabbits; blank group: the rabbit left ear margin was injected with an equal volume of physiological saline. Each group was administered 1 time a day for 5 days continuously, and whether or not there was irritation such as redness, swelling, and the like in the injection site and surrounding tissues was observed visually.
TABLE 4 results of vascular irritation test on the products of examples 1-4, comparative examples 7-8
As can be seen from Table 4, examples 1-4 of the present application were less irritating to blood vessels than comparative examples 7-8.
Test example 4: long-term stability investigation of products
The stability test examination (accelerated, long-term test) was carried out on the optimally combined sample prepared in example 1 according to the general rule 9001 of the edition of chinese pharmacopoeia 2020 and the stability test guidelines of the formulation, and comparative example 9 (original formulation), comparative example 11 (example 1 in CN113143859 a), and ratio 12 (example 1 in CN 102225050B) were used as comparisons.
Acceleration test: four batches of samples of example 1, comparative example 9, comparative example 11 and proportion 12 were taken, respectively, and placed at 40 ℃ + -2, RH75% + -5% for 3 months, respectively, sampled at l and 3 months, and inspected according to stability key investigation projects, and compared with the test results of 0 month.
Long-term test: four batches of samples of example 1, comparative example 9, comparative example 11 and comparative example 12 were taken, individually packaged and placed for 6 months at 25 ℃ ± 2, rh60% ± 5%, and sampled for 6 months, and examined according to stability emphasis and compared with the test results of 0 month. The results of the accelerated experiments are summarized in Table 5, and the results of the long-term experiments are summarized in Table 6.
TABLE 5 results summary of results of accelerated experiments
TABLE 6 summary of results of long-term experiments
The accelerated test (40 ℃) for 3 months and the long-term test (25 ℃) for 6 months compared with 0 day, the contents of the comparative examples 9-12 are reduced under the conditions of the accelerated test and the long-term test, and the total impurities are obviously increased. The quality of the homemade product under the preferred recipe (example 1) showed significantly slower trend, and the related impurities showed slower trend and little change in pH. All the quality meets the regulations, and the famotidine injection prepared by the technical scheme of the invention has stable and controllable quality.
The above embodiments are only for illustrating the technical solutions of the present application and not for limiting the same, and although the present application has been described in detail with reference to examples, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made to the technical solutions of the present application without departing from the scope of the technical solutions of the present application, and all the modifications or equivalent are included in the scope of the claims of the present application.
Claims (9)
1. H (H) 2 A receptor antagonist pharmaceutical composition comprising famotidine, vitamin C, nicotinamide, phosphoric acid, tromethamine, sodium hydroxide and water for injection.
2. The pharmaceutical composition according to claim 1, characterized in that it comprises, in terms of mass-to-volume ratio, famotidine 10mg/ml, vitamin c1.2mg/ml, nicotinamide 5mg/ml, phosphoric acid 2mg/ml, an amount of tromethamine, an amount of sodium hydroxide and the balance of water for injection.
3. The pharmaceutical composition according to claim 1 or 2, wherein the phosphoric acid is added in the form of a 10% (w/w) phosphoric acid solution.
4. Pharmaceutical composition according to claim 1 or 2, characterized in that the sodium hydroxide is added in the form of a 0.1M sodium hydroxide solution.
5. The pharmaceutical composition according to claim 1 or 2, wherein the pH of the pharmaceutical composition is 6.5-8.0.
6. The pharmaceutical composition according to any one of claims 1-5, wherein the method of preparing the pharmaceutical composition comprises the steps of:
step 1: taking injection water with the prescription amount of 80%, adding vitamin C and nicotinamide with the prescription amount, and uniformly stirring;
step 2: adding 10% (w/w) phosphoric acid solution with a prescription amount to reduce the pH of the solution, adding famotidine with a prescription amount, and stirring to dissolve completely;
step 3: firstly adding a proper amount of tromethamine to adjust the pH to 6.0-6.2, and then adding 0.1M sodium hydroxide to adjust the pH to 6.5-8.0;
step 4: and quantifying the rest water for injection to a full amount, sterilizing and filtering the liquid medicine by a filter membrane, and filling and sealing the ampoule to obtain the famotidine injection.
7. The method according to claim 6, wherein the water for injection in step 1 has a temperature of 40 ℃.
8. The method according to claim 6, wherein the prescribed amount of 10% (w/w) phosphoric acid solution is added in step 2 to lower the pH of the solution to 3-4.
9. The method according to claim 6, wherein the sterilization filtration in the step 4 is performed by using a 0.22 μm filter.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311572886.2A CN117442615A (en) | 2023-11-23 | 2023-11-23 | H (H) 2 Receptor antagonist pharmaceutical composition and preparation method thereof |
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| CN202311572886.2A CN117442615A (en) | 2023-11-23 | 2023-11-23 | H (H) 2 Receptor antagonist pharmaceutical composition and preparation method thereof |
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Effective date of registration: 20240411 Address after: 710100, 1st Floor, Building B2, Tianhaixing Digital Workshop, Fengdong New City, Xi'an City, Shaanxi Province Applicant after: Xi'an Licai Pharmaceutical R&D Co.,Ltd. Country or region after: China Address before: 712000 floor 29, block B, Licai Golden Square, 29 Renmin West Road, Qindu District, Xianyang City, Shaanxi Province Applicant before: Shaanxi Li Cai Pharmaceutical Co.,Ltd. Country or region before: China |