CN117797091A - Digoxin injection, injection and preparation method thereof - Google Patents
Digoxin injection, injection and preparation method thereof Download PDFInfo
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- CN117797091A CN117797091A CN202311867845.6A CN202311867845A CN117797091A CN 117797091 A CN117797091 A CN 117797091A CN 202311867845 A CN202311867845 A CN 202311867845A CN 117797091 A CN117797091 A CN 117797091A
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- digoxin
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- 229940004223 digoxin injection Drugs 0.000 title claims abstract description 45
- 238000002347 injection Methods 0.000 title claims abstract description 21
- 239000007924 injection Substances 0.000 title claims abstract description 21
- 229940090044 injection Drugs 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title abstract description 15
- LTMHDMANZUZIPE-AMTYYWEZSA-N Digoxin Natural products O([C@H]1[C@H](C)O[C@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@](C)([C@H](O)C4)[C@H](C4=CC(=O)OC4)CC5)CC3)CC2)C[C@@H]1O)[C@H]1O[C@H](C)[C@@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](O)C2)[C@@H](O)C1 LTMHDMANZUZIPE-AMTYYWEZSA-N 0.000 claims abstract description 43
- 229960005156 digoxin Drugs 0.000 claims abstract description 43
- LTMHDMANZUZIPE-PUGKRICDSA-N digoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LTMHDMANZUZIPE-PUGKRICDSA-N 0.000 claims abstract description 43
- LTMHDMANZUZIPE-UHFFFAOYSA-N digoxine Natural products C1C(O)C(O)C(C)OC1OC1C(C)OC(OC2C(OC(OC3CC4C(C5C(C6(CCC(C6(C)C(O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)CC2O)C)CC1O LTMHDMANZUZIPE-UHFFFAOYSA-N 0.000 claims abstract description 43
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- QONQRTHLHBTMGP-UHFFFAOYSA-N digitoxigenin Natural products CC12CCC(C3(CCC(O)CC3CC3)C)C3C11OC1CC2C1=CC(=O)OC1 QONQRTHLHBTMGP-UHFFFAOYSA-N 0.000 description 2
- SHIBSTMRCDJXLN-KCZCNTNESA-N digoxigenin Chemical compound C1([C@@H]2[C@@]3([C@@](CC2)(O)[C@H]2[C@@H]([C@@]4(C)CC[C@H](O)C[C@H]4CC2)C[C@H]3O)C)=CC(=O)OC1 SHIBSTMRCDJXLN-KCZCNTNESA-N 0.000 description 2
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Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the technical field of medicinal preparations, and provides a digoxin injection, an injection and a preparation method thereof. The digoxin injection comprises the following components: digoxin, inclusion agents, and inclusion stabilizers. The digoxin injection prepared by the inclusion agent and the inclusion stabilizer has obvious solubilization effect, and the inclusion agent and the inclusion stabilizer not only provide medicine stability and solubility, but also reduce the use of organic solvents, are safe and free of side effects, can reduce renal toxicity, alleviate medicine hemolysis and the like, and provide technical support for the development of the digoxin injection.
Description
Technical Field
The invention belongs to the technical field of medicinal preparations, and relates to a digoxin injection and a preparation method thereof.
Background
Digoxin, chemical formula C 41 H 64 O 14 The chemical structure is shown as formula I, and the chemical name is 3β - [ [0-2, 6-dideoxy- β -D-nuclear-hexopyranosyl- (1- > 4) -O-2, 6-dideoxy- β -D-nuclear-hexopyranosyl- (1- > 4) -2, 6-dideoxy- β -D-nuclear hexopyranosyl]Oxo-radicals]12 beta, 14 beta-dihydroxy-5 beta-cardioid-20 (22) enelactones, also known as digoxigenin, digoxin, jiang Xinsu, digoxigenin.
Digoxin is a medium-effect cardiac glycoside drug, and has positive inotropic effect on the heart during treatment, and can slow down heart rate and inhibit heart conduction. Is suitable for low output congestive heart failure, atrial fibrillation, atrial flutter, paroxysmal supraventricular tachycardia. Can be used for treating acute and chronic cardiac insufficiency, supraventricular tachycardia, atrial fibrillation, and flutter. The oral administration is rapid and complete, the bioavailability is up to more than 90%, the plasma drug concentration reaches peak value 1h after taking, the effect is obvious after 4h, the peak effect is reached 6-12h, the serum therapeutic concentration is 15-25ng/mL, and the plasma protein binding rate reaches 97%. The elimination half-life is generally 4-7 days due to disappearance of enzyme metabolism mainly by hepatic microsomes. Discharged from bile, recirculated, and discharged from urine. The common dosage forms include injection, tablet, etc., and intravenous injection is adopted for patients with severe heart failure.
Because digoxin is insoluble in water and slightly soluble in dilute alcohol, a large amount of organic solvents such as ethanol, propylene glycol and digoxin injection developed by COVIS PHARMA BV company are usually added during the development of the injection, and the trade name isIn order to dissolve digoxin and ensure that the digoxin is stable and not precipitated during stability, 10% and 42% of propylene glycol is used in the prescription, but ethanol has an inhibitory effect on the central nervous system, and the light people can have different degrees of muscular disharmony, vision damage and unclear vomiting, and the heavy people can lead to reduced spinal cord reaction, hypoglycemia, coma, numbness and respiratory depressionThe preparation, cardiovascular failure and the like, therefore, the drug administration suggests to control the ethanol dosage in the injection to be 5-10%; high concentrations of propylene glycol can cause pain and irritation, and up to 35% can cause hemolysis in humans, so it is believed that currently commercially available mainstream injections may have some potential safety risk.
In order to increase the solubility of digoxin, micronization processes are also often used in pharmaceutical technology to reduce the particle size, for example by jet milling, grinding, etc., which are based on mechanical forces, but digoxin is very unstable to mechanical treatments, which can lead to significant changes in the color of the powder and severe degradation. U.S. patent No. 5062959a discloses increasing the solubility of digoxin by precipitation from a concentrated solution of purified digoxin in methanol/chloroform to obtain the digoxin as a solid product. Chinese patent application CN108024963a employs non-mechanical micronization to reduce the particle size of digoxin from conventional levels to a selected micrometer range while concentrating and combining with an organic solvent of methanol in methylene chloride to form solid particles to provide solubility of digoxin. Because the crushing technology has complex process and large batch-to-batch variation, and a large amount of organic solvent (methanol/chloroform) is needed for concentration and combination, the crushing technology is not applied to injection at present.
Therefore, on the premise of reducing the dosage of the organic solvent in the preparation process of the digoxin injection, the improvement of the solubility of the digoxin is still a problem to be solved in the industry.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention provides a digoxin injection, an injection and a preparation method thereof, wherein the inclusion treatment process of an inclusion agent and an inclusion stabilizer on the digoxin replaces the traditional solvent dissolution and dissolution assisting process, so that the dosage of an organic solvent propylene glycol and the like is greatly reduced; the safety is high, the nephrotoxicity can be reduced, the drug hemolysis can be alleviated, and the like, and the clinical use safety of the digoxin injection and the injection can be provided.
One of the technical schemes of the invention is as follows:
there is provided a digoxin injection comprising: digoxin, inclusion agents, and inclusion stabilizers; the inclusion agent is sodium sulfobutyl betacyclodextrin; the inclusion stabilizer is urea.
The sulfobutyl betacyclodextrin sodium is an anionic and high water-solubility beta-CD derivative, and can well form a non-covalent compound with drug molecules, thereby improving the stability, water solubility and safety of the drug, reducing the nephrotoxicity, relieving the hemolytic property of the drug and the like. Compared with beta-CD, it has better water solubility, less hemolysis and low renal toxicity.
Urea is also named as carbamide, carbamide and urea, is used for synthesizing medicines, plastics and the like, is also a medicine per se, has obvious curative effects on lowering intracranial pressure and intraocular pressure, and is generally used as a medicinal auxiliary material in a medicinal preparation, such as a medicine skeleton supporting material and the like. In the invention, it is unexpectedly found that the use of urea can further stabilize the inclusion effect of sodium sulfobutylbetacyclodextrin on the active ingredient, thereby improving the stability of the formulation.
Further, the digoxin injection comprises the following components in parts by weight: 0.2-0.3 part of digoxin, 3.0-3.5 parts of inclusion agent and 8-12 parts of inclusion stabilizer.
Further, the digoxin injection composition further comprises: anhydrous disodium hydrogen phosphate and anhydrous sodium citrate.
Still further, the digoxin injection comprises the following components in parts by weight: 0.2-0.3 part of digoxin, 3.0-3.5 parts of inclusion agent, 8-12 parts of inclusion stabilizer, 1.5-1.9 parts of anhydrous disodium hydrogen phosphate and 0.6-1.0 part of anhydrous sodium citrate.
Preferably, the digoxin injection comprises the following components in parts by weight: 0.25 part of digoxin, 3.25 parts of inclusion agent, 10 parts of inclusion stabilizer, 1.7 parts of anhydrous disodium hydrogen phosphate and 0.8 part of anhydrous sodium citrate.
Further, the mass ratio of the digoxin to the inclusion agent to the inclusion stabilizer is 1:12-14:36-44.
The second technical scheme of the invention is as follows:
the digoxin injection comprises any one of the digoxin injection, a pharmaceutical adjuvant and an injection solution.
Further, the injection solution is a mixed solution of propylene glycol and water for injection.
The third technical scheme of the invention is as follows:
the preparation method of the digoxin injection comprises the following steps:
(1) Adding propylene glycol into part of water for injection to obtain injection solution;
(2) Adding digoxin, inclusion agent and inclusion stabilizer into the injection solution, adding or not adding anhydrous disodium hydrogen phosphate and anhydrous sodium citrate, stirring and dispersing;
(3) Then heating, keeping constant temperature and cooling in a stirring state to obtain digoxin inclusion liquid;
(4) Adding medicinal adjuvants into digoxin inclusion liquid, adding the rest water for injection to constant volume, stirring for dissolving, filtering, bottling, and sterilizing.
Further, in the step (2), the stirring time is 5-10min.
Further, in the step (3), the heating, constant temperature and cooling treatment process comprises the following steps: heating to 50-60deg.C at constant speed within 30-60min, stirring for 30-40min to obtain clear solution, and cooling to room temperature at constant speed within 30-60 min.
Further, the sterilization temperature in the step (4) is 121 ℃, and the sterilization time is 12min.
Compared with the prior art, the invention has the following beneficial effects:
(1) According to the invention, a large number of experiments show that the sodium sulfobutyl betacyclodextrin is used as a coating agent, and urea is used as an inclusion stabilizer, so that an obvious dissolution assisting effect can be achieved;
(2) Further, the inclusion treatment process of digoxin replaces the traditional solvent dissolution and dissolution assisting process, so that the consumption of the organic solvent propylene glycol and the like is greatly reduced;
(3) The inclusion agent adopted by the invention has high safety, can reduce renal toxicity, alleviate drug hemolysis and the like, and provides the clinical use safety of digoxin injection and injection;
(4) The invention further improves the stability of the product by controlling the temperature rise and fall rate in the inclusion process, has simple process and is suitable for industrial production.
Drawings
FIG. 1 is a photograph of the digoxin injection prepared in example 1 of the present invention before (A) and after (B) the accelerated test;
FIG. 2 is a photograph of the digoxin injection prepared in comparative example 1 of the present invention before (A) and after (B) the accelerated test;
FIG. 3 is a photograph of the digoxin injection prepared in comparative example 2 of the present invention before (A) and after (B) the accelerated test;
FIG. 4 is a photograph of the digoxin injection prepared in comparative example 3 of the present invention before (A) and after (B) the accelerated test;
FIG. 5 is a photograph of the digoxin injection prepared in comparative example 4 of the present invention before (A) and after (B) the accelerated test;
FIG. 6 is a photograph of the digoxin injection prepared in comparative example 5 of the present invention before (A) and after (B) acceleration tests;
FIG. 7 is a photograph of the digoxin injection prepared in comparative example 6 of the present invention before (A) and after (B) the acceleration test;
FIG. 8 is a photograph of the digoxin injection prepared in comparative example 7 of the present invention before (A) and after (B) the acceleration test;
FIG. 9 is a photograph of the digoxin injection prepared in comparative example 8 of the present invention before (A) and after (B) the acceleration test;
FIG. 10 is a photograph of the digoxin injection prepared in comparative example 9 of the present invention before (A) and after (B) the acceleration test;
FIG. 11 is a photograph of the digoxin injection prepared in comparative example 10 of the present invention before (A) and after (B) the acceleration test;
FIG. 12 is a photograph of the digoxin injection prepared in comparative example 11 of the present invention before (A) and after (B) acceleration tests;
FIG. 13 is a photograph of the digoxin injection prepared in comparative example 12 of the present invention before (A) and after (B) acceleration tests;
FIG. 14 is a photograph of the digoxin injection prepared in comparative example 13 of the present invention before (A) and after (B) acceleration tests;
FIG. 15 is a photograph of the digoxin injection prepared in comparative example 14 of the present invention before (A) and after (B) the acceleration test.
Detailed Description
The following non-limiting examples will enable those of ordinary skill in the art to more fully understand the invention and are not intended to limit the invention in any way. The following is merely exemplary of the scope of the invention as claimed and many variations and modifications of the invention will be apparent to those skilled in the art in light of the disclosure, which are intended to be within the scope of the invention as claimed.
The raw materials and auxiliary materials adopted in the embodiment and the comparative example are as follows:
the invention relates to a substance detection method, which comprises the following steps: referring to the edition 2020 of Chinese pharmacopoeia, chromatographic column: c18 column, mobile phase a: acetonitrile-water (10:90), mobile phase B: acetonitrile-water (90:10), detection wavelength: 220nm; flow rate: 1.5mL/min; sample injection amount: 10. Mu.L; column temperature: gradient elution at 25 ℃.
Example 1:
the prescription of this example is shown in the following table:
| prescription composition | Dosage of | Ratio (%) W/V |
| Digoxin | 0.25g | 0.025 |
| Sulfobutyl betacyclodextrin sodium | 3.25g | 0.325 |
| Urea (sodium benzoate) | 10g | 1 |
| Propylene glycol | 10g | 1 |
| Anhydrous disodium hydrogen phosphate | 1.7g | 0.17 |
| Citric acid anhydrous | 0.8mg | 0.08 |
| Water for injection | To 1000mL | To 100 |
The preparation method comprises the following steps:
(1) Mixing propylene glycol with 500mL of water for injection for later use;
(2) Adding the prescribed amounts of digoxin, sulfobutyl betacyclodextrin sodium and urea together in a stirring state, stirring for 10min to uniformly disperse, then uniformly heating to 50 ℃ in 40min in the stirring state, stirring for 40min to form a clear solution, then uniformly cooling to room temperature in 40min, continuously stirring for 50min, and filtering for later use;
(3) Adding other adjuvants (anhydrous disodium hydrogen phosphate and anhydrous citric acid), adding injectable water to 1000mL, stirring, filtering, packaging, and sterilizing (at 121deg.C for 12 min)
Comparative example 1:
the prescription of the original grinding product (COVIS PHARMA BV) is shown in the following table:
| prescription composition | Dosage of | Ratio (%) W/V |
| Digoxin | 0.250g | 0.025 |
| Propylene glycol (for injection) | 42.5g | 4.25 |
| Absolute ethyl alcohol | 100mL | 10(V/V) |
| Anhydrous disodium hydrogen phosphate | 1.7g | 0.17 |
| Citric acid anhydrous | 0.8mg | 0.08 |
| Water for injection | To 1000mL | To 100 |
The preparation method comprises the following steps:
(1) Accurately weighing the raw materials and the auxiliary materials according to the formula;
(2) Adding 500mL of water for injection (40-50 ℃) into a liquid preparation tank, starting a stirrer, adding anhydrous disodium hydrogen phosphate and anhydrous citric acid, and stirring until the anhydrous disodium hydrogen phosphate and the anhydrous citric acid are completely dissolved;
(3) Propylene glycol is added and stirred uniformly;
(4) Dispersing digoxin in ethanol, adding the digoxin into the solution (3), and stirring until the digoxin is completely dissolved;
(5) The volume is fixed to 1000mL by water for injection, and the mixture is uniformly mixed;
(6) Filtering the uniformly mixed liquid medicine by two filters made of PES material with the aperture of 0.22 μm, filling the liquid medicine in a 2mL colorless transparent ampoule bottle, wherein the filling volume is 2mL;
(7) Sterilizing the ampoule obtained in the step (6) at 121 ℃ for 12min to obtain a sterile product.
Comparative examples 2 to 5: investigation of the inclusion Effect of digoxin by the differences in the amount of the inclusion Agents
The difference compared with example 1 is that the dosage of sulfobutyl betacyclodextrin sodium in the prescription is adjusted from 3.25g/L to 2.5g/L, 3.0g/L, 3.5g/L and 4.0g/L respectively.
Comparative example 6: investigation of the inclusion Effect of different types of inclusion Agents on digoxin
The only difference compared to example 1 is that the sodium sulfobutylbetacyclodextrin is replaced by sodium hydroxypropyl betacyclodextrin in the formulation.
Comparative examples 7-9: investigation of the stability of the clathrate of digoxin by different types of clathrate stabilizers and without the addition of stabilizers
The only difference compared to example 1 is that the inclusion stabilizer in the formulation is replaced by sodium benzoate, ascorbic acid and no stabilizer is added, respectively.
Comparative examples 10 to 13: investigation of the stability of the clathrate of digoxin by the amount of the clathrate stabilizer
The difference compared with example 1 is that the dosage of urea as the inclusion stabilizer in the prescription is adjusted from 10g/L to 8g/L, 9g/L, 11g/L and 12g/L respectively.
Comparative example 14: investigation of stability of clathrate compound of digoxin by lifting temperature difference in preparation process
The difference compared to example 1 is only that the heating time is less than 30min and the cooling time is less than 30min.
In addition, after the temperature rise and fall time is more than 60min, the device can be uncontrollable, so that the continuous extension of the temperature rise and fall time is not suitable.
The corresponding products are placed for 3 months under the condition of acceleration (40 ℃ and 75% RH), the property and content results are summarized in Table 1, the photographs of the products before acceleration (A) and after acceleration (B) of the example 1 and the comparative examples 1-14 are shown in figures 1-15, the good encapsulation effect is clear and colorless, no floccules or white crystals are separated out, crystals are separated out when inclusion is incomplete, and floccules are formed when the inclusion compound and the inclusion stabilizer are excessively used, so that the clarity of the solution is affected.
Table 1 results of product properties and encapsulation efficiency prepared in examples
The stability examination results of the products of comparative example 1 (reference formulation) and inventive example 1 show that the stability of the product is comparable to that of the reference formulation.
As can be seen from comparison of examples 2-5 with example 1, when the amount of inclusion agent is 3.0-3.5mg/mL (preferably 3.25 mg/mL), good solubilization effect can be maintained, and the properties and content of the product can be ensured to meet the requirements, and less than or higher than this range is not desirable.
As can be seen from comparison of example 6 with example 1, the inclusion effect of the sodium sulfobutylbetacyclodextrin is better, the sodium sulfobutylbetacyclodextrin is replaced by sodium hydroxypropyl betacyclodextrin, and the properties and the content of the product are not satisfactory.
As can be seen from the comparison of comparative examples 7 to 9 with example 1, the effect of helping stability of urea is better, the property and content index of the product are better, and the effect of inclusion is not good without adding urea.
As can be seen from comparison of examples 10-13 with example 1, urea was used in an amount of 9-11mg/mL (preferably 10 mg/mL), and the stability of the product was optimal.
As can be seen from comparison of comparative example 14 with example 1, too fast heating and cooling have a certain influence on the properties and content index of the product; and the heating and cooling are too slow to be beneficial to production control, and the heating and cooling time can ensure that the quality of the product meets the requirements in the control range of the invention.
Finally, it should be noted that the above description is only for illustrating the technical solution of the present invention, and not for limiting the scope of the present invention, and that the simple modification and equivalent substitution of the technical solution of the present invention can be made by those skilled in the art without departing from the spirit and scope of the technical solution of the present invention.
Claims (10)
1. The digoxin injection is characterized by comprising the following components: digoxin, inclusion agents, and inclusion stabilizers; the inclusion agent is sodium sulfobutyl betacyclodextrin; the inclusion stabilizer is urea.
2. The digoxin injection as set forth in claim 1, comprising, in parts by weight: 0.2-0.3 part of digoxin, 3.0-3.5 parts of inclusion agent and 8-12 parts of inclusion stabilizer.
3. The digoxin injection of claim 1 or 2, characterized in that the digoxin injection composition further comprises: anhydrous disodium hydrogen phosphate and anhydrous sodium citrate.
4. The digoxin injection of claim 3, comprising, in parts by weight: 0.2-0.3 part of digoxin, 3.0-3.5 parts of sulfobutyl betacyclodextrin sodium, 8-12 parts of urea, 1.5-1.9 parts of anhydrous disodium hydrogen phosphate and 0.6-1.0 part of anhydrous sodium citrate.
5. The digoxin injection according to claim 1, wherein the mass ratio of the digoxin, the inclusion agent and the inclusion stabilizer is 1:12-14:36-44.
6. A digoxin injection, which is characterized by comprising the digoxin injection, a pharmaceutic adjuvant and an injection solution according to any one of claims 1-5.
7. The digoxin injection of claim 6, wherein the injection solution is a mixed solution of propylene glycol and water for injection.
8. The method for preparing the digoxin injection as set forth in claim 6 or 7, characterized by comprising the steps of:
(1) Adding propylene glycol into part of water for injection to obtain injection solution;
(2) Adding digoxin, inclusion agent and inclusion stabilizer into the injection solution, and stirring and dispersing with or without adding anhydrous disodium hydrogen phosphate and anhydrous sodium citrate;
(3) Then heating, keeping constant temperature and cooling in a stirring state to obtain digoxin inclusion liquid;
(4) Adding medicinal adjuvants into digoxin inclusion liquid, adding the rest water for injection to constant volume, stirring for dissolving, filtering, bottling, and sterilizing.
9. The method according to claim 8, wherein in the step (2), the stirring time is 5 to 10 minutes.
10. The method according to claim 8, wherein in the step (3), the heating, constant temperature and cooling treatment process comprises: heating to 50-60deg.C at constant speed within 30-60min, stirring for 30-40min to obtain clear solution, and cooling to room temperature at constant speed within 30-60 min.
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| CN202311867845.6A CN117797091A (en) | 2023-12-29 | 2023-12-29 | Digoxin injection, injection and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311867845.6A CN117797091A (en) | 2023-12-29 | 2023-12-29 | Digoxin injection, injection and preparation method thereof |
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| CN117797091A true CN117797091A (en) | 2024-04-02 |
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