CN114886851A - Milrinone liposome, preparation and preparation method thereof - Google Patents
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Abstract
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a milrinone liposome, a preparation and a preparation method thereof.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a milrinone liposome, a preparation and a preparation method thereof.
Background
Almost all cardiovascular diseases can finally cause the occurrence of heart failure, and myocardial damage caused by any reasons such as myocardial infarction, cardiomyopathy, hemodynamic overload, inflammation and the like can cause the change of myocardial structure and function, and finally, the ventricular pump blood and/or the filling function are low.
Milrinone, chemical name 2-methyl-6-oxo-1, 6-dihydro-3, 4' -bipyridine-5-carbonitrile, molecular formula C 12 H 9 N 3 And O. The cardiovascular effect of milrinone is related to dosage, and the small dosage is mainly characterized by positive inotropic effect, and when the dosage is increased, the maximum positive inotropic effect of steady state is gradually reachedThe vasodilation effect may also be gradually increased with increasing dosage. In clinic, milrinone is mainly suitable for acute and chronic intractable congestive heart failure caused by various reasons of ineffective or poor treatment effect on digitalis, diuretics and vasodilators.
However, milrinone is difficult to dissolve in water or ethanol and slightly soluble in an acidic solvent, and in order to solve the technical problem, the Chinese patent CN100337629 uses lactic acid as a solubilizer and discloses a milrinone sodium chloride injection for treating congestive heart failure and a preparation method thereof; chinese patent CN100589804 uses acetic acid, phosphoric acid or sulfur to adjust pH of acid to 2.8-3.5 to increase solubility of milrinone, and makes into injection; chinese patent application CN102552115 discloses a milrinone injection and a preparation method thereof, wherein hydrochloric acid is taken as a pH regulator, and glucose is taken as an osmotic pressure regulator.
Although the solubility of milrinone can be increased by adding lactic acid, acetic acid, phosphoric acid or sulfuric acid at present, the milrinone injection dissolved by using the acidic substance has poor stability, and the phenomena of discoloration, precipitation or generation of other related substances are easy to occur in the process of illumination or long-term storage, so the product quality of the milrinone injection is seriously influenced, and the application of the milrinone injection is greatly limited.
Chinese patent CN101028266 discloses a milrinone liposome, which is obtained by mixing 300-1000ml milrinone (4mg/ml) liquid, 450g lecithin ethanol liquid of 300mg/ml and dichlorodifluoromethane into an organic phase, fully and uniformly mixing the organic phase with 4000ml water phase of 5 percent ethanol liquid, subpackaging the organic phase in a pressure-resistant container and installing a valve system.
The existing milrinone preparation technology has more defects, and the quality problem of the milrinone injection is seriously influenced. The problems of dissolution and stability of milrinone are urgently needed to be solved.
Disclosure of Invention
On the basis of the prior art, the application overcomes the defects of the prior art, and the milrinone is encapsulated by relying on a liposome technology to form a liposome drug-loaded transportation system, so that the preparation is further prepared. Firstly, the liposome technology is utilized to solve the problem of poor solubility of milrinone, and secondly, a novel milrinone liposome drug-carrying system is provided, the milrinone liposome system has higher drug-carrying capacity and encapsulation efficiency and good stability, and lays a tamping foundation for further preparation of a preparation.
The first purpose of the invention is to provide a milrinone liposome, which comprises milrinone, phospholipid and ergosterol.
The milrinone is found to be easily degraded in an acid environment, and is particularly unstable to light, so neutral phospholipid is selected to carry out coating and carrying on the milrinone, and the neutral phospholipid is selected from one or more of phosphatidylcholine, dipalmitoyl choline, distearoyl choline, dimyristoyl phosphatidylcholine and phosphatidylethanolamine.
Furthermore, the inventors tried to add cholesterol or ergosterol as a membrane fluidity regulator into a lipid system in order to improve membrane fluidity, and found that the conventional cholesterol membrane fluidity regulator is not ideal, while ergosterol has a better effect of improving membrane fluidity, thereby effectively improving the stability of liposome membrane and reducing the leakage rate.
Furthermore, the inventors have conducted a one-factor variable test on the neutral phospholipids, and have studied the encapsulation effect of milrinone by using phosphatidylcholine, dipalmitoylcholine, distearoyl choline, dimyristoylphosphatidylcholine, phosphatidylethanolamine and combinations thereof, respectively, and have found that the encapsulation effect of phosphatidylethanolamine and/or phosphatidylcholine on milrinone is better.
Specifically, the milrinone liposome comprises the following components in parts by weight: 1 part of milrinone, 2-6 parts of neutral phospholipid and 1-3 parts of ergosterol.
The second purpose of the invention is to provide a method for preparing the milrinone liposome, which comprises the following steps:
(1) dissolving phospholipid in an organic solvent A, dissolving ergoline in an organic solvent B, and dissolving milrinone in an organic solvent C for later use;
(2) mixing the three solutions in the step (1), carrying out rotary reduced pressure rotary evaporation in a water bath at 15-35 ℃, and removing the organic solvent to obtain a film liposome;
(3) and (3) carrying out high-pressure extrusion on the thin-film liposome obtained in the step (2), wherein the extrusion time is 2-15min, and obtaining the unilamellar liposome with uniform particle size.
Further, the organic solvent A is trichloromethane, the organic solvent B is cyclohexane, and the organic solvent C is methanol.
The step (2) is specifically as follows: and (2) mixing the three solutions in the step (1), placing the mixture in a water bath, performing rotary reduced pressure rotary evaporation, gradually heating the mixture to 30 ℃ at the initial water bath temperature of 15 ℃, adding a proper amount of phosphate buffer solution with the pH value of 6.0-7.5, preferably 7.0, heating the mixture again to 35 ℃, performing rotary reduced pressure rotary evaporation in the water bath, and removing the organic solvent to obtain the thin film liposome.
The high pressure extrusion is 150000-200000kPa, the extrusion time is 8-10min, and the particle size of the obtained liposome is uniform and is 30-80nm by controlling the high pressure.
The third purpose of the invention is to provide a milrinone preparation, which is further prepared from the milrinone liposome, and the preparation is preferably an injection.
Compared with the prior art, the invention has the beneficial effects that:
(1) the milrinone liposome is prepared by using a liposome technology, so that the problem of poor solubility of milrinone is solved, the problem of poor stability of the milrinone injection is solved, and the milrinone liposome injection has small content change of related substances and high stability under the conditions of illumination, high temperature and high humidity.
(2) The invention optimizes liposome membrane material, optimizes preparation process, improves membrane fluidity, improves drug-loading capacity, encapsulation efficiency and stability of the milrinone liposome, and has uniform particle size distribution.
Drawings
FIG. 1 example 7 evaluation of drug-loading and encapsulation efficiency of various groups of Milrinone liposomes
FIG. 2 example 7 Milrinone liposome leakage rates (a) group A; (b) group C; (c) group D; (d) group E
FIG. 3 evaluation of drug loading and encapsulation efficiency of Milrinone liposomes in each group of example 8
FIG. 4 particle size distribution diagram of example 8
FIG. 5 stability test (light test) of Milrinone injection of the present invention and commercially available injection
FIG. 6 stability test (accelerated test) of Milrinone injection of the present invention and commercially available injection
Detailed Description
In order to make the purpose and technical solution of the present invention more clear, the present invention is further described with reference to the following examples, but the scope of the present invention is not limited to these examples, and the examples are only used for explaining the present invention. It will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true scope of the invention.
EXAMPLE 1 preparation of Milrinone liposomes
10g milrinone
Phosphatidylethanolamine 40g
Ergosterol 20g
The preparation method comprises the following steps:
(1) dissolving phospholipid in chloroform, ergoline in cyclohexane, and milrinone in methanol;
(2) and (2) mixing the three solutions in the step (1), placing the three solutions in a water bath, performing rotary reduced pressure rotary evaporation, wherein the initial water bath temperature is 15 ℃, gradually heating to 30 ℃, adding a proper amount of phosphate buffer solution, the pH value is 7.0, heating to 35 ℃ again, performing rotary reduced pressure rotary evaporation in the water bath, and removing the organic solvent to obtain the thin film liposome. (ii) a
(3) And (3) carrying out 180000kPa high-pressure extrusion on the thin-film liposome obtained in the step (2), wherein the extrusion time is 8-10min, so as to obtain the unilamellar liposome with uniform particle size.
EXAMPLE 2 preparation of Milrinone liposomes
10g milrinone
40g of phosphatidylcholine
Ergosterol 20g
The preparation method comprises the following steps:
(1) dissolving phospholipid in chloroform, dissolving ergoline in cyclohexane, and dissolving milrinone in methanol;
(2) and (2) mixing the three solutions in the step (1), placing the three solutions in a water bath, performing rotary reduced pressure rotary evaporation, wherein the initial water bath temperature is 15 ℃, gradually heating to 30 ℃, adding a proper amount of phosphate buffer solution, the pH value is 6.0, heating to 35 ℃ again, performing rotary reduced pressure rotary evaporation in the water bath, and removing the organic solvent to obtain the thin film liposome. (ii) a
(3) And (3) carrying out 180000kPa high-pressure extrusion on the thin-film liposome obtained in the step (2), wherein the extrusion time is 8-10min, so as to obtain the unilamellar liposome with uniform particle size.
EXAMPLE 3 preparation of Milrinone liposomes
The preparation method comprises the following steps:
(1) dissolving phospholipid in chloroform, ergoline in cyclohexane, and milrinone in methanol;
(2) and (2) mixing the three solutions in the step (1), placing the three solutions in a water bath, performing rotary reduced pressure rotary evaporation, wherein the initial water bath temperature is 15 ℃, gradually heating to 30 ℃, adding a proper amount of phosphate buffer solution, the pH value is 7.5, heating to 35 ℃ again, performing rotary reduced pressure rotary evaporation in the water bath, and removing the organic solvent to obtain the thin film liposome. (ii) a
(3) And (3) carrying out 180000kPa high-pressure extrusion on the thin-film liposome obtained in the step (2), wherein the extrusion time is 8-10min, so as to obtain the unilamellar liposome with uniform particle size.
EXAMPLE 4 preparation of Milrinone liposomes
The preparation method comprises the following steps:
(1) dissolving phospholipid in chloroform, ergoline in cyclohexane, and milrinone in methanol;
(2) and (2) mixing the three solutions in the step (1), placing the three solutions in a water bath, performing rotary reduced pressure rotary evaporation, wherein the initial water bath temperature is 15 ℃, gradually heating to 30 ℃, adding a proper amount of phosphate buffer solution, the pH value is 6.5, heating to 35 ℃ again, performing rotary reduced pressure rotary evaporation in the water bath, and removing the organic solvent to obtain the thin film liposome. (ii) a
(3) And (3) carrying out high-pressure extrusion on the thin film liposome obtained in the step (2) at 150000kPa for 8-10min to obtain the unilamellar liposome with uniform particle size.
EXAMPLE 5 preparation of Milrinone liposomes
The preparation method comprises the following steps:
(1) dissolving phospholipid in chloroform, ergoline in cyclohexane, and milrinone in methanol;
(2) and (2) mixing the three solutions in the step (1), placing the three solutions in a water bath, performing rotary reduced pressure rotary evaporation, wherein the initial water bath temperature is 15 ℃, gradually heating to 30 ℃, adding a proper amount of phosphate buffer solution, the pH value is 7.0, heating to 35 ℃ again, performing rotary reduced pressure rotary evaporation in the water bath, and removing the organic solvent to obtain the thin film liposome. (ii) a
(3) And (3) carrying out 200000kPa high-pressure extrusion on the thin-film liposome obtained in the step (2), wherein the extrusion time is 8-10min, and obtaining the unilamellar liposome with uniform particle size.
Example 6 quality evaluation of liposomes of milrinone in examples 1 to 5
1. Particle size distribution
TABLE 1 examples 1-5 milrinone liposomes mean particle size (nm)
| Average particle diameter (nm) | |
| Example 1 | 45.30±2.81 |
| Example 2 | 49.64±3.98 |
| Example 3 | 50.08±2.17 |
| Example 4 | 53.66±4.06 |
| Example 5 | 46.34±3.87 |
2. Drug loading and encapsulation efficiency
Table 2 drug loading (%) and encapsulation efficiency (%) of the liposomes of examples 1 to 5 milrinone%
| Drug loading (%) | Encapsulation efficiency (%) | |
| Example 1 | 27.44±1.02 | 91.08±2.03 |
| Example 2 | 27.05±1.58 | 90.87±1.94 |
| Example 3 | 28.19±1.26 | 92.03±1.66 |
| Example 4 | 25.41±1.89 | 88.42±1.43 |
| Example 5 | 25.01±2.02 | 89.14±2.21 |
3. Stability of liposomes
3.1 leakage Rate
TABLE 3 leakage (%). of the liposomes of examples 1-5 milrinone stored at 25 deg.C
3.2 degree of Oxidation of Phospholipids
Phospholipids are easily oxidized, and in liposome mixtures containing unsaturated fatty acids, the degree of oxidation of phospholipids is divided into three stages: coupling of single double bonds, formation of oxidation products, formation of acetaldehyde and cleavage of the bond.
The oxidation index is an index for detecting double bond coupling, the double bond coupling is also the first stage of phospholipid oxidation, and the oxidation index is used for objectively evaluating the oxidation degree of phospholipid.
Table 4 examples 1-5 milrinone liposomes oxidation index of phospholipids
| Oxidation index | |
| Example 1 | 0.05 |
| Example 2 | 0.06 |
| Example 3 | 0.04 |
| Example 4 | 0.10 |
| Example 5 | 0.08 |
In conclusion, the quality of the milrinone liposome of the examples 1-5 of the present invention was evaluated by using the average particle size, drug loading amount and encapsulation efficiency, and the stability of the milrinone liposome of the present invention was evaluated by using the oxidation index and storage leakage rate of phospholipid. The results show that the milrinone liposome has uniform particle size distribution, small span, high drug-loading rate, easy clinical requirement meeting, high entrapment rate and high stability. Therefore, the milrinone liposome has high quality and high drug loading efficiency.
Example 7 investigation of the Effect of Liposome Carrier materials on drug Loading, encapsulation efficiency, and leakage Rate
A single factor test was designed with the control variables grouped as:
other conditions refer to example 3.
FIG. 1 shows the drug loading and encapsulation efficiency evaluation of the milrinone liposomes of the above groups A to E. In addition, the inventors also found that ergosterol is an important factor affecting the stability of milrinone liposomes (fig. 2).
Example 8 study of the effects of the preparation method on drug loading, encapsulation efficiency and particle size distribution of milrinone liposomes
A single factor test was designed with the control variables grouped as:
a: the organic solvent A is ethanol, the organic solvent B is dichloromethane, and the organic solvent C is methanol
B; pH of buffer 5.2
C; pH of buffer 8.0
D; extrusion conditions: 100000kPa, 6min
E; extrusion conditions: 250000kPa, 12min
Other conditions refer to example 1.
FIG. 3 shows the drug loading and encapsulation efficiency evaluation of the milrinone liposomes of the above groups A to E. The results show that the pH of the organic solvent and the buffer solution has certain influence on the encapsulation efficiency and the drug loading capacity of the milrinone liposome, and the influence of the extrusion conditions in D, E groups of preparation processes on the encapsulation efficiency and the drug loading capacity of the milrinone liposome is small. However, fig. 4 shows that the extrusion conditions in the preparation process have a large influence on the particle size of the milrinone liposomes.
EXAMPLE 9 Milrinone injection (specification 10 ml: 10mg) (100 pieces)
3.644g of the milrinone liposome prepared in example 1 was added with an appropriate amount of glucose, and water for injection was added to 1000 ml.
EXAMPLE 10 milrinone injection (specification 10 ml: 10mg) (100 pieces)
3.697g of the milrinone liposome prepared in example 2 was added with an appropriate amount of glucose, and water for injection was added to 1000 ml.
EXAMPLE 11 Milrinone injection (specification 10 ml: 10mg) (100 pieces)
3.547g of milrinone liposome prepared in example 3 was added with an appropriate amount of sodium chloride, and water for injection was added to 1000 ml.
EXAMPLE 12 comparison of the stability of the commercially available milrinone injection with the injection of examples 9 to 11 according to the invention
And (3) illumination test:
the milrinone liposome injection prepared in the embodiments 9-11 of the invention and the milrinone injection sold in the market are placed in an illumination device, and the illumination intensity is 1.2 multiplied by 10 6 Placed under lx conditions, and examined in a high light irradiation experiment. Sampling at 1 day, 5 days, 10 days, 21 days and 30 days respectively, and detecting the content of related substances.
And (3) accelerated test:
the milrinone liposome injection prepared in the embodiments 9-11 of the invention is packaged according to the market, and is placed with the milrinone injection in the market under the conditions of the temperature of 40 +/-2 ℃ and the relative humidity of 75% +/-5% for 6 months, and samples are respectively taken at the end of the 1 st month, the 2 th month, the 3 th month and the 6 th month during the test period to measure the content of related substances.
Claims (10)
1. A milrinone liposome is characterized by comprising milrinone, neutral phospholipid and ergosterol.
2. The milrinone liposome of claim 1, wherein the neutral phospholipid is selected from one or more of phosphatidylcholine, dipalmitoylcholine, distearoylcholine, dimyristoylphosphatidylcholine, and phosphatidylethanolamine.
3. The milrinone liposome of claim 2, wherein the neutral phospholipid is phosphatidylethanolamine and/or phosphatidylcholine.
4. The milrinone liposome of claim 1, wherein the weight ratio of each component is: 1 part of milrinone, 2-6 parts of neutral phospholipid and 1-3 parts of ergosterol.
5. A method for preparing the milrinone liposome of claim 1, comprising the steps of:
(1) dissolving phospholipid in an organic solvent A, dissolving ergoline in an organic solvent B, and dissolving milrinone in an organic solvent C for later use;
(2) mixing the three solutions in the step (1), carrying out rotary reduced pressure rotary evaporation in a water bath at 15-35 ℃, and removing the organic solvent to obtain a film liposome;
(3) and (3) carrying out high-pressure extrusion on the thin-film liposome obtained in the step (2) to obtain a single-layer liposome with uniform particle size.
6. The method according to claim 5, wherein the organic solvent A is chloroform, the organic solvent B is cyclohexane, and the organic solvent C is methanol.
7. The method of claim 5, wherein the step (2) is: and (2) mixing the three solutions in the step (1), placing the mixture in a water bath, performing rotary reduced pressure rotary evaporation, wherein the initial water bath temperature is 15 ℃, gradually heating to 30 ℃, adding a proper amount of phosphate buffer solution, the pH value is 6.0-7.5, heating to 35 ℃ again, performing rotary reduced pressure rotary evaporation in the water bath, and removing the organic solvent to obtain the film liposome.
8. The method as claimed in claim 5, wherein the high pressure extrusion is 150000-.
9. The milrinone liposome of claim 1, wherein the milrinone liposome has a particle size of 30-80 nm.
10. The milrinone liposome of claim 1, wherein the milrinone liposome can be prepared into a preparation with pharmaceutically acceptable adjuvants, and the preparation is preferably an injection.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1679566A (en) * | 2004-04-07 | 2005-10-12 | 鲁南制药集团股份有限公司 | Milrinone sodium chloride injection and production thereof |
| CN101028266A (en) * | 2006-03-02 | 2007-09-05 | 鲁南制药集团股份有限公司 | Lung medicine-feeding preparation containing Mulinong |
| CN101152180A (en) * | 2007-09-06 | 2008-04-02 | 鲁南制药集团股份有限公司 | Pharmaceutical composition containing milrinone |
| CN102552115A (en) * | 2010-12-17 | 2012-07-11 | 北大方正集团有限公司 | Milrinone injection and preparation method thereof |
| EP3520819A1 (en) * | 2018-01-31 | 2019-08-07 | Universität Basel | Shear stress sensitive liposomes |
-
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- 2022-06-01 CN CN202210614022.1A patent/CN114886851B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1679566A (en) * | 2004-04-07 | 2005-10-12 | 鲁南制药集团股份有限公司 | Milrinone sodium chloride injection and production thereof |
| CN101028266A (en) * | 2006-03-02 | 2007-09-05 | 鲁南制药集团股份有限公司 | Lung medicine-feeding preparation containing Mulinong |
| CN101152180A (en) * | 2007-09-06 | 2008-04-02 | 鲁南制药集团股份有限公司 | Pharmaceutical composition containing milrinone |
| CN102552115A (en) * | 2010-12-17 | 2012-07-11 | 北大方正集团有限公司 | Milrinone injection and preparation method thereof |
| EP3520819A1 (en) * | 2018-01-31 | 2019-08-07 | Universität Basel | Shear stress sensitive liposomes |
Non-Patent Citations (1)
| Title |
|---|
| 蒋小宏 等: "肺动脉高压的药物治疗及药物递送策略" * |
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