CN112156067B - Pharmaceutical composition containing milrinone and preparation method thereof - Google Patents
Pharmaceutical composition containing milrinone and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a milrinone-containing pharmaceutical composition and a preparation method thereof. The invention provides a milrinone injection pharmaceutical composition, which contains milrinone, a surfactant, a pH regulator and water for injection, wherein the pH value of the pharmaceutical composition is 4-6. The invention meets the solubility requirement of the product by adding the surfactant, thereby reducing the irritation of low pH value to the injection part and simultaneously reducing the generation of impurity 5-hydroxymethylfurfural; the production equipment is simple, the cost is low, the operation is simple and convenient, the control is easy, the milrinone in the preparation process is always at the normal temperature, and the damage of high temperature to the raw material medicines is reduced.
Description
Technical Field
The invention relates to a milrinone pharmaceutical composition, belongs to a preparation method of the pharmaceutical composition, and relates to a preparation which is prepared from milrinone and has proper content, isotonicity, proper pH value and capability of injection administration, and the problems of dissolution of insoluble drugs and impurity growth in the preparation and storage processes are mainly solved.
Background
Milrinone is a phosphodiesterase inhibitor, is mainly used for congestive heart failure, pulmonary hypertension, low heart rate syndrome after cardiac operation and cardiomyopathy clinically, and needs to be injected for administration. Milrinone is a white crystalline powder insoluble drug, has a pKa constant of 9.67, is almost insoluble in water or ethanol, and is slightly soluble in dilute acid. Therefore, the acidic substance is needed to be added in the preparation process when the injection is prepared, and the solubility of the raw material medicine is improved by utilizing the characteristic of better solubility of the raw material medicine under the condition of low pH value, so that the problem of medicine dissolution is solved.
The patent documents CN108158988A and CN105796487A, etc. disclose a milrinone injection and a preparation method thereof, wherein the injection adopts lactic acid and/or sodium hydroxide as an acid-base regulator to regulate the pH value to be 2.9-4.4 so as to improve the solubility of the milrinone injection. CN108158988A further adopts technical means such as ultrafiltration and the like to solve the problem of activated carbon adsorption.
Patent document CN100589804C discloses a milrinone injection and a preparation method thereof, wherein the pH value is adjusted to be between 2.8 and 3.5 by any one of acetic acid, phosphoric acid or sulfuric acid, so as to achieve the effects of dissolving milrinone and better treatment. The stability of the injection is improved by further adding isotonic regulator glucose in CN102525890A, and the preparation method of the formula is simple, low in cost and good in stability.
Patent document CN100581546C discloses a milrinone hydrochloride injection and a preparation method thereof, wherein the milrinone hydrochloride injection contains milrinone, hydrochloric acid, sodium chloride and water for injection, and the hydrochloric acid adjusts the pH range of the injection to be between 2.8 and 3.5, and the provided injection has the advantages of high purity, simple preparation process, convenient clinical use and good treatment effect.
Patent document CN103655562A discloses a milrinone pharmaceutical composition and a preparation method thereof, which adopts cysteine hydrochloride and calcium sodium edetate to provide an injection with high stability, simple preparation process, convenient clinical use and easy industrial implementation, wherein the pH value is controlled at 2.5-3.CN104739759 uses glucose, methionine and lactic acid to control pH to 3.4-3.8, the injection has stable property, is not easy to degrade, and has no obvious change in the contents of impurity A, impurity B and other impurities after being stored for a certain time under a certain condition; meanwhile, the milrinone injection provided by the invention can protect cardiac muscle more effectively when treating acute and chronic intractable congestive heart failure.
Patent document CN107405504 and others adopt a new administration mode to prepare milrinone inhalation preparation, and adopt a surface active inhalation solution mode to solve the static problem.
Patent document CN102579329A discloses milrinone injection, which comprises active raw material drugs of milrinone, meglumine, sodium chloride, vitamins and lactic acid, and the pH of the liquid medicine is controlled to be 2.9-3.4.
Therefore, in order to solve the problems of solubility and stability of milrinone injection in the prior art, acidic substances such as lactic acid, hydrochloric acid, sulfuric acid, malic acid and the like are generally added as a pH regulator to increase the solubility and stability, or some auxiliary solvents are further added to improve the solubility, but the final pH is controlled to be basically less than 4 no matter what regulating method is adopted. The pH value of the injection is equal to or similar to that of blood as much as possible, and the injection with too low acidity is easy to cause irritation and influence the compliance of patients; meanwhile, the preparation process in the prior art needs heating, active carbon addition, ultrafiltration and other technical problems, but the dissolution time is still long, the clarity of the product is easy to fail, the product is easy to discolor in the storage process, the shelf life is shortened due to improper storage, and the application of the milrinone injection is greatly limited. On the other hand, the weakly acidic environment can increase the production of 5-hydroxymethylfurfural which is a glucose dehydration product, and the 5-hydroxymethylfurfural has damage to striated muscles and internal organs of a human body, and the content of the 5-hydroxymethylfurfural is strictly controlled.
Disclosure of Invention
In order to solve the technical problems of milrinone in the prior art, the invention aims to provide a milrinone injection and a preparation method thereof, which can quickly dissolve milrinone within a pH range suitable for human body injection, maintain long-term stability and have simple process operation.
In order to realize the purpose of the invention, the invention adopts the following technical scheme:
the milrinone injection medicine composition contains milrinone, surfactant, pH regulator and water for injection, and has pH value of 4-6.
The surfactant of the pharmaceutical composition of the present invention may be selected from different types of pharmaceutically acceptable surfactants. As classified according to its polar part, it contains both hydrophobic and hydrophilic surfactants, the hydrophobic part being generally readily soluble in organic solvents but sparingly soluble or insoluble in water, and the hydrophilic part being sparingly soluble or insoluble in organic solvents but readily soluble in water. Further, surfactants having a negatively charged polar moiety are classified according to their charge, as anionic surfactants, having a positively charged polar moiety as cationic surfactants, uncharged surfactants are generally known as nonionic surfactants, and surfactants that are both positively and negatively charged as zwitterionic surfactants. For example, but not limited to, anionic surfactants may include aluminum monostearate, calcium stearoyl lactylate, sodium cetostearyl sulfate, sodium cocoyl sarcosinate, sodium lauryl sulfate, sodium lauroyl sarcosinate or sodium cocoyl sarcosinate, sodium lauroyl sarcosinate, sodium oleate, sodium stearate, sodium stearoyl lactylate, and sulfated castor oil; cationic surfactants are generally based on polar groups containing amino groups, such as wool-onium bromide; zwitterionic surfactants are generally characterized by having a polar group formed by a quaternary amine and a sulfate or carboxyl group and can include aminocarboxylic acids, alanine derivatives, imidazoline derivatives, and doxine; the most common nonionic surfactants are based on oligo (ethylene oxide) -containing polar groups and may include glycerol acetate, diethylene glycol ester, diethylene glycol ether, ethylene glycol ester, glycerol behenate, mono and diglycerides of glycerol, glycerol monodecanodecanoate, glycerol monolinoleate, glycerol monooleate, glycerol stearate, polyethylene glycol cetearyl ether, polyethylene glycol/glycerol ester, polyethylene glycol 6 glycerol decanoyl decanoate, polyethylene glycol 20 glycerol monostearate, polyethylene glycol 15 hydroxystearate, polyethylene glycol laurate, polyethylene glycol lauryl ether, polyethylene glycol monomethyl ether, polyethylene glycol oleate, polyethylene glycol oleyl ether, polyethylene glycol 40 sorbitol heptaoleate, polyethylene glycol stearate, coco polyethylene glycol glycerides, nonoxynol, octoxynol, oleyl oleate, palmitic acid, poloxamers, polyethylene glycol castor oil, polyethylene glycol hydrogenated castor oil, polysorbates (such as polysorbate 80, polysorbate 60, polysorbate 40, polysorbate 20, and the like), polyvinyl alcohol, propylene glycol caprylate, propylene glycol diacetate, propylene glycol laurate, propylene glycol monopalmitostearate, bark, sorbitol ester, sucrose ester, glyceryl diisostearate and tyloxapol. The preferred surfactant of the present invention is a nonionic surfactant, more preferably polysorbate, further preferably polysorbate 80 (tween 80), polysorbate 60 (tween 60), polysorbate 40 (tween 40), polysorbate 20 (tween 20), and further preferably polysorbate 80.
The pharmaceutical composition of the present invention may contain milrinone in an amount of 0.5 to 1.5mg/ml (e.g., 0.5mg/ml, 0.8mg/ml, 1.0mg/ml, 1.2mg/ml, 1.5 mg/ml), and preferably contains milrinone in an amount of 1.0mg/ml.
The content of the surfactant in the pharmaceutical composition of the present invention may be 0.5 to 1.5mg/ml (e.g., 0.5mg/ml, 0.8mg/ml, 1.0mg/ml, 1.2mg/ml, 1.5 mg/ml), preferably 0.8 to 1.2mg/ml, and more preferably 1.0mg/ml.
Preferably, the milrinone and the surfactant are contained in the pharmaceutical composition of the present invention in the same amount (by mass).
The purpose of the invention can be achieved by using any one or the combination of pH regulators for regulating the pH value of the injection to be in the range of 4-6 in the pharmaceutical composition. For example: lactic acid, acetic acid, hydrochloric acid, sulfuric acid, citric acid, phosphate buffer solution and combination use alkali for acid-base regulation; the pH regulator is preferably an acid pH regulator, and the acid pH regulator is preferably one or more of lactic acid, citric acid and hydrochloric acid; the pH regulator of the invention can also be a composition of an acid pH regulator and an alkali pH regulator, wherein the acid pH regulator is preferably one or more of lactic acid, citric acid and hydrochloric acid, and the alkali pH regulator is preferably sodium hydroxide. The content of the acid pH regulator in the pharmaceutical composition can be 0.05-0.15 mg/ml, and the appropriate amount of the alkali pH regulator and the water for injection is regulated to the required pH range.
In the pharmaceutical composition of the present invention, the pharmaceutical composition may further comprise an osmotic pressure regulator, preferably anhydrous glucose, and the content of the osmotic pressure regulator in the pharmaceutical composition may be 40 to 50mg/ml.
In some embodiments of the present invention, the milrinone injection pharmaceutical composition comprises the above milrinone, the above surfactant, the above pH regulator, the above osmotic pressure regulator, and water for injection, wherein the pH of the pharmaceutical composition is 4 to 6.
In certain embodiments of the present invention, the milrinone injection pharmaceutical composition comprises milrinone, polysorbate, lactic acid, anhydrous glucose, sodium hydroxide and water for injection, wherein the pH of the pharmaceutical composition is 4 to 6.
In some embodiments of the present invention, the milrinone injection pharmaceutical composition consists of milrinone, polysorbate, lactic acid, anhydrous glucose, sodium hydroxide and water for injection, wherein the pH of the pharmaceutical composition is 4 to 6.
In some embodiments of the invention, the milrinone injection pharmaceutical composition contains 0.5-1.5 mg/ml milrinone, 0.5-1.5 mg/ml tween 80, 0.05-0.15 mg/ml lactic acid, 40-50 mg/ml anhydrous glucose, sodium hydroxide and water for injection, wherein the pH value of the pharmaceutical composition is 4-6.
In some embodiments of the invention, the milrinone injection pharmaceutical composition contains 0.5-1.5 mg/ml milrinone, 0.5-1.5 mg/ml tween 60, 0.05-0.15 mg/ml lactic acid, 40-50 mg/ml anhydrous glucose, sodium hydroxide and water for injection, wherein the pH value of the pharmaceutical composition is 4-6.
In some embodiments of the invention, the milrinone injection pharmaceutical composition contains 0.5-1.5 mg/ml milrinone, 0.5-1.5 mg/ml tween 40, 0.05-0.15 mg/ml lactic acid, 40-50 mg/ml anhydrous glucose, sodium hydroxide and water for injection, wherein the pH value of the pharmaceutical composition is 4-6.
In some embodiments of the invention, the milrinone injection pharmaceutical composition consists of 0.5-1.5 mg/ml milrinone, 0.5-1.5 mg/ml tween 80, 0.05-0.15 mg/ml lactic acid, 40-50 mg/ml anhydrous glucose, sodium hydroxide and water for injection, wherein the pH value of the pharmaceutical composition is 4-6.
In some embodiments of the invention, the milrinone injection pharmaceutical composition consists of 0.5 to 1.5mg/ml milrinone, 0.5 to 1.5mg/ml tween 60, 0.05 to 0.15mg/ml lactic acid, 40 to 50mg/ml anhydrous glucose, sodium hydroxide and water for injection, wherein the pH value of the pharmaceutical composition is 4 to 6.
In some embodiments of the invention, the milrinone injection pharmaceutical composition consists of 0.5 to 1.5mg/ml milrinone, 0.5 to 1.5mg/ml tween 40, 0.05 to 0.15mg/ml lactic acid, 40 to 50mg/ml anhydrous glucose, sodium hydroxide and water for injection, wherein the pH value of the pharmaceutical composition is 4 to 6.
In the pharmaceutical composition of the present invention, the pH of the pharmaceutical composition may be 5 to 6. When the pH value of the pharmaceutical composition is in the range of 5-6, the contents of related substances and 5-hydroxymethylfurfural in the pharmaceutical composition are lower; and the pH value is closer to the pH value of blood at 5-6, so that the composition is more suitable for human bodies.
In certain embodiments of the invention, the pharmaceutical compositions of the invention do not contain activated carbon.
The invention also provides a preparation method of the milrinone injection, which mainly comprises the following steps:
dispersing the surfactant in 10-20 times of hot water for injection, adding 50-70% of the total amount of normal-temperature water for injection, stirring until the surfactant is dissolved, and adding the pH regulator; then adding the milrinone, stirring to dissolve the milrinone, adding the osmotic pressure regulator, regulating the pH value of the liquid medicine to 4-6, and stirring to completely dissolve the milrinone; filtering the medicinal liquid, filling into ampoule bottle, and sterilizing.
In certain embodiments of the invention, the preparation process does not use activated carbon.
The invention also provides the milrinone injection prepared by the preparation method of the milrinone injection.
In the invention, the temperature of the hot injection water is 40-80 ℃.
The preparation method only adopts a small amount of hot water in the surfactant concentration process, other operation steps are carried out in a normal-temperature medium, the product is encapsulated by adopting a double nitrogen filling mode, and the terminal sterilization temperature is 121 ℃ for 15 minutes.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The invention has the following beneficial effects:
1. the surfactant is added to meet the solubility requirement of the product, so that the irritation of low pH value to an injection part is reduced, and the generation of impurity 5-hydroxymethylfurfural is reduced;
2. the production equipment is simple, the cost is lower, the operation is simple and convenient, the control is easy, the milrinone in the preparation process is always under the normal temperature condition, and the damage of high temperature to the raw material medicine is reduced;
3. active carbon is not used, so that the problems of the risk of introducing impurities into the active carbon and more adsorption to milrinone are solved.
The milrinone injection prepared according to the prescription and the process described in the technical scheme of the invention has stable quality and low impurity content, and is subjected to high temperature (60 +/-2 ℃), low temperature (5 +/-3 ℃), and illumination (the total illumination intensity is more than 1.2 multiplied by 10 in 30 days) 6 Lux. Hr) for 30 days, the results show that the product quality is stable and the impurity growth is small. The sample is accelerated for 1, 2 and 3 months at the temperature of 40 ℃, and the content, related substances and other items have no obvious change.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
In the following examples, the temperature of hot water for injection is 40 to 80 ℃.
The method for measuring the content of the milrinone injection and related substances comprises the following steps:
1. content determination method
Chromatographic conditions and System suitability test
Octadecylsilane chemically bonded silica is used as a filling agent; taking water-methanol-sodium borate buffer solution (31 g of boric acid, 800ml of water is taken, a proper amount of 20% sodium hydroxide solution is slowly added, fully shaking is carried out to completely dissolve the boric acid, the pH value is adjusted to 7.0 by the 20% sodium hydroxide solution, the pH value is diluted to 1000ml by water, and shaking is carried out uniformly, thus obtaining the temporary preparation) (725; the flow rate was 1.0ml/min, the detection wavelength was 254nm, and the column temperature was 35 ℃. Taking a proper amount of each of milrinone, impurity I and impurity II as reference substances, dissolving and diluting with a mobile phase to prepare mixed solutions containing 100 mu g of each in 1ml, taking 20 mu l of the mixed solutions as system applicability solutions, injecting into a liquid chromatograph, and recording a chromatogram. The number of theoretical plates is not less than 2000 calculated according to milrinone peak, and the separation degree of the impurity I and milrinone is not less than 4.
Assay method
Precisely measuring 5ml of the product, placing in a 50ml measuring flask, diluting to scale with mobile phase, shaking, precisely measuring 20 μ l, injecting into liquid chromatograph, and recording chromatogram; taking milrinone reference substance, precisely weighing, adding mobile phase for dissolving, quantitatively diluting to obtain solution containing about 0.1mg per 1ml, and measuring by the same method. And calculating according to the peak area by an external standard method to obtain the product.
2. Related substance and method for measuring content of 5-hydroxymethylfurfural
Taking the product as a test solution; precisely measuring a proper amount, and quantitatively diluting with a mobile phase to prepare a solution containing about 2 mu g of milrinone in each 1ml as a self control solution; taking another appropriate amount of 5-hydroxymethylfurfural reference substance, precisely weighing, adding mobile phase for dissolving, and quantitatively diluting to obtain solutions each containing 10 μ g in each 1ml as reference substance solutions; then taking appropriate amount of 5-hydroxymethylfurfural and milrinone reference substance, precisely weighing, adding mobile phase for dissolving, and quantitatively diluting to obtain mixed solution containing about 20 microgram and 100 microgram in each 1ml, and using the mixed solution as system applicability solution. The detection wavelengths were 284nm and 254nm, with reference to the chromatographic conditions in the content measurement section. And (4) taking 20 mu l of the system applicability solution, injecting the solution into a liquid chromatograph, and recording a chromatogram. In a chromatogram with the wavelength of 284nm, the separation degree of the 5-hydroxymethylfurfural and the milrinone peak is in accordance with the requirement. Precisely measuring 20 μ l of each of the test solution, the self-contrast solution and the contrast solution, respectively injecting into a liquid chromatograph, and recording the chromatogram until the retention time of the main component peak is 3 times. In the chromatogram of 254nm, the content of related substances is calculated according to a self-comparison method, in the chromatogram of 284nm, if a chromatographic peak with the same retention time as the peak of 5-hydroxymethylfurfural in the comparison solution exists in the sample solution, the peak area is calculated according to an external standard method.
Example 1
The prescription composition is as follows:
dispersing Tween 80 of a prescription amount in a small amount of hot injection water, adding 70ml of normal-temperature injection water, stirring until the Tween is dissolved, adding lactic acid of the prescription amount, stirring until the lactic acid is dissolved, adding milrinone of the prescription amount, stirring until the milrinone is dissolved, adding anhydrous glucose of the prescription amount, stirring until the anhydrous glucose is dissolved, measuring the pH value, and adjusting the pH value to a specified range by using sodium hydroxide. Water for injection was added to 100ml. After the solution is filtered, the solution is encapsulated in a 10ml ampoule in a double nitrogen filling mode before and after encapsulation. Sterilizing at 121 deg.C for 15 min.
The above prescription was tested and the results were as follows:
example 2
The stability tests were performed on the formula 3 and formula 6 samples, with the following results:
the results show that the total illumination intensity is more than 1.2 multiplied by 10 after passing through high temperature (60 +/-2 ℃), low temperature (5 +/-3 ℃), and illumination (the total illumination intensity is more than 1.2 multiplied by 10 in 30 days) 6 Lux. Hr) for 30 days, the product quality is stable, and the impurity growth is small. The sample is accelerated for 1, 2 and 3 months at the temperature of 40 ℃, the content, related substances and other items have no obvious change, and in the later stage of the stability test, the product (formula 3) with the added surfactant and the product (formula 6) with the 5-hydroxymethylfurfural content are far lower than those of the product (formula 6) without the added surfactant.
Example 3
The prescription composition is as follows:
dispersing Tween 60 of a prescription amount in a small amount of hot injection water, adding 70ml of normal-temperature injection water, stirring until the Tween is dissolved, adding lactic acid of the prescription amount, stirring until the lactic acid is dissolved, adding milrinone of the prescription amount, stirring until the milrinone is dissolved, adding anhydrous glucose of the prescription amount, stirring until the anhydrous glucose is dissolved, measuring the pH value, and adjusting the pH value to a specified range by using sodium hydroxide. Water for injection was added to 100ml. After the solution is filtered, the solution is encapsulated in a 10ml ampoule in a double nitrogen filling mode before and after encapsulation. Sterilizing at 121 deg.C for 15 min.
The above prescription was tested and the results are as follows:
| prescription 7 | Prescription 8 | Prescription 9 | |
| Traits | Colorless and clear | Colorless and clear | Colorless and clear |
| Content (mg/ml) | 0.503 | 0.99 | 1.51 |
| pH | 5.98 | 4.99 | 4.01 |
| Related substances | 0.078％ | 0.079％ | 0.082％ |
| 5-hydroxymethylfurfural | 0.002％ | 0.001％ | 0.002％ |
Example 4
The prescription composition is as follows:
dispersing Tween 40 of a prescription amount in a small amount of hot injection water, adding 70ml of normal-temperature injection water, stirring until the Tween is dissolved, adding lactic acid of the prescription amount, stirring until the lactic acid is dissolved, adding milrinone of the prescription amount, stirring until the milrinone is dissolved, adding anhydrous glucose of the prescription amount, stirring until the anhydrous glucose is dissolved, measuring the pH value, and adjusting the pH value to a specified range by using sodium hydroxide. Water for injection was added to 100ml. After the solution is filtered, the solution is encapsulated in a 10ml ampoule in a double nitrogen filling mode before and after encapsulation. Sterilizing at 121 deg.C for 15 min.
The above prescription was tested and the results were as follows:
| prescription 10 | Prescription 11 | Prescription 12 | |
| Traits | Colorless and clear | Colorless and clear | Colorless and clear |
| Content (mg/ml) | 0.499 | 1.00 | 1.47 |
| pH | 6.01 | 5.02 | 3.98 |
| Related substances | 0.080％ | 0.078％ | 0.083％ |
| 5-hydroxymethylfurfural | 0.002％ | 0.002％ | 0.002％ |
Example 5
The stability tests were performed on the formula 8 and formula 11 samples, with the following results:
the results show that the total illumination intensity is more than 1.2 multiplied by 10 after passing through high temperature (60 +/-2 ℃), low temperature (5 +/-3 ℃), and illumination (the total illumination intensity is more than 1.2 multiplied by 10 in 30 days) 6 Lux hr) for 30 days, the product quality is stable, and the impurity growth is small. The sample is accelerated for 1, 2 and 3 months at the temperature of 40 ℃, the content, related substances and other items have no obvious change, the 5-hydroxymethylfurfural slightly rises, but still meets the standard of Chinese pharmacopoeia.
It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.
Claims (8)
1. The milrinone injection pharmaceutical composition is characterized by comprising milrinone, a surfactant, lactic acid, an alkali pH regulator, an osmotic pressure regulator and water for injection, wherein the pH value of the pharmaceutical composition is 4-6, the surfactant is polysorbate, the osmotic pressure regulator is anhydrous glucose, the alkali pH regulator is sodium hydroxide, the milrinone content is 0.5-1.5 mg/ml, the surfactant content is 0.5-1.5 mg/ml, the lactic acid content is 0.05-0.15 mg/ml, and the mass ratio of the milrinone, the surfactant and the lactic acid is 1.1; the preparation method of the composition comprises the steps of dispersing the surfactant in hot water for injection with the weight of 10-20 times, adding normal-temperature water for injection with the total weight of 50-70%, stirring until the total weight is dissolved, adding the lactic acid, and stirring until the lactic acid is dissolved; adding the milrinone, stirring to dissolve the milrinone, adding the osmotic pressure regulator, regulating the pH value of the liquid medicine to be 4-6 by using the alkali pH regulator, and stirring to completely dissolve the milrinone; filtering the medicinal liquid, filling into ampoule bottle, and sterilizing.
2. The milrinone injection pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a pH of 5 to 6.
3. The milrinone injection pharmaceutical composition of claim 2, wherein the milrinone is present in an amount of 1.0mg/ml; and/or the content of the surfactant is 0.8-1.2 mg/ml; and/or the content of the osmotic pressure regulator is 40-50 mg/ml.
4. The milrinone injection pharmaceutical composition of claim 3, wherein the surfactant is polysorbate 80, polysorbate 60, polysorbate 40 or polysorbate 20; the content of the surfactant is 1.0mg/ml.
5. The milrinone injection pharmaceutical composition of claim 1, wherein the milrinone injection pharmaceutical composition comprises milrinone, polysorbate, lactic acid, anhydrous glucose, sodium hydroxide and water for injection, wherein the pharmaceutical composition has a pH of 4 to 6.
6. The milrinone injection pharmaceutical composition of claim 1, which comprises milrinone at 0.5 to 1.5mg/ml, polysorbate 80 at 0.5 to 1.5mg/ml, lactic acid at 0.05 to 0.15mg/ml, anhydrous glucose at 40 to 50mg/ml, sodium hydroxide and water for injection, wherein the pH of the pharmaceutical composition is 4 to 6;
or the milrinone injection pharmaceutical composition contains 0.5 to 1.5mg/ml milrinone, 0.5 to 1.5mg/ml polysorbate 60, 0.05 to 0.15mg/ml lactic acid, 40 to 50mg/ml anhydrous glucose, sodium hydroxide and water for injection, wherein the pH value of the pharmaceutical composition is 4 to 6;
or the milrinone injection medicine composition contains 0.5-1.5 mg/ml milrinone, 0.5-1.5 mg/ml polysorbate 40, 0.05-0.15 mg/ml lactic acid, 40-50 mg/ml anhydrous glucose, sodium hydroxide and water for injection, wherein the pH value of the medicine composition is 4-6.
7. The milrinone injection pharmaceutical composition of claim 1, which consists of milrinone at 0.5 to 1.5mg/ml, polysorbate 80 at 0.5 to 1.5mg/ml, lactic acid at 0.05 to 0.15mg/ml, anhydrous glucose at 40 to 50mg/ml, sodium hydroxide and water for injection, wherein the pH of the pharmaceutical composition is 4 to 6;
or the milrinone injection medicine composition consists of 0.5 to 1.5mg/ml milrinone, 0.5 to 1.5mg/ml polysorbate 60, 0.05 to 0.15mg/ml lactic acid, 40 to 50mg/ml anhydrous glucose, sodium hydroxide and water for injection, wherein the pH value of the medicine composition is 4 to 6;
or the milrinone injection medicine composition consists of 0.5-1.5 mg/ml milrinone, 0.5-1.5 mg/ml polysorbate 40, 0.05-0.15 mg/ml lactic acid, 40-50 mg/ml anhydrous glucose, sodium hydroxide and water for injection, wherein the pH value of the medicine composition is 4-6.
8. A method for preparing the milrinone injection pharmaceutical composition as claimed in any one of claims 1 to 7, which comprises the main steps of: dispersing the surfactant in 10-20 times of hot water for injection, adding normal temperature water for injection accounting for 50-70% of the total weight of the surfactant, stirring until the surfactant is dissolved, adding the lactic acid, and stirring until the lactic acid is dissolved; adding the milrinone, stirring to dissolve the milrinone, adding the osmotic pressure regulator, regulating the pH value of the liquid medicine to be 4-6 by using the alkaline pH regulator, and stirring to completely dissolve the milrinone; filtering the medicinal liquid, filling into ampoule bottle, and sterilizing.
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