CN114272210A - Doxofylline injection preparation and preparation method thereof - Google Patents
Doxofylline injection preparation and preparation method thereof Download PDFInfo
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- CN114272210A CN114272210A CN202111640095.XA CN202111640095A CN114272210A CN 114272210 A CN114272210 A CN 114272210A CN 202111640095 A CN202111640095 A CN 202111640095A CN 114272210 A CN114272210 A CN 114272210A
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- doxofylline
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Abstract
The invention discloses a doxofylline injection preparation and a preparation method thereof, belonging to the technical field of doxofylline injection preparations, wherein the raw materials comprise 1.5-3.2 wt% of doxofylline liposome, 0.5-1.5 wt% of surfactant, 1-3 wt% of guiding agent and the balance of deionized water; the doxofylline liposome is prepared by dissolving doxofylline micropowder with particle size of 10-15nm in water, and performing ultrasonic treatment with ultrasonic treatment parameter of 40-80W for 0.5-1 min; adding phospholipid and cholesterol lipid, performing ultrasonic treatment again with ultrasonic treatment parameter of 60-100W for 1-2.5min, and vacuum freeze drying to obtain doxofylline liposome. In the doxofylline injection preparation, the particle size of the doxofylline liposome is small, and the doxofylline liposome can be rapidly deposited in a targeting manner in the lung after injection and is more easily absorbed by the cell walls of bronchial cells and alveolar cells, so that the doxofylline injection preparation has better stability and curative effect.
Description
Technical Field
The invention belongs to the field of doxofylline preparations, and particularly relates to a doxofylline injection preparation and a preparation method thereof.
Background
Doxofylline is a common xanthine anti-asthma drug, and is usually marketed in the form of small-volume injection, tablets and syrup, wherein the small-volume injection is widely applied and is generally injected in a mode of intravenous drip after dilution. The common injection preparation types of doxofylline are freeze-dried preparations in addition to liquid preparations.
For example, chinese patent application CN111840235A provides a doxofylline injection and its preparation method, wherein the preparation is prepared from doxofylline, mannitol and water for injection, and packaged and sold in 10ml injection bottle. For another example, chinese patent application CN110613682A provides a doxofylline injection, which comprises raw materials of doxofylline, trehalose, poloxamer and citric acid. Both of the doxofylline injections have good stability within 36 months. For another example, chinese patent application CN109966246A provides a doxofylline injection composition, which comprises doxofylline in the form of crystalline powder, glucose, inorganic acid, water for injection, melatonin, cyclodextrin and polyethylene glycol. For another example, chinese patent application CN112618519A provides a compound doxofylline solution for inhalation and a preparation method thereof, comprising raw material drugs doxofylline and ipratropium bromide, and further comprising an isotonic regulator, an antioxidant, a pH regulator and water for injection, the prepared inhalant is stable and safe, and does not cause bronchoconstriction.
However, these drugs have limited targeting effects on the lung due to their involvement in the systemic circulation.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a nano liposome type doxofylline injection preparation, which utilizes the self characteristics of a nano carrier and the coating property of doxofylline, obviously improves the targeted deposition of doxofylline drugs in the lung and obviously improves the curative effect on asthma lung and respiratory diseases. Specifically, the following technique is used.
A doxofylline injection comprises doxofylline liposome 1.5-3.8 wt%, surfactant 0.5-1.5 wt%, guiding agent 1-3 wt%, and deionized water in balance;
the preparation method of the doxofylline liposome comprises the steps of dissolving doxofylline micro powder with the particle size of 10-15nm in water for ultrasonic treatment, wherein the ultrasonic treatment parameter is 40-80W for 0.5-1 min; adding phospholipid and cholesterol lipid, performing ultrasonic treatment again with ultrasonic treatment parameter of 60-100W for 1-2.5min, and vacuum freeze drying to obtain doxofylline liposome.
The phospholipid used in the doxofylline liposome is one or a mixture of two or more of lecithin, soybean phospholipid, hydrogenated soybean lecithin, phosphatidylethanolamine, synthetic phosphatidylserine, phosphatidylinositol, sphingomyelin, egg phosphatidylcholine, dicetyl phospholipid, dimyristoyl lecithin, distearoyl phosphatidylethanolamine, polyethylene glycol distearoyl phosphatidylethanolamine and methoxy polyethylene glycol distearoyl phosphatidylethanolamine; the cholesterol lipid is one or more of cholesterol, cholesterol acetyl ester, cholesterol hemisuccinate, beta-sitosterol, cholesterol stearate, cholesterol palmitate, monomethyl polyethylene glycol-cholesterol, and folic acid ligand modified polyethylene glycol-cholesterol.
The doxofylline injection is a nano injection with a water-in-oil-in-water structure, and the particle size of the doxofylline liposome is small and is not more than 30 nm; the doxofylline is prepared into a liposome form and combined with the action of a guiding agent, so that the doxofylline can be rapidly deposited in a targeted manner in the lung and is more easily absorbed by the cell walls of bronchial cells and alveolar cells, and the doxofylline not only has very good stability during storage, but also has the effects of taking effect more quickly and having better curative effect.
Preferably, the raw materials comprise 3 wt% of doxofylline liposome, 1.2 wt% of surfactant, 2.5 wt% of guiding agent and the balance of deionized water.
Preferably, in the preparation method of the doxofylline liposome, the weight ratio of the doxofylline micro powder to the phospholipids to the cholesterol lipid is 1 (3-6.5) to (1.8-2.5).
More preferably, in the preparation method of the doxofylline liposome, the weight ratio of the doxofylline micropowder, the phospholipid and the cholesterol lipid is 1:6: 2.
Preferably, the guiding agent is mannitol and/or glucose.
More preferably, the guiding agent consists of mannitol and glucose in a weight ratio of 2 (0.5-1).
Preferably, the surfactant is at least one of tween series, sucrose fatty acid ester, polyoxyethylene monooleate, polyoxyethylene hydrogenated castor oil and polyoxyethylene alkyl ether.
The invention also provides a preparation method of the doxofylline injection preparation, which comprises the steps of uniformly stirring and mixing the surfactant, the guiding agent and the deionized water, then adding the nadolol liposome, and uniformly stirring to prepare a finished injection product.
Compared with the prior art, the invention has the advantages that: in the doxofylline injection preparation, the particle size of the doxofylline liposome is small, and the doxofylline liposome can be rapidly deposited in a targeting manner in the lung after injection and is more easily absorbed by the cell walls of bronchial cells and alveolar cells, so that the doxofylline injection preparation has better stability and curative effect.
Detailed Description
The technical solutions of the present invention will be described clearly and completely below, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The phospholipids used in the following examples and comparative examples are lecithin and the cholesterol lipids are cholesterol. Tween-80 is selected as surfactant, and mannitol and/or D-glucose is selected as guiding agent according to different embodiments.
Example 1
The doxofylline injection preparation prepared in the embodiment comprises 3 wt% of doxofylline liposome, 1.2 wt% of surfactant, 2.5 wt% of guiding agent and the balance of deionized water. The guiding agent consists of mannitol and glucose in a weight ratio of 2: 1.
The doxofylline liposome is prepared by dissolving doxofylline micropowder with particle size of 10-15nm in water, and treating for 1min with ultrasonic treatment parameter of about 80W; adding phospholipid and cholesterol lipid, performing ultrasonic treatment again with ultrasonic treatment parameter of 80W for 2.5min, and vacuum freeze drying to obtain doxofylline liposome. The weight ratio of the doxofylline micro powder to the phospholipid to the cholesterol lipid is 1:6: 2.
The doxofylline injection is prepared by mixing surfactant, guiding agent, and deionized water, adding nadolol liposome, and stirring to obtain injection.
Example 2
The doxofylline injection preparation prepared in this example comprises raw materials of doxofylline liposome 1.5 wt%, surfactant 0.5 wt%, guiding agent 1 wt%, and the balance of deionized water.
Example 3
The doxofylline injection preparation prepared in this example was prepared from doxofylline liposome, surfactant, guiding agent and deionized water in the same amount as in example 1.
In the raw materials of the doxofylline liposome, the weight ratio of the doxofylline micro powder to the phospholipid to the cholesterol lipid is 1:3: 2.5.
Example 4
The doxofylline injection preparation prepared in this example was prepared from doxofylline liposome, surfactant, guiding agent and deionized water in the same amount as in example 1.
In the raw materials of the doxofylline liposome, the weight ratio of the doxofylline micro powder to the phospholipid to the cholesterol lipid is 1:6.5: 1.8.
Example 5
The doxofylline injection preparation prepared in this example was prepared from doxofylline liposome, surfactant, guiding agent and deionized water in the same amount as in example 1, except that mannitol was used as the guiding agent. The starting materials and preparation methods of doxofylline liposome were the same as in example 1.
Example 6
The doxofylline injection preparation prepared in this example was prepared from doxofylline liposome, surfactant, guiding agent and deionized water in the same amount as in example 1, except that D-glucose was used as the guiding agent. The starting materials and preparation methods of doxofylline liposome were the same as in example 1.
Example 7
The doxofylline injection preparation prepared in this example was prepared from doxofylline liposome, surfactant, guiding agent and deionized water in the same amount as in example 1, except that the guiding agent was composed of mannitol and glucose in a weight ratio of 2: 0.5. The starting materials and preparation methods of doxofylline liposome were the same as in example 1.
Comparative example 1
The doxofylline injection preparation prepared by the comparative example comprises 1.5 wt% of doxofylline liposome, 1.5 wt% of surfactant, 3 wt% of guiding agent and the balance of deionized water. The starting materials and preparation methods of doxofylline liposome were the same as in example 1.
Comparative example 2
The doxofylline injection preparation prepared by the comparative example comprises 3.2 wt% of doxofylline liposome, 0.5 wt% of surfactant, 1 wt% of guiding agent and the balance of deionized water. The starting materials and preparation methods of doxofylline liposome were the same as in example 1.
Comparative example 3
The raw materials of the doxofylline injection preparation prepared by the comparative example are the same as those of the example 1, but the raw material of the doxofylline liposome only contains doxofylline micro powder and phospholipid, and the weight ratio of the doxofylline micro powder to the phospholipid is 1: 8; the preparation method comprises dissolving doxofylline micropowder with particle size of 10-15nm in water, and performing ultrasonic treatment with ultrasonic treatment parameter of 8W for 1 min; adding phospholipid, performing ultrasonic treatment again with ultrasonic treatment parameter of 80W for 2.5min, and vacuum freeze drying to obtain doxofylline liposome.
Comparative example 4
The raw materials of the doxofylline injection preparation prepared by the comparative example are the same as those of example 1, but the raw material of the doxofylline liposome only contains doxofylline micro powder and cholesterol lipid, and the weight ratio of the doxofylline micro powder to the cholesterol lipid is 1: 8; the preparation method comprises dissolving doxofylline micropowder with particle size of 10-15nm in water, and performing ultrasonic treatment with ultrasonic treatment parameter of 8W for 1 min; adding cholesterol lipid, performing ultrasonic treatment again with ultrasonic treatment parameter of 80W for 2.5min, and vacuum freeze drying to obtain doxofylline liposome. Application example 1: evaluation of stability of doxofylline injection preparation (refer to the method mentioned in the specification of Chinese granted patent CN 101474155)
1. Sensory evaluation: for the doxofylline injection formulations prepared in examples 1-7 and comparative examples 1-4 above, 3 batches of samples were continuously taken and observed to be colorless clear transparent liquid;
2. particle size distribution: according to the clinical requirement, after diluting 100 times with 5% (weight fraction) glucose aqueous solution, the liposome particle size was measured by using a laser particle size meter, and it was found that the mean particle size of the liposomes in the doxofylline injection preparations of examples 1-7 was 25. + -.5 nm, and the mean particle size of the liposomes in the doxofylline injection preparations of comparative examples 1-4 was varied from 20 to 50 nm.
3. Evaluation of stability
(1) Influence factor test: the doxofylline injection preparations prepared in the examples 1-7 and the comparative examples 1-4 are examined for 5d and 10d under the conditions of high temperature (60 ℃), strong light (4500 +/-500 lx) and high humidity (RH 75 +/-5%) for 3 batches of samples to be tested in the examples and the comparative examples, and the content of the doxofylline drug is examined, so that all indexes meet the requirements.
(2) And (3) accelerated test: the product is packaged on the market in a simulated way, and is examined for 6 months under the conditions of high temperature of 25 ℃ and RH being 75% +/-5%, and the quality is stable.
(3) And (3) long-term test: the packaging on the market is simulated, the vacuum condition of 4-8 ℃ is planned to be examined for 12 months, more than 7 months are examined at present, and the quality is stable.
Application example 2: evaluation of drug biodistribution in lungs in doxofylline injection formulation (refer to the method mentioned in the specification of Chinese granted patent CN 101474155)
1. Animal(s) production
The animals used in this study were 110 healthy white rabbits (female halves), weighing 2.00kg + -0.05 kg, and animals were allowed free access to food and water before testing. After the experiment, the rabbits were all injected until death.
2. Procedure of the test
(1) 30 rabbits were randomly divided into 6 groups of 5, 1-6 groups.
Groups 1-5, the doxofylline injection formulation of example 1 was administered intravenously from the rabbit ear margin at a dose of 1mg doxofylline per kg body weight; the 6 groups were not dosed, as blank plasma and tissue. Sacrifice 0.25, 1.5, 4, 8h after group 1-4 administration; after 5 groups of administration, blood is collected from the marginal vein of the ear for 0.083, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours, and the patients are sacrificed immediately after blood collection;
centrifuging the collected blood sample at 5000rpm for 5min, and separating plasma; the sacrificed rabbits were harvested from heart, liver, spleen, lung, kidney, stomach and brain tissues, blotted to dry the surface water of the tissues, weighed accurately, and then homogenized with 2ml of physiological saline per 1 g.
(2) The test treatments were carried out in the same manner as in the above step (1) for the doxofylline injection formulations prepared in examples 5 to 7 and comparative examples 3 and 4, respectively.
(3) Taking blank plasma and heart, liver, spleen, lung, kidney, stomach and brain homogenate samples respectively, precisely adding different amounts of doxofylline stock solutions, preparing to obtain the final concentration of 0.05ug/ml-102.4ug/ml, and preparing a standard curve. Taking 1ml of plasma or tissue, adding 50ul (50ug/ml) of doxofylline internal standard methanol solution, adding 2.5ml of mixed solution, vortexing for 6min, performing water bath ultrasonic treatment at 40 ℃ for 10min, then centrifuging at 10000rpm for 8min, transferring the solution into a test tube, diluting with water by about 4 times, slowly adding the diluted solution into a C18 column (previously activated by 2ml of methanol and 2ml of 0.01M ammonium acetate buffer solution), sequentially washing with 2ml of 0.01M ammonium acetate buffer solution, 2ml of methanol and 0.01M ammonium acetate buffer solution in a volume ratio of 1:9, 2ml of 2:8 methanol and 0.01M ammonium acetate buffer solution in a volume ratio, and performing vacuum drying; finally eluting doxofylline with 2ml of acetonitrile-methanol mixed solution with the volume ratio of 1:1, volatilizing nitrogen at 40 ℃ to remove organic solvent, redissolving with 0.2ml of mobile phase, centrifuging at 10000rpm for 8min, and taking 25ul of supernatant for HPLC determination.
3. Results
After the determination, the groups corresponding to examples 1, 5-7 and comparative examples 3 and 4 show that the in vivo drug concentration distribution of doxofylline injection is highest in lung after 0.25h after administration, then in turn in kidney, liver, and finally in spleen, stomach, heart and brain, wherein the lung drug concentration of example 1 at 0.25h is 348.23 mug/g, and the concentration is continuously increased in the first 4h until the highest concentration is 579.95 mug/g; subsequently, the lung drug concentration gradually decreased and the spleen, kidney and liver drug concentration gradually increased until 24h, indicating that rapid deposition of doxofylline mainly in the lung was achieved within the first 4 h.
However, the pulmonary drug concentrations of examples 5-7 at 0.25h were the same highest in the organs, but did not exceed 280 μ g/g, and were not much different from the concentration values of the second high-concentration organs; the lung drug concentrations of comparative examples 3 and 4 were the same and highest in the organs, but the concentrations were lower at 117.39 μ g/g and 142.63 μ g/g, respectively. This suggests that changes in the composition and amount of the targeting agent may affect targeted deposition of doxofylline in the lung, and changes in the composition of phospholipids and cholesterol may affect absorption of doxofylline in various organs.
Claims (8)
1. A doxofylline injection is characterized in that the raw materials comprise 1.5-3.2 wt% of doxofylline liposome, 0.5-1.5 wt% of surfactant, 1-3 wt% of guiding agent and the balance of deionized water;
the preparation method of the doxofylline liposome comprises the steps of dissolving doxofylline micro powder with the particle size of 10-15nm in water for ultrasonic treatment, wherein the ultrasonic treatment parameter is 40-80W for 0.5-1 min; adding phospholipid and cholesterol lipid, performing ultrasonic treatment again with ultrasonic treatment parameter of 60-100W for 1-2.5min, and vacuum freeze drying to obtain doxofylline liposome.
2. The doxofylline injection formulation of claim 1, wherein the starting materials comprise doxofylline liposome 3 wt%, surfactant 1.2 wt%, guiding agent 2.5 wt%, and the balance deionized water.
3. The doxofylline injection formulation of claim 1 or 2, wherein the weight ratio of doxofylline micropowder, phospholipids, and cholesterol lipids in the preparation method of doxofylline liposomes is 1 (3-6.5) to (1.8-2.5).
4. The doxofylline injection formulation of claim 3, wherein the weight ratio of doxofylline micropowder, phospholipids, and cholesterol lipids in the preparation method of doxofylline liposomes is 1:6: 2.
5. The doxofylline injectable formulation of claim 1, wherein the guiding agent is mannitol and/or glucose.
6. The doxofylline injectable formulation of claim 5, wherein the guiding agent consists of mannitol and glucose in a weight ratio of 2 (0.5-1).
7. The doxofylline injection formulation of claim 1, wherein said surfactant is at least one of tween series, sucrose fatty acid ester, polyoxyethylene monooleate, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether.
8. A preparation method of the doxofylline injection preparation according to claim 1, wherein the surfactant, the guiding agent and the deionized water are stirred and mixed uniformly, and then the nadolol liposome is added and stirred uniformly to prepare the finished injection preparation.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040045546A1 (en) * | 2002-09-05 | 2004-03-11 | Peirce Management, Llc | Pharmaceutical delivery system for oral inhalation through nebulization consisting of inert substrate impregnated with substance (S) to be solubilized or suspended prior to use |
| CN1864684A (en) * | 2005-05-20 | 2006-11-22 | 姜昱 | Lyophilized powder injection of doxofylline and preparation method thereof |
| CN111840235A (en) * | 2020-08-06 | 2020-10-30 | 武汉人福药业有限责任公司 | Doxofylline injection and preparation method thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040045546A1 (en) * | 2002-09-05 | 2004-03-11 | Peirce Management, Llc | Pharmaceutical delivery system for oral inhalation through nebulization consisting of inert substrate impregnated with substance (S) to be solubilized or suspended prior to use |
| CN1864684A (en) * | 2005-05-20 | 2006-11-22 | 姜昱 | Lyophilized powder injection of doxofylline and preparation method thereof |
| CN111840235A (en) * | 2020-08-06 | 2020-10-30 | 武汉人福药业有限责任公司 | Doxofylline injection and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 吴正红等: "《药剂学》", 30 April 2020 * |
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