CN116407500A - Diclofenac fat emulsion, preparation method and application thereof - Google Patents
Diclofenac fat emulsion, preparation method and application thereof Download PDFInfo
- Publication number
- CN116407500A CN116407500A CN202210775209.XA CN202210775209A CN116407500A CN 116407500 A CN116407500 A CN 116407500A CN 202210775209 A CN202210775209 A CN 202210775209A CN 116407500 A CN116407500 A CN 116407500A
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- CN
- China
- Prior art keywords
- fat emulsion
- soybean oil
- water
- diclofenac
- injection
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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Abstract
The invention provides a diclofenac fat emulsion, a preparation method and application thereof. The diclofenac fat emulsion comprises an oil phase and a water phase, wherein the oil phase consists of 0.7-1.4 g/L of diclofenac, 100-300 g/L of soybean oil, 10-15 g/L of egg yolk lecithin and 0.1-1 g/L of oleic acid; the water phase consists of 0.1-5g/L of metal chelating agent, 18-24 g/L of glycerol and the balance of water for injection; the g/L is the ratio of the mass of each component to the total volume of the fat emulsion; the fat emulsion is oil-in-water type. The diclofenac fat emulsion improves the stability of diclofenac, reduces the irritation of intravenous injection, can carry out terminal high-pressure sterilization, has small particle size and high distribution uniformity, and has certain targeting function.
Description
Technical Field
The invention provides a diclofenac fat emulsion, a preparation method and application thereof.
Background
Diclofenac (Diclofenac) has the chemical structure shown in the formula (I), and is 2- (2, 6-dichlorophenylamino) phenylacetic acid, belongs to phenylacetic acid non-steroidal anti-inflammatory drugs, has strong anti-rheumatism, anti-inflammatory, analgesic and antipyretic effects, and is commonly used for acute or chronic rheumatoid arthritis, osteoarthritis, trauma, postoperative inflammatory pain and the like. The main mechanism of action of diclofenac is to inhibit the activity of cyclooxygenase, thereby blocking the conversion of arachidonic acid to prostaglandins. Meanwhile, the combination of arachidonic acid and triglyceride can be promoted, the concentration of intracellular free arachidonic acid can be reduced, and the synthesis of leukotriene can be indirectly inhibited, so that the purposes of easing pain and diminishing inflammation can be achieved.
The common administration routes of diclofenac and its salts include oral administration, transdermal administration, ophthalmic external application, rectal administration, injection administration, etc., and the dosage forms already on the market include tablets, capsules, gels, eye drops and injections. Patients with advanced cancer and patients after surgery often experience breakthrough pain, in breakthrough pain treatment, diclofenac and salts thereof are often used as non-steroidal anti-inflammatory drugs in combination with opioid drugs, the analgesic effect can be obviously improved under the condition of not increasing the dosage and side effects of the opioid drugs, but the oral administration has low bioavailability, slower onset time and short duration time, can cause serious gastrointestinal reaction, the breakthrough pain analgesic effect is not obvious, and the injection can rapidly and continuously take effect so as to overcome the defects, but the solubility of the diclofenac and the salts thereof in water is lower, the structure contains groups which are easy to oxidize, the stability of the prepared injection is reduced, and the problems of precipitation, color change, content reduction and the like generally occur. 75mg/3mL of diclofenac sodium injection (the commercial name is Voltarol) is developed by NOVARTIS company in Europe, the administration mode is intramuscular injection or intravenous injection, the main indications are fever and relieving acute light and moderate pain, the preparation is added with higher content of propylene glycol and benzyl alcohol in order to increase the solubility of the diclofenac sodium in water, but the preparation has stronger irritation to blood vessels, the pain of patients is strong when the preparation is administrated, sodium bicarbonate buffer solution must be used for dilution and drip infusion is needed for reducing the incidence rate of phlebitis before intravenous injection; 75mg/2mL of diclofenac sodium cyclodextrin inclusion injection (trade name Dyroject) is developed by Javelin company in the United kingdom, the administration mode is intramuscular injection or intravenous injection, the clinic is mainly intramuscular injection, the main indication is fever and relieving acute light and moderate pain, the preparation uses hydroxypropyl-beta-cyclodextrin to include diclofenac sodium and adds antioxidant thioglycerol to increase the solubility and stability of diclofenac sodium, but the preparation totally recalls and pauses sales due to the fact that some batches find unknown white particles, the stability of the injection is poor for long-term placement of the cyclodextrin aqueous solution on the diclofenac sodium inclusion, and meanwhile, the literature reports show that the hydroxypropyl-beta-cyclodextrin has renal toxicity, bone loss and the like (Liu Yan, cheng Xiaoxiang and the like. Compared with the toxicity of the hydroxypropyl-beta-cyclodextrin administered by abdominal cavity and vein of rats, compared with the experiment research [ J ]. Modern medicine and clinic, 2009,24 (6): -364), so the diclofenac injection containing the hydroxypropyl-beta-cyclodextrin still has a certain potential safety hazard 361. Meanwhile, the diclofenac sodium injection can not be subjected to terminal sterilization, so that the residual probability of microorganisms is high, and the potential safety hazard is high. 2mL/50mg diclofenac sodium injection is mainly marketed in China, and the prescription mainly follows the company NOVARTIS and Javelin, is added with a large amount of propylene glycol or is solubilized by using hydroxypropyl-beta-cyclodextrin, and can only be intramuscular injected. Therefore, there is no related art for diclofenac injection which solves the above-mentioned stability and irritation problems and can be administered mainly by intravenous injection.
Disclosure of Invention
In order to solve the problems of low stability and certain irritation of the diclofenac preparation in the prior art, the invention provides the diclofenac fat emulsion, the preparation method and the application thereof, and the fat emulsion improves the stability of the diclofenac, reduces the irritation of intravenous injection, can perform terminal high-pressure sterilization, has small particle size and high distribution uniformity, and has certain targeting effect.
The invention provides a fat emulsion, which consists of an oil phase and a water phase, wherein the oil phase consists of 0.7-1.4 g/L of diclofenac, 100-300 g/L of soybean oil, 10-15 g/L of egg yolk lecithin and 0.1-1 g/L of oleic acid; the water phase consists of 0.1-5g/L of metal chelating agent, 18-24 g/L of glycerol and the balance of water for injection; the g/L is the ratio of the mass of each component to the total volume of the fat emulsion;
the fat emulsion is oil-in-water type.
The balance of water for injection is: the diclofenac, the soybean oil, the egg yolk lecithin, the oleic acid, the metal chelating agent and the glycerol in the fat emulsion and the balance of the water for injection, so that the mass-volume ratio of the components is within the range of a prescription.
The volume of the fat emulsion may vary slightly with temperature, but the mass of each component in the fat emulsion is constant.
The pH of the fat emulsion may be in the range of 4.5 to 5.5, for example 4.8 to 5.0, and for example 4.81 to 4.93.
The particle size of the fat emulsion may be from 100 to 500nm, for example from 200 to 400nm.
The soybean oil may be used in an amount of 200g/L.
The soybean oil may be a pale yellow liquid. The relative density (d) 20 20 ) 0.9160 to 0.9220. The refractive index of the soybean oil (n=20℃) may be 1.4720 to 1.4760.
The dosage of the egg yolk lecithin can be 12g/L.
The content of phosphorus in the egg yolk lecithin can be 3.5-4.1%. The content of phosphatidylcholine in the egg yolk lecithin can be more than or equal to 68 percent. The content of phosphatidylethanolamine in the yolk lecithin is less than or equal to 20 percent. The sum of the phosphatidylcholine and the phosphatidylethanolamine can be more than or equal to 80 percent.
The oleic acid may be used in an amount of 0.5g/L.
The metal chelator may be used in an amount of 0.3g/L.
The metal chelator may be disodium edetate, disodium edentate hydrate, calcium sodium edentate or calcium sodium edentate hydrate, such as disodium edentate.
The glycerol may be used in an amount of 22g/L.
The water for injection may be used in an amount of 775 to 794g/L, for example 780g/L.
The fat emulsion is preferably a fat emulsion injection.
The fat emulsion may be a fat emulsion for treating pain caused by inflammation, neuralgia, cancer pain, post-traumatic pain and fever caused by inflammation.
The fat emulsion provided by the invention is preferably composed of the following components: 0.7-1.4 g/L diclofenac, 200g/L soybean oil, 12g/L egg yolk lecithin, 0.5g/L oleic acid, 0.3g/L metal chelating agent, 22g/L glycerol and 775-794 g/L water for injection.
In a preferred embodiment of the present invention, the fat emulsion preferably consists of: 0.7g/L diclofenac, 200g/L soybean oil, 12g/L egg yolk lecithin, 0.5g/L oleic acid, 0.3g/L edetate disodium, 22g/L glycerol and 780g/L water for injection.
In a preferred embodiment of the present invention, the fat emulsion preferably consists of: 1.4g/L diclofenac, 200g/L soybean oil, 12g/L egg yolk lecithin, 0.5g/L oleic acid, 0.3g/L edetate disodium, 22g/L glycerol and 780g/L water for injection.
The invention provides a fat emulsion, which comprises the following raw materials: 0.7-1.4 g/L of diclofenac, 100-300 g/L of soybean oil, 10-15 g/L of egg yolk lecithin, 0.1-1 g/L of oleic acid, 0.1-5g/L of metal chelating agent, 18-24 g/L of glycerol and the balance of water for injection; the g/L is the ratio of the mass of each component to the total volume of the fat emulsion.
The parameters of soybean oil, egg yolk lecithin, oleic acid, metal chelating agent, glycerol, water for injection, PH of the fat emulsion and particle size of the fat emulsion can be defined as described above.
The raw materials of the fat emulsion provided by the invention preferably comprise the following components: 0.7-1.4 g/L diclofenac, 200g/L soybean oil, 12g/L egg yolk lecithin, 0.5g/L oleic acid, 0.3g/L metal chelating agent, 22g/L glycerol and 775-794 g/L water for injection.
In a preferred embodiment of the present invention, the raw materials of the fat emulsion preferably consist of the following components: 0.7g/L diclofenac, 200g/L soybean oil, 120g/L egg yolk lecithin, 0.5g/L oleic acid, 0.3g/L edetate disodium, 22g/L glycerol and 780g/L water for injection.
In a preferred embodiment of the present invention, the raw materials of the fat emulsion preferably consist of the following components: 1.4g/L diclofenac, 200g/L soybean oil, 12g/L egg yolk lecithin, 0.5g/L oleic acid, 0.3g/L edetate disodium, 22g/L glycerol and 780g/L water for injection.
The invention also provides a preparation method of the fat emulsion, which comprises the following steps: adding the mixture A into the mixture B, shearing, homogenizing, pretreating, and hot-pressing for sterilization to obtain fat emulsion;
the mixture A consists of 0.7-1.4 g/L of dichlorophenol, 100-300 g/L of soybean oil, 10-15 g/L of egg yolk lecithin and 0.1-1 g/L of oleic acid; the mixture B consists of 18-24 g/L of glycerol, 0.1-5g/L of metal chelating agent and the balance of water for injection; the g/L is the ratio of the mass of each component to the total volume of the fat emulsion.
The balance of water for injection is: the diclofenac, the soybean oil, the egg yolk lecithin, the oleic acid, the metal chelating agent and the glycerol in the fat emulsion and the balance of the water for injection, so that the mass-volume ratio of the components is within the range of a prescription.
The pH of the fat emulsion prepared by the preparation method can be 4.5-5.5, such as 4.8-5.0, and also such as 4.81-4.93.
The particle size of the fat emulsion prepared by the preparation method can be 100-500 nm, such as 200-400 nm.
In the preparation method, the soybean oil can be used in an amount of 200g/L.
The soybean oil may be a pale yellow liquid. The relative density (d) 20 20 ) 0.9160 to 0.9220. The refractive index of the soybean oil (n=20℃) may be 1.4720 to 1.4760.
In the preparation method, the dosage of the egg yolk lecithin can be 12g/L.
The content of phosphorus in the egg yolk lecithin can be 3.5-4.1%. The content of phosphatidylcholine in the egg yolk lecithin can be more than or equal to 68 percent. The content of phosphatidylethanolamine in the yolk lecithin is less than or equal to 20 percent. The sum of the phosphatidylcholine and the phosphatidylethanolamine can be more than or equal to 80 percent.
In the preparation method, the dosage of the oleic acid can be 0.5g/L.
In the preparation method, the metal chelating agent can be used in an amount of 0.3g/L.
In the preparation method, the metal chelating agent may be disodium edetate, disodium edetate hydrate, calcium sodium edetate or calcium sodium edetate hydrate, such as disodium edetate.
In the preparation method, the glycerol can be used in an amount of 22g/L.
In the preparation method, the dosage of the water for injection can be 775-794 g/L, such as 780g/L.
In the preparation method, the mixture A can be subjected to constant-temperature water bath to 60-80 ℃ for standby, and the temperature is preferably 70 ℃.
In the preparation method, the mixture B can be used for standby at 60-80 ℃ in a constant-temperature water bath, and the temperature is preferably 70 ℃.
In the preparation method, the shearing can be performed while adding, the shearing speed is increased after the liquid adding is completed, and the shearing is continued for 5-15 minutes, for example, 10 minutes. The shear rate of the liquid adding and the shearing can be 6000rpm/min. The shear rate after the completion of the liquid addition may be 10000rpm/min.
In the preparation method, the homogenization pretreatment is preferably carried out by pretreating 1-2 times by a high-pressure homogenizer at 5000-10000psi pressure, and then improving the pressure of the homogenizer to 20000psi for 3 times or 15000psi for 5 times or 15000psi for 10 times.
In the preparation method, the hot press sterilization may further include the steps of: canning, introducing inert gas, and hot-pressing for sterilization. The inert gas is preferably nitrogen. The temperature of the autoclaving is preferably 115-121 ℃. The time for the autoclaving is preferably 15 to 30 minutes.
In the preparation method, the autoclaving is preferably autoclaving at 121 ℃ for 15 minutes or autoclaving at 115 ℃ for 30 minutes.
The preparation method can further comprise the following steps:
s1, taking 200g/L soybean oil, placing the soybean oil into a container, heating the soybean oil to 70 ℃ in a constant-temperature water bath, adding 12g/L egg yolk lecithin and 0.5g/L oleic acid, shearing the soybean oil at a high speed of 9000rpm/min until the soybean oil is completely dissolved, adding 0.7-1.4 g/L diclofenac, shearing the soybean oil at a high speed for 10min to obtain a clear solution, obtaining an oil phase solution, and preserving the heat for later use;
s2, taking 775-794 g/L of water for injection, placing the water into a container, adding 22g/L of glycerol and 0.3g/L of edetate disodium, stirring and mixing uniformly, and carrying out water bath at 70 ℃ for standby to obtain a water phase solution;
s3, adding the oil phase solution obtained in the step S1 into the water phase solution obtained in the step S2 at a constant speed, controlling the water bath temperature to be constant at 70 ℃, adding and shearing at a high speed, wherein the liquid adding shearing speed is 6000rpm/min, and after the liquid adding is finished, increasing the shearing speed to 10000rpm/min, and shearing for 10 minutes to obtain colostrum;
s4, pretreating the colostrum for 2 times by using a high-pressure homogenizer at 5000-10000psi, and then improving the pressure of the homogenizer to 10000-15000 psi for 10 times to obtain white emulsion;
s5, filling the white emulsion, introducing nitrogen, sealing, and performing hot press sterilization at 121 ℃ for 15 minutes or 115 ℃ for 30 minutes to obtain the white emulsion.
The invention also provides a fat emulsion which is prepared by the preparation method.
The fat emulsion may be a fat emulsion for treating pain caused by inflammation, neuralgia, cancer pain, post-traumatic pain and fever caused by inflammation.
The invention also provides the use of a fat emulsion as described above for the manufacture of a medicament for the treatment of a disease including pain caused by inflammation, neuralgia, cancer pain, post-traumatic pain and fever caused by inflammation.
The inflammation may be one or more of rheumatoid arthritis, osteoarthritis, adhesive spondylitis, or non-articular inflammation.
The above-mentioned preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, so as to obtain the preferred embodiments of the present invention.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that: the fat emulsion can be subjected to terminal hot-press sterilization, improves the stability of the medicine, has small particle size and uniform distribution, and has a certain targeting effect.
Drawings
FIG. 1 shows the results of a rabbit vascular irritation study. The left side is the test group study results, and the right side is the control group study results.
FIG. 2 shows a histopathological examination of the convalescence of the injection site of rabbit ears, wherein a and b are the tissue structures of the administration site of right ear (HE; X40 and X200, respectively) of the rabbits of the test group after 14 days of administration; c and d are tissue structures of the right ear administration site of the rabbits of the control group (HE; X40 and X200, respectively) after 14 days of administration; blue arrows indicate connective tissue arrangement porosity; black arrows indicate that small amounts of collagen fibril necrosis are visible to the dermis; grey arrows indicate small amounts of new capillaries; orange arrows indicate small amounts of vasodilation; red arrows indicate infiltration with a large number of lymphocytes.
FIG. 3 shows the results of hemolysis test.
Fig. 4 is a graph of drug concentration versus time for two diclofenac injections.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
The material information in the following examples is as follows:
wherein the soybean oil is a pale yellow transparent liquid, and the relative density (d 20 20 ) 0.9160 to 0.9220, and a refractive index (n=20℃) of 1.4720 to 1.4760; the content of phosphorus in the egg yolk lecithin is 3.5-4.1%, the phosphatidylcholine is more than or equal to 68%, the phosphatidylethanolamine is less than or equal to 20%, and the sum of the phosphatidylcholine and the phosphatidylethanolamine is more than or equal to 80%.
Example 1 bischlorophenate fat emulsion injection
The components and the amounts of the dichlorophenolic acid fat emulsion injection are shown in Table 1:
TABLE 1
The preparation method comprises the following steps:
s1, taking soybean oil with a prescription amount, placing the soybean oil into a proper container, heating the soybean oil to 70 ℃ in a constant-temperature water bath, adding yolk lecithin and oleic acid with corresponding prescription amounts, shearing the soybean oil at a high speed of 9000rpm/min until the soybean oil is completely dissolved, adding diclofenac with the prescription amounts, shearing the soybean oil at a high speed for 10min to obtain a clear solution, obtaining an oil phase solution, and preserving the heat for later use;
s2, additionally taking the prescription amount of water for injection, putting the water into a proper container, adding the corresponding prescription amount of glycerin and edetate disodium, stirring and mixing uniformly, and carrying out water bath at 70 ℃ for standby to obtain aqueous phase solution;
s3, adding the oil phase solution obtained in the step S1 into the water phase solution obtained in the step S2 at a constant speed, controlling the water bath temperature to be 70 ℃, shearing at a high speed while adding, wherein the liquid adding shearing speed is 6000rpm/min, and after the liquid adding is finished, increasing the shearing speed to 10000rpm/min, and shearing for 10 minutes to obtain the colostrum;
s4, pre-treating the colostrum for 2 times by a high-pressure homogenizer at 5000-10000psi, and then treating the colostrum for 10 times by 10000-15000 psi to obtain white uniform emulsion;
s5, filling the liquid, introducing nitrogen, sealing, and performing hot-press sterilization at 121 ℃ for 15 minutes to obtain the product.
Example 2 diclofenac fat emulsion injection
The components and the amounts of the dichlorophenolic acid fat emulsion injection are shown in Table 2:
TABLE 2
The preparation method comprises the following steps:
s1, taking soybean oil with a prescription amount, placing the soybean oil into a proper container, heating the soybean oil to 70 ℃ in a constant-temperature water bath, adding yolk lecithin and oleic acid with corresponding prescription amounts, shearing the soybean oil at a high speed of 9000rpm/min until the soybean oil is completely dissolved, adding diclofenac with the prescription amounts, shearing the soybean oil at a high speed for 10min to obtain a clear solution, obtaining an oil phase solution, and preserving the heat for later use;
s2, additionally taking the prescription amount of water for injection, putting the water into a proper container, adding the corresponding prescription amount of glycerin and edetate disodium, stirring and mixing uniformly, and carrying out water bath at 70 ℃ for standby to obtain aqueous phase solution;
s3, adding the oil phase solution obtained in the step S1 into the water phase solution obtained in the step S2 at a constant speed, controlling the water bath temperature to be 70 ℃, shearing at a high speed while adding, wherein the liquid adding shearing speed is 6000rpm/min, and after the liquid adding is finished, increasing the shearing speed to 10000rpm/min, and shearing for 10 minutes to obtain the colostrum;
s4, pre-treating the colostrum for 2 times by a high-pressure homogenizer with 5000-10000psi, and then treating the colostrum for 10 times by 10000-15000 psi to obtain white uniform emulsion;
s5, filling the liquid, introducing nitrogen, sealing, and performing hot-press sterilization at 121 ℃ for 15 minutes to obtain the product.
Comparative example 1: prescription optimization experiment
TABLE 3 Table 3
The preparation method comprises the following steps:
s1, taking soybean oil with a prescription amount, placing the soybean oil into a proper container, heating the soybean oil to 70 ℃ in a constant-temperature water bath, adding yolk lecithin and oleic acid (if any) with corresponding prescription amounts, shearing the soybean oil at a high speed of 9000rpm/min until the soybean oil is completely dissolved, adding diclofenac with the prescription amounts, shearing the soybean oil at a high speed for 10min to obtain a clear solution, obtaining an oil phase solution, and preserving heat for later use;
s2, additionally taking the prescription amount of water for injection, putting the water into a proper container, adding the corresponding prescription amount of glycerin and edetate disodium (if any), stirring and mixing uniformly, and carrying out water bath at 70 ℃ for standby to obtain aqueous phase solution;
s3, adding the oil phase solution obtained in the step S1 into the water phase solution obtained in the step S2 at a constant speed, controlling the water bath temperature to be 70 ℃, shearing at a high speed from side to side, increasing the shearing speed to 6000rpm/min after the liquid adding is completed, and shearing for 10 minutes to obtain primary emulsion, wherein the pH regulator is 0.1mol/L hydrochloric acid solution or 0.1mol/L sodium hydroxide solution in the comparative examples C-E, and the required pH regulator is selected according to the target pH;
s4, pre-treating the colostrum for 2 times by a high-pressure homogenizer with 5000-10000psi, and then treating the colostrum for 10 times by 10000-15000 psi to obtain white uniform emulsion;
s5, filling the liquid, introducing nitrogen, sealing, and performing hot-press sterilization at 121 ℃ for 15 minutes to obtain the product.
Examples 1 to 2, comparative examples A to E and commercially available water needle samples (trade name: voltarol, 3mL:75mg, lot number KR0163,) were autoclaved at 121℃for 15 minutes, and the results of the changes of the related substances before and after the measurement using the high performance liquid phase were as follows:
TABLE 4 Table 4
The experimental results show that after the auxiliary emulsifier oleic acid is added, the combination of the fat emulsion is more stable, and no oil drops are generated after sterilization; the related substances in the fat emulsion after autoclaving of diclofenac are lower after adding the metal chelating agent edetate disodium; the pH regulator is not added into the fat emulsion, the pH of the whole emulsion is 4.8-5.0, the stability of the fat emulsion is better, the diclofenac related substances are basically unchanged after hot press sterilization, the stability of the fat emulsion is reduced after the pH is increased or reduced, and the diclofenac related substances are increased after hot press sterilization; the commercial water needle sample has larger change of the related substances of the diclofenac after the heat press sterilization at 121 ℃, and the prescription has small change of the related substances of the diclofenac after the heat press sterilization at 121 ℃.
Experimental example 1 solubility of diclofenac in oil phase
To select the best oil phase while guaranteeing the physicochemical properties of the fat emulsion, the following oil phase was tested for the solubility of diclofenac.
Taking 10g of different oil phases, heating to 60 ℃, preserving heat, adding excessive diclofenac into the oil phases, continuously stirring and preserving heat for 24 hours, filtering by using a 0.45 mu m microporous filter membrane, diluting filtrate to a proper concentration by using methanol, measuring the concentration of the diclofenac by using a high performance liquid phase meter by adopting an external standard method, and calculating to obtain the solubility of the diclofenac in different oil phases as shown in the following table 5:
TABLE 5 solubility of diclofenac in different oil phases
| Oil phase | Solubility% (w/w) |
| Soybean oil | 2.55 |
| Peanut oil | 1.93 |
| Corn oil | 1.75 |
| Cottonseed oil | 1.41 |
| Sunflower seed oil | 1.25 |
| Olive oil | 1.12 |
| Coconut oil | 1.48 |
| Sesame oil | 1.54 |
| Flax oil | 1.18 |
| Medium chain triglycerides | 2.16 |
The results show that the solubility of diclofenac in soybean oil is maximum, and the solubility in the above oil phases is far greater than the concentration of diclofenac dissolved in the oil phase during the emulsion formulation.
Experimental example 2 stability test
Example 1, example 2 (after autoclaving at 121 ℃) and commercially available water needle samples (specification 3mL:75mg, lot number KR0163, trade name: voltarol) were left for 6 months at 30 ℃ + -2℃with a relative humidity of 65% + -5%, and were sampled once for 0,1,3,6 months, and the properties, pH, particle size, content, and stability of the relevant substances were examined, and the results are shown in Table 6:
table 6 stability data for self-made fat milk samples and commercial water needle samples
The results show that the preparation has better stability when the preparation is placed for 6 months under the acceleration condition of 30+/-2 ℃ and 65+/-5% relative humidity in the examples 1 and 2 without great changes in the properties, pH, particle size and content of related substances.
TABLE 7 particle size test results for month 0 of example 1
The average volume particle diameter of example 1 was tested to be 0.378 μm and the peak particle diameter was tested to be 0.346 μm.
Experimental example 3 vascular irritation experiment
1. Purpose of experiment
The vascular irritation effect of diclofenac fat emulsion and commercial water needle samples on rabbit ears was compared.
2. Experimental method
8 rabbits were selected and randomly divided into 2 groups of 4 rabbits (male and female half). One group is a control group and one group is a test group. Both groups used autologous control on the left and right sides of the same body, i.e. the right auricle was given intravenous test drug, and the left auricle was given an equal volume of saline at the same rate as the negative control. Wherein, the commercial water needle sample (trade name: voltarol, specification: 75mg/3mL, which was prepared into a solution of 1.4mg/mL with physiological saline and 0.4% sodium bicarbonate solution at the time of use; administration volume: 10 mL/kg) was intravenously administered to the right ear margin of the control group, and the diclofenac fat emulsion injection of example 2 of the present invention (specification: 70mg/50mL, which was directly used without dilution; administration volume: 10 mL/kg) was intravenously administered to the right ear margin of the test group. Instillation was performed at an infusion rate of 15mL/h, each infusion time period of 0.5h, 1 infusion per day for 2 consecutive days.
Clinical observation: the animals were visually observed 24h, 48h, 72h and 96h before and after each administration and the presence or absence of symptoms such as edema, congestion, erythema, denaturation, necrosis, etc. at the site of administration and the general state, behavior signs were recorded. Recovery phase observations were made 14 days after the last dose, and the sites of administration of rabbits were observed once a day, and a irritation score was made (the scoring criteria are shown in table 8).
TABLE 8 vascular stimulation response scoring criteria
Histopathological examination: after the end of the observation period of the last administration (namely 96h after the last administration) and the end of the recovery period (14 d after the last administration), 2 animals (1 female and 1 male) are respectively taken from the two groups, after the animals are euthanized, 0.5cm sections of blood vessels are taken from the needle insertion point every 1.5cm each ear, 3 sections of blood vessels are taken together with surrounding tissues together, the fixing solution is used for fixing, pathological sections are prepared, and histopathological examination is carried out to observe inflammatory cell infiltration and inflammatory reaction.
3. Experimental results
Results of two groups of clinical observations and recovery after dosing are shown (fig. 1, fig. 2, table 9, table 10):
(1) No erythema or swelling was seen at the intravenous injection site at the rabbit ear edge of the test group. Histopathological examination shows that the left and right ear tissue epidermis layers of the rabbits have complete structures, the squamous epithelial cells have normal morphological structures and are closely arranged, the dermis layer has rich collagen fiber content, and the accessory organs such as the pilosebaceous glands and the like can be seen without obvious inflammation.
(2) The intravenous injection site of the ear margin of the rabbit of the control group is engorged with blood and changed in a branch shape. Histopathological examination shows that the dermis of the right ear tissue of the rabbit of the control group is severely edematous, the connective tissue is loose in arrangement, small collagen fibers of the dermis are necrotic, acidophilic homogeneous substances are formed, bleeding is caused, more connective tissue is proliferated, and the tissue is scattered in lymphocyte infiltration, so that more vasodilation is visible.
TABLE 9 left ear vascular irritation response score recording Table for rabbit vascular irritation test
TABLE 10 record of the vascular irritation response score of the right ear for the vascular irritation test of rabbits
Remarks: the left ear was injected with 0.9% sodium chloride injection and the right ear was injected with the fat emulsion of the present invention or a commercially available water needle sample. The important point is to observe that the administration needle point is about 1 cm to 3.5cm toward the auricle.
4. Conclusion of the experiment
Compared with a commercial water needle sample, the diclofenac fat emulsion injection provided by the invention has no vascular irritation and is more suitable for intravenous injection administration.
Experimental example 4 hemolysis experiment
1. The purpose of the experiment is as follows:
the in vitro hemolytic properties of diclofenac fat emulsions and commercial water needle samples were compared.
2. Experimental method
Preparation of 2% erythrocyte suspension: 1 healthy rabbit (weight 2-3 kg) was selected, blood was collected by ear vein for 10mL, placed in a triangular flask with glass beads, and shaken in the same direction for 10min to remove fibrinogen, or the blood was stirred with a glass rod. The defibrinated blood was transferred to a centrifuge tube containing 10 volumes of saline. Centrifuging at 2500r/min for 5min after mixing, and discarding supernatant. Repeatedly washing the precipitated red blood cells with normal saline for 3-4 times until the supernatant is colorless and transparent. The washed red blood cells were prepared into a 2% cell suspension with physiological saline for use.
Test article: diclofenac fat emulsion injection (70 mg/50 mL) of example 2 of the invention
Control: 1 commercial water needle sample (trade name: voltarol, specification: 75mg/3 mL) was taken, 50mL of physiological saline and 0.5mL of 0.4% sodium bicarbonate solution were added to prepare a 1.4mg/mL solution for use.
The test method comprises the following steps: the test is divided into a test sample group (1.4 mg/mL), a control group (1.4 mg/mL), a negative control group (0.9% sodium chloride injection) and a positive control group (distilled water) 4 groups. In each preparation test, 12 clean test tubes are respectively taken, and the test tubes are numbered 1-12, the test sample tubes are numbered 1-5, the reference sample tubes are numbered 6-10, the negative reference tube is numbered 11, and the positive reference tube is numbered 12. According to Table 11, each test tube was sequentially added with 2% erythrocyte suspension, 0.9% sodium chloride injection or distilled water, and test object, and after mixing, immediately placed in 37 ℃ constant humidity cabinet for warm bath and observation respectively, 1 time every 15min for 1 hour, 1 time every 1 hour after 1 hour, and continuous observation for 3 hours. The hemolysis and erythrocyte aggregation of each tube were visually observed, and if necessary, microscopic examination was performed.
TABLE 11 sample addition Table for hemolysis test
3. Experimental results
Except for the No. 12 positive control tube, no hemolysis reaction was observed in the other test tubes for 0.5-3 hours, the upper layer was colorless clear or milky liquid, the red blood cells were deposited on the lower layer (FIG. 3), and the red blood cells were uniformly dispersed after slight shaking.
4. Conclusion of the experiment
The diclofenac fat emulsion injection with the concentration of 70mg/50mL has no hemolysis risk and can be used for intravenous injection.
Experimental example 5 in vivo pharmacokinetic experiments
1. Purpose of experiment
Comparing the pharmacokinetic behavior of diclofenac fat emulsion and commercial water needle sample in healthy beagle dogs by intravenous injection.
2. Experimental method
2 healthy male beagle dogs (9-12 kg) are selected, and after being adaptively fed for 5-7 days, the male beagle dogs are randomly divided into a tested preparation group (T) and a reference preparation group (R), wherein each group comprises 1 animal. Wherein, the diclofenac fat emulsion injection in the example 2 is intravenously administered in the T group, and the commercial water needle sample is intravenously administered in the R group. The methods and dosages of each group are shown in Table 9. The drug was administered by subcutaneous arm head intravenous drip on the inner side of the left forelimb of the dog using a constant speed pump, the intravenous drip time was 0.5h, and the speed was 100mL/h (about 25 drops/min). Two cycles of administration were interleaved at RT/TR with 1 day of each cycle of washout period. 1mL of blood is taken through the subcutaneous brachiocephalic vein at the inner side of the right forelimb of the dog within 1h (0 h) before administration and 2min, 5min, 10min, 15min, 30min, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 8h, 10h and 24h after administration is started respectively. Immediately after blood collection, the blood collection tube was gently and completely inverted 3 times and mixed with the anticoagulant (avoiding severe shaking), centrifuged at 3500rpm for 10min, and plasma was separated. The concentration of diclofenac in the plasma was measured by HPLC-MS/MS. Analyzing diclofenac blood concentration data by Phoenix Winnlin 7.0 software, and calculating by adopting a non-atrioventricular model methodPharmacokinetic parameters (t) 1/2 、t max 、Cmax、AUC 0-t 、AUC 0-∞ CL, vd) as a blood concentration-time curve.
Preparation of reference preparation R: 1 bottle of a commercially available water injection preparation (trade name: voltarol, specification: 75mg/3 mL) was diluted with 46.6mL of physiological saline, and 0.4mL of sodium hydrogencarbonate solution (4.2%) was added thereto to prepare a 75mg/50mL solution for use.
3. Experimental results
Drug concentrations of beagle dogs at different blood sampling points are shown in table 12, pharmacokinetic parameters are shown in table 13, and drug concentration-time curves are shown in fig. 4. The pharmacokinetic parameters of the two formulations are substantially similar, but the absorption of the diclofenac fat emulsion injection according to the invention is slightly higher than that of the reference formulation.
TABLE 12 blood concentration data (ng/mL) of diclofenac in EDTA-K2 anticoagulated plasma after injection of diclofenac in beagle dogs
TABLE 13 pharmacokinetic parameters
4. Conclusion of the experiment
The two preparations have similar pharmacokinetics in vivo, so that the diclofenac fat emulsion injection has the same analgesic effect compared with a commercial water injection sample.
Comparative example 2 high drug loading experiment
In the development process, an attempt was made to increase the concentration of diclofenac to 23.5g/L, the formulation shown in the following table, the process was prepared according to example 1, and the emulsion produced had a phenomenon of white powder adhesion on both the inner wall and the bottom of the container, which was found to be undissolved diclofenac after detection. This result indicates that the concentration of diclofenac in this formulation exceeded the maximum drug loading of the formulation.
Comparative example 3 lactation after esterification of diclofenac
The preparation of diclofenac and diclofenac DMDO esters by esterifying diclofenac to increase its solubility in soybean oil was carried out according to the procedure of example 1, wherein the concentrations of diclofenac acetoxyethyl and diclofenac DMDO esters are calculated in equal proportions according to the concentration of diclofenac acid as indicated in the following table. The final result shows that the diclofenac acetoxy ethyl ester has better milk forming property, but the degradation degree reaches 25% after sterilization; the DMDO ester of diclofenac behaves like diclofenac in an emulsion and is not completely soluble at this concentration. From the above phenomena and results, diclofenac is more likely to develop into an emulsion than diclofenac esters.
Claims (13)
1. The fat emulsion is characterized by comprising an oil phase and a water phase, wherein the oil phase comprises 0.7-1.4 g/L of diclofenac, 100-300 g/L of soybean oil, 10-15 g/L of egg yolk lecithin and 0.1-1 g/L of oleic acid; the water phase consists of 0.1-5g/L of metal chelating agent, 18-24 g/L of glycerol and the balance of water for injection; the g/L is the ratio of the mass of each component to the total volume of the fat emulsion;
the fat emulsion is oil-in-water type.
2. The fat emulsion of claim 1, wherein the fat emulsion satisfies one or more of the following conditions:
(1) The pH of the fat emulsion is from 4.5 to 5.5, for example from 4.8 to 5.0, for example from 4.81 to 4.93;
(2) The particle size of the fat emulsion is 100-500 nm, such as 200-400 nm;
(3) The dosage of the soybean oil is 200g/L;
(4) The soybean oil is light yellow liquid; the relative density of the soybean oil can be 0.9160-0.9220; the refractive index of the soybean oil can be 1.4720-1.4760;
(5) The dosage of the egg yolk lecithin is 12g/L;
(6) The content of phosphorus in the egg yolk lecithin is 3.5-4.1%; the content of phosphatidylcholine in the egg yolk lecithin can be more than or equal to 68%; the content of phosphatidylethanolamine in the egg yolk lecithin is less than or equal to 20 percent; the sum of the phosphatidylcholine and the phosphatidylethanolamine can be more than or equal to 80 percent;
(7) The dosage of the oleic acid is 0.5g/L;
(8) The dosage of the metal chelating agent is 0.3g/L;
(9) The metal chelating agent is disodium edentate, disodium edentate hydrate, calcium sodium edentate or calcium sodium edentate hydrate;
(10) The dosage of the glycerol is 22g/L;
(11) The dosage of the water for injection is 775-794 g/L, for example 780g/L;
(12) The fat emulsion is fat emulsion injection;
(13) The fat emulsion is used for treating pain caused by inflammation, neuralgia, cancer pain, post-traumatic pain and fever caused by inflammation.
3. The fat emulsion of claim 1, wherein the fat emulsion consists of: 0.7-1.4 g/L diclofenac, 200g/L soybean oil, 12g/L egg yolk lecithin, 0.5g/L oleic acid, 0.3g/L metal chelating agent, 22g/L glycerol and 775-794 g/L water for injection.
4. A fat emulsion according to claim 3, wherein the fat emulsion consists of: 0.7g/L diclofenac, 200g/L soybean oil, 12g/L egg yolk lecithin, 0.5g/L oleic acid, 0.3g/L disodium edentate, 22g/L glycerol and 780g/L water for injection;
or, the fat emulsion is composed of the following components: 1.4g/L diclofenac, 200g/L soybean oil, 12g/L egg yolk lecithin, 0.5g/L oleic acid, 0.3g/L edetate disodium, 22g/L glycerol and 780g/L water for injection.
5. The fat emulsion is characterized by comprising the following raw materials: 0.7-1.4 g/L of diclofenac, 100-300 g/L of soybean oil, 10-15 g/L of egg yolk lecithin, 0.1-1 g/L of oleic acid, 0.1-5g/L of metal chelating agent, 18-24 g/L of glycerol and the balance of water for injection; the g/L is the ratio of the mass of each component to the total volume of the fat emulsion;
the parameters of soybean oil, egg yolk lecithin, oleic acid, metal chelating agent, glycerol, water for injection, PH of the fat emulsion and particle size of the fat emulsion are defined in claim 1 or 2.
6. The fat emulsion according to claim 5, wherein the fat emulsion comprises the following components: 0.7-1.4 g/L diclofenac, 200g/L soybean oil, 12g/L egg yolk lecithin, 0.5g/L oleic acid, 0.3g/L metal chelating agent, 22g/L glycerol and 775-794 g/L water for injection.
7. The fat emulsion according to claim 6, wherein the fat emulsion comprises the following components: 0.7g/L diclofenac, 200g/L soybean oil, 12g/L egg yolk lecithin, 0.5g/L oleic acid, 0.3g/L disodium edentate, 22g/L glycerol and 780g/L water for injection;
or, the raw materials of the fat emulsion comprise the following components: 1.4g/L diclofenac, 200g/L soybean oil, 12g/L egg yolk lecithin, 0.5g/L oleic acid, 0.3g/L edetate disodium, 22g/L glycerol and 780g/L water for injection.
8. A method for preparing a fat emulsion, comprising the steps of: adding the mixture A into the mixture B, shearing, homogenizing, pretreating, and hot-pressing for sterilization to obtain fat emulsion;
the mixture A consists of 0.7-1.4 g/L of dichlorophenol, 100-300 g/L of soybean oil, 10-15 g/L of egg yolk lecithin and 0.1-1 g/L of oleic acid; the mixture B consists of 18-24 g/L of glycerol, 0.1-5g/L of metal chelating agent and the balance of water for injection; the g/L is the ratio of the mass of each component to the total volume of the fat emulsion.
9. The method of preparation of claim 8, wherein the method of preparation satisfies one or more of the following conditions:
(1) The pH of the fat emulsion prepared by the preparation method is 4.5-5.5, such as 4.8-5.0, and such as 4.81-4.93;
(2) The particle size of the fat emulsion prepared by the preparation method is 100-500 nm, such as 200-400 nm;
(3) The dosage of the soybean oil is 200g/L;
(4) The soybean oil is light yellow liquid; the relative density of the soybean oil can be 0.9160-0.9220; the refractive index of the soybean oil can be 1.4720-1.4760;
(5) The dosage of the egg yolk lecithin is 12g/L;
(6) The content of phosphorus in the egg yolk lecithin is 3.5-4.1%; the content of phosphatidylcholine in the egg yolk lecithin can be more than or equal to 68%; the content of phosphatidylethanolamine in the egg yolk lecithin is less than or equal to 20 percent; the sum of the phosphatidylcholine and the phosphatidylethanolamine can be more than or equal to 80 percent;
(7) The dosage of the oleic acid is 0.5g/L;
(8) The dosage of the metal chelating agent is 0.3g/L;
(9) The metal chelator is disodium edetate, disodium edentate hydrate, calcium sodium edentate or calcium sodium edentate hydrate, such as disodium edentate;
(10) The dosage of the glycerol is 22g/L;
(11) The dosage of the water for injection is 775-794 g/L, for example 780g/L;
(12) The mixture A is subjected to constant temperature water bath to 60-80 ℃ for standby, preferably 70 ℃;
(13) The mixture B is subjected to constant temperature water bath to 60-80 ℃ for standby, preferably 70 ℃;
(14) The shearing is to add and shear at the same time, the shearing speed is increased after the liquid adding is completed, and the shearing is continued for 5 to 15 minutes, for example, 10 minutes; the shearing speed of the shearing while adding can be 6000rpm/min; the shearing speed after the liquid adding is finished can be 10000rpm/min;
(15) The homogenizing pretreatment is to pretreat 1-2 times by using a high-pressure homogenizer at 5000-10000psi pressure, and then to increase the pressure of the homogenizer to 20000psi for 3 times, or to treat 5 times of 15000psi or 10 times of 15000 psi;
(16) The hot press sterilization further comprises the following steps: canning, introducing inert gas, and performing hot press sterilization; the inert gas is preferably nitrogen; the temperature of the hot press sterilization is preferably 115-121 ℃; the time for the autoclaving is preferably 15 to 30 minutes.
10. The method of preparing as claimed in claim 8, comprising the steps of:
s1, taking 200g/L soybean oil, placing the soybean oil into a container, heating the soybean oil to 70 ℃ in a constant-temperature water bath, adding 12g/L egg yolk lecithin and 0.5g/L oleic acid, shearing the soybean oil at a high speed of 9000rpm/min until the soybean oil is completely dissolved, adding 0.7-1.4 g/L diclofenac, shearing the soybean oil at a high speed for 10min to obtain a clear solution, obtaining an oil phase solution, and preserving the heat for later use;
s2, taking 775-794 g/L of water for injection, placing the water into a container, adding 22g/L of glycerol and 0.3g/L of edetate disodium, stirring and mixing uniformly, and carrying out water bath at 70 ℃ for standby to obtain a water phase solution;
s3, adding the oil phase solution obtained in the step S1 into the water phase solution obtained in the step S2 at a constant speed, controlling the water bath temperature to be constant at 70 ℃, adding and shearing at a high speed, wherein the liquid adding shearing speed is 6000rpm/min, and after the liquid adding is finished, increasing the shearing speed to 10000rpm/min, and shearing for 10 minutes to obtain colostrum;
s4, pretreating the colostrum for 2 times by using a high-pressure homogenizer at 5000-10000psi, wherein the homogenizing pretreatment is to pretreat the colostrum for 1-2 times by using the high-pressure homogenizer at 5000-10000psi, and then to treat the colostrum for 10 times by increasing the pressure of the homogenizer to 10000-15000 psi, so as to obtain white emulsion;
s5, filling the white emulsion, introducing nitrogen, sealing, and performing hot press sterilization at 121 ℃ for 15 minutes or 115 ℃ for 30 minutes to obtain the white emulsion.
11. A fat emulsion prepared by the preparation method according to any one of claims 8 to 10.
12. The fat emulsion of claim 11, wherein the fat emulsion is a fat emulsion for use in the treatment of pain caused by inflammation, neuralgia, cancer pain, post-traumatic pain and fever caused by inflammation.
13. Use of a fat emulsion as claimed in any one of claims 1 to 7 and 11 in the manufacture of a medicament for the treatment of a disease including pain caused by inflammation, neuralgia, cancer pain, post-traumatic pain and fever caused by inflammation; the inflammation may be one or more of rheumatoid arthritis, osteoarthritis, adhesive spondylitis, and non-articular inflammation.
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