CN114259461B - Diclofenac sodium gel and preparation method thereof - Google Patents
Diclofenac sodium gel and preparation method thereof Download PDFInfo
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- CN114259461B CN114259461B CN202111431585.9A CN202111431585A CN114259461B CN 114259461 B CN114259461 B CN 114259461B CN 202111431585 A CN202111431585 A CN 202111431585A CN 114259461 B CN114259461 B CN 114259461B
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Abstract
The invention provides diclofenac sodium gel and a preparation method thereof, wherein each kilogram of raw materials comprises the following components in parts by weight: 10g of diclofenac sodium, 8-12g of carbomer homopolymer, 60-110g of propylene glycol, 30-60g of isopropanol, 0.8-1.2g of edetate disodium, 3-5g of sodium hydroxide and the balance of purified water, wherein the carbomer homopolymer consists of carbomer homopolymer A type 971P NF and carbomer homopolymer C type 980 NF. The invention takes diclofenac sodium as a main medicine, takes the combination of carbomer homopolymer A type 971P NF and carbomer homopolymer C type 980NF as a matrix, propylene glycol as a cosolvent, isopropanol as a permeation promoter, edetate disodium as a complexing agent, sodium hydroxide as a pH regulator, purified water as a solvent, and the scientific proportioning is carried out, so that the prepared diclofenac sodium gel obviously reduces the swelling degree of the foot and the plantar of rats, obviously reduces the TNF-alpha activity of rats, and simultaneously obviously reduces PGE 2 Effectively improves the drug effect and reduces inflammatory reaction.
Description
Technical Field
The invention relates to the field of diclofenac sodium preparations, in particular to a diclofenac sodium gel and a preparation method thereof.
Background
The diclofenac sodium gel is mainly used for relieving light to moderate pains of muscles, soft tissues and joints, such as pains caused by sprains, strains, contusions, strains and injuries of the back and the waist, joint pains and the like of the muscles, the soft tissues, and can also be used for symptomatic treatment of osteoarthritis. The product is prostaglandin synthesis inhibitor, and has antiinflammatory and analgesic effects. The effective components of the composition can penetrate the skin to reach the inflammatory region, relieve acute and chronic inflammatory reactions, and relieve inflammatory swelling and pain. The pharmaceutical excipients are basic materials and important components of the pharmaceutical preparation, and play a key role in preparation formulation and production. It not only gives the medicine a certain dosage form, but also improves the curative effect of the medicine and has great relationship in reducing toxic and side effects. The drug effect of the existing diclofenac sodium gel needs to be further improved.
Disclosure of Invention
In view of the above, the invention provides a diclofenac sodium gel and a preparation method thereof.
The technical scheme of the invention is realized as follows: the diclofenac sodium gel comprises the following components in parts by weight per kilogram of raw materials: 10g of sodium clofenate, 8-12g of carbomer homopolymer, 60-110g of propylene glycol, 30-60g of isopropanol, 0.8-1.2g of edetate disodium, 3-5g of sodium hydroxide and the balance of purified water, wherein the carbomer homopolymer consists of carbomer homopolymer A type 971P NF and carbomer homopolymer C type 980 NF.
Further, each kilogram of raw materials comprises the following components in parts by weight: 10g of diclofenac sodium, 10g of carbomer homopolymer, 100g of propylene glycol, 50g of isopropanol, 1g of edetate disodium, 4g of sodium hydroxide and the balance of purified water, wherein the carbomer homopolymer consists of equal mass carbomer homopolymer A type 971P NF and carbomer homopolymer C type 980 NF.
Further, each kilogram of raw materials comprises the following components in parts by weight: 10g of diclofenac sodium, 10g of carbomer homopolymer, 60g of propylene glycol, 50g of isopropanol, 1g of edetate disodium, 4g of sodium hydroxide and the balance of purified water, wherein the carbomer homopolymer consists of the following components in mass ratio of 3:7 carbomer homopolymer type a 971P NF and carbomer homopolymer type C980 NF.
Further, the preparation method of the diclofenac sodium gel comprises the following steps:
(1) Preparation of mixture I: adding purified water with the prescription amount of 45-55% into a clean water phase tank, heating to 40-50 ℃ by steam, adding edetate disodium with the prescription amount under stirring, stirring for 3-5 minutes to dissolve, adding carbomer homopolymer with the prescription amount under stirring, stirring for 3-4 hours to suspend, soaking and swelling for 12-14 hours to prepare a mixture I for later use;
(2) Preparation of mixture II: adding purified water with the prescription amount of 8-12% into a stainless steel barrel, adding sodium hydroxide with the prescription amount under stirring, stirring for 3-5 min to dissolve to obtain sodium hydroxide solution, and collecting mixture II with volume recorded as V 0 Standby;
(3) Preparation of mixture III:
adding prescribed amount of isopropyl alcohol and propylene glycol into a clean stainless steel barrel, stirring for 6-8 minutes, uniformly mixing, adding prescribed amount of diclofenac sodium in a stirring state, and stirring for 7-10 minutes, uniformly mixing to obtain a raw material mixed solution;
adding 36-40% of purified water into an oil phase tank, adding raw material mixed solution in a stirring state, leaching a stainless steel barrel by using the residual purified water with the prescription amount, adding leaching water into the oil phase tank, and continuing stirring for 22-25 minutes until the diclofenac sodium is completely dissolved to obtain a mixture III for later use;
(4) Gel preparation: selecting an emulsifying tank, opening vacuum, connecting a feeding pipeline when the vacuum degree in the emulsifying tank reaches-0.08 to-0.10 Mpa, opening a discharging valve of a water phase tank, opening the feeding valve, adding the mixture I into the emulsifying tank, stirring for the first time for 30-40 minutes until carbomer homopolymer is uniformly dispersed,
adjusting the pH value to 6.0-6.5 by using a mixture II, wherein the using amount of the mixture II is recorded as V 1 ；
Finally, adding the mixture III into an emulsifying tank, and after the addition, leaching the oil phase tank by using purified water, wherein the amount of the purified water is the total amount V of the mixture II 0 And the actual amount V of the mixture II 1 Adding the leaching water into the emulsifying tank, stirring for the second time, and stirring for 30-40 minutes; the target diclofenac sodium gel is prepared.
Further preferably, the preparation method of the diclofenac sodium gel comprises the following steps:
(1) Preparation of mixture I: adding purified water with the prescription amount of 50% into a clean water phase tank, heating to 40-50 ℃ by steam, adding edetate disodium with the prescription amount under stirring, stirring for 3 minutes to completely dissolve, continuing stirring, adding carbomer homopolymer with the prescription amount, stirring for 3 hours to suspend, soaking and swelling for 12 hours to prepare a mixture I for later use;
(2) Preparation of mixture II: adding purified water with a prescription amount of 10% into a stainless steel barrel, adding sodium hydroxide with a prescription amount under stirring, stirring for 3 min to dissolve to obtain sodium hydroxide solution to obtain a mixture II with volume recorded as V 0 Standby;
(3) Preparation of mixture III:
adding prescribed amount of isopropyl alcohol and propylene glycol into a clean stainless steel barrel, stirring for 6 minutes to uniformly mix, adding prescribed amount of diclofenac sodium in a stirring state, and stirring for 7 minutes to uniformly mix to obtain a raw material mixed solution;
adding purified water with the prescription amount of 38% into an oil phase tank, adding a raw material mixed solution in a stirring state, leaching a stainless steel barrel of the raw material mixed solution twice by using purified water with the prescription amount of 2%, finally adding leaching water into the oil phase tank, and continuously stirring for 22 minutes until the diclofenac sodium is completely dissolved to obtain a mixture III for later use;
(4) Gel preparation: selecting an emulsifying tank, opening vacuum, connecting a feeding pipeline when the vacuum degree in the emulsifying tank reaches-0.09 Mpa, opening a discharging valve of a water phase tank, opening the feeding valve, adding the mixture I into the emulsifying tank, stirring for the first time, setting slow stirring at 35Hz, emulsifying and stirring at 25Hz, stirring for 30 minutes until carbomer homopolymer is uniformly dispersed,
adjusting the pH value to 6.0-6.5 by using a mixture II, wherein the using amount of the mixture II is recorded as V 1 ；
Finally, adding the mixture III into an emulsifying tank, and after the addition, leaching the oil phase tank by using purified water, wherein the amount of the purified water is the total amount V of the mixture II 0 And the actual amount V of the mixture II 1 Adding the leaching water into the emulsifying tank, stirring for the second time, wherein the slow stirring speed is set to be 35Hz, the emulsifying stirring speed is set to be 25Hz, and the stirring time is set to be 30 minutes; the target diclofenac sodium gel is prepared.
Further, each kilogram of raw materials also comprises the following components in parts by weight: 1.3-1.5g of alpha, beta-trehalose and 0.2-0.4g of calcium alginate.
Further, each kilogram of raw materials comprises the following components in parts by weight: 10g of diclofenac sodium, 1.4g of alpha, beta-trehalose, 0.3g of calcium alginate, 10g of carbomer homopolymer, 60g of propylene glycol, 50g of isopropanol, 1g of edetate disodium, 4g of sodium hydroxide and the balance of purified water.
Further, the preparation method of the diclofenac sodium gel comprises the following steps:
(1) Preparation of mixture I: adding purified water with the prescription amount of 45-55% into a clean water phase tank, heating to 40-50 ℃ by steam, adding disodium edentate with the prescription amount under stirring, stirring for 3-5 minutes to dissolve, adding carbomer homopolymer with the prescription amount under stirring, stirring for 3-4 hours to suspend, adding alpha, beta-trehalose and calcium alginate with the prescription amount, stirring, soaking and swelling for 12-14 hours to prepare a mixture I for later use;
(2) Preparation of mixture II: adding purified water with the prescription amount of 8-12% into a stainless steel barrel, adding sodium hydroxide with the prescription amount under stirring, stirring for 3-5 min to dissolve to obtain sodium hydroxide solution, and collecting mixture II with volume recorded as V 0 Standby;
(3) Preparation of mixture III:
adding prescribed amount of isopropyl alcohol and propylene glycol into a clean stainless steel barrel, stirring for 6-8 minutes, uniformly mixing, adding prescribed amount of diclofenac sodium in a stirring state, and stirring for 7-10 minutes, uniformly mixing to obtain a raw material mixed solution;
adding 36-40% of purified water into an oil phase tank, adding raw material mixed solution in a stirring state, leaching a stainless steel barrel by using the residual purified water with the prescription amount, adding leaching water into the oil phase tank, and continuing stirring for 22-25 minutes until the diclofenac sodium is completely dissolved to obtain a mixture III for later use;
(4) Gel preparation: selecting an emulsifying tank, opening vacuum, connecting a feeding pipeline when the vacuum degree in the emulsifying tank reaches-0.08 to-0.10 Mpa, opening a discharging valve of a water phase tank, opening the feeding valve, adding the mixture I into the emulsifying tank, stirring for the first time for 30-40 minutes until carbomer homopolymer is uniformly dispersed,
adjusting the pH value to 6.0-6.5 by using a mixture II, wherein the using amount of the mixture II is recorded as V 1 ；
Finally, adding the mixture III into an emulsifying tank, and after the addition, leaching the oil phase tank once by using purified water, wherein the amount of the purified water is the total amount V of the mixture II 0 And the actual amount V of the mixture II 1 Adding the leaching water into the emulsifying tank, stirring for the second time, and stirring for 30-40 minutes; the target diclofenac sodium gel is prepared.
Still more preferably, the preparation method of the diclofenac sodium gel comprises the following steps:
(1) Preparation of mixture I: adding purified water with the prescription amount of 50% into a clean water phase tank, heating to 40-50 ℃ by steam, adding disodium edentate with the prescription amount under stirring, stirring for 3 minutes to completely dissolve the disodium edentate, continuing stirring, adding carbomer homopolymer with the prescription amount, stirring for 3 hours to suspend the carbomer homopolymer with the prescription amount, adding alpha, beta-trehalose and calcium alginate with the prescription amount, stirring, soaking and swelling for 12 hours to prepare a mixture I for later use;
(2) Preparation of mixture II: adding purified water with a prescription amount of 10% into a stainless steel barrel, adding sodium hydroxide with a prescription amount under stirring, stirring for 3 min to dissolve to obtain sodium hydroxide solution to obtain a mixture II with volume recorded as V 0 Standby;
(3) Preparation of mixture III:
adding prescribed amount of isopropyl alcohol and propylene glycol into a clean stainless steel barrel, stirring for 6 minutes to uniformly mix, adding prescribed amount of diclofenac sodium in a stirring state, and stirring for 7 minutes to uniformly mix to obtain a raw material mixed solution;
adding purified water with the prescription amount of 38% into an oil phase tank, adding a raw material mixed solution in a stirring state, leaching a stainless steel barrel of the raw material mixed solution twice by using purified water with the prescription amount of 2%, finally adding leaching water into the oil phase tank, and continuously stirring for 22 minutes until the diclofenac sodium is completely dissolved to obtain a mixture III for later use;
(4) Gel preparation: selecting an emulsifying tank, opening vacuum, connecting a feeding pipeline when the vacuum degree in the emulsifying tank reaches minus 0.09Mpa, opening a discharging valve of a water phase tank, opening the feeding valve, adding the mixture I into the emulsifying tank, stirring for the first time for 30 minutes, setting slow stirring at 35Hz and emulsifying stirring at 25Hz, regulating the pH value to 6.0-6.5 by using the mixture II after the carbomer homopolymer is uniformly dispersed, wherein the using amount of the mixture II is recorded as V 1 ；
Finally, adding the mixture III into an emulsifying tank, and after the addition, leaching the oil phase tank once by using purified water, wherein the amount of the purified water is the total amount V of the mixture II 0 And the actual amount V of the mixture II 1 Adding the leaching water into the emulsifying tank, stirring for the second time, wherein the slow stirring speed is set to be 35Hz, the emulsifying stirring speed is set to be 25Hz, and the stirring time is set to be 30 minutes; the target diclofenac sodium gel is prepared.
Further, the stirring time is 5 to 10 minutes.
Compared with the prior art, the invention has the beneficial effects that:
the invention takes diclofenac sodium as a main medicine, takes the combination of carbomer homopolymer A type 971P NF and carbomer homopolymer C type 980NF as a matrix, propylene glycol as a cosolvent, isopropanol as a permeation promoter, edetate disodium as a complexing agent, sodium hydroxide as a pH regulator, purified water as a solvent, and the scientific proportioning is carried out, so that the prepared diclofenac sodium gel obviously reduces the swelling degree of the foot and the plantar of rats, obviously reduces the TNF-alpha activity of rats, and simultaneously obviously reduces PGE 2 Effectively improveThe medicine effect is that the inflammatory reaction is reduced. The invention adopts a certain proportion of carbomer homopolymer A type 971P NF and carbomer homopolymer C type 980NF to form, which is favorable for releasing sodium diclofenac, improves the drug effect of the sodium diclofenac and can reduce the dosage of propylene glycol. In addition, the invention adds alpha, beta-trehalose and calcium alginate to effectively promote the absorption of diclofenac sodium, improve the drug effect and reduce the dosage of isopropanol.
Detailed Description
In order to better understand the technical content of the present invention, the following provides specific examples to further illustrate the present invention.
The experimental methods used in the embodiment of the invention are conventional methods unless otherwise specified.
Materials, reagents, and the like used in the examples of the present invention are commercially available unless otherwise specified.
Example 1
The diclofenac sodium gel comprises the following components in parts by weight per kilogram of raw materials: 10g of diclofenac sodium, 10g of carbomer homopolymer, 100g of propylene glycol, 50g of isopropanol, 1g of edetate disodium, 4g of sodium hydroxide and the balance of purified water, wherein the carbomer homopolymer consists of carbomer homopolymer A type 971P NF and carbomer homopolymer C type 980NF in equal mass ratio.
Example 2
The diclofenac sodium gel comprises the following components in parts by weight per kilogram of raw materials: 10g of diclofenac sodium, 8g of carbomer homopolymer, 110g of propylene glycol, 40g of isopropanol, 0.8g of edetate disodium, 3g of sodium hydroxide and the balance of purified water, wherein the carbomer homopolymer consists of carbomer homopolymer A type 971P NF and carbomer homopolymer C type 980NF in equal mass ratio.
Example 3
The diclofenac sodium gel comprises the following components in parts by weight per kilogram of raw materials: 10g of diclofenac sodium, 12g of carbomer homopolymer, 90g of propylene glycol, 60g of isopropanol, 1.2g of edetate disodium, 5g of sodium hydroxide and the balance of purified water, wherein the carbomer homopolymer consists of carbomer homopolymer A type 971P NF and carbomer homopolymer C type 980NF in equal mass ratio.
Examples 1-3 sodium diclofenac gel was prepared as follows:
(1) Preparation of mixture I: adding purified water with the prescription amount of 50% into a clean water phase tank, heating to 40-50 ℃ by steam, adding edetate disodium with the prescription amount under stirring, stirring for 3 minutes to completely dissolve, continuing stirring, adding carbomer homopolymer with the prescription amount, stirring for 3 hours to suspend, soaking and swelling for 12 hours to prepare a mixture I for later use;
(2) Preparation of mixture II: adding purified water with a prescription amount of 10% into a stainless steel barrel, adding sodium hydroxide with a prescription amount under stirring, stirring for 3 min to dissolve to obtain sodium hydroxide solution to obtain a mixture II with volume recorded as V 0 Standby;
(3) Preparation of mixture III:
adding prescribed amount of isopropyl alcohol and propylene glycol into a clean stainless steel barrel, stirring for 6 minutes to uniformly mix, adding prescribed amount of diclofenac sodium in a stirring state, and stirring for 7 minutes to uniformly mix to obtain a raw material mixed solution;
adding purified water with the prescription amount of 38% into an oil phase tank, adding a raw material mixed solution in a stirring state, leaching a stainless steel barrel of the raw material mixed solution twice by using purified water with the prescription amount of 2%, finally adding leaching water into the oil phase tank, and continuously stirring for 22 minutes until the diclofenac sodium is completely dissolved to obtain a mixture III for later use;
(4) Gel preparation: selecting an emulsifying tank, opening vacuum, connecting a feeding pipeline when the vacuum degree in the emulsifying tank reaches-0.09 Mpa, opening a discharging valve of a water phase tank, opening the feeding valve, adding the mixture I into the emulsifying tank, stirring for the first time, setting slow stirring at 35Hz, emulsifying and stirring at 25Hz, stirring for 30 minutes until carbomer homopolymer is uniformly dispersed,
adjusting the pH value to 6.0-6.5 by using a mixture II, wherein the using amount of the mixture II is recorded as V 1 ；
Finally, adding the mixture III into an emulsifying tank, and after the addition, leaching the oil phase tank by using purified water, wherein the amount of the purified water is the total amount V of the mixture II 0 And the actual amount V of the mixture II 1 Adding the leaching water into the emulsifying tank, stirring for the second time, wherein the slow stirring speed is set to be 35Hz, the emulsifying stirring speed is set to be 25Hz, and the stirring time is set to be 30 minutes; the target diclofenac sodium gel is prepared.
Example 4
The diclofenac sodium gel is prepared by mainly adopting the mass ratio of carbomer homopolymer and reducing the addition amount of propylene glycol as in the embodiment 1, wherein each kilogram of raw materials comprises the following components in parts by weight: 10g of diclofenac sodium, 10g of carbomer homopolymer, 60g of propylene glycol, 50g of isopropanol, 1g of edetate disodium, 4g of sodium hydroxide and the balance of purified water, wherein the carbomer homopolymer is prepared by the following components in percentage by mass: 7 carbomer homopolymer type a 971P NF and carbomer homopolymer type C980 NF.
Example 5
The diclofenac sodium gel is different from example 4 in that alpha, beta-trehalose and calcium alginate are added, and the addition amount of isopropanol is reduced. Each kilogram of raw materials comprises the following components in parts by weight: 10g of diclofenac sodium, 1.4g of alpha, beta-trehalose, 0.3g of calcium alginate, 10g of carbomer homopolymer, 60g of propylene glycol, 30g of isopropanol, 1g of edetate disodium, 4g of sodium hydroxide and the balance of purified water, wherein the carbomer homopolymer is prepared from the following components in percentage by mass: 7 carbomer homopolymer type a 971P NF and carbomer homopolymer type C980 NF.
The preparation method of the diclofenac sodium gel comprises the following steps:
(1) Preparation of mixture I: adding purified water with the prescription amount of 50% into a clean water phase tank, heating to 40-50 ℃ by steam, adding disodium edentate with the prescription amount under stirring, stirring for 3 minutes to completely dissolve the disodium edentate, continuing stirring, adding carbomer homopolymer with the prescription amount, stirring for 3 hours to suspend the carbomer homopolymer, adding alpha, beta-trehalose and calcium alginate with the prescription amount, stirring for 8 minutes, soaking and swelling for 12 hours to prepare a mixture I for later use;
(2) Preparation of mixture II: adding purified water with a prescription amount of 10% into a stainless steel barrel, adding sodium hydroxide with a prescription amount under stirring, stirring for 3 min to dissolve to obtain sodium hydroxide solution to obtain a mixture II with volume recorded as V 0 Standby;
(3) Preparation of mixture III:
adding prescribed amount of isopropyl alcohol and propylene glycol into a clean stainless steel barrel, stirring for 6 minutes to uniformly mix, adding prescribed amount of diclofenac sodium in a stirring state, and stirring for 7 minutes to uniformly mix to obtain a raw material mixed solution;
adding purified water with the prescription amount of 38% into an oil phase tank, adding a raw material mixed solution in a stirring state, leaching a stainless steel barrel of the raw material mixed solution twice by using purified water with the prescription amount of 2%, finally adding leaching water into the oil phase tank, and continuously stirring for 22 minutes until the diclofenac sodium is completely dissolved to obtain a mixture III for later use;
(4) Gel preparation: selecting an emulsifying tank, opening vacuum, connecting a feeding pipeline when the vacuum degree in the emulsifying tank reaches minus 0.09Mpa, opening a discharging valve of a water phase tank, opening the feeding valve, adding the mixture I into the emulsifying tank, stirring for the first time for 30 minutes, setting slow stirring at 35Hz and emulsifying stirring at 25Hz, regulating the pH value to 6.0-6.5 by using the mixture II after the carbomer homopolymer is uniformly dispersed, wherein the using amount of the mixture II is recorded as V 1 ；
Finally, adding the mixture III into an emulsifying tank, and after the addition, leaching the oil phase tank once by using purified water, wherein the amount of the purified water is the total amount V of the mixture II 0 And the actual amount V of the mixture II 1 Adding the leaching water into the emulsifying tank, stirring for the second time, wherein the slow stirring speed is set to be 35Hz, the emulsifying stirring speed is set to be 25Hz, and the stirring time is set to be 30 minutes; the target diclofenac sodium gel is prepared.
Comparative example 1
The diclofenac sodium gel, which is the same as that of the example 1, mainly comprises the following components in parts by weight per kilogram of raw materials: 10g of diclofenac sodium, 7g of carbomer homopolymer, 120g of propylene glycol, 65g of isopropanol, 1.0g of edetate disodium, 4g of sodium hydroxide and the balance of purified water, wherein the carbomer homopolymer consists of carbomer homopolymer A type 971P NF and carbomer homopolymer C type 980NF with equal mass.
Comparative example 2
The main difference between the diclofenac sodium gel and example 1 is that carbomer homopolymer a 971PNF and carbomer homopolymer C980 NF are replaced with carbomer 940. Each kilogram of raw materials comprises the following components in parts by weight: 10g of diclofenac sodium, 94010g of carbomer, 100g of propylene glycol, 50g of isopropanol, 1g of edetate disodium, 4g of sodium hydroxide and the balance of purified water.
1. Anti-arthritic rat test
The experimental method comprises the following steps: about 200g of SD rats were selected 90, randomly grouped, and 10 in each group, including model group, positive control group (Findi sodium diclofenac gel), test groups 1-5 (diclofenac sodium gel of examples 1-5), and 9 total groups. And (3) molding: a pathological model of adjuvant arthritis was established by intradermally injecting 0.1mL of Freund's complete adjuvant into the plantar portion of the right hind limb of the rat. On day 4 after molding, rats of positive control group and test group 1-5 were given a dose of 3.0mg/kg by intragastric administration 1 time per day for 21 days. The change in plantar circumference of the right hind limb immobilization site was measured before molding, before dosing, and 21 days after dosing, respectively. 5h after the last administration, aseptic operation under ether anesthesia, blood drawing from heart for 2mL, heparin anticoagulation, separation of plasma, storage at-20 ℃ and measurement of the TNF-alpha activity of the plasma. The inflammatory swollen feet were cut off 0.5cm above the left posterior ankle joint of each rat, weighed, peeled, sheared, soaked in 5mL of physiological saline for 1 hour, the paws were removed, the soaked solution was centrifuged, 0.1mL of the supernatant was sucked, 2mL of 0.5M potassium hydroxide-methanol solution was added, isomerized in a water bath at 50℃for 20 minutes, diluted to 20mL with methanol, and the optical density value was measured at a wavelength of 278 nm. PGE is expressed as a value of the absorbance density equivalent per gram of tissue 2 As an index for evaluating anti-inflammatory properties. The test results are shown in tables 1 to 2 below:
table 1 comparison of plantar circumference of right hind limb before and after dosing
Compared with the model group, P < 0.05, P < 0.01
TABLE 2 plasma TNF-alpha Activity and PGE in tissues 2 Comparison of results
| Group of | TNF-α(mg/ml) | PGE 2 (mg/g) |
| Model group | 1.56±0.24 | 4.59±0.22 |
| Positive control group | 1.47±0.26 | 3.45±0.19* |
| Example 1 | 1.13±0.12** | 3.21±0.18** |
| Example 2 | 1.15±0.14** | 3.27±0.17** |
| Example 3 | 1.19±0.13** | 3.29±0.16** |
| Example 4 | 0.95±0.11** | 3.15±0.15** |
| Example 5 | 0.76±0.14** | 2.95±0.12** |
| Comparative example 1 | 1.42±0.17** | 3.43±0.18* |
| Comparative example 2 | 1.35±0.16* | 3.41±0.15* |
Compared with the model group, P < 0.05, P < 0.01
From the above results, it can be seen that the diclofenac sodium gels prepared in examples 1-5 significantly reduced the extent of plantar swelling in rats, significantly reduced TNF- α activity in rats, and simultaneously significantly reduced PGE 2 。
The effect of the embodiment 4 is better than that of the embodiment 1, and the carbomer homopolymer A type 971PNF and the carbomer homopolymer C type 980NF are combined in a certain proportion, so that the effect of the diclofenac sodium is improved, and the dosage of propylene glycol can be reduced. Especially, the effect of the embodiment 5 is obviously better than that of the embodiment 1, and the addition of the alpha, beta-trehalose and calcium alginate effectively promotes the absorption of the diclofenac sodium, improves the drug effect and can reduce the dosage of isopropanol. In addition, comparison of example 1 with comparative example 1 shows that the invention adopts components in a certain proportion, and the anti-arthritis effect is obviously improved. Compared with comparative example 2, the invention consists of carbomer homopolymer A type 971P NF and carbomer homopolymer C type 980NF, is favorable for releasing diclofenac sodium and improves the drug effect.
2. Quality standard control
TABLE 3 test results
The above results indicate that the sodium diclofenac gel prepared in examples 1-5 meets the quality standard requirements.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.
Claims (9)
1. The diclofenac sodium gel is characterized by comprising the following components in parts by weight per kilogram of raw materials: 10g of diclofenac sodium, 8-12g of carbomer homopolymer, 60-110g of propylene glycol, 30-60g of isopropanol, 0.8-1.2g of edetate disodium, 3-5g of sodium hydroxide and the balance of purified water; the carbomer homopolymer consists of equal mass carbomer homopolymer A type 971P NF and carbomer homopolymer C type 980NF, or consists of the following components in mass ratio 3: carbomer homopolymer type a 971P NF of 7 and carbomer homopolymer type C980 NF.
2. The diclofenac sodium gel according to claim 1, wherein each kilogram of raw material comprises the following components in parts by weight: 10g of diclofenac sodium, 10g of carbomer homopolymer, 100g of propylene glycol, 50g of isopropanol, 1g of edetate disodium, 4g of sodium hydroxide and the balance of purified water, wherein the carbomer homopolymer consists of equal mass carbomer homopolymer A type 971P NF and carbomer homopolymer C type 980 NF.
3. The diclofenac sodium gel according to claim 1, wherein each kilogram of raw material comprises the following components in parts by weight: 10g of diclofenac sodium, 10g of carbomer homopolymer, 60g of propylene glycol, 50g of isopropanol, 1g of edetate disodium, 4g of sodium hydroxide and the balance of purified water, wherein the carbomer homopolymer consists of the following components in mass ratio of 3: carbomer homopolymer type a 971P NF of 7 and carbomer homopolymer type C980 NF.
4. A diclofenac sodium gel according to claim 1 or 3, characterized in that it further comprises the following components in parts by weight per kg of raw material: 1.3-1.5g of alpha, beta-trehalose and 0.2-0.4g of calcium alginate.
5. The diclofenac sodium gel according to claim 4, wherein each kilogram of raw material comprises the following components in parts by weight: 10g of diclofenac sodium, 1.4g of alpha, beta-trehalose, 0.3g of calcium alginate, 10g of carbomer homopolymer, 60g of propylene glycol, 50g of isopropanol, 1g of edetate disodium, 4g of sodium hydroxide and the balance of purified water.
6. The method for preparing diclofenac sodium gel according to claim 1, comprising the steps of:
(1) Preparation of mixture I: adding purified water with the prescription amount of 45-55% into a clean water phase tank, heating to 40-50 ℃ by steam, adding edetate disodium with the prescription amount under stirring, stirring for 3-5 minutes to dissolve, adding carbomer homopolymer with the prescription amount under stirring, stirring for 3-4 hours to suspend, and soaking and swelling for 12-14 hours to prepare a mixture I for later use;
(2) Preparation of mixture II: adding purified water with the prescription amount of 8-12% into a stainless steel barrel, adding sodium hydroxide with the prescription amount under stirring, stirring for 3-5 min to dissolve to obtain sodium hydroxide solution, and collecting mixture II with volume recorded as V 0 Standby;
(3) Preparation of mixture III:
adding prescribed amount of isopropyl alcohol and propylene glycol into a clean stainless steel barrel, stirring for 6-8 minutes, uniformly mixing, adding prescribed amount of diclofenac sodium in a stirring state, and stirring for 7-10 minutes, uniformly mixing to obtain a raw material mixed solution;
adding 36-40% of purified water into an oil phase tank, adding raw material mixed solution in a stirring state, leaching a stainless steel barrel by using the residual purified water with the prescription amount, adding leaching water into the oil phase tank, and continuing stirring for 22-25 minutes until the diclofenac sodium is completely dissolved to obtain a mixture III for later use;
(4) Gel preparation: selecting an emulsifying tank, opening vacuum, connecting a feeding pipeline when the vacuum degree in the emulsifying tank reaches-0.08 to-0.10 Mpa, opening a discharging valve of a water phase tank, opening the feeding valve, adding the mixture I into the emulsifying tank, stirring for the first time for 30-40 minutes until carbomer homopolymer is uniformly dispersed,
adjusting the pH value to 6.0-6.5 by using a mixture II, wherein the use amount of the mixture II is recorded as V 1 ；
Finally, adding the mixture III into an emulsifying tank, and after the addition, leaching the oil phase tank by using purified water, wherein the amount of the purified water is the total amount V of the mixture II 0 And the actual amount V of the mixture II 1 Adding the leaching water into the emulsifying tank, stirring for the second time, and stirring for 30-40 minutes; the target diclofenac sodium gel is prepared.
7. The method for preparing diclofenac sodium gel according to claim 6, comprising the steps of:
(1) Preparation of mixture I: adding purified water with the prescription amount of 50% into a clean water phase tank, heating to 40-50 ℃ by steam, adding edetate disodium with the prescription amount under stirring, stirring for 3 minutes to completely dissolve, continuing stirring, adding carbomer homopolymer with the prescription amount, stirring for 3 hours to suspend, soaking and swelling for 12 hours to prepare a mixture I for later use;
(2) Preparation of mixture II: adding purified water with a prescription amount of 10% into a stainless steel barrel, adding sodium hydroxide with a prescription amount under stirring, stirring for 3 min to dissolve to obtain sodium hydroxide solution to obtain a mixture II with volume recorded as V 0 Standby;
(3) Preparation of mixture III:
adding prescribed amount of isopropyl alcohol and propylene glycol into a clean stainless steel barrel, stirring for 6 minutes to uniformly mix, adding prescribed amount of diclofenac sodium in a stirring state, and stirring for 7 minutes to uniformly mix to obtain a raw material mixed solution;
adding purified water with the prescription amount of 38% into an oil phase tank, adding a raw material mixed solution in a stirring state, leaching a stainless steel barrel of the raw material mixed solution twice by using purified water with the prescription amount of 2%, finally adding leaching water into the oil phase tank, and continuously stirring for 22 minutes until the diclofenac sodium is completely dissolved to obtain a mixture III for later use;
(4) Gel preparation: selecting an emulsifying tank, opening vacuum, connecting a feeding pipeline when the vacuum degree in the emulsifying tank reaches-0.09 Mpa, opening a discharging valve of a water phase tank, opening the feeding valve, adding the mixture I into the emulsifying tank, stirring for the first time, setting slow stirring at 35Hz, emulsifying and stirring at 25Hz, stirring for 30 minutes until carbomer homopolymer is uniformly dispersed,
adjusting the pH value to 6.0-6.5 by using a mixture II, wherein the use amount of the mixture II is recorded as V 1 ；
Finally, adding the mixture III into an emulsifying tank, and after the addition, leaching the oil phase tank by using purified water, wherein the amount of the purified water is the total amount V of the mixture II 0 And the actual amount V of the mixture II 1 Adding the leaching water into the emulsifying tank, stirring for the second time, wherein the slow stirring speed is set to be 35Hz, the emulsifying stirring speed is set to be 25Hz, and the stirring time is set to be 30 minutes; the target diclofenac sodium gel is prepared.
8. A method for preparing a diclofenac sodium gel according to claim 4 or 5, comprising the steps of:
(1) Preparation of mixture I: adding purified water with the prescription amount of 45-55% into a clean water phase tank, heating to 40-50 ℃ by steam, adding disodium edentate with the prescription amount under stirring, stirring for 3-5 minutes to dissolve the disodium edentate, adding carbomer homopolymer with the prescription amount under stirring, stirring for 3-4 hours to suspend the carbomer homopolymer with the prescription amount, adding alpha, beta-trehalose and calcium alginate with the prescription amount, stirring, soaking and swelling for 12-14 hours to prepare a mixture I for later use;
(2) Preparation of mixture II: adding purified water with the prescription amount of 8-12% into a stainless steel barrel, adding sodium hydroxide with the prescription amount under stirring, stirring for 3-5 min to dissolve to obtain sodium hydroxide solution, and collecting mixture II with volume recorded as V 0 Standby;
(3) Preparation of mixture III:
adding prescribed amount of isopropyl alcohol and propylene glycol into a clean stainless steel barrel, stirring for 6-8 minutes, uniformly mixing, adding prescribed amount of diclofenac sodium in a stirring state, and stirring for 7-10 minutes, uniformly mixing to obtain a raw material mixed solution;
adding 36-40% of purified water into an oil phase tank, adding raw material mixed solution in a stirring state, leaching a stainless steel barrel by using the residual purified water with the prescription amount, adding leaching water into the oil phase tank, and continuing stirring for 22-25 minutes until the diclofenac sodium is completely dissolved to obtain a mixture III for later use;
(4) Gel preparation: selecting an emulsifying tank, opening vacuum, connecting a feeding pipeline when the vacuum degree in the emulsifying tank reaches-0.08 to-0.10 Mpa, opening a discharging valve of a water phase tank, opening the feeding valve, adding the mixture I into the emulsifying tank, stirring for the first time for 30-40 minutes until carbomer homopolymer is uniformly dispersed,
adjusting the pH value to 6.0-6.5 by using a mixture II, wherein the use amount of the mixture II is recorded as V 1 ；
Finally, adding the mixture III into an emulsifying tank, and after the addition, leaching the oil phase tank once by using purified water, wherein the amount of the purified water is the total amount V of the mixture II 0 And the actual amount V of the mixture II 1 Adding the leaching water into the emulsifying tank, stirring for the second time, and stirring for 30-40 minutes; the target diclofenac sodium gel is prepared.
9. The method for preparing diclofenac sodium gel according to claim 8, comprising the steps of:
(1) Preparation of mixture I: adding purified water with the prescription amount of 50% into a clean water phase tank, heating to 40-50 ℃ by steam, adding disodium edentate with the prescription amount under stirring, stirring for 3 minutes to completely dissolve the disodium edentate, continuing stirring, adding carbomer homopolymer with the prescription amount, stirring for 3 hours to suspend the carbomer homopolymer with the prescription amount, adding alpha, beta-trehalose and calcium alginate with the prescription amount, stirring, soaking and swelling for 12 hours to prepare a mixture I for later use;
(2) Preparation of mixture II: adding purified water with a prescription amount of 10% into a stainless steel barrel, adding sodium hydroxide with a prescription amount under stirring, and stirring for 3 min to dissolve to obtain sodium hydroxide solutionThe liquid, namely a mixture II, the volume of which is recorded as V 0 Standby;
(3) Preparation of mixture III:
adding prescribed amount of isopropyl alcohol and propylene glycol into a clean stainless steel barrel, stirring for 6 minutes to uniformly mix, adding prescribed amount of diclofenac sodium in a stirring state, and stirring for 7 minutes to uniformly mix to obtain a raw material mixed solution;
adding purified water with the prescription amount of 38% into an oil phase tank, adding a raw material mixed solution in a stirring state, leaching a stainless steel barrel of the raw material mixed solution twice by using purified water with the prescription amount of 2%, finally adding leaching water into the oil phase tank, and continuously stirring for 22 minutes until the diclofenac sodium is completely dissolved to obtain a mixture III for later use;
(4) Gel preparation: selecting an emulsifying tank, opening vacuum, connecting a feeding pipeline when the vacuum degree in the emulsifying tank reaches minus 0.09Mpa, opening a discharging valve of a water phase tank, opening the feeding valve, adding the mixture I into the emulsifying tank, stirring for the first time for 30 minutes, setting slow stirring at 35Hz and emulsifying stirring at 25Hz, regulating the pH value to 6.0-6.5 by using the mixture II after stirring until carbomer homopolymer is uniformly dispersed, wherein the using amount of the mixture II is recorded as V 1 ；
Finally, adding the mixture III into an emulsifying tank, and after the addition, leaching the oil phase tank once by using purified water, wherein the amount of the purified water is the total amount V of the mixture II 0 And the actual amount V of the mixture II 1 Adding the leaching water into the emulsifying tank, stirring for the second time, wherein the slow stirring speed is set to be 35Hz, the emulsifying stirring speed is set to be 25Hz, and the stirring time is set to be 30 minutes; the target diclofenac sodium gel is prepared.
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