CN114259461A - Diclofenac sodium gel and preparation method thereof - Google Patents
Diclofenac sodium gel and preparation method thereof Download PDFInfo
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Abstract
The invention provides a diclofenac sodium gel and a preparation method thereof, wherein each kilogram of raw materials comprises the following components in parts by weight: diclofenac sodium 10g and carbomer8-12g 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 diclofenac sodium gel prepared by using diclofenac sodium as a main drug, combining carbomer homopolymer A type 971P NF and carbomer homopolymer C type 980NF as a matrix, using propylene glycol as a cosolvent, using isopropanol as a penetration enhancer, using edetate disodium as a complexing agent, using sodium hydroxide as a pH regulator and using purified water as a solvent according to a scientific proportion obviously reduces the plantar swelling degree of rats, obviously reduces the TNF-alpha activity of the rats and obviously reduces PGE (PGE)2Effectively improve the drug effect and reduce the inflammatory reaction.
Description
Technical Field
The invention relates to the field of diclofenac sodium preparations, in particular to 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 relieving pains caused by sprain, strain, contusion, strain, waist and back injuries, joint pain and the like of the muscles and 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. When the Chinese medicinal composition is applied topically, the effective components of the Chinese medicinal composition can penetrate skin to reach inflammation area, relieve acute and chronic inflammation reaction, relieve inflammatory swelling and pain. The pharmaceutic adjuvant is a basic material and an important component of the pharmaceutical preparation, and plays a key role in preparation formulation and production. It not only endows the medicine with a certain dosage form, but also improves the curative effect of the medicine and has great relation to reducing the toxic and side effect. The drug effect of the existing diclofenac sodium gel needs to be further improved.
Disclosure of Invention
In view of this, the invention provides a diclofenac sodium gel and a preparation method thereof.
The technical scheme of the invention is realized as follows: each kilogram of raw materials of the diclofenac sodium gel comprises the following components in parts by weight: 10g of sodium clorfenite, 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 carbomer homopolymer A type 971P NF and carbomer homopolymer C type 980NF in equal mass.
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 is prepared from the following components in percentage by mass 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 amount of 45-55% of the prescription into a clean water phase tank, heating the purified water to 40-50 ℃ by steam, adding edetate disodium with the amount of the prescription under the stirring state, stirring for 3-5 minutes to dissolve the edetate disodium, adding carbomer homopolymer with the amount of the prescription under the stirring state, stirring for 3-4 hours to suspend the carbomer homopolymer, and soaking and swelling for 12-14 hours to obtain a mixture I for later use;
(2) preparation of mixture II: adding 8-12% of purified water into a stainless steel barrel, adding sodium hydroxide under stirring, stirring for 3-5 min to obtain sodium hydroxide solution, and mixing to obtain mixture II with volume V0And is ready for use;
(3) preparation of mixture III:
adding isopropanol and propylene glycol in a formula amount into a clean stainless steel barrel, stirring for 6-8 minutes, uniformly mixing, adding diclofenac sodium in a formula amount under a stirring state, stirring for 7-10 minutes, and uniformly mixing to obtain a raw material mixed solution;
adding purified water with the formula amount of 36-40% into the oil phase tank, adding the raw material mixed solution under stirring, leaching a stainless steel barrel with the residual purified water with the formula amount, finally adding the leaching water into the oil phase tank, and continuously stirring for 22-25 minutes until the diclofenac sodium is completely dissolved to obtain a mixture III for later use;
(4) preparing gel: selecting an emulsifying tank, starting vacuum, connecting a feeding pipeline when the vacuum degree in the emulsifying tank reaches-0.08 to-0.10 Mpa, starting a discharge valve of a water phase tank, starting a 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 usage amount of the mixture II is recorded as V1；
Finally, adding the mixture III into an emulsification tank, and leaching the oil phase tank by using purified water after the addition is finished, wherein the amount of the purified water is the total amount V of the mixture II0And the actual amount V of the mixture II1Adding the leaching water into the emulsifying tank, and stirring for the second time for 30-40 minutes; the objective 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 amount of 50% of the prescription into a clean water phase tank, heating the purified water to 40-50 ℃ by using steam, adding edetate disodium with the amount of the prescription under the stirring state, stirring for 3 minutes to completely dissolve the edetate disodium, continuing stirring, adding carbomer homopolymer with the amount of the prescription, stirring for 3 hours to suspend the carbomer homopolymer, and soaking and swelling the carbomer homopolymer for 12 hours to obtain a mixture I for later use;
(2) preparation of mixture II: adding purified water with the amount of 10 percent of the prescription into a stainless steel barrel, adding sodium hydroxide with the amount of the prescription under the stirring state, stirring for 3 minutes to dissolve the sodium hydroxide to prepare a sodium hydroxide solution, thus obtaining a mixture II, wherein the volume of the mixture II is recorded as V0And is ready for use;
(3) preparation of mixture III:
adding isopropanol and propylene glycol in a prescription amount into a clean stainless steel barrel, stirring for 6 minutes, uniformly mixing, adding diclofenac sodium in the prescription amount under a stirring state, stirring for 7 minutes, and uniformly mixing to obtain a raw material mixed solution;
adding 38% of purified water according to the formula amount into an oil phase tank, adding the raw material mixed solution under the stirring state, leaching a stainless steel barrel twice with 2% of purified water according to the formula amount, finally adding the 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) preparing gel: selecting an emulsifying tank, starting vacuum, connecting a feeding pipeline when the vacuum degree in the emulsifying tank reaches-0.09 Mpa, starting a discharge valve of a water phase tank, starting a feeding valve, adding the mixture I into the emulsifying tank, stirring for the first time, setting slow stirring speed to be 35Hz, emulsifying stirring speed to be 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 usage amount of the mixture II is recorded as V1；
Finally, adding the mixture III into an emulsification tank, and leaching the oil phase tank by using purified water after the addition is finished, wherein the amount of the purified water is the total amount V of the mixture II0And the actual amount V of the mixture II1Adding the leaching water into the emulsifying tank for second stirring, 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 objective diclofenac sodium gel is prepared.
Furthermore, each kilogram of raw materials also contains 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 amount of 45-55% of the prescription into a clean water phase tank, heating the purified water to 40-50 ℃ by steam, adding edetate disodium with the amount of the prescription under the stirring state, stirring for 3-5 minutes to dissolve the edetate disodium, adding carbomer homopolymer with the amount of the prescription under the stirring state, stirring for 3-4 hours to suspend the carbomer homopolymer, adding alpha, beta-trehalose and calcium alginate with the amount of the prescription, stirring, soaking and swelling for 12-14 hours to prepare a mixture I for later use;
(2) preparation of mixture II: to a great extentAdding purified water 8-12% of the prescription amount into a steel barrel, adding sodium hydroxide of the prescription amount under stirring, stirring for 3-5 min to dissolve to obtain sodium hydroxide solution to obtain mixture II, wherein the volume of the mixture II is recorded as V0And is ready for use;
(3) preparation of mixture III:
adding isopropanol and propylene glycol in a formula amount into a clean stainless steel barrel, stirring for 6-8 minutes, uniformly mixing, adding diclofenac sodium in a formula amount under a stirring state, stirring for 7-10 minutes, and uniformly mixing to obtain a raw material mixed solution;
adding purified water with the formula amount of 36-40% into the oil phase tank, adding the raw material mixed solution under stirring, leaching a stainless steel barrel with the residual purified water with the formula amount, finally adding the leaching water into the oil phase tank, and continuously stirring for 22-25 minutes until the diclofenac sodium is completely dissolved to obtain a mixture III for later use;
(4) preparing gel: selecting an emulsifying tank, starting vacuum, connecting a feeding pipeline when the vacuum degree in the emulsifying tank reaches-0.08 to-0.10 Mpa, starting a discharge valve of a water phase tank, starting a 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 usage amount of the mixture II is recorded as V1；
Finally, adding the mixture III into an emulsification tank, and leaching the oil phase tank once by using purified water after the addition is finished, wherein the amount of the purified water is the total amount V of the mixture II0And the actual amount V of the mixture II1Adding the leaching water into the emulsifying tank, and stirring for the second time for 30-40 minutes; the objective diclofenac sodium gel is prepared.
Still further preferably, the preparation method of the diclofenac sodium gel comprises the following steps:
(1) preparation of mixture I: adding purified water with the amount of 50% of the prescription amount into a clean water phase tank, heating the purified water to 40-50 ℃ by steam, adding edetate disodium with the prescription amount under the stirring state, stirring for 3 minutes to completely dissolve the edetate disodium, 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, soaking and swelling for 12 hours to obtain a mixture I for later use;
(2) preparation of mixture II: adding purified water with the amount of 10 percent of the prescription into a stainless steel barrel, adding sodium hydroxide with the amount of the prescription under the stirring state, stirring for 3 minutes to dissolve the sodium hydroxide to prepare a sodium hydroxide solution, thus obtaining a mixture II, wherein the volume of the mixture II is recorded as V0And is ready for use;
(3) preparation of mixture III:
adding isopropanol and propylene glycol in a prescription amount into a clean stainless steel barrel, stirring for 6 minutes, uniformly mixing, adding diclofenac sodium in the prescription amount under a stirring state, stirring for 7 minutes, and uniformly mixing to obtain a raw material mixed solution;
adding 38% of purified water according to the formula amount into an oil phase tank, adding the raw material mixed solution under the stirring state, leaching a stainless steel barrel twice with 2% of purified water according to the formula amount, finally adding the 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) preparing gel: selecting an emulsifying tank, starting vacuum, connecting a feeding pipeline when the vacuum degree in the emulsifying tank reaches-0.09 Mpa, starting a discharge valve of a water phase tank, starting a feeding valve, adding the mixture I into the emulsifying tank, stirring for the first time, wherein the stirring time is 30 minutes, the slow stirring speed is set to 35Hz, the emulsifying stirring speed is set to 25Hz, after stirring is carried out until carbomer homopolymer is uniformly dispersed, the pH value is adjusted to 6.0-6.5 by using a mixture II, and the using amount of the mixture II is recorded as V1；
Finally, adding the mixture III into an emulsification tank, and leaching the oil phase tank once by using purified water after the addition is finished, wherein the amount of the purified water is the total amount V of the mixture II0And the actual amount V of the mixture II1Adding the leaching water into the emulsifying tank for second stirring, 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 objective 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 diclofenac sodium gel prepared by using diclofenac sodium as a main drug, combining carbomer homopolymer A type 971P NF and carbomer homopolymer C type 980NF as a matrix, using propylene glycol as a cosolvent, using isopropanol as a penetration enhancer, using edetate disodium as a complexing agent, using sodium hydroxide as a pH regulator and using purified water as a solvent according to a scientific proportion obviously reduces the plantar swelling degree of rats, obviously reduces the TNF-alpha activity of the rats and obviously reduces PGE (PGE)2Effectively improve the drug effect and reduce the inflammatory reaction. The invention is composed of carbomer homopolymer A-type 971P NF and carbomer homopolymer C-type 980NF in a certain proportion, which is beneficial to the release of diclofenac sodium, improves the drug effect of diclofenac sodium, and can reduce the dosage of propylene glycol. In addition, the addition of the alpha, beta-trehalose and the calcium alginate effectively promotes the absorption of the diclofenac sodium, improves the drug effect, and can reduce the dosage of the isopropanol.
Detailed Description
In order to better understand the technical content of the invention, specific examples are provided below to further illustrate the invention.
The experimental methods used in the examples of the present invention are all conventional methods unless otherwise specified.
The materials, reagents and the like used in the examples of the present invention can be obtained commercially without specific description.
Example 1
Each kilogram of raw materials of the diclofenac sodium gel 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 carbomer homopolymer A type 971P NF and carbomer homopolymer C type 980NF in equal mass ratio.
Example 2
Each kilogram of raw materials of the diclofenac sodium gel comprises the following components in parts by weight: 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
Each kilogram of raw materials of the diclofenac sodium gel comprises the following components in parts by weight: 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 diclofenac sodium gels were prepared as follows:
(1) preparation of mixture I: adding purified water with the amount of 50% of the prescription into a clean water phase tank, heating the purified water to 40-50 ℃ by using steam, adding edetate disodium with the amount of the prescription under the stirring state, stirring for 3 minutes to completely dissolve the edetate disodium, continuing stirring, adding carbomer homopolymer with the amount of the prescription, stirring for 3 hours to suspend the carbomer homopolymer, and soaking and swelling the carbomer homopolymer for 12 hours to obtain a mixture I for later use;
(2) preparation of mixture II: adding purified water with the amount of 10 percent of the prescription into a stainless steel barrel, adding sodium hydroxide with the amount of the prescription under the stirring state, stirring for 3 minutes to dissolve the sodium hydroxide to prepare a sodium hydroxide solution, thus obtaining a mixture II, wherein the volume of the mixture II is recorded as V0And is ready for use;
(3) preparation of mixture III:
adding isopropanol and propylene glycol in a prescription amount into a clean stainless steel barrel, stirring for 6 minutes, uniformly mixing, adding diclofenac sodium in the prescription amount under a stirring state, stirring for 7 minutes, and uniformly mixing to obtain a raw material mixed solution;
adding 38% of purified water according to the formula amount into an oil phase tank, adding the raw material mixed solution under the stirring state, leaching a stainless steel barrel twice with 2% of purified water according to the formula amount, finally adding the 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) preparing gel: selecting an emulsifying tank, starting vacuum, connecting a feeding pipeline when the vacuum degree in the emulsifying tank reaches-0.09 Mpa, starting a discharge valve of a water phase tank, starting a feeding valve, adding the mixture I into the emulsifying tank, stirring for the first time, setting slow stirring speed to be 35Hz, emulsifying stirring speed to be 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 usage amount of the mixture II is recorded as V1；
Finally, adding the mixture III into an emulsification tank, and leaching the oil phase tank by using purified water after the addition is finished, wherein the amount of the purified water is the total amount V of the mixture II0And the actual amount V of the mixture II1Adding the leaching water into the emulsifying tank for second stirring, 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 objective diclofenac sodium gel is prepared.
Example 4
Compared with the example 1, the diclofenac sodium gel mainly comprises the following components in parts by weight per kilogram of raw materials: 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 from the following components in percentage by mass of 3: 7 carbomer homopolymer type a 971P NF and carbomer homopolymer type C980 NF.
Example 5
A diclofenac sodium gel is different from the diclofenac sodium gel in 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 of 3: 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 amount of 50% of the prescription amount into a clean water phase tank, heating the purified water to 40-50 ℃ by steam, adding edetate disodium with the prescription amount under the stirring state, stirring for 3 minutes to completely dissolve the edetate disodium, 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, and soaking and swelling for 12 hours to obtain a mixture I for later use;
(2) preparation of mixture II: adding purified water with the amount of 10 percent of the prescription into a stainless steel barrel, adding sodium hydroxide with the amount of the prescription under the stirring state, stirring for 3 minutes to dissolve the sodium hydroxide to prepare a sodium hydroxide solution, thus obtaining a mixture II, wherein the volume of the mixture II is recorded as V0And is ready for use;
(3) preparation of mixture III:
adding isopropanol and propylene glycol in a prescription amount into a clean stainless steel barrel, stirring for 6 minutes, uniformly mixing, adding diclofenac sodium in the prescription amount under a stirring state, stirring for 7 minutes, and uniformly mixing to obtain a raw material mixed solution;
adding 38% of purified water according to the formula amount into an oil phase tank, adding the raw material mixed solution under the stirring state, leaching a stainless steel barrel twice with 2% of purified water according to the formula amount, finally adding the 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) preparing gel: selecting an emulsifying tank, starting vacuum, connecting a feeding pipeline when the vacuum degree in the emulsifying tank reaches-0.09 Mpa, starting a discharge valve of a water phase tank, starting a feeding valve, adding the mixture I into the emulsifying tank, stirring for the first time, wherein the stirring time is 30 minutes, the slow stirring speed is set to 35Hz, the emulsifying stirring speed is set to 25Hz, after stirring is carried out until carbomer homopolymer is uniformly dispersed, the pH value is adjusted to 6.0-6.5 by using a mixture II, and the using amount of the mixture II is recorded as V1；
Finally, adding the mixture III into an emulsification tank, and leaching the oil phase tank once by using purified water after the addition is finished, wherein the amount of the purified water is the total amount V of the mixture II0And the actual amount V of the mixture II1Adding the leaching water into the emulsifying tank for second stirring, 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 objective diclofenac sodium gel is prepared.
Comparative example 1
The diclofenac sodium gel mainly comprises the following components in parts by weight per kilogram of raw materials as compared with the diclofenac sodium gel prepared in the embodiment 1: 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 in equal mass.
Comparative example 2
A diclofenac sodium gel, differing primarily from example 1 in that carbomer homopolymer type a 971PNF and carbomer homopolymer type C980 NF was 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.
Anti-arthritis rat test
The experimental method comprises the following steps: about 200g of SD rats were selected in 90 groups, which were randomly divided into 10 groups, including model group, positive control group (diclofenac sodium gel of Fendi brand), test groups 1-5 (diclofenac sodium gel of examples 1-5), and 9 groups in total. Molding: 0.1mL of Freund's complete adjuvant is injected into the plantar area of the right hind limb of a rat in an intradermal mode, and a pathological model of adjuvant arthritis is established. On the 4 th day after the model building, the rats of the positive control group and the test groups 1-5 are administered with the gavage, the dosage is 3.0mg/kg, 1 time per day, and the total 21 days. Changes in the plantar circumference of the right hind limb fixation site were measured before molding, before administration, and 21 days after administration, respectively. 5h after the last administration, performing aseptic operation under ether anesthesia, drawing 2mL of blood from the heart, performing heparin anticoagulation, separating out plasma, storing at-20 ℃, and detecting the TNF-alpha activity of the plasma. The inflammatory swelling foot was cut at 0.5cm above the left posterior ankle of each rat, weighed, peeled, minced, soaked in 5mL of physiological saline for 1h, the rat paw was removed, the soak was centrifuged, 0.1mL of supernatant was aspirated, 2mL of 0.5M potassium hydroxide-methanol solution was added, isomerized in a water bath at 50 ℃ for 20min, diluted to 20mL with methanol, and the optical density value was measured at a wavelength of 278 nm. PGE is expressed as the equivalent absorbance density per gram of tissue2As an index for evaluating anti-inflammatory activity. The test results are shown in the following tables 1-2:
TABLE 1 comparison of the circumference of the foot of the right hind limb before and after administration
Comparing with model group, P < 0.05, P < 0.01
TABLE 2 plasma TNF-. alpha.Activity and PGE in tissues2Comparison of results
| Group of | TNF-α(mg/ml) | PGE2(mg/g) |
| Model set | 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* |
Comparing with model group, P < 0.05, P < 0.01
From the above results, it can be seen that the diclofenac sodium gel prepared in examples 1-5 significantly reduces the degree of swelling of rat foot, significantly reduces the activity of rat TNF-alpha, and significantly reduces PGE2。
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 which are combined in a certain proportion not only are beneficial to improving the drug effect of diclofenac sodium, but also can reduce the dosage of propylene glycol. Especially, the effect of the embodiment 5 is obviously better than that of the embodiment 1, the absorption of the diclofenac sodium is effectively promoted by adding the alpha, beta-trehalose and the calcium alginate, the drug effect is improved, and the dosage of the isopropanol can be reduced. In addition, the comparison between the example 1 and the comparative example 1 shows that the anti-arthritis effect is obviously improved by adopting the components in a certain proportion. Compared with the comparative example 2, the invention adopts the carbomer homopolymer A type 971P NF and the carbomer homopolymer C type 980NF to be composed, which is beneficial to the release of diclofenac sodium and improves the drug effect.
Quality standard control
TABLE 3 test results
The above results show that the diclofenac sodium gel prepared in examples 1-5 meets the quality standard requirements.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (10)
1. The diclofenac sodium gel is characterized in that 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.
2. The diclofenac sodium gel of claim 1, characterized in that 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 carbomer homopolymer A type 971P NF and carbomer homopolymer C type 980NF in equal mass.
3. The diclofenac sodium gel of claim 1, characterized in that 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 is prepared from the following components in percentage by mass of 3: 7 carbomer homopolymer type a 971P NF and carbomer homopolymer type C980 NF.
4. The diclofenac sodium gel according to claim 1 or 3, characterized in that it further comprises the following components in parts by weight per kilogram of raw material: 1.3-1.5g of alpha, beta-trehalose and 0.2-0.4g of calcium alginate.
5. The diclofenac sodium gel of claim 4, characterized in that 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, characterized by comprising the steps of:
(1) preparation of mixture I: adding purified water with the amount of 45-55% of the prescription into a clean water phase tank, heating the purified water to 40-50 ℃ by steam, adding edetate disodium with the amount of the prescription under the stirring state, stirring for 3-5 minutes to dissolve the edetate disodium, adding carbomer homopolymer with the amount of the prescription under the stirring state, stirring for 3-4 hours to suspend the carbomer homopolymer, and soaking and swelling for 12-14 hours to obtain a mixture I for later use;
(2) preparation of mixture II: adding 8-12% of purified water into a stainless steel barrel, adding sodium hydroxide under stirring, stirring for 3-5 min to obtain sodium hydroxide solution, and mixing to obtain mixture II with volume V0And is ready for use;
(3) preparation of mixture III:
adding isopropanol and propylene glycol in a formula amount into a clean stainless steel barrel, stirring for 6-8 minutes, uniformly mixing, adding diclofenac sodium in a formula amount under a stirring state, stirring for 7-10 minutes, and uniformly mixing to obtain a raw material mixed solution;
adding purified water with the formula amount of 36-40% into the oil phase tank, adding the raw material mixed solution under stirring, leaching a stainless steel barrel with the residual purified water with the formula amount, finally adding the leaching water into the oil phase tank, and continuously stirring for 22-25 minutes until the diclofenac sodium is completely dissolved to obtain a mixture III for later use;
(4) preparing gel: selecting an emulsifying tank, starting vacuum, connecting a feeding pipeline when the vacuum degree in the emulsifying tank reaches-0.08 to-0.10 Mpa, starting a discharge valve of a water phase tank, starting a 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 usage amount of the mixture II is recorded as V1；
Finally, adding the mixture III into an emulsification tank, and leaching the oil phase tank by using purified water after the addition is finished, wherein the amount of the purified water is the total amount V of the mixture II0And the actual amount V of the mixture II1Adding the leaching water into the emulsifying tank, and stirring for the second time for 30-40 minutes; the objective diclofenac sodium gel is prepared.
7. The method for preparing diclofenac sodium gel according to claim 6, characterized by comprising the steps of:
(1) preparation of mixture I: adding purified water with the amount of 50% of the prescription into a clean water phase tank, heating the purified water to 40-50 ℃ by using steam, adding edetate disodium with the amount of the prescription under the stirring state, stirring for 3 minutes to completely dissolve the edetate disodium, continuing stirring, adding carbomer homopolymer with the amount of the prescription, stirring for 3 hours to suspend the carbomer homopolymer, and soaking and swelling the carbomer homopolymer for 12 hours to obtain a mixture I for later use;
(2) preparation of mixture II: adding purified water with the amount of 10 percent of the prescription into a stainless steel barrel, adding sodium hydroxide with the amount of the prescription under the stirring state, stirring for 3 minutes to dissolve the sodium hydroxide to prepare a sodium hydroxide solution, thus obtaining a mixture II, wherein the volume of the mixture II is recorded as V0And is ready for use;
(3) preparation of mixture III:
adding isopropanol and propylene glycol in a prescription amount into a clean stainless steel barrel, stirring for 6 minutes, uniformly mixing, adding diclofenac sodium in the prescription amount under a stirring state, stirring for 7 minutes, and uniformly mixing to obtain a raw material mixed solution;
adding 38% of purified water according to the formula amount into an oil phase tank, adding the raw material mixed solution under the stirring state, leaching a stainless steel barrel twice with 2% of purified water according to the formula amount, finally adding the 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) preparing gel: selecting an emulsifying tank, starting vacuum, connecting a feeding pipeline when the vacuum degree in the emulsifying tank reaches-0.09 Mpa, starting a discharge valve of a water phase tank, starting a feeding valve, adding the mixture I into the emulsifying tank, stirring for the first time, setting slow stirring speed to be 35Hz, emulsifying stirring speed to be 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 usage amount of the mixture II is recorded as V1；
Finally, adding the mixture III into an emulsification tank, and leaching the oil phase tank by using purified water after the addition is finished, wherein the amount of the purified water is the total amount V of the mixture II0And the actual amount V of the mixture II1Adding the leaching water into the emulsifying tank for second stirring, 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 objective diclofenac sodium gel is prepared.
8. The method for preparing diclofenac sodium gel according to claim 4 or 5, characterized in that it comprises the following steps:
(1) preparation of mixture I: adding purified water with the amount of 45-55% of the prescription into a clean water phase tank, heating the purified water to 40-50 ℃ by steam, adding edetate disodium with the amount of the prescription under the stirring state, stirring for 3-5 minutes to dissolve the edetate disodium, adding carbomer homopolymer with the amount of the prescription under the stirring state, stirring for 3-4 hours to suspend the carbomer homopolymer, adding alpha, beta-trehalose and calcium alginate with the amount of the prescription, 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 amount of 8-12% of the prescription into a stainless steel barrel, and adding hydrogen hydroxide with the amount of the prescription under stirringStirring sodium for 3-5 min to obtain sodium hydroxide solution, and recording volume as V0And is ready for use;
(3) preparation of mixture III:
adding isopropanol and propylene glycol in a formula amount into a clean stainless steel barrel, stirring for 6-8 minutes, uniformly mixing, adding diclofenac sodium in a formula amount under a stirring state, stirring for 7-10 minutes, and uniformly mixing to obtain a raw material mixed solution;
adding purified water with the formula amount of 36-40% into the oil phase tank, adding the raw material mixed solution under stirring, leaching a stainless steel barrel with the residual purified water with the formula amount, finally adding the leaching water into the oil phase tank, and continuously stirring for 22-25 minutes until the diclofenac sodium is completely dissolved to obtain a mixture III for later use;
(4) preparing gel: selecting an emulsifying tank, starting vacuum, connecting a feeding pipeline when the vacuum degree in the emulsifying tank reaches-0.08 to-0.10 Mpa, starting a discharge valve of a water phase tank, starting a 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 usage amount of the mixture II is recorded as V1；
Finally, adding the mixture III into an emulsification tank, and leaching the oil phase tank once by using purified water after the addition is finished, wherein the amount of the purified water is the total amount V of the mixture II0And the actual amount V of the mixture II1Adding the leaching water into the emulsifying tank, and stirring for the second time for 30-40 minutes; the objective diclofenac sodium gel is prepared.
9. The method for preparing diclofenac sodium gel according to claim 8, characterized by comprising the steps of:
(1) preparation of mixture I: adding purified water with the amount of 50% of the prescription amount into a clean water phase tank, heating the purified water to 40-50 ℃ by steam, adding edetate disodium with the prescription amount under the stirring state, stirring for 3 minutes to completely dissolve the edetate disodium, 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, soaking and swelling for 12 hours to obtain a mixture I for later use;
(2) preparation of mixture II: adding purified water with the amount of 10 percent of the prescription into a stainless steel barrel, adding sodium hydroxide with the amount of the prescription under the stirring state, stirring for 3 minutes to dissolve the sodium hydroxide to prepare a sodium hydroxide solution, thus obtaining a mixture II, wherein the volume of the mixture II is recorded as V0And is ready for use;
(3) preparation of mixture III:
adding isopropanol and propylene glycol in a prescription amount into a clean stainless steel barrel, stirring for 6 minutes, uniformly mixing, adding diclofenac sodium in the prescription amount under a stirring state, stirring for 7 minutes, and uniformly mixing to obtain a raw material mixed solution;
adding 38% of purified water according to the formula amount into an oil phase tank, adding the raw material mixed solution under the stirring state, leaching a stainless steel barrel twice with 2% of purified water according to the formula amount, finally adding the 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) preparing gel: selecting an emulsifying tank, starting vacuum, connecting a feeding pipeline when the vacuum degree in the emulsifying tank reaches-0.09 Mpa, starting a discharge valve of a water phase tank, starting a feeding valve, adding the mixture I into the emulsifying tank, stirring for the first time, wherein the stirring time is 30 minutes, the slow stirring speed is set to 35Hz, the emulsifying stirring speed is set to 25Hz, after stirring is carried out until carbomer homopolymer is uniformly dispersed, the pH value is adjusted to 6.0-6.5 by using a mixture II, and the using amount of the mixture II is recorded as V1；
Finally, adding the mixture III into an emulsification tank, and leaching the oil phase tank once by using purified water after the addition is finished, wherein the amount of the purified water is the total amount V of the mixture II0And the actual amount V of the mixture II1Adding the leaching water into the emulsifying tank for second stirring, 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 objective diclofenac sodium gel is prepared.
10. The method for preparing diclofenac sodium gel according to claim 9, characterized in that the stirring time is 5-10 minutes.
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Citations (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1209479A (en) * | 1983-12-14 | 1986-08-12 | Takuzo Kamishita | Gel preparations for external application |
| US4670254A (en) * | 1983-12-09 | 1987-06-02 | Toko Yakuhin Industry Co., Ltd. | Gel preparations for topical application of diclofenac sodium |
| US5374661A (en) * | 1991-07-03 | 1994-12-20 | Sano Corporation | Composition and method for transdermal delivery of diclofenac |
| CN1151285A (en) * | 1995-12-05 | 1997-06-11 | 中山医科大学科技开发部 | Diclofenac ointment and its prepn. method |
| KR19980053291A (en) * | 1996-12-26 | 1998-09-25 | 구형우 | Percutaneous Absorption of Diclofenac Sodium |
| CN1249930A (en) * | 1998-10-07 | 2000-04-12 | 江苏省药物研究所 | Diclofenac potassium gel and ointment and the preparation thereof |
| JP2004123575A (en) * | 2002-09-30 | 2004-04-22 | Rohto Pharmaceut Co Ltd | Gel-like composition for external use |
| CA2500907A1 (en) * | 2005-03-15 | 2006-09-15 | Alpharx Inc. | Vehicle for topical delivery of anti-inflammatory compounds |
| CN101588791A (en) * | 2006-10-17 | 2009-11-25 | 纽沃研究公司 | Diclofenac gel |
| WO2010048788A1 (en) * | 2008-10-30 | 2010-05-06 | 中国科学院上海药物研究所 | A ophthalmic flurbiprofen ester nano-emulsion in-situ gel formulation and the preparation method thereof |
| US8217078B1 (en) * | 2009-03-31 | 2012-07-10 | Nuvo Research Inc. | Treatment of pain with topical diclofenac |
| CN103126974A (en) * | 2011-11-30 | 2013-06-05 | 王冕 | Gel |
| CN104415024A (en) * | 2013-08-22 | 2015-03-18 | 和心医药科技（上海）有限公司 | Diclofenac-containing cataplasm, and composition and preparation method thereof |
| US20160166524A1 (en) * | 2014-12-12 | 2016-06-16 | Gavis Pharmaceuticals | Topical pharmaceutical gel composition of diclofenac sodium |
| CN110302141A (en) * | 2019-07-11 | 2019-10-08 | 烟台绿叶动物保健品有限公司 | Diclofenac sodium injection situ-gel and preparation method thereof |
| CN111904926A (en) * | 2014-09-10 | 2020-11-10 | Gsk消费者健康有限公司 | Topical diclofenac sodium compositions |
-
2021
- 2021-11-29 CN CN202111431585.9A patent/CN114259461B/en active Active
Patent Citations (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4670254A (en) * | 1983-12-09 | 1987-06-02 | Toko Yakuhin Industry Co., Ltd. | Gel preparations for topical application of diclofenac sodium |
| CA1209479A (en) * | 1983-12-14 | 1986-08-12 | Takuzo Kamishita | Gel preparations for external application |
| US5374661A (en) * | 1991-07-03 | 1994-12-20 | Sano Corporation | Composition and method for transdermal delivery of diclofenac |
| CN1151285A (en) * | 1995-12-05 | 1997-06-11 | 中山医科大学科技开发部 | Diclofenac ointment and its prepn. method |
| KR19980053291A (en) * | 1996-12-26 | 1998-09-25 | 구형우 | Percutaneous Absorption of Diclofenac Sodium |
| CN1249930A (en) * | 1998-10-07 | 2000-04-12 | 江苏省药物研究所 | Diclofenac potassium gel and ointment and the preparation thereof |
| JP2004123575A (en) * | 2002-09-30 | 2004-04-22 | Rohto Pharmaceut Co Ltd | Gel-like composition for external use |
| CA2500907A1 (en) * | 2005-03-15 | 2006-09-15 | Alpharx Inc. | Vehicle for topical delivery of anti-inflammatory compounds |
| CN101588791A (en) * | 2006-10-17 | 2009-11-25 | 纽沃研究公司 | Diclofenac gel |
| WO2010048788A1 (en) * | 2008-10-30 | 2010-05-06 | 中国科学院上海药物研究所 | A ophthalmic flurbiprofen ester nano-emulsion in-situ gel formulation and the preparation method thereof |
| US8217078B1 (en) * | 2009-03-31 | 2012-07-10 | Nuvo Research Inc. | Treatment of pain with topical diclofenac |
| CN103126974A (en) * | 2011-11-30 | 2013-06-05 | 王冕 | Gel |
| CN104415024A (en) * | 2013-08-22 | 2015-03-18 | 和心医药科技（上海）有限公司 | Diclofenac-containing cataplasm, and composition and preparation method thereof |
| CN111904926A (en) * | 2014-09-10 | 2020-11-10 | Gsk消费者健康有限公司 | Topical diclofenac sodium compositions |
| US20160166524A1 (en) * | 2014-12-12 | 2016-06-16 | Gavis Pharmaceuticals | Topical pharmaceutical gel composition of diclofenac sodium |
| CN110302141A (en) * | 2019-07-11 | 2019-10-08 | 烟台绿叶动物保健品有限公司 | Diclofenac sodium injection situ-gel and preparation method thereof |
Non-Patent Citations (5)
| Title |
|---|
| SUHAIL MUHAMMAD: "Using Carbomer-Based Hydrogels for Control the Release Rate of Diclofenac Sodium: Preparation and In Vitro Evaluation", 《PHARMACEUTICALS》, vol. 13, no. 11, pages 399 * |
| 刘玲玲: "双氯芬酸钠微乳凝胶的研制与体外透皮性能的初步考察", 《中国医药工业杂志》, vol. 44, no. 11, pages 1111 - 1114 * |
| 柳晓凤: "不同基质的双氯芬酸钠凝胶透皮吸收的比较", 《广东化工》, vol. 45, no. 5, pages 33 - 34 * |
| 王敏: "卡波姆凝胶剂的临床应用研究进展", 《医学综述》, vol. 19, no. 6, pages 1078 - 1080 * |
| 陈静: "药用辅料卡波姆在药物制剂中的应用探讨", 《企业科技与发展》, no. 9, pages 150 - 153 * |
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