CN112972385A - Inflammation-diminishing and pain-relieving aerosol and preparation method thereof - Google Patents
Inflammation-diminishing and pain-relieving aerosol and preparation method thereof Download PDFInfo
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Abstract
The invention provides an anti-inflammatory analgesic aerosol and a preparation method thereof, relating to the field of medicine, wherein the aerosol consists of a gas phase and a liquid phase, wherein the liquid phase comprises the following raw materials: diclofenac sodium, laurocapram, propylene glycol, ethanol, polyethylene glycol, synergist and peppermint oil. The aerosol has simple preparation method, and the prepared product has good curative effect and quick response, thereby preventing excessive consumption of the product while ensuring that a patient is well treated, and effectively treating sports injury or acute attack of acute arthritis such as gout and degenerative arthritis.
Description
Technical Field
The invention relates to the field of medicines, in particular to an anti-inflammatory analgesic aerosol and a preparation method thereof.
Background
Diclofenac sodium is a novel non-steroidal anti-inflammatory analgesic, has good antipyretic and analgesic effects, and is suitable for various rheumatism, rheumatoid arthritis, lupus erythematosus, ankylosing spondylitis, various postoperative pains, various fever caused by various reasons and the like. The diclofenac sodium anti-inflammatory analgesic has the advantages of good curative effect, small side effect, no accumulation in long-term application and the like in the similar medicaments. At present, diclofenac sodium in the market has more dosage forms and has better treatment effect, for example, diclofenac sodium oral tablets have better anti-inflammatory and analgesic effects, and diclofenac sodium gel has the effects of diminishing inflammation, resisting rheumatism, relieving pain, relieving fever and the like. However, these different dosage forms have various disadvantages while exerting their effects, such as adverse gastrointestinal effects caused by oral administration of non-steroidal analgesic anti-inflammatory drugs, liver first pass effect, and further problems of unpleasant odor and difficulty in swallowing.
Chinese patent CN106562928A discloses an anti-inflammatory analgesic aerosol and a preparation method thereof, the aerosol is composed of a gas phase and a liquid phase, wherein the liquid phase is composed of the following raw materials in parts by mass: 10-20 parts of diclofenac sodium; 5-10 parts of laurocapram; 20-50 parts of propylene glycol; 30-40 parts of ethanol; 10-20 parts of polyethylene glycol, and the obtained aerosol has the effects of diminishing inflammation, reducing swelling, relieving fever, easing pain and the like. The literature: wanlehong, Linvinghui, Linguangyi, environment-friendly diclofenac sodium aerosol preparation process and quality standard research [ J ] aerosol communication, 2007(5) 1-3, disclose an environment-friendly diclofenac sodium aerosol, the prescription is diclofenac sodium 12.5g, 1-2 propylene glycol 20.0g, laurocapram 12.5g, ethanol 700.0g, propane butane 253.0g, the total amount makes 1000g, the product quality prepared finally is stable, accord with the requirement of industrialized large production. The aerosol in the technology can effectively avoid various problems existing in oral medicines and the like, but the anti-inflammatory and analgesic effects of the aerosol are still limited compared with oral or injection preparations and the like on the whole, so that the problem of serious aerosol consumption often exists in use.
Aiming at the problems of gastrointestinal stimulation, liver first-pass effect, limited aerosol efficacy and large consumption of analgesic drugs in the prior art, a product with good curative effect and quick response needs to be found urgently, so that patients can be treated well and excessive consumption of the product is avoided.
Disclosure of Invention
The invention provides an anti-inflammatory analgesic aerosol and a preparation method thereof, aiming at the problems in the prior art, the aerosol has good curative effect and takes effect quickly, so that the excessive consumption of the product is avoided while patients are treated well.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the invention provides an aerosol, which consists of a gas phase and a liquid phase, wherein the liquid phase comprises the following raw materials: diclofenac sodium, laurocapram, propylene glycol, ethanol, polyethylene glycol, synergist and peppermint oil.
Further, the liquid phase comprises the following raw materials in parts by weight: 10-20 parts of diclofenac sodium, 6-11 parts of laurocapram, 15-20 parts of propylene glycol, 25-30 parts of ethanol, 12-22 parts of polyethylene glycol, 3-8 parts of a synergist and 5-8 parts of peppermint oil.
Preferably, the liquid phase comprises the following raw materials in parts by weight: 12-18 parts of diclofenac sodium, 8-10 parts of laurocapram, 16-18 parts of propylene glycol, 28-30 parts of ethanol, 15-20 parts of polyethylene glycol, 4-6 parts of a synergist and 6-7 parts of peppermint oil.
Further preferably, the liquid phase comprises the following raw materials in parts by weight: 15 parts of diclofenac sodium, 9 parts of laurocapram, 16 parts of propylene glycol, 30 parts of ethanol, 18 parts of polyethylene glycol, 5 parts of a synergist and 6 parts of peppermint oil.
Further, the synergist comprises tween-80, folinic acid and propyl gallate.
Preferably, the weight ratio of the tween-80 to the folinic acid to the propyl gallate is 5-10:1: 6-9. Still more preferably 8:1: 8.
Further, the gas phase is a propellant.
Further, the propellant is one or more of propane, butane, isobutane, tetrafluoroethane, heptafluoropropane or dimethyl ether. Isobutane is preferred.
Further, the weight ratio of the liquid phase to the gas phase is 1:2 to 6, preferably 1: 5.
The invention also provides a preparation method of the aerosol, which comprises the following steps:
(1) after being crushed, the diclofenac sodium is added into ethanol, and the mixture is stirred and mixed evenly to obtain a mixed solution A;
(2) uniformly mixing laurocapram, propylene glycol, ethanol, polyethylene glycol, a synergist and peppermint oil to obtain a mixed solution B;
(3) mixing the mixed solution A and the mixed solution B, and shearing and stirring the mixed solution A and the mixed solution B until the mixed solution is a micron-sized micro-emulsion solution;
(4) and (4) injecting the micron-sized micro-emulsion solution obtained in the step (3) into a container, sealing the container, injecting a gas phase, and pressing the cover to obtain the aerosol.
Further, the particle size of the micro-emulsion is 5-10 μm, preferably 5-6 μm.
The technical effects obtained by the invention are as follows:
the aerosol provided by the invention takes diclofenac sodium as a main material, and by adding laurocapram, propylene glycol, ethanol, polyethylene glycol, a synergist and peppermint oil, the obtained aerosol can effectively avoid stimulation to the stomach and intestine and first-pass effect of the liver, and also has the effects of diminishing inflammation, diminishing swelling, relieving fever, easing pain and the like. The components and the content of the raw materials are adjusted and changed, the raw materials are mutually cooperated, the anti-inflammation and analgesic effects of the aerosol are further improved, the uniform dispersion degree of the components is higher, the using amount of the aerosol can be effectively reduced, the utilization rate is improved, and meanwhile, a good treatment effect is achieved, and related treatment diseases include but are not limited to sports injury or acute attack of acute arthritis such as gout and degenerative arthritis.
Detailed Description
It should be noted that the raw materials used in the present invention are all common commercial products, and thus the sources thereof are not particularly limited.
Example 1
An aerosol consists of a gas phase and a liquid phase in a weight ratio of 1:2, wherein the liquid phase comprises the following raw materials: 10 parts of diclofenac sodium, 6 parts of laurocapram, 15 parts of propylene glycol, 25 parts of ethanol, 12 parts of polyethylene glycol, 3 parts of a synergist and 5 parts of peppermint oil. The synergist is Tween-80, folinic acid and propyl gallate at a weight ratio of 5:1: 6. The gas phase is a propellant, and the propellant is propane and butane.
The preparation method of the aerosol comprises the following steps:
(1) after being crushed, the diclofenac sodium is added into ethanol, and the mixture is stirred and mixed evenly to obtain a mixed solution A;
(2) uniformly mixing laurocapram, propylene glycol, ethanol, polyethylene glycol, a synergist and peppermint oil to obtain a mixed solution B;
(3) mixing the mixed solution A and the mixed solution B, and shearing and stirring the mixed solution A and the mixed solution B until the mixed solution is a micron-sized micro-emulsion solution, wherein the grain diameter of the micro-emulsion is 5 mu m;
(4) and (4) injecting the micron-sized micro-emulsion solution obtained in the step (3) into a container, sealing the container, injecting a gas phase, and pressing the cover to obtain the aerosol.
Example 2
An aerosol consists of a gas phase and a liquid phase in a weight ratio of 1:6, wherein the liquid phase comprises the following raw materials: 20 parts of diclofenac sodium, 11 parts of laurocapram, 20 parts of propylene glycol, 30 parts of ethanol, 22 parts of polyethylene glycol, 8 parts of a synergist and 8 parts of peppermint oil. The synergist is tween-80, folinic acid and propyl gallate with the weight ratio of 10:1: 9. The gas phase is a propellant, which is tetrafluoroethane.
The preparation method of the aerosol comprises the following steps:
(1) after being crushed, the diclofenac sodium is added into ethanol, and the mixture is stirred and mixed evenly to obtain a mixed solution A;
(2) uniformly mixing laurocapram, propylene glycol, ethanol, polyethylene glycol, a synergist and peppermint oil to obtain a mixed solution B;
(3) mixing the mixed solution A and the mixed solution B, and shearing and stirring the mixed solution A and the mixed solution B until the mixed solution is a micron-sized micro-emulsion solution, wherein the grain diameter of the micro-emulsion is 10 mu m;
(4) and (4) injecting the micron-sized micro-emulsion solution obtained in the step (3) into a container, sealing the container, injecting a gas phase, and pressing the cover to obtain the aerosol.
Example 3
An aerosol consists of a gas phase and a liquid phase in a weight ratio of 1:5, wherein the liquid phase comprises the following raw materials: 15 parts of diclofenac sodium, 9 parts of laurocapram, 16 parts of propylene glycol, 30 parts of ethanol, 18 parts of polyethylene glycol, 5 parts of a synergist and 6 parts of peppermint oil. The synergist is Tween-80, folinic acid and propyl gallate at a weight ratio of 8:1: 8. The gaseous phase is a propellant, which is isobutane.
The preparation method of the aerosol comprises the following steps:
(1) after being crushed, the diclofenac sodium is added into ethanol, and the mixture is stirred and mixed evenly to obtain a mixed solution A;
(2) uniformly mixing laurocapram, propylene glycol, ethanol, polyethylene glycol, a synergist and peppermint oil to obtain a mixed solution B;
(3) mixing the mixed solution A and the mixed solution B, and shearing and stirring the mixed solution A and the mixed solution B until the mixed solution is a micron-sized micro-emulsion solution, wherein the grain diameter of the micro-emulsion is 5 mu m;
(4) and (4) injecting the micron-sized micro-emulsion solution obtained in the step (3) into a container, sealing the container, injecting a gas phase, and pressing the cover to obtain the aerosol.
Example 4
An aerosol consists of a gas phase and a liquid phase in a weight ratio of 1:2, wherein the liquid phase comprises the following raw materials: 12 parts of diclofenac sodium, 8 parts of laurocapram, 16 parts of propylene glycol, 28 parts of ethanol, 15 parts of polyethylene glycol, 4 parts of a synergist and 6 parts of peppermint oil. The synergist is Tween-80, folinic acid and propyl gallate at a weight ratio of 8:1: 8. The gas phase is a propellant, which is heptafluoropropane.
The preparation method of the aerosol comprises the following steps:
(1) after being crushed, the diclofenac sodium is added into ethanol, and the mixture is stirred and mixed evenly to obtain a mixed solution A;
(2) uniformly mixing laurocapram, propylene glycol, ethanol, polyethylene glycol, a synergist and peppermint oil to obtain a mixed solution B;
(3) mixing the mixed solution A and the mixed solution B, and shearing and stirring the mixed solution A and the mixed solution B until the mixed solution is a micron-sized micro-emulsion solution, wherein the grain diameter of the micro-emulsion is 5 mu m;
(4) and (4) injecting the micron-sized micro-emulsion solution obtained in the step (3) into a container, sealing the container, injecting a gas phase, and pressing the cover to obtain the aerosol.
Example 5
An aerosol consists of a gas phase and a liquid phase in a weight ratio of 1:6, wherein the liquid phase comprises the following raw materials: 18 parts of diclofenac sodium, 10 parts of laurocapram, 18 parts of propylene glycol, 30 parts of ethanol, 20 parts of polyethylene glycol, 6 parts of a synergist and 7 parts of peppermint oil. The synergist is Tween-80, folinic acid and propyl gallate at a weight ratio of 8:1: 8. The gas phase is propellant, and the propellant is dimethyl ether.
The preparation method of the aerosol comprises the following steps:
(1) after being crushed, the diclofenac sodium is added into ethanol, and the mixture is stirred and mixed evenly to obtain a mixed solution A;
(2) uniformly mixing laurocapram, propylene glycol, ethanol, polyethylene glycol, a synergist and peppermint oil to obtain a mixed solution B;
(3) mixing the mixed solution A and the mixed solution B, and shearing and stirring the mixed solution A and the mixed solution B until the mixed solution is a micron-sized micro-emulsion solution, wherein the grain diameter of the micro-emulsion is 6 mu m;
(4) and (4) injecting the micron-sized micro-emulsion solution obtained in the step (3) into a container, sealing the container, injecting a gas phase, and pressing the cover to obtain the aerosol.
Comparative example 1
The difference from the example 3 is only that the raw materials of the liquid phase comprise, in parts by weight: 8 parts of diclofenac sodium, 15 parts of laurocapram, 12 parts of propylene glycol, 35 parts of ethanol, 10 parts of polyethylene glycol and 10 parts of synergist, namely 3 parts of peppermint oil.
Comparative example 2
The only difference from example 3 is that the weight ratio of tween-80, folinic acid and propyl gallate is 3:1:10 (the total weight of the three is identical to example 3).
Comparative example 3
The only difference from example 3 is that no synergist was added.
Comparative example 4
The aerosol of example 2 in chinese patent CN 106562928A.
First, testing physicochemical Properties of Aerosol
The anti-inflammatory and analgesic aerosols prepared in examples 1 to 5 and comparative examples 1 to 4 were tested for their performance, with reference to diclofenac sodium aerosol quality standard (WS1- (X-384) -2003Z) and method in aerosol 0113, the four ministry of general rules of the Chinese pharmacopoeia 2020 edition, and the test results are shown in Table 1 below.
TABLE 1
| Examples of the invention | Total ejection (%) | Injection Rate (g/s) | Droplet size (mum) |
| Example 1 | 99.2 | 0.92 | 93% of 20-50 μm and 7% of less than 20 μm |
| Example 2 | 98.5 | 0.93 | 95% of 20-50 μm and 5% of less than 20 μm |
| Example 3 | 99.2 | 0.95 | 96% of 20-50 μm and 4% of less than 20 μm |
| Example 4 | 99.3 | 0.94 | 95% of 20-50 μm and 5% of less than 20 μm |
| Example 5 | 99.0 | 0.93 | 95% of 20-50 μm and 5% of less than 20 μm |
| Comparative example 1 | 93.2 | 0.74 | 78% of 20-50 μm and 22% of < 20 μm |
| Comparative example 2 | 98.4 | 0.92 | 90% of 20-50 μm and 10% of less than 20 μm |
| Comparative example 3 | 97.0 | 0.88 | 88% of 20-50 μm, 12% of < 20 μm |
| Comparative example 4 | 97.6 | 0.93 | 93% of 20-50 μm and 7% of less than 20 μm |
The aerosol quality standard (WS1- (X-384) -2003Z) and the standard in the aerosol 0113 according to the general rule of the four departments of the 2020 edition of Chinese pharmacopoeia require that the total amount of the sprayed aerosol is not less than 85 percent and is qualified, and the spraying rate is 0.7 to 1.3 g/s.
Evaluation criteria for other properties of aerosol:
the particle diameter of the fog drops is less than 50 μm, and the judgment standard of the uniformity of the fog drops is as follows:
difference: the particle size of the fog drops is less than 60 percent within 20-50 mu m;
in general: the particle size of the fog drops is 60-80% within 20-50 μm;
good: 80-90% of fog drops with the particle size of 20-50 μm;
and (3) excellent: the fog drop has particle size of 20-50 μm and accounts for 90-100%.
As can be seen from table 1, the aerosol of each example satisfies the aerosol quality standard, and although the mass ratio of the gas phase and the liquid phase in the aerosol has a greater influence on the physicochemical properties of the aerosol, the content and composition of each component in the aerosol may have agglomeration and dispersion effects, which may affect the final spraying effect. Overall, the aerosol of the present invention has excellent physical and chemical properties.
Second, evaluation of curative effect of aerosol for diminishing inflammation and easing pain
Test 1: anti-inflammatory action of aerosols
Test animals: the body weight of an SPF male SD rat of 8 weeks old is 200 +/-10 g, and the total number is 110;
the test method comprises the following steps: rats were randomly divided into 11 groups of 10 rats, one group was a normal group, one group was a model group, and the other groups were test groups, and the test was started after 1 week of free diet, wherein 0.1mL of NaCl solution with a mass fraction of 0.9% was administered to each normal group, and 0.02ML of Sodium Urate (MSU) solution with a mass fraction of 25% was injected subcutaneously into the right hind plantar aspect of the feet of the rats in the remaining groups. The normal group was not administered 1h after the inflammation, the aerosol of each of the remaining test groups of examples 1 to 5 and comparative examples 1 to 4 was administered in an amount of 50. mu.L/rat, and the model group was administered with an equivalent amount of 0.9% by mass NaCl solution sprayed on the right hind paw of the rat until the skin was slightly dry. The swelling volumes of the rat footpads before, 1h, 2h and 5h after the model creation after the inflammation are measured, the swelling degree of the rat joint is calculated, wherein the swelling degree (mL) of the rat joint is the volume of the rat hind foot after the inflammation-the volume of the rat hind foot before the model creation, and the results are counted in the table 2.
TABLE 2 Effect of Aerosol on the degree of swelling of the foot sole of MSU-induced gouty arthritis rats
(Note: Delta: P < 0.05 in comparison with model group; Delta: P < 0.01 in comparison with model group)
As can be seen from Table 2, the swelling degree of toes of the rats in each example group was significantly decreased after 1h, 2h and 5h after the inflammation, and particularly, the rats showed good effect at 2h after the inflammation and were substantially recovered to normal at 5h after the inflammation. The swelling degree of the ratio of the other groups also showed a decreasing trend, but the effect was overall worse than that of example 3, especially comparative example 3 was not significant compared to the model group at 1h after inflammation. In conclusion, the aerosol of the present invention has a good anti-inflammatory effect.
Test 2: analgesic effect of aerosol
Test animals: the 6-week-old Kunming mice have both male and female bodies, and the weight of the Kunming mice is 20 +/-2 g, and the total number of the Kunming mice is 100.
The test method comprises the following steps: the mice were randomly divided into 10 groups, 10 mice in each group were used as a blank control group, the remaining groups were used as test groups, the blank control group was not administered, the test groups were administered with the products of examples 1-5 and comparative examples 1-4, respectively, the administration method was to spray feet externally, the administration amount was 0.1 mL/mouse, 30min after administration, 200 μ L of glacial acetic acid with a mass fraction of 0.6% was injected into the abdominal cavity of each group of mice, the number of writhing of the mice within 15min after injection (writhing specifically means that the abdomen is concave, the waist is bee-shaped, the trunk and the back are stretched, the hip is raised), and the test results were counted to table 3.
TABLE 3 inhibition of gout aerosols on writhing response in mice
| Examples of the invention | Number of times of twisting |
| Blank control group | 29.8±2.3 |
| Example 1 | 16.0±2.2* |
| Example 2 | 15.2±3.0* |
| Example 3 | 13.2±2.1** |
| Example 4 | 14.4±1.8** |
| Example 5 | 13.8±1.5** |
| Comparative example 1 | 17.3±2.0* |
| Comparative example 2 | 15.7±2.2* |
| Comparative example 3 | 19.9±2.6* |
| Comparative example 4 | 20.7±1.9* |
(Note: P < 0.05 in comparison with blank control group; P < 0.01 in comparison with blank control group)
As can be seen from table 3, the number of writhes in mice was significantly reduced after administration of the aerosol of the present invention, particularly when the aerosol of example 3 was sprayed on the mice, to 13.2 times, compared to the blank control group. In contrast, when no synergist was added to the aerosol composition or the content of the components was significantly changed, the effect was significantly inferior to that of example 3, although the composition also had a certain significant effect compared to the blank control group. In conclusion, the aerosol of the invention has obvious analgesic effect.
Finally, it should be noted that the above-mentioned contents are only used for illustrating the technical solutions of the present invention, and not for limiting the protection scope of the present invention, and that the simple modifications or equivalent substitutions of the technical solutions of the present invention by those of ordinary skill in the art can be made without departing from the spirit and scope of the technical solutions of the present invention.
Claims (10)
1. An aerosol formulation, characterized by: the aerosol consists of a gas phase and a liquid phase, wherein the liquid phase comprises the following raw materials: diclofenac sodium, laurocapram, propylene glycol, ethanol, polyethylene glycol, synergist and peppermint oil.
2. The aerosol formulation of claim 1, wherein: the liquid phase comprises the following raw materials in parts by weight: 10-20 parts of diclofenac sodium, 6-11 parts of laurocapram, 15-20 parts of propylene glycol, 25-30 parts of ethanol, 12-22 parts of polyethylene glycol, 3-8 parts of a synergist and 5-8 parts of peppermint oil.
3. The aerosol formulation of claim 2, wherein: the liquid phase comprises the following raw materials in parts by weight: 12-18 parts of diclofenac sodium, 8-10 parts of laurocapram, 16-18 parts of propylene glycol, 28-30 parts of ethanol, 15-20 parts of polyethylene glycol, 4-6 parts of a synergist and 6-7 parts of peppermint oil.
4. The aerosol formulation of claim 1, wherein: the synergist comprises tween-80, folinic acid and propyl gallate.
5. Aerosol according to claim 4, characterized in that: the weight ratio of the tween-80 to the folinic acid to the propyl gallate is 5-10:1: 6-9.
6. The aerosol formulation of claim 1, wherein: the gas phase is a propellant.
7. Aerosol according to claim 6, characterized in that: the propellant is one or more of propane, butane, isobutane, tetrafluoroethane, heptafluoropropane or dimethyl ether.
8. The aerosol formulation of claim 1, wherein: the weight ratio of the liquid phase to the gas phase is 1: 2-6.
9. A method of producing an aerosol formulation as claimed in any one of claims 1 to 8, wherein: the method comprises the following steps:
(1) after being crushed, the diclofenac sodium is added into ethanol, and the mixture is stirred and mixed evenly to obtain a mixed solution A;
(2) uniformly mixing laurocapram, propylene glycol, ethanol, polyethylene glycol, a synergist and peppermint oil to obtain a mixed solution B;
(3) mixing the mixed solution A and the mixed solution B, and shearing and stirring the mixed solution A and the mixed solution B until the mixed solution is a micron-sized micro-emulsion solution;
(4) and (4) injecting the micron-sized micro-emulsion solution obtained in the step (3) into a container, sealing the container, injecting a gas phase, and pressing the cover to obtain the aerosol.
10. The method of claim 9, wherein: the particle size of the micron-sized microemulsion is 5-10 mu m.
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