CN117224510A - External preparation for relieving pain and preparation method thereof - Google Patents
External preparation for relieving pain and preparation method thereof Download PDFInfo
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- CN117224510A CN117224510A CN202311066249.8A CN202311066249A CN117224510A CN 117224510 A CN117224510 A CN 117224510A CN 202311066249 A CN202311066249 A CN 202311066249A CN 117224510 A CN117224510 A CN 117224510A
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- 208000002193 Pain Diseases 0.000 title claims abstract description 17
- 230000036407 pain Effects 0.000 title claims abstract description 17
- VHUXSAWXWSTUOD-UHFFFAOYSA-L fenoprofen calcium (anhydrous) Chemical compound [Ca+2].[O-]C(=O)C(C)C1=CC=CC(OC=2C=CC=CC=2)=C1.[O-]C(=O)C(C)C1=CC=CC(OC=2C=CC=CC=2)=C1 VHUXSAWXWSTUOD-UHFFFAOYSA-L 0.000 claims abstract description 24
- 229960005341 fenoprofen calcium Drugs 0.000 claims abstract description 23
- 239000003814 drug Substances 0.000 claims abstract description 22
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Abstract
The invention relates to the technical field of external analgesic drugs, in particular to an external preparation for relieving pain and a preparation method thereof, wherein the external preparation comprises fenoprofen calcium, a surfactant, a solvent system and a film forming agent in parts by weight; the topical formulation has a viscosity that adheres to the skin surface and forms a drug film layer, and the drug film layer delivers the drug at a therapeutically effective rate for at least about 2 hours. The invention has simple preparation, improves the dispersibility of the fenoprofen calcium by a microemulsifying mode, realizes solubilization of the fenoprofen calcium, effectively increases the solubility of insoluble drugs, improves the bioavailability, and ensures that the prepared microemulsion gel can directly act on lesion sites, improves the curative effect of the drugs on the affected parts and reduces adverse reactions of the whole body.
Description
Technical Field
The invention relates to the technical field of external analgesic drugs, in particular to an external preparation for relieving pain and a preparation method thereof.
Background
Fenoprofen calcium is a non-steroidal anti-inflammatory agent that is useful in a variety of arthritic conditions including rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, gouty arthritis and other soft tissue pain. It can also be used for treating other pains such as dysmenorrhea, toothache, injury, traumatic pain, etc. The common side effects of non-steroidal anti-inflammatory drugs can increase the risk of developing hypertension, stroke or heart disease, and the appearance of symptoms associated with gastric disorders, such as heartburn, bleeding, ulcers, and the like. These side effects cause great trouble for patients who need to take medicine for a long period of time.
Conventional dermal drug delivery systems can generally be divided into two forms: semi-solid formulations and skin patch formulations. Semi-solid formulations come in several different forms, including ointments, creams, foams, pastes, gels or lotions, and are applied topically to the skin. Skin patch dosage forms also exist in several different forms, including matrix patch structures and reservoir patch structures. In matrix patches, the active agent is mixed in an adhesive that is coated onto a backing film. The drug-loaded adhesive layer is typically applied directly to the skin and functions as a means of adhering the patch to the skin and as a reservoir or carrier for facilitating drug delivery. In contrast, in a reservoir patch, the drug is typically incorporated into a solvent system contained by a thin bag, which may be a thin flexible container. The pouch may include a permeable or semi-permeable membrane surface coated with an adhesive for adhering the membrane to the skin.
The skin drug delivery system can directly act on the lesion part, improve the drug curative effect of the affected part and reduce the adverse reaction of the whole body. However, fenoprofen calcium is soluble in ethanol, slightly soluble in methanol, very slightly soluble in water, and hardly soluble in chloroform. Belongs to a poorly soluble drug, has poor skin permeability, and has low drug solubility when being prepared into an external preparation, so that only a fenoprofen calcium oral preparation is available in China at present, and no external preparation exists. Therefore, developing a transdermal drug delivery system of external analgesic drugs with high bioavailability, good stability and convenient cleaning is a technical problem that one skilled in the art wants to solve.
Disclosure of Invention
In order to overcome the defects of the technology, the invention provides an external preparation for relieving pain and a preparation method thereof, and the external preparation has the advantages of good biocompatibility and stability, simple preparation, convenient cleaning and the like.
The invention is realized by the following technical scheme:
in one aspect, the invention provides an external preparation for relieving pain, which is characterized by comprising the following components in parts by weight:
1-10 parts of fenoprofen calcium, 1-10 parts of surfactant, 80-100 parts of solvent system and 0.1-1 part of film forming agent; the topical formulation has a viscosity that adheres to the skin surface and forms a drug film layer, and the drug film layer delivers the drug at a therapeutically effective rate for at least about 2 hours; according to the preferred embodiment of the invention, 3-8 parts of fenoprofen calcium, 3-8 parts of surfactant, 85-95 parts of solvent system and 0.5-1 part of film forming agent.
Further, the surfactant is selected from one or a combination of poloxamer, tween, polyethylene glycol and tyloxapol.
Further, the surfactant is selected from poloxamers.
Further, the film forming agent is selected from one or a combination of polyvinyl alcohol, pregelatinized starch, ethylcellulose, fish gelatin, silica gel, guar gum, gluten, casein, calcium caseinate, methyl acrylate, xanthan gum, siloxytrimethyl ester, polacrilin, poloxamer, carbomer, polyethylene oxide, poly G-lactic acid/poly L-lactic acid, terpenoid, locust bean gum acrylic acid copolymer, polyurethane dispersion, dextrin.
Further, the film forming agent is selected from carbomers.
Further, the solvent system includes water and a non-volatile solvent.
Further, the non-volatile solvent is selected from one of anise oil, almond oil, dimethyl isosorbide, alkyl glucosides, benzyl alcohol, beeswax, benzyl benzoate, butylene glycol, mountain soybean oil, castor oil, cinnamaldehyde, cinnamon oil, clove oil, coconut oil, cocoa butter, coconut glyceride, corn oil, coriander oil, corn syrup, cottonseed oil, cresol, diacetin, diacetyl monoglyceride, triethanolamine, triglycerides, ethylene glycol, eucalyptus oil, hydrogenated castor oil, IP palmitate, lemon oil, lime oil, glycerol, limonene, monoacetin, monoglyceride, nutmeg oil, octyldodecanol, sweet orange oil, palm oil, peanut oil, PEG vegetable oil, peppermint oil, vaseline oil, phenol, pine needle oil, propylene glycol, sesame oil, spearmint oil, soybean oil, vegetable oil, or a combination thereof; according to a preferred embodiment of the present invention, the non-volatile solvent is selected from one or a combination of anise oil, almond oil, triethanolamine, triglycerides, ethylene glycol, pine needle oil, propylene glycol, hydrogenated castor oil, monoglycerides.
Further, the drug film layer forms within about 15 minutes of application to the skin surface under standard skin conditions and ambient conditions; according to the preferred embodiment of the invention, the film forming time of the medicine film layer is 8-10 minutes.
Further, the formulation has an initial viscosity of about 100-3,000,000cp prior to application to the skin surface; according to a preferred embodiment of the invention, the initial viscosity of the formulation is 5000-20000cP.
On the other hand, the invention provides a preparation method of an external preparation, which is characterized in that: uniformly mixing the fenoprofen calcium, the surfactant and part of the solvent system in parts by mass, then adding the rest of the solvent system and the film forming agent, and uniformly mixing; according to the preferred embodiment of the invention, the film forming agent is firstly mixed with part of water by mass to form hydrogel, the fenoprofen calcium, the emulsifier, the nonvolatile solvent by mass and part of water are uniformly mixed to form emulsion, and then the hydrogel and the emulsion are uniformly mixed to prepare the aqueous emulsion.
The beneficial effects are that: the invention has simple preparation, improves the dispersibility of the fenoprofen calcium by a microemulsifying mode, realizes solubilization of the fenoprofen calcium, effectively increases the solubility of insoluble drugs, improves the bioavailability, and ensures that the prepared microemulsion gel can directly act on lesion sites, improves the curative effect of the drugs on the affected parts and reduces adverse reactions of the whole body.
Detailed Description
The present invention will be described in detail with reference to specific embodiments thereof, so that those skilled in the art can better understand the technical solutions of the present invention. The experimental procedures, which do not address the specific conditions in the examples below, are generally carried out under conventional conditions or under conditions recommended by the manufacturer. The test materials used in the examples described below, unless otherwise specified, were purchased from conventional biochemical reagent stores. Percentages and parts are by weight unless otherwise indicated. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.
Example 1
Adding 5 parts of fenoprofen calcium into 10 parts of triglyceride, stirring and dispersing, adding 5 parts of poloxamer and 2 parts of propylene glycol, uniformly mixing, adding a mixed solution of 3 parts of triethanolamine and 25 parts of water, dissolving 0.5 part of carbomer into 50 parts of water to prepare carbomer hydrogel, and adding the mixed solution into the carbomer hydrogel, and uniformly mixing to prepare the external preparation.
Example 2
Adding 5 parts of fenoprofen calcium into 8 parts of castor oil, stirring and dispersing, adding 8 parts of poloxamer and 2 parts of glycerin, uniformly mixing, adding a mixed solution of 3 parts of triethanolamine and 25 parts of water, dissolving 0.5 part of carbomer into 50 parts of water to prepare carbomer hydrogel, and adding the mixed solution into the carbomer hydrogel, and uniformly mixing to prepare the external preparation.
Example 3
3 parts of fenoprofen calcium is added into 8 parts of coconut oil, stirred and dispersed, 8 parts of poloxamer and 2 parts of ethylene glycol are added, mixed solution of 5 parts of triethanolamine and 25 parts of water is added, 0.8 part of carbomer is dissolved in 55 parts of water to prepare carbomer hydrogel, and then the mixed solution is added into the carbomer hydrogel and mixed uniformly to prepare the external preparation.
Example 4
Adding 8 parts of fenoprofen calcium into 10 parts of clove oil, stirring and dispersing, adding 3 parts of poloxamer and 2 parts of butanediol, uniformly mixing, adding a mixed solution of 3 parts of triethanolamine and 20 parts of water, dissolving 0.8 part of carbomer into 55 parts of water to prepare carbomer hydrogel, and adding the mixed solution into the carbomer hydrogel, and uniformly mixing to prepare the external preparation.
Example 5
10 parts of fenoprofen calcium is added into 8 parts of castor oil, stirred and dispersed, 7 parts of poloxamer and 2 parts of propylene glycol are added, mixed solution of 4 parts of triethanolamine and 25 parts of water is added, 0.5 part of carbomer is dissolved in 60 parts of water to prepare carbomer hydrogel, and then the mixed solution is added into the carbomer hydrogel and mixed uniformly to prepare the external preparation.
Example 6
Adding 2 parts of fenoprofen calcium into 5 parts of triglyceride, stirring and dispersing, adding 7 parts of poloxamer and 2 parts of glycerol, uniformly mixing, adding a mixed solution of 5 parts of triethanolamine and 25 parts of water, dissolving 0.3 part of carbomer into 50 parts of water to prepare carbomer hydrogel, and adding the mixed solution into the carbomer hydrogel, and uniformly mixing to prepare the external preparation.
Comparative example 1
Unlike example 1, no poloxamer was added.
Comparative example 2
Unlike example 2, the calcium fenoprofen was directly added to the carbomer hydrogel for mixing without the addition of castor oil, poloxamer and glycerin.
Performance test of inventive examples and comparative examples
(1) Skin irritation test: selecting rabbits as tested animals, wherein each group comprises 4 rabbits, each male and female animals are half, each test animal is tested in parallel with 3 groups in each example/comparative example, and the tested animals are respectively subjected to dehairing treatment, the dehairing range is 3cm multiplied by 3cm, and the dehairing treatment is ensured that skin injury is not caused; uniformly coating the sample on the dehaired rabbit skin, covering with two layers of gauze (2.5 cm×2.5 cm) and a layer of cellophane, fixing with non-irritating adhesive tape and bandage, and applying for 4 hr; after the application, the sample was removed and the administration site was cleaned with warm water, and the results were shown in Table 1, using the degree of erythema and edema on the skin as an evaluation index.
The scoring criteria were: no erythema 0 score, mild erythema 1 score, moderate erythema (visibly apparent) 2 score, severe erythema 3 score, mauve erythema to mild eschar formation 4 score, no edema 0 score, mild edema (marginally visible) 1 score, moderate edema (visibly elevated) 2 score, severe edema (skin elevated 1mm, clearly outlined) 3 score, severe edema (skin elevated 1mm above and enlarged) 4 score.
| Group of | Score value |
| Example 1 | 0.26 |
| Example 2 | 0.29 |
| Example 3 | 0.31 |
| Example 4 | 0.34 |
| Example 5 | 0.36 |
| Example 6 | 0.23 |
| Comparative example 1 | 1.45 |
| Comparative example 1 | 1.62 |
As can be seen from the above table, the microemulsion gel of the present invention was not irritating to rabbit skin, whereas the gels prepared in comparative examples 1-2 were slightly irritating to rabbit skin. From the above table, it is demonstrated that the gel is prepared after the fenoprofen calcium is encapsulated in ethosomes, so that the irritation caused by the fenoprofen calcium directly contacting the skin is reduced.
(2) And (3) packet rate measurement: precisely transferring the sample to be tested, placing the sample in a pretreated dialysis bag, placing the dialysis bag in 300mL of dialysis medium for dialysis, wherein the dialysis medium is a mixed solution of ethanol and water in a ratio of 3:7, and updating the dialysis medium after dialysis for 12 hours, and then dialyzing for 12 hours; measuring the amount of fenoprofen calcium in a sample to be tested before and after dialysis, wherein the amounts are respectively W1 and W2; encapsulation efficiency was calculated as follows: encapsulation efficiency% = W2/W1 x 100%. The test results are shown in Table 2.
| Group of | Packet rate |
| Example 1 | 86.7 |
| Example 2 | 85.9 |
| Example 3 | 82.8 |
| Example 4 | 84.1 |
| Example 5 | 83.4 |
| Example 6 | 81.3 |
| Comparative example 1 | 46.1 |
| Comparative example 2 | 37.9 |
As can be seen from the above table, the microemulsion gel of the present invention has a higher encapsulation efficiency than comparative examples 1-2, and the microemulsion gel prepared in examples 1-2 has a high encapsulation efficiency, a large drug-loading capacity, and a good percutaneous permeation effect.
Finally, it should be noted that the above description is only a preferred embodiment of the present invention, and that many similar changes can be made by those skilled in the art without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (10)
1. An external preparation for relieving pain is characterized by comprising the following components in parts by mass: 1-10 parts of fenoprofen calcium, 1-10 parts of surfactant, 80-100 parts of solvent system and 0.1-1 part of film forming agent; the topical formulation has a viscosity that adheres to the skin surface and forms a drug film layer, and the drug film layer delivers the drug at a therapeutically effective rate for at least about 2 hours.
2. An external preparation for relieving pain according to claim 1, wherein: the surfactant is selected from one or a combination of poloxamer, tween, polyethylene glycol and tyloxapol.
3. An external preparation for relieving pain according to claim 2, wherein: the surfactant is selected from poloxamers.
4. An external preparation for relieving pain according to claim 1, wherein: the film forming agent is selected from one or a combination of polyvinyl alcohol, pregelatinized starch, ethylcellulose, fish gelatin, silica gel, guar gum, gluten, casein, calcium caseinate, methyl acrylate, xanthan gum, siloxytrimethyl ester, polaxlin, poloxamer, carbomer, polyethylene oxide, poly G-lactic acid/poly L-lactic acid, terpenoid resin, locust bean gum acrylic acid copolymer, polyurethane dispersion, dextrin.
5. An external preparation for relieving pain according to claim 4, wherein: the film forming agent is selected from carbomers.
6. An external preparation for relieving pain according to claim 1, wherein: the solvent system includes water and a non-volatile solvent.
7. An external preparation for relieving pain according to claim 6, wherein: the non-volatile solvent is selected from one or a combination of anise oil, almond oil, dimethyl isosorbide, alkyl glucosides, benzyl alcohol, beeswax, benzyl benzoate, butylene glycol, mountain flat soybean oil, castor oil, cinnamaldehyde, cinnamon oil, clove oil, coconut oil, cocoa butter, coconut glyceride, corn oil, coriander oil, corn syrup, cottonseed oil, cresol, diacetin, diacetyl monoglyceride, triethanolamine, triglyceride, ethylene glycol, eucalyptus oil, hydrogenated castor oil, IP palmitate, lemon oil, lime oil, glycerin, limonene, monoacetin, monoglyceride, nutmeg oil, octyldodecanol, sweet orange oil, palm oil, peanut oil, PEG vegetable oil, peppermint oil, vaseline oil, phenol, pine needle oil, propylene glycol, sesame oil, spearmint oil, soybean oil, and vegetable oil.
8. An external preparation for relieving pain according to claim 1, wherein: the drug film layer formed within about 15 minutes of application to the skin surface under standard skin conditions and ambient conditions.
9. An external preparation for relieving pain according to claim 1, wherein: the formulation has an initial viscosity of about 100-3,000,000cp prior to application to the skin surface.
10. A method for preparing the external preparation according to claim 1, wherein: uniformly mixing the fenoprofen calcium, the surfactant and part of the solvent system in parts by mass, then adding the rest of the solvent system and the film forming agent, and uniformly mixing.
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