CN116059383A - Flurbiprofen salt gel and crystallization inhibitor thereof - Google Patents
Flurbiprofen salt gel and crystallization inhibitor thereof Download PDFInfo
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- CN116059383A CN116059383A CN202310051945.5A CN202310051945A CN116059383A CN 116059383 A CN116059383 A CN 116059383A CN 202310051945 A CN202310051945 A CN 202310051945A CN 116059383 A CN116059383 A CN 116059383A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract
The invention belongs to the field of medicines, and in particular relates to an anti-crystallization agent for inhibiting flurbiprofen salt crystallization in a gel preparation, which comprises propylene glycol and menthol in a weight ratio of 20-100:1. The invention also comprises the application of the anti-crystallization agent in preparing flurbiprofen sodium gel preparation. According to the invention, through the use of the anti-crystallization agent, the problem of freeze thawing crystallization of flurbiprofen sodium in a gel preparation can be effectively reduced.
Description
Technical field:
the invention belongs to the technical field of transdermal administration preparations, and particularly relates to a flurbiprofen gel composition and a preparation method thereof.
The background technology is as follows:
flurbiprofen salts such as flurbiprofen sodium are (RS) -2- (2-fluorobiphenyl-4-yl) propionic acid sodium salt dihydrate and are phenylpropionic acid non-steroidal anti-inflammatory analgesics. Animal studies have shown that it has analgesic, antipyretic and anti-inflammatory effects, and its mechanism of action is mainly to inhibit Cyclooxygenase (COX) activity, block prostaglandin synthesis, and alleviate inflammatory reactions. Widely used for musculoskeletal and joint diseases, but has the same gastrointestinal side effects of peptic ulcer, hemorrhage and the like caused by oral administration as other non-steroidal anti-inflammatory drugs. The transdermal administration preparation can increase local drug concentration of flurbiprofen at pain part, enhance anti-inflammatory effect, and avoid adverse reaction of gastrointestinal tract administration. Flurbiprofen gel, ointment, liniment, film, patch and the like are available. However, the external preparation is added with a plurality of auxiliary materials and auxiliary agents, which has obvious influence on the stability of active ingredients of the main medicine, so that the pharmaceutical preparation is unstable.
The gel is a thick semisolid preparation, has the advantages of high absorption speed, good biocompatibility, uniform texture, easy spreading and washing out, convenient use, good patient compliance and the like, and the main component of the hydrogel preparation is water, a small amount of gel matrix, humectant, bacteriostat and the like, and the possibility of adverse reaction caused by the matrix is obviously reduced. Therefore, the flurbiprofen gel can be researched and developed, the drug effect can be rapidly exerted, the compliance of the gel is enhanced, and the adverse reaction rate is reduced.
The Chinese patent application CN111904925A discloses a flurbiprofen sodium gel preparation, a preparation method and application thereof, and provides a flurbiprofen gel with good transdermal absorption effect, simple preparation process and stable product quality, which comprises the following components: 0.5 to 5 percent of flurbiprofen sodium, 0.5 to 5 percent of matrix, 50 to 95 percent of solvent, 0 to 5 percent of pH regulator, 0.1 to 20 percent of percutaneous absorption permeation enhancer and 0.1 to 1.0 percent of preservative. The non-clinical study results showed that: the flurbiprofen sodium gel has obvious improvement on acute soft tissue injury, osteoarthritis and tendon injury models. However, the formula product still has certain defects that the active ingredient can generate crystals under the low temperature and freeze thawing conditions, and the transdermal absorption effect is affected. In order to avoid crystallization of active ingredients, the pH value of the product can be improved, but under the high pH value, the antibacterial agent is degraded, and the degradation products, main medicine ingredients and other auxiliary materials act to generate new substances and other impurities which are obviously increased, so that the safety of the product is seriously influenced.
Disclosure of Invention
The invention aims to solve the problem of crystallization of flurbiprofen salt in a gel preparation.
The second object of the present invention is to provide the use of said anti-crystallization agent for inhibiting the crystallization of flurbiprofen axetil in a gel.
A third object of the present invention is to provide a flurbiprofen axetil gel to which the anti-crystallization agent is added.
The flurbiprofen salt in the gel preparation is easy to generate crystals under the conditions of low temperature and freeze thawing, and the gel quality and the drug effect stability are affected. Although the problems of low temperature and freeze thawing crystallization can be reduced to a certain extent by increasing the pH of the gel, the content of relevant impurities is easily increased, and the stability of the gel product is affected. In order to solve the problem, the invention provides the following improvement scheme:
an anti-crystallization agent for inhibiting the crystallization of flurbiprofen salt in a gel preparation comprises propylene glycol and menthol in a weight ratio of 20-100:1.
The research of the invention shows that the propylene glycol and menthol are combined, and the combination control of the weight ratio of the propylene glycol and menthol is further matched, so that the synergy can be realized unexpectedly, the problem of low-temperature crystallization of flurbiprofen salt in a gel preparation can be effectively inhibited unexpectedly, and the quality and the drug effect stability of the flurbiprofen salt gel are improved.
In the invention, the combined control of the components and the proportion of the propylene glycol and the menthol is the key to cooperatively solve the problem of salting-out crystal of flurbiprofen in the gel.
In the invention, the anti-crystallization agent consists of propylene glycol and menthol according to the weight ratio.
Preferably, in the anti-crystallization agent, propylene glycol: the weight ratio of menthol is 24-100:1; more preferably 40 to 75:1. The research of the invention shows that under the preferable proportion, not only the good gel freeze-thawing resistant effect can be obtained, but also the stability of the gel can be further improved, and the content of related substances can be reduced.
In the invention, the flurbiprofen salt is a pharmaceutically acceptable salt of flurbiprofen, preferably flurbiprofen sodium.
The invention also provides an application of the anti-crystallization agent, which is used as the anti-crystallization agent for inhibiting the crystallization of flurbiprofen salt and is used for preparing gel medicines containing the flurbiprofen salt.
The invention develops a brand new application of the crystallizing inhibitor with the specific proportion in inhibiting the low-temperature crystallization of flurbiprofen salt in the gel preparation. According to the invention, the gel preparation is prepared by combining the anti-crystallization agent and the flurbiprofen salt in specific combination and proportion, so that the crystallization of the flurbiprofen salt in the gel preparation at low temperature can be effectively inhibited, and the quality stability and the drug effect problems of the gel preparation can be improved.
Preferably, in said application, said anti-crystallization agent is used for preparing transdermal absorption gel medicaments containing flurbiprofen salts.
Preferably, in the application, the propylene glycol in the crystallization inhibitor is used in an amount of 12-25% of the total weight of the gel preparation; more preferably 12 to 20%. In the invention, under the use of the crystallization inhibitor, good freezing and thawing resistant effect can be obtained, and gel has excellent stability and can reduce degradation and release of related substances.
The invention also provides flurbiprofen salt gel, which is gel containing flurbiprofen salt, a matrix, a solvent, a bacteriostat, a pH regulator and the anti-crystallization agent.
The flurbiprofen salt gel disclosed by the invention is beneficial to the use of the anti-crystallization agent with the special proportion and the combination of other components, so that the problem of low-temperature crystallization of the flurbiprofen salt in a gel system can be cooperatively solved, the antibacterial performance can be cooperatively improved, the impurity growth rate is slowed down, and the quality and the effect stability of the gel are improved.
Preferably, the solvent is at least one of isopropanol, ethanol and water; further preferred is a mixed solvent of isopropyl alcohol and water, wherein the sum of the amounts of isopropyl alcohol and propylene glycol is 20 to 30%.
Preferably, the bacteriostatic agent is at least one of methyl benzoate, ethyl benzoate, propyl benzoate and butyl benzoate.
Preferably, the pH regulator is at least one of triethanolamine, diethanolamine, tromethamine, sodium hydroxide and triethylamine.
Preferably, the matrix is at least one of carbomer, hypromellose and sodium carboxymethyl cellulose.
Preferably, the flurbiprofen axetil gel comprises the following components in percentage by weight:
0.5 to 4.0wt.% flurbiprofen salt (calculated as flurbiprofen);
12 to 25.5wt.% of an anti-crystallization agent;
0.5 to 3.0wt.% of matrix;
0.05 to 1.0wt.% of bacteriostat;
0.5 to 3.0wt.% of pH regulator;
the balance being solvent.
Further preferably, the flurbiprofen axetil gel comprises the following components in percentage by weight:
0.5 to 2.0wt.% flurbiprofen salt (calculated as flurbiprofen);
12 to 25.5wt.% of an anti-crystallization agent;
0.7 to 2.0wt.% of matrix;
0.05 to 0.2wt.% of nipagin ester;
0.5 to 2.0wt.% of pH regulator;
the balance being solvent.
Preferably, the flurbiprofen axetil gel according to the present invention is a homogeneous gel comprising flurbiprofen axetil, an anti-crystallization agent, a matrix, a solvent, and nipagin ester.
In the present invention, it is not necessary to construct an alkaline gel environment thanks to the use of the anti-crystallization agent, for example, the flurbiprofen axetil gel according to the present invention may have a pH of 6.0 to 7.4.
Preferably, the flurbiprofen axetil gel is a transdermal absorption external gel.
The invention also provides a preparation method of the flurbiprofen axetil gel, which comprises the steps of swelling a matrix with a solvent, and mixing the matrix with other components to form the gel.
The invention also provides application of the flurbiprofen axetil gel in preparing external pharmaceutical preparations for relieving fever, easing pain or resisting inflammation.
Advantageous effects
In order to avoid the problems of gel product quality and drug effect instability caused by low-temperature freeze thawing crystallization of flurbiprofen salt in a gel preparation, the invention discovers that the combination of propylene glycol and menthol required by the special proportion can realize unexpected synergy, can obviously solve the crystallization problem of the flurbiprofen salt in the gel preparation, and improves the quality and the preparation stability of the flurbiprofen salt gel preparation.
In the invention, due to the use of the crystallization resistance, the problem of low-temperature crystallization of flurbiprofen salt in a gel preparation can be solved without an alkaline condition, thereby being beneficial to cooperatively reducing the growth of impurities and improving the stability of the API.
In the invention, the proportion of the propylene glycol to the menthol and the addition amount of the anti-crystallization agent are further controlled, which is helpful for further synergistically improving the performance of the gel, so that the gel has excellent freeze-thawing resistance and stability.
Detailed description of the preferred embodiments
Examples:
the recipe is shown in table 1 below: (wherein the content of flurbiprofen sodium is calculated as flurbiprofen)
TABLE 1
The preparation process comprises the following steps:
1. weighing the materials according to a proportion;
2. carbomers were added to the appropriate amount of purified water to fully swell.
3. And adding triethanolamine into the swelled solution, and stirring to obtain a gel matrix.
4. Adding the anti-crystallization agent, isopropanol and ethylparaben into the residual purified water, uniformly stirring, adding flurbiprofen sodium, and stirring for dissolution.
5. And (3) adding the solution obtained in the step (4) into the gel matrix obtained in the step (3), stirring, and filling and sealing to obtain the flurbiprofen sodium gel.
The formulation of the comparative example is shown in the following table:
comparative example 1
The only difference compared to example 2 is that propylene glycol is replaced with an equal weight of isopropanol, and other operations and parameters are the same as in example 2.
Comparative example 2
The only difference compared to example 2 is that propylene glycol is replaced with equal weight of glycerol, other operations and parameters are the same as in example 2.
Comparative example 3
The only difference compared to example 7 is that propylene glycol is replaced with equal weight of glycerol, and other operations and parameters are the same as in example 7.
Comparative example 4
The only difference compared to example 2 is that menthol is replaced with an equal weight of isopropyl myristate, the other procedures and parameters being the same as in example 2.
Comparative example 5
The only difference compared to example 2 is that the total amount of anti-crystallization agent is unchanged, propylene glycol: menthol is 200:1 by weight, and other operations and parameters are the same as in example 2.
Comparative example 6
The only difference compared to example 2 is that the total amount of anti-crystallization agent is unchanged, propylene glycol: menthol was used in a weight ratio of 121:1, with other procedures and parameters being the same as in example 2.
Comparative examples 1-6 the preparation was the same as in examples.
Example 12
The only difference compared to example 2 is that the total amount of anti-crystallization agent is unchanged, propylene glycol: menthol is present in a weight ratio of 20:1, and other procedures and parameters are the same as in example 2.
Example 13
In comparison with example 2, the difference is that propylene glycol: the menthol proportion was unchanged, the propylene glycol content was 30%, and other operations and parameters were the same as in example 2.
The results of examining the properties of the samples of examples 1 to 13 and comparative examples 1 to 6 are shown in Table 2.
TABLE 2 observations of sample Properties
a: low temperature freeze thawing test:
1) For medicines with temperature variation range above freezing point, the thermal cycle experiment should include three cycles, each cycle should be at 2-8deg.C for two days, and then examined at 40deg.C for two days under acceleration. (Low temperature condition investigation)
2) For drugs that may be exposed below freezing, the thermal cycling test should include three cycles, each cycle at-10 to-20 ℃ for two days, followed by two days of investigation at 40 ℃ acceleration. (Freeze-thawing condition investigation)
As can be seen from table 2, the crystallization inhibitor according to the present invention can realize synergy based on the control of the components and the content, and can solve the problem of low-temperature freeze-thawing crystallization.
Experimental example two acceleration stability investigation
A typical non-freeze-thaw gel was subjected to stability testing.
The results of the accelerated test of the flurbiprofen sodium gel preparations prepared in examples 1,2,3,5,7, 12 and 13 using the drug stability test method in four parts of the 2020 edition of chinese pharmacopoeia are shown in table 3 below.
TABLE 3 stability test
Therefore, the gel prepared by adopting the crystallization inhibitor can obtain good freezing and thawing resistance effect and good stability. It was also found by comparing examples 1,2,3,5, and 7 with examples 12 to 13 that the stability of the gel formulation can be further improved by further controlling the proportion thereof in the gel formulation and the addition amount thereof under the anti-crystallization agent.
According to the experimental study, in the flurbiprofen sodium gel preparation, the combination of menthol and propylene glycol can be used as a solubilizer, so that the solubility of the flurbiprofen sodium in the preparation is improved, the problem of crystallization of the API in the preparation is solved under the condition that other organic solvents for increasing skin irritation are avoided, and meanwhile, the total impurity amount of the preparation is obviously reduced compared with the prior art, and the content of the API can be kept stable.
Claims (10)
1. An anti-crystallization agent for inhibiting the crystallization of flurbiprofen salt in a gel preparation is characterized by comprising propylene glycol and menthol in a weight ratio of 20-100:1.
2. An anti-crystallization agent according to claim 1, consisting of propylene glycol and menthol in the stated weight ratio;
preferably, the flurbiprofen salt is a pharmaceutically acceptable salt of flurbiprofen, preferably sodium flurbiprofen;
preferably, the weight ratio of the propylene glycol to the menthol is 24-100:1; more preferably 40 to 75:1.
3. Use of an anti-crystallization agent according to claim 1 or 2 as an anti-crystallization agent for inhibiting crystallization of flurbiprofen salt for the preparation of a gel medicament for external use containing flurbiprofen salt.
4. The use of an anti-crystallization agent according to claim 3, wherein the amount of propylene glycol in the anti-crystallization agent is 12-25% of the total weight of the gel formulation; more preferably 12 to 20%.
5. A flurbiprofen axetil gel comprising a flurbiprofen axetil salt, a matrix, a solvent, a bacteriostat, a pH adjuster, and the anti-crystallization agent of claim 1.
6. The flurbiprofen axetil gel according to claim 5, wherein the solvent is at least one of isopropanol, ethanol and water;
preferably, the solvent is a mixed solvent of isopropanol and water;
preferably, the solvent is isopropanol and water, wherein the sum of the dosages of the isopropanol and the propylene glycol is 20-30%;
preferably, the matrix is at least one of carbomer, hypromellose and sodium carboxymethyl cellulose.
7. The flurbiprofen axetil gel according to claim 5, wherein the antibacterial agent is at least one of methyl paraben, ethyl paraben, propyl paraben, and butyl paraben;
preferably, the pH regulator is at least one of triethanolamine, diethanolamine, tromethamine, sodium hydroxide and triethylamine.
8. Flurbiprofen axetil gel according to any one of claims 5 to 7, comprising the following components in percentage by weight:
0.5 to 4.0wt.% flurbiprofen salt;
12 to 25.5wt.% of an anti-crystallization agent;
0.5 to 3.0wt.% of matrix;
0.05 to 1.0wt.% of bacteriostat;
0.5 to 3.0wt.% of pH regulator;
the balance being solvent.
9. Flurbiprofen axetil gel according to any one of claims 5 to 8, which is a homogeneous gel comprising flurbiprofen axetil, an anti-crystallization agent, a matrix, a solvent, and a paraben;
preferably, the flurbiprofen axetil gel is a transdermal absorption external gel;
preferably, the flurbiprofen axetil gel has a pH of 6.0 to 7.4.
10. Use of a flurbiprofen axetil gel according to any one of claims 5 to 9 for the preparation of a topical pharmaceutical formulation for the treatment of fever, pain or inflammation.
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| CN202310051945.5A CN116059383B (en) | 2023-02-02 | 2023-02-02 | Flurbiprofen salt gel and crystallization inhibitor thereof |
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| CN202310051945.5A CN116059383B (en) | 2023-02-02 | 2023-02-02 | Flurbiprofen salt gel and crystallization inhibitor thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111012737A (en) * | 2019-02-23 | 2020-04-17 | 湖南九典制药股份有限公司 | Flurbiprofen sodium gel and preparation method thereof |
| CN111615381A (en) * | 2018-01-18 | 2020-09-01 | 大化制药株式会社 | Pharmaceutical composition for transdermal administration in the form of a hydrogel patch |
| CN111904925A (en) * | 2020-04-28 | 2020-11-10 | 湖南九典制药股份有限公司 | Flurbiprofen sodium gel preparation and preparation method and application thereof |
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- 2023-02-02 CN CN202310051945.5A patent/CN116059383B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111615381A (en) * | 2018-01-18 | 2020-09-01 | 大化制药株式会社 | Pharmaceutical composition for transdermal administration in the form of a hydrogel patch |
| CN111012737A (en) * | 2019-02-23 | 2020-04-17 | 湖南九典制药股份有限公司 | Flurbiprofen sodium gel and preparation method thereof |
| CN111904925A (en) * | 2020-04-28 | 2020-11-10 | 湖南九典制药股份有限公司 | Flurbiprofen sodium gel preparation and preparation method and application thereof |
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