CN113559057A - Timolol maleate gel and preparation method thereof - Google Patents
Timolol maleate gel and preparation method thereof Download PDFInfo
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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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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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
- 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
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention discloses a timolol maleate gel and a preparation method thereof, and particularly relates to the technical field of medicines, wherein the used raw materials (in percentage by weight) comprise 1-4.5% of timolol maleate, 8-12% of a combined penetration enhancer, 4-11% of a humectant, 0.05-0.15% of a preservative, 10.5-29% of a gel matrix and water, wherein the water accounts for the rest. The timolol maleate gel prepared by the invention has the characteristics of uniformity, fineness, proper viscosity, easiness in spreading, no stimulation to skin and the like. In the hydrogel preparation, the permeation promoting mechanism of azone can disturb the ordered structure of the stratum corneum and influence the fluidity of cell membranes, propylene glycol can improve the solubility of the medicament in the stratum corneum to promote the percutaneous absorption of the medicament, and the propylene glycol and the stratum corneum have the combined and synergistic permeation promoting effects so as to improve the percutaneous absorption performance and reduce the irritation to the skin.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a timolol maleate gel and a preparation method thereof.
Background
The infantile hemangioma is a benign tumor frequently occurring in infants, the incidence rate of the infantile hemangioma is 1.1% -2.6% in newborns, 2/3 occurs at the head and neck parts, wherein the prevalence rate of infants under 1 year of age is as high as 10% -12%, the incidence rate of the infantile hemangioma is high, the symptoms are light under general conditions, the tumor body is small, and the infantile hemangioma can be automatically regressed, but the infantile hemangioma occurring at special parts, such as face, oral cavity, eyes, respiratory tract and the like can cause disfigurement and functional damage, and complications, such as ulcer, bleeding and the like can be accompanied in some cases, even the life can be endangered, so the infantile hemangioma must be reasonably treated. The beta-receptor blocking drug (propranolol hydrochloride) is used for treating the infantile hemangioma for the first time reported on New England medical journal from Leaute-LabrezeC equal to 2008.6.C. of French doctors, the method immediately draws the attention of students, opens up a new way for the treatment of the infantile hemangioma, and opens up the way for the beta-receptor blocking drug to treat the infantile hemangioma. It was subsequently found that timolol maleate eye drops which are also beta-receptor inhibitors can be used topically for the treatment of hemangiomas in infants and young children, and that a very satisfactory therapeutic effect is obtained. And because the composition is locally externally used, side effects such as bradycardia and the like caused by oral administration of beta-receptor inhibitor medicines can be avoided, the medication safety is improved, and the composition has very important significance for safe medication of infants.
Timolol maleate is a non-selective beta-receptor blocker, and the mechanism for treating infantile hemangioma is as follows: promote vasoconstriction in a short term, inhibit a plurality of angiogenesis signal paths in a middle term, and induce endothelial cell apoptosis in a long term, thereby finally causing tumor regression. However, in recent years, studies show that adverse reactions frequently occur, such as bradycardia, bronchospasm, folds of superficial skin, diarrhea, milk overflow, irritability, cold limbs and the like during administration.
Since patients are most infants under 1 year of age, the requirement for transdermal absorption performance and skin irritation of the gel preparation is higher. Timolol maleate is a water-soluble drug, the transdermal absorption performance of timolol maleate is extremely poor, and the improvement on the transdermal absorption performance is not obvious in the prior art; the common transdermal penetration enhancer such as peppermint oil, camphor, borneol and the like in the gel preparation has strong volatility and irritation; turpentine, anethole and the like have certain skin toxicity, are easy to cause irritation and anaphylactic reaction such as red swelling, hot pain and the like on the skin of infants, and are not suitable for the infants.
Disclosure of Invention
Therefore, the timolol maleate gel and the preparation method thereof provided by the invention disturb the ordered structure of the horny layer by utilizing a permeation promoting mechanism of azone, influence the fluidity of cell membranes, improve the solubility of the drug in the horny layer by utilizing propylene glycol to promote the percutaneous absorption of the drug, and the two have the combined and synergistic permeation promoting effects so as to improve the percutaneous absorption performance and reduce the irritation to the skin, so that the timolol maleate gel is convenient to administer and avoids the first pass effect of the liver, forms a drug reservoir in the skin to play a sustained-release role, has better compliance of a patient, and solves the problems of poor percutaneous absorption and skin irritation caused by the timolol maleate as a water-soluble drug in the prior art.
In order to achieve the above object, the embodiments of the present invention provide the following technical solutions: the timolol maleate gel comprises, by weight, 1-4.5% of timolol maleate, 8-12% of a combined penetration enhancer, 4-11% of a humectant, 0.05-0.15% of a preservative, 10.5-29% of a gel matrix and water, wherein the water accounts for the remaining balance, the combined penetration enhancer is azone and propylene glycol, the gel matrix is poloxamer P407, poloxamer P188 or sodium alginate, the preservative is benzoic acid, sorbic acid or ethylparaben, and the humectant is glycerol or propylene glycol.
Further, the raw materials (by weight percentage) used include timolol maleate 3%, azone 4%, propylene glycol 5%, ethylparaben 0.1%, glycerin 5%, poloxamer P40720% and water 62.9%.
Further, the raw materials (by weight percentage) used include timolol maleate 3%, azone 5%, propylene glycol 5%, sorbic acid 0.1%, glycerin 5%, sodium alginate 20% and water 61.9%.
Further, the raw materials used (by weight percentage) include timolol maleate 3%, azone 4%, propylene glycol 6%, ethylparaben 0.1%, glycerol 5%, poloxamer P18820% and water 61.9%.
The invention also comprises a preparation method of the timolol maleate gel, which comprises the following three steps:
dissolving and dispersing timolol maleate and a preservative by using a proper amount of water for later use;
step two, slowly adding the gel matrix into the solution prepared in the step one, uniformly stirring to ensure that the gel matrix is completely immersed in water, and fully swelling at 4 ℃;
taking out the mixture after swelling for 24 hours, stirring the mixture, adding the humectant and the combined penetration enhancer, stirring the mixture uniformly, and sealing the mixture for storage; standing overnight in shade, and packaging.
Further, the stirring speed in the third step is 100-500 rpm/min, and the stirring time is 5-10 min.
Furthermore, the timolol maleate gel is applied to preparing medicines for treating infantile hemangioma.
The invention has the following advantages:
1. the timolol maleate gel prepared by the invention has the characteristics of uniformity, fineness, proper viscosity, easiness in spreading, no stimulation to skin and the like. In the hydrogel preparation, the permeation promoting mechanism of azone is related to the disturbance of the ordered structure of the horny layer and the influence on the fluidity of cell membranes, propylene glycol promotes the percutaneous absorption of the medicament by improving the solubility of the medicament in the horny layer, and the propylene glycol and the medicament have the combined and synergistic permeation promoting effects so as to improve the percutaneous absorption performance and reduce the irritation to the skin;
2. the timolol maleate gel provided by the invention replaces timolol maleate eye drops when used for treating superficial infantile hemangioma, is not only convenient to administer, but also has a sustained release effect as the gel forms a drug reservoir on the skin, and meanwhile, the compliance of an infant patient is better.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below. It should be apparent that the drawings in the following description are merely exemplary, and that other embodiments can be derived from the drawings provided by those of ordinary skill in the art without inventive effort.
The structures, ratios, sizes, and the like shown in the present specification are only used for matching with the contents disclosed in the specification, so as to be understood and read by those skilled in the art, and are not used to limit the conditions that the present invention can be implemented, so that the present invention has no technical significance, and any structural modifications, changes in the ratio relationship, or adjustments of the sizes, without affecting the effects and the achievable by the present invention, should still fall within the range that the technical contents disclosed in the present invention can cover.
FIG. 1 is a graph of in vitro cumulative transdermal flux versus time provided by the present invention;
FIG. 2 is a standard HPLC chromatogram;
FIG. 3 is a sample HPLC chromatogram;
FIG. 4 is a three-dimensional effect plot of the effect of percent azone and percent propylene glycol on cumulative transdermal mass;
FIG. 5 is a two-dimensional contour plot of the effect of percent azone and percent propylene glycol on cumulative transdermal flux.
Detailed Description
The present invention is described in terms of particular embodiments, other advantages and features of the invention will become apparent to those skilled in the art from the following disclosure, and it is to be understood that the described embodiments are merely exemplary of the invention and that it is not intended to limit the invention to the particular embodiments disclosed. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The materials used in the examples of the invention and their sources are as follows:
timolol maleate (batch No. 20190301, national pharmaceutical group chemical Co., Ltd.);
1, 2-propanediol (batch number: lot. No.20180503, Yonghua chemical science and technology Co., Ltd.);
azone (batch No. 20171115, chemical reagents of national drug group, Ltd.);
poloxamer P407 (batch No. 20180713, Shanghai Changli pharmaceutical excipients technical Co., Ltd.);
glycerin (batch No. 20170907, national drug group chemical agents limited);
ethylparaben (batch No. 20171104, Shanghai Lingfeng Chemicals Co., Ltd.);
KM mice, males, weighing 20. + -.2 g, were provided by the animal testing center of second university of military medical science. The license number of the experimental animal: SCXK (Shanghai) 2017 and 0002.
Example 1:
the invention provides a timolol maleate gel, which comprises the following raw materials (by weight percentage) 1-4.5% of timolol maleate, 8-12% of a combined penetration enhancer, 4-11% of a humectant, 0.05-0.15% of a preservative, 10.5-29% of a gel matrix and water, wherein the water accounts for the rest.
The combined transdermal enhancer is azone and propylene glycol, the gel matrix is poloxamer P407, poloxamer P188 or sodium alginate, the preservative is benzoic acid, sorbic acid or ethylparaben, and the humectant is glycerol or propylene glycol. In this embodiment, azone and propylene glycol are preferably selected as the combined penetration enhancer, ethyl hydroxybenzoate is preferably used as the preservative, glycerin is preferably used as the humectant, and poloxamer P407 is preferably used as the gel matrix.
Specifically, in this embodiment, the raw materials include (by weight percentage) timolol maleate 3%, azone 4%, propylene glycol 5%, ethylparaben 0.1%, glycerin 5%, poloxamer P40720%, and water 62.9%.
The invention also comprises a preparation method of the timolol maleate gel, which comprises the following specific steps:
step one, weighing 3g of timolol maleate and 0.1g of ethylparaben, and adding a proper amount of purified water to dissolve and disperse for later use;
step two, slowly adding 20g of poloxamer (P407) into the solution prepared in the step one, uniformly stirring the solution to ensure that the poloxamer P407 is completely submerged below the water surface, and placing the solution in a refrigerator at 4 ℃ to fully swell the poloxamer;
and step three, after swelling for 24 hours, taking out the swelled solution, adding 5g of propylene glycol, 4g of azone and 5g of glycerol while stirring, and uniformly stirring, wherein the stirring speed is 100rpm/min, and the stirring time is 5min, so that the colorless and transparent timolol maleate gel preparation is obtained.
Example 2:
the invention provides a timolol maleate gel, which comprises the following raw materials (by weight percentage) 1-4.5% of timolol maleate, 8-12% of a combined penetration enhancer, 4-11% of a humectant, 0.05-0.15% of a preservative, 10.5-29% of a gel matrix and water, wherein the water accounts for the rest.
The combined transdermal enhancer is azone and propylene glycol, the gel matrix is poloxamer P407, poloxamer P188 or sodium alginate, the preservative is benzoic acid, sorbic acid or ethylparaben, and the humectant is glycerol or propylene glycol. In the embodiment, azone and propylene glycol are preferably selected as the combined transdermal enhancer, sorbic acid is preferably used as a preservative, glycerin is preferably used as a humectant, and sodium alginate is preferably used as a gel matrix.
Specifically, the raw materials used in this example include (by weight percentage) timolol maleate 3%, azone 5%, propylene glycol 5%, sorbic acid 0.1%, glycerin 5%, sodium alginate 20%, and water 61.9%.
The invention also comprises a preparation method of the timolol maleate gel, which comprises the following specific steps:
step one, weighing 3g of timolol maleate and 0.1g of sorbic acid, and adding a proper amount of purified water to dissolve and disperse for later use;
and step two, slowly adding 20g of sodium alginate into the solution obtained in the step one, uniformly stirring the solution to ensure that the sodium alginate is totally submerged below the water surface, and placing the solution in a refrigerator at 4 ℃ to fully swell the sodium alginate.
And step three, after swelling for 24 hours, taking out the swelled solution, adding 5g of propylene glycol, 5g of azone and 5g of glycerol while stirring, and uniformly stirring, wherein the stirring speed is 300rpm/min, and the stirring time is 7min, so that the colorless and transparent timolol maleate gel preparation is obtained.
Example 3:
the invention provides a timolol maleate gel, which comprises the following raw materials (by weight percentage) 1-4.5% of timolol maleate, 8-12% of a combined penetration enhancer, 4-11% of a humectant, 0.05-0.15% of a preservative, 10.5-29% of a gel matrix and water, wherein the water accounts for the rest.
The combined transdermal enhancer is azone and propylene glycol, the gel matrix is poloxamer P407, poloxamer P188 or sodium alginate, the preservative is benzoic acid, sorbic acid or ethylparaben, and the humectant is glycerol or propylene glycol. In this example, azone and propylene glycol are preferred as the combined penetration enhancer, ethylparaben is preferred as the preservative, glycerol is preferred as the humectant, and poloxamer P188 is preferred as the gel matrix.
Specifically, in this embodiment, the raw materials used include (by weight percentage) timolol maleate 3%, azone 4%, propylene glycol 6%, ethylparaben 0.1%, glycerin 5%, poloxamer P18820%, and water 61.9%.
The invention also comprises a preparation method of the timolol maleate gel, which comprises the following specific steps:
step one, weighing 3g of timolol maleate and 0.1g of ethylparaben, adding a proper amount of purified water for dissolving and dispersing for later use;
and step two, slowly adding 20g of poloxamer P188 into the solution obtained in the step one, uniformly stirring the solution to enable the poloxamer P188 to be totally immersed below the water surface, and placing the solution in a refrigerator at 4 ℃ to enable the solution to be fully swelled.
And step three, after swelling for 24 hours, taking out the swelled solution, adding 5g of glycerol, 6g of propylene glycol and 4g of azone while stirring, and uniformly stirring, wherein the stirring speed is 500rpm/min, and the stirring time is 10min, so that the colorless and transparent timolol maleate gel preparation is obtained.
Example 4:
an in vitro transdermal experiment was performed using the timolol maleate gel formulation prepared in example 1, with the following specific steps:
(1) preparation of in vitro skin: the KM mouse is unhaired at the abdomen and kept for 1d to ensure that the skin at the abdomen is not damaged, the whole skin at the abdomen is taken immediately after being killed, the redundant fat and tissues on the skin are scraped, and then the KM mouse is cleaned by normal saline and is soaked in fresh normal saline at the temperature of 4 ℃.
(2) The method is carried out by adopting a Franz diffusion cell method: normal saline which is in constant temperature water bath at 32 ℃ and stirred at a constant speed is taken as receiving liquid. The treated excised skin was fixed on a Franz diffusion cell with the stratum corneum facing upward, and 0.1g of prepared timolol maleate gel was uniformly applied and sealed with aluminum foil. Taking 1ml of receiving solution for content detection at 1, 2, 3, 4, 6, 8 and 12 hours respectively, and adding 1ml of fresh physiological saline with the same temperature into a receiving pool.
(3) Calculation of in vitro transdermal cumulative permeation:
the cumulative permeation amount of the drug per unit area was calculated from Q = [ CnV + Σ (C ᵢ × 1) ]/S. Wherein Q is the cumulative transdermal flux of the drug per unit area, Cn is the concentration of the drug in the receiving solution at the sampling point, V is the volume of the receiving solution, C ᵢ is the cumulative concentration of the drug in the receiving solution from the 1 st sampling point to the last sampling point, and S is the effective transdermal area of the drug.
The experimental results are as follows: the in vitro cumulative transdermal penetration at different sampling points is shown in figure 1 of the attached drawings of the specification.
As can be seen from figure 1, the timolol maleate external gel preparation has good in-vitro transdermal effect, can well penetrate through skin barriers, provides guarantee for effectively treating infantile hemangioma, has long drug release time, and reduces the administration times.
The timolol maleate gel prepared in the example 1 is taken to clinically treat 21 infants with infantile hemangioma (plastic surgery in Shanghai Changhai Hospital), 12 infants with the age of less than 1 year old and 9 infants with the age of 1-6 years old, and after treatment for 4 weeks, the clinical effective rate is 85.7%, and the timolol maleate gel has no irritation to skin and no obvious adverse reaction.
Example 5:
the formula of timolol maleate gel is optimized by adopting an asterisk design-effect surface method, and the specific steps are as follows:
(1) establishment of content determination method
1.1 chromatographic conditions: a chromatographic column: ODSC18 column (250 mm. times.4.6 mm, 5 μm); mobile phase: methanol-0.05 mol/L potassium dihydrogen phosphate solution (64: 36) containing 0.1% sodium heptanesulfonate; flow rate: 1.0 ml/min; detection wavelength: 290 nm; column temperature: 30 ℃; sample introduction amount: 20 μ l.
1.2 preparation of the solution:
and precisely weighing 20mg of timolol maleate reference substance into a 100ml volumetric flask, adding a proper amount of purified water to dissolve, fixing the volume, and shaking up to obtain the timolol maleate standard substance solution.
0.9980g of timolol maleate gel is precisely weighed, 100ml of purified water is added for dissolving, 1ml of the solution is taken and dissolved in a 10ml volumetric flask by the purified water, and the solution is shaken up, thus obtaining the timolol maleate test solution.
The timolol maleate standard solution and the sample solution are filtered by 0.45 μm microporous membrane, and chromatograms obtained under 1.1 chromatographic conditions are shown in fig. 2 and fig. 3. From the chromatogram, the peak shapes of timolol maleate in the standard substance and the gel are good, and other components in the gel have no interference to the absorption of timolol.
1.3 establishing a standard curve: accurately sucking 0.5, 1.0, 1.5, 2.0, 2.5, 3.0 and 3.5ml of standard substance solution in 1.2 items into a 10ml volumetric flask, fixing the volume by using purified water to obtain a series of concentrations, shaking up, injecting according to 1.1 chromatographic conditions, measuring peak area (A), and performing linear regression on the concentration (C) by using A to obtain a regression equation: a =28775C-2160.7(r2= 0.9997). The linear range of the concentration of timolol maleate is 10.00-70.00 mu g/ml.
1.4 precision: taking the standard solution in item 1.2, repeatedly injecting sample for 6 times according to the chromatographic conditions of item 1.1, recording peak area, and determining results shown in Table 1, wherein the results show that the precision of the instrument test is good.
TABLE 1 precision test results
| Numbering | 1 | 2 | 3 | 4 | 5 | 6 | RSD(%) |
| Peak area | 1416181 | 1479035 | 1473242 | 1470165 | 1477175 | 1497460 | 1.87 |
1.5 repeatability: 6 parts of timolol maleate gel test sample solution (the sample prepared in example 1) is prepared in parallel, sample injection is carried out according to 1.1 chromatographic conditions, the measurement result is shown in table 2, and the result shows that the method has good repeatability.
TABLE 2 results of the repeatability experiments
| Numbering | 1 | 2 | 3 | 4 | 5 | 6 | RSD(%) |
| Peak area | 580302 | 581824 | 582063 | 568361 | 568925 | 568761 | 1.22 |
1.6 sample loading and recovery: an appropriate amount of a precisely measured control solution, 3 parts for 1 group, was added to 6 parts of timolol maleate gel (sample prepared in example 1) of known content, respectively, dissolved in an appropriate amount of purified water and filtered, sample injection was performed under 1.1 chromatographic conditions, peak areas were recorded, and the measurement results are shown in table 3. The result shows that the method has good recovery rate, and other components in the preparation have no interference on the content measurement of the timolol maleate.
TABLE 3 sample recovery test results
1.7 content determination: taking 3 batches of 3% timolol maleate gel, preparing a sample solution according to the method of 1.2, injecting samples according to the chromatographic conditions of 1.1, recording peak areas, and calculating the content of timolol maleate in the gel according to linear regression. The measurement results in table 4 show that the measurement method meets the requirement of content measurement.
TABLE 4.3 measurement of timolol maleate gel sample content
| Batch number | Content (%) | RSD（%） |
| 20190714 | 3.27 | 2.76 |
| 20190715 | 3.21 | 0.80 |
| 20190803 | 3.10 | 0.84 |
(2) Preparation process of timolol maleate gel
2.1 prescription composition of timolol maleate gel: 3.0g of timolol maleate, 0.1g of ethylparaben, 20.0g of poloxamer (P407), 5.0g of glycerol, 10.0g of propylene glycol and 3.0g of azone, and a proper amount of purified water is added to 100 g.
2.2 preparation of timolol maleate gel: dissolving timolol maleate and ethylparaben in a proper amount of purified water, dispersing, slowly adding poloxamer P407, uniformly stirring until the timolol maleate and the ethylparaben are completely immersed in the water, swelling at 4 ℃ for 24h, taking out, sequentially adding glycerol, propylene glycol and azone under the stirring condition, uniformly stirring, and sealing. Standing overnight in shade, and packaging to obtain colorless transparent gel preparation. The pH value of the prepared gel preparation is 6.5-6.8.
(3) In vitro transdermal test
3.1 preparation of excised skin: the KM mice were depilated on their abdomen to ensure no damage to the abdominal skin. And (3) killing the mice after 1d, immediately taking the complete abdomen of the mice to remove the skin, scraping redundant fat and tissues on the skin, cleaning and soaking the skin by using normal saline, and storing the skin for a short time at 4 ℃ for later use.
3.2 in vitro transdermal experiments: the Franz diffusion cell method is adopted. The devices used are Franz diffusion cell and self-made transdermal diffusion apparatus, the effective diffusion inner diameter is 0.9cm, the volume of the receiving chamber is 5ml, and normal saline is used as receiving liquid and stirred at uniform speed in a constant temperature water bath at 32 ℃. The excised skin treated under 3.1 items was taken, excess water on the surface was blotted off with filter paper, the stratum corneum was fixed upward on a Franz diffusion cell, 0.1g timolol maleate gel was evenly spread on the mouse skin, and sealed with aluminum foil. 1ml of receiving solution is taken at 1, 2, 3, 4, 6, 8 and 12 hours respectively, and 1ml of fresh physiological saline with the same temperature is added into a receiving pool. The received solution was filtered through a 0.45 μm microporous membrane, and sample injection was carried out under 1.1 chromatographic conditions, and the peak area was recorded.
3.3 calculation of in vitro cumulative permeation: calculating the content of timolol maleate in the receiving pool at different time points by a regression equation, and calculating the cumulative permeation amount of the medicine per unit area by Q = [ CnV + Σ (C ᵢ × 1) ]/S. Wherein Q is the cumulative transdermal flux of the drug per unit area, Cn is the concentration of the drug in the receiving solution at the sampling point, V is the volume of the receiving solution, C ᵢ is the cumulative concentration of the drug in the receiving solution from the 1 st sampling point to the last sampling point, and S is the effective transdermal area of the drug.
(4) Optimization prescription of star point design-effect surface method
4.1 star point design: single factor investigation found that the content of the transdermal enhancer azone and propylene glycol has the most significant influence on the in vitro transdermal permeation amount of the timolol maleate gel. Design-Expert software (8.0.5 b master) was used to Design 2-factor 5-level prescription optimization experiments based on two-level factorial Design. The 5 levels of the code are 0, ± 1, ± α, α = F, respectively1/4F =2k, F is the number of partial experiments for factorial design, and k is the number of factors. By azone content (X)1) And propylene glycol content (X)2) The amount of transdermal penetration (Y) is used as independent variable and as dependent variable. The factor level settings and experimental star point design are shown in tables 5 and 6.
TABLE 5 factor horizon of star point design
TABLE 6 Star design experiment table and results
Wherein, 9-13 are repeated experiments, and the numerical value is expressed by average value.
4.2 optimization of the effect surface method: regression analysis was performed using Design-Expert software (8.0.5 b original edition) with confidence (P) as a criterion for model judgment [12 ]]Establishing a quadratic polynomial regression model: y = a1X1+a2X2 +a3X1X2+a4X1 2+a5X2 2+a6. Drawing a three-dimensional effect surface and a two-dimensional contour map according to a polynomial regression equation, and determining better penetration promotion from the relationship between effect values and investigation factorsAnd (4) the content of the agent.
The quadratic polynomial regression equation obtained was based on the cumulative permeation at each factor level (see table 6): y = 1606.595-556.426X1－224.665*X2－44.926*X1*X2+212.211*X1 2+21.308*X2 2. Three-dimensional effect surfaces and two-dimensional contour maps are drawn by polynomial regression equations, see fig. 4 and 5.
According to the fitting equation and the comprehensive evaluation of the effect surface, the optimization scheme obtained by software is X1=4%，X2=5%，Y=1287.11μg/cm2。
4.3 optimal prescription verification: preparing 3 batches of timolol maleate gels according to an optimal formula, carrying out transdermal experiments according to an in vitro transdermal experiment method, and calculating in vitro accumulated transdermal permeation quantity according to a formula. The deviation was used as an index of whether the model was predicted well or not, and the deviation (%) = (measured value-predicted value)/predicted value × 100%, and the average cumulative transdermal penetration amount (1377.81 μ g/cm 2) and the predicted value (1287.11 μ g/cm 2) of the 3 batches of the preparations were substituted into the deviation formula to obtain 7.05% deviation. This indicates that the predictability of this experiment is good. See table 7 for details.
TABLE 7 prescription verification results
The experimental results show that: when the optimal proportion of the timolol maleate gel transdermal enhancer is 4% of azone and 5% of propylene glycol, the cumulative transdermal penetration amount in 12 hours is 1377.81 mug/cm 2, and the timolol maleate gel transdermal enhancer has good conformity with a predicted value.
Although the invention has been described in detail above with reference to a general description and specific examples, it will be apparent to one skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (7)
1. A timolol maleate gel, which is characterized in that: the raw materials comprise, by weight, 1-4.5% of timolol maleate, 8-12% of a combined penetration enhancer, 4-11% of a humectant, 0.05-0.15% of a preservative, 10.5-29% of a gel matrix and water, wherein the water accounts for the rest, the combined penetration enhancer is azone and propylene glycol, the gel matrix is poloxamer P407, poloxamer P188 or sodium alginate, the preservative is benzoic acid, sorbic acid or ethylparaben, and the humectant is glycerol or propylene glycol.
2. A timolol maleate gel in accordance with claim 1, wherein: the raw materials (by weight percentage) used comprise 3% of timolol maleate, 4% of azone, 5% of propylene glycol, 0.1% of ethylparaben, 5% of glycerol, 40720% of poloxamer P and 62.9% of water.
3. A timolol maleate gel in accordance with claim 1, wherein: the raw materials (by weight percentage) used comprise 3% of timolol maleate, 5% of azone, 5% of propylene glycol, 0.1% of sorbic acid, 5% of glycerol, 20% of sodium alginate and 61.9% of water.
4. A timolol maleate gel in accordance with claim 1, wherein: the raw materials comprise (by weight percentage) 3% of timolol maleate, 4% of azone, 6% of propylene glycol, 0.1% of ethylparaben, 5% of glycerol, 61.9% of poloxamer P18820% and water.
5. A method of preparing a timolol maleate gel according to any of claims 1 to 4, wherein: the method comprises the following three steps:
dissolving and dispersing timolol maleate and a preservative by using a proper amount of water for later use;
step two, slowly adding the gel matrix into the solution prepared in the step one, uniformly stirring to ensure that the gel matrix is completely immersed in water, and fully swelling at 4 ℃;
taking out the mixture after swelling for 24 hours, stirring the mixture, adding the humectant and the combined penetration enhancer, stirring the mixture uniformly, and sealing the mixture for storage; standing overnight in shade, and packaging.
6. The method for preparing timolol maleate gel according to claim 5, which is characterized in that: the stirring speed in the third step is 100-500 rpm/min, and the stirring time is 5-10 min.
7. Use of timolol maleate gel according to any of claims 1 to 4, characterized in that: the timolol maleate gel is applied to preparing medicines for treating infantile hemangioma.
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| CN114129509A (en) * | 2021-12-03 | 2022-03-04 | 药酚享科技(北京)有限公司 | Moisturizing NMN hydrophilic gel and preparation method thereof |
| CN114504549A (en) * | 2022-02-24 | 2022-05-17 | 北京斯利安药业有限公司 | Aqueous biotin gel and preparation method and application thereof |
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| CN106619486A (en) * | 2016-11-03 | 2017-05-10 | 中国人民解放军第二军医大学 | Propranolole hydrochloride gel and preparation method thereof |
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| CN106619486A (en) * | 2016-11-03 | 2017-05-10 | 中国人民解放军第二军医大学 | Propranolole hydrochloride gel and preparation method thereof |
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| CN114129509B (en) * | 2021-12-03 | 2023-12-01 | 药酚享科技(北京)有限公司 | Moisturizing NMN hydrophilic gel and preparation method thereof |
| CN114504549A (en) * | 2022-02-24 | 2022-05-17 | 北京斯利安药业有限公司 | Aqueous biotin gel and preparation method and application thereof |
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