CN107184551B - Liranaftate double-particle-size distribution emulsion and preparation method thereof - Google Patents
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Abstract
A liranaftate double-particle size distribution emulsion contains liranaftate as active component. The invention also discloses a preparation method of the composition. The emulsion of the invention not only solves the problem that the medicine is insoluble in water, but also ensures that the medicine has good transdermal property, improves the bioavailability, improves the safety and reduces the cost. Moreover, the emulsion is distributed in double particle sizes, the specific surface area of the medicament is greatly increased due to small size effect, the small particle size medicament can quickly penetrate into the dermis layer to directly inhibit and kill fungi, the large particle size medicament can slowly penetrate into the cortex layer but can be temporarily kept under the skin to slowly release the medicament, the treatment time is prolonged, the administration frequency is reduced, the bioavailability of the medicament is greatly improved on the whole, the treatment course is shortened, and the market ointment has a wider prospect.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a liranaftate double-particle-size distribution emulsion and a preparation method thereof.
Background
Liranaftate, chemically known as N-hypo (6-methoxy-2-pyridyl) -N-methylcarbamic acid (5, 6, 7, 8-tetrahydro) -2-naphthyl ester, is a relatively new antifungal drug in recent years, and exerts antifungal activity by inhibiting squalene epoxidation reaction of fungal cells to inhibit synthesis of ergosterol, a cell constituent. Clinical experiments show that compared with the traditional antifungal medicine, the product has more excellent effect and lower drug resistance, and still has ideal treatment effect on long-lasting tinea pedis and tinea corporis. Compared with the traditional medicine tolnaftate, the effect is improved by 7 times, the curative effect on ringworm is better than that of clotrimazole, and the market share of the tolnaftate tends to rise year by year in the coming years.
However, because liranaftate is insoluble in water, in order to make a liquid preparation, a large amount of organic solvent is needed to be dissolved, the cost is high, the organic solvent has a certain damage effect on skin, and the liquid preparation prepared by the organic solvent belongs to a conventional preparation form.
Disclosure of Invention
The invention aims to provide a liranaftate double-particle size distribution emulsion, and simultaneously provides a preparation method thereof, which is another aim of the invention.
Based on the purpose, the invention adopts the following technical scheme:
a liranaftate double-particle size distribution emulsion contains liranaftate as active component.
The weight percentage of the liranaftate is 0.01-5.0%.
The emulsion comprises the following components in percentage by weight: 0.01-5.0% of liranaftate, 0.1-12.0% of oil phase, 0.5-6.0% of first surfactant, 15.0-30.0% of second surfactant, 0.1-8.0% of cosurfactant and the balance of deionized water; the first surfactant is one or a mixture of two of polyoxyethylene 40 hydrogenated castor oil (RH-40), castor oil polyoxyethylene ether 40(EL-40), emulsifier OP-10, Tween 80 and Tween 20; the second surfactant is one or two of span-80, span-20, tween-85 and triethanolamine oleate.
The oil is selected from one or two of ethyl acetate, soybean oil, ethyl oleate, isopropyl myristate (IPM), corn oil, Medium Chain Triglyceride (MCT) and olive oil.
The cosurfactant is one of absolute ethyl alcohol, 1, 2-propylene glycol, polyethylene glycol 200, triethylene glycol, isopropanol and glycerol.
The preparation method of the liranaftate double-particle size distribution emulsion comprises the following steps:
1) adding liranaftate into an oil phase for dissolving to obtain a system I;
2) dividing a system I into A, B two parts, wherein the proportion of A to B is 1 (3-10);
3) adding a first surfactant into the part A, mixing, and adding deionized water with the weight 2 times that of the part A to obtain a system A1; adding a second surfactant into the part B, mixing, and adding deionized water with the weight 2 times that of the part B to obtain a system B1; then, the cosurfactant is distributed according to the proportion of A, B and then is respectively added into the system A1 and the system B1 to be mixed to obtain a system II and a system III;
4) respectively carrying out ultrasonic treatment on the system II and the system III, and emulsifying until the two systems are uniform, transparent and free of layering;
5) and mixing the system II and the system III after the ultrasonic emulsification, and adding the rest deionized water for mixing.
In the step 4), the ultrasonic emulsification frequency is 18KHZ, and the ultrasonic emulsification time is more than 30 min.
The double-particle size distribution emulsion prepared by the invention can be added with deionized water continuously to obtain thinner double-particle size distribution emulsion of liranaftate.
The liranaftate double-particle-size distribution emulsion has a small particle size distribution range of 1-30 nm and a large particle size distribution range of 200-400 nm.
After the conventional preparation is smeared on the surface of skin, due to the blocking effect of the natural stratum corneum of the skin, the quantity of the medicine which can actually penetrate into the subcutaneous part is not large, most of the medicine still remains on the surface of the skin, most of fungus microorganisms propagate in deep skin tissues after the fungal infection of the skin, and if the medicine cannot penetrate into the hypodermal layer of the subcutaneous part, the bioavailability is limited, so that the treatment time is long, and the diseases are frequently repeated and difficult to completely treat. The invention adopts nano-emulsification technology, uses oil phase, surfactant, cosurfactant and deionized water which have strong skin affinity and high safety as main auxiliary materials, prepares the medicament into a nano-emulsion liquid formulation with double particle size distribution, and converts the medicament into a bicontinuous phase distribution emulsion, thereby not only solving the problem that the medicament is insoluble in water, but also ensuring good transdermal property of the medicament, improving bioavailability, improving safety and reducing cost. Moreover, the emulsion is distributed in double particle sizes, the specific surface area of the medicament is greatly increased due to small size effect, the small particle size medicament can quickly penetrate into the dermis layer to directly inhibit and kill fungi, the large particle size medicament can slowly penetrate into the cortex layer but can be temporarily kept under the skin to slowly release the medicament, the treatment time is prolonged, the administration frequency is reduced, the bioavailability of the medicament is greatly improved on the whole, the treatment course is shortened, and the market ointment has a wider prospect.
Specifically, the technical scheme of the invention has the following advantages:
(1) quick acting: the prepared double-particle-size-distribution emulsion has small particle size distribution of 1-30 nm, is smaller than the intercellular space, has better skin affinity under the action of a surfactant, reduces the surface tension of a drug interface, is easy to enter a corium layer to inhibit and kill fungi, and has quick response;
(2) the slow release effect is as follows: the prepared double-particle-size-distribution emulsion has large particle size distribution of 200-400 nm, can enter below a cortex layer, has slow release speed due to large particle size, increases a slow-release effect on the basis of quick effect, prolongs the action time of the medicament, reduces the administration frequency and is more convenient to use;
(3) good water solubility: the liranaftate which is insoluble in water is changed into the liranaftate which is easily soluble in water, can be infinitely diluted without precipitation, demulsification, layering and precipitation, can be stored, can be administered at any time and is convenient to use;
(4) the invention has simple and feasible process, is beneficial to large-scale industrial transformation, provides a new liranaftate medicinal preparation for the market, and has better curative effect, shorter treatment period and lower cost compared with the old preparation;
(5) the medicine provided by the invention has strong stability, does not demulsify or delaminate at the temperature of-20-40 ℃, does not precipitate or degrade, and does not change the curative effect.
Detailed Description
The present invention is further illustrated by the following specific examples, wherein the preparation method of the present invention is performed at room temperature, which is 15-25 ℃ unless otherwise specified.
Examples 1 to 10
In order to simplify the description, specific examples are given below in the form of a list in order to further illustrate the invention.
TABLE 1 compositions of the components of examples 1-10
Taking example 1 as an example, the preparation method of the liranaftate double-particle size distribution emulsion is detailed and comprises the following steps:
1) adding 8.0g of olive oil and 2.0g of IPM into a container, uniformly mixing to obtain an oil phase, adding 2.0g of liranaftate into the oil phase, and stirring for dissolving to obtain a system I;
2) dividing the system I into A, B parts, wherein the proportion of A to B is 1 to 5, namely the part A is 2g and the part B is 10 g;
3) adding a first surfactant RH-404.0 g and Tween-801.5 g into the part A, adding 4.0g of deionized water and 1.0g of 1, 2-propylene glycol, and stirring and mixing uniformly to obtain a system II; adding 2025g of second surfactant span-B into the part B, adding 20.0g of deionized water and 5.0g of 1, 2-propylene glycol, and stirring and mixing uniformly to obtain a system III;
4) respectively putting the system II and the system III in ultrasonic emulsification at the ultrasonic frequency of 18KHZ for more than 30min, and stirring while ultrasonic treatment until the two systems are uniform and transparent, have no delamination and no precipitation;
5) mixing the system II and the system III, adding 27.5g of deionized water to ensure that the total mass reaches 100g, and stirring and mixing uniformly to obtain the catalyst.
Examples 2-10 were prepared as in example 1 except that in example 2, the partition ratio was a: B ═ 1: 3; in example 3, the distribution ratio is a: B ═ 1: 10.
Example 11 stability test
The emulsion products having two particle sizes in examples 1 to 10 were subjected to a time-lapse test, an acceleration test, a freezing stability resistance test and a centrifugal stability test, respectively, to observe the stability of the emulsion having two particle sizes in accordance with the present invention, and to confirm whether or not unstable phenomena such as delamination, emulsion breaking or drug precipitation occurred.
1. Time of flight test
The double-particle size distribution emulsions of examples 1 to 10 were stored for 12 months under natural variation conditions at room temperature, and the properties and content variations of the double-particle size distribution emulsions were examined, and the results showed that the emulsions had a long-lasting, clear and transparent appearance, and no instability such as delamination, emulsion breaking or drug precipitation was observed, indicating good stability over time.
2. Accelerated test
The double-particle size distribution emulsions of examples 1 to 10 were dispensed into 100ml glass bottles, sealed and stored in an accelerated test chamber at 40 ℃ and 75% relative humidity for 60 days, and sampled every 10 days for observation. The results show that the double-particle size distribution emulsions of examples 1 to 10 did not show any instability such as demixing, demulsification or drug precipitation, indicating good accelerated stability.
3. Stability against freezing
The double-particle size distribution emulsions of examples 1 to 10 were dispensed into 100ml glass bottles, stored continuously at-20 ℃ for one month in a refrigerator, taken out every 10 days, thawed to room temperature, and observed. The results show that the double-particle size distribution emulsions of examples 1-10 did not show any instability such as demixing, demulsification or drug precipitation, indicating good freeze resistance.
4. Centrifugal stability
The double-particle-size-distribution emulsion obtained in the example 1 to 10 is placed in a centrifuge tube, sealed, and observed after being centrifuged at the rotating speed of 3000r/min for 30 minutes, and no unstable phenomena such as layering, emulsion breaking or drug precipitation are found after dilution inspection, which indicates that the centrifugal stability is good.
The safety and efficacy of the drug of the present invention on animals are further illustrated by the drug safety test and the drug efficacy test.
Example 12 safety test
The following safety tests were carried out using the double particle size distribution emulsion of liranaftate prepared in example 1 as a sample.
And (3) safety test: 30 Kunming mice with the body weight of about 20g are randomly divided into three groups, 10 mice in each group, and each half of a male mouse and a female mouse, wherein the first group is a blank control group, the second group is a healthy skin group, and the third group is a damaged skin group. The abdominal skin of three groups of mice were depilated by applying 8% sodium sulfide solution to the skin, the area of the skin was about 2.0cm by 2.0cm, while the depilated skin of the third group of mice was lined with a sterile needle to the extent of slightly oozing blood, and the first and second groups of mice were not treated. After 12 hours of observation after the completion of the treatment, the test was started after the mice of each group had no abnormal behavior, the first group of mice were rubbed on the depilated area with physiological saline, and the second and third groups of mice were rubbed with the emulsion of example 1 of the present invention as the healthy skin and damaged skin test groups. The mice were observed once a day, in the morning and evening, for 3 consecutive days, and then 3 additional days, during which skin irritation, mouse performance, and death were observed and recorded.
By adopting the test method, the liranaftate double-particle size distribution emulsion prepared in other examples is used as a sample for safety test.
And (3) test results: the skin of each group of mice is normal, the skin of the drug application part of the second group and the third group of mice has no difference compared with the skin of the first group of control group, the behavioral manifestation and the health state are normal, and no death condition occurs. 2 mice in each group are randomly selected for observation through a caesarean examination, and each visceral organ has no abnormal pathological changes and no difference among the groups, which indicates that the double-particle-size distribution emulsion liquid has good safety.
Example 13 drug efficacy test
The efficacy test of the treatment of dermatophyte infection was carried out using the double particle size distribution emulsion of liranaftate prepared in example 1 as a sample.
And (3) pharmacodynamic test: 40 rabbits with a body weight of about 2kg and suffering from dermatophytosis (dermatophyte infection) were randomly divided into 4 groups of 10 rabbits each, each half of the male and female rabbits. Group 1 was a control group, and only shearing was performed on psoriasis without medication; groups 2 and 3, except for shearing hairs at the tinea, are respectively smeared with liranaftate 2% cream which is the most common preparation formulation at the focus, the group 2 is smeared once every day at regular time, and the group 3 is smeared 3 times every day; and 4, the liranaftate double-particle-size-distribution emulsion disclosed in the embodiment 1 is applied once a day, each group of mice needs to be continuously applied with the drug for 7 days, then the rehabilitation condition of the psoriasis part is observed, after the test is finished, the continuous observation is carried out for 15 days, whether the psoriasis part recurs or not is observed, and detailed test records are made in the period according to result judgment.
Standard of rehabilitation:
the skin of the affected part is scabbed and falls off, new granulation tissues are exposed, and new hair is regrown for rehabilitation;
the scab of the skin of the affected part does not fall off completely, the affected part is already converged, and the new granulation tissue has growth signs and is classified as the outcome;
the skin of the affected part is scabbed and enlarged, the local part is moist or bleeding, and the rabbit still bites the skin to show ineffectiveness;
effective rate (recovery number + return number)/total number 100%
TABLE 2 Linaphthalene double-particle size distribution emulsion for testing the drug effect of rabbit psoriasis
| Group of | Total number of rabbits (/ only) | Kangya (/ only) | Return number (/ only) | Invalid number (/ only) | High efficiency | Number of relapses (/ only) |
| Group 1 | 10 | 0 | 1 | 9 | 10％ | --- |
| Group 2 | 10 | 2 | 3 | 5 | 50％ | 1 |
| Group 3 | 10 | 6 | 2 | 2 | 80％ | 2 |
| Group 4 | 10 | 7 | 2 | 1 | 90％ | 0 |
The results show that:
1. under the condition of no medicine, the skin depilatory ringworm disease has the self-healing rate of only 10 percent by depending on the resistance of the rabbit; 2. after the liranaftate is used for treatment, the effective rate is remarkably improved, which shows that liranaftate has a treatment effect on rabbit skin depilatory ringworm;
3. under the same dosage condition, compared with the results of the group 2 and the group 4, the same medication method and the same medication frequency result that the effective rate of the liranaftate double-particle-size-distribution emulsion is 40 percent higher than that of the common paste, which shows that the curative effect of the emulsion is superior to that of the traditional paste;
4. compared with the results of the 3 rd group and the 4 th group under the same dosage condition, the traditional ointment is taken 3 times a day, the curative effect is finally equivalent to the effect that the double-particle size distribution emulsion is taken 1 time a day, and the invention has obvious slow release effect, can reduce the administration frequency, saves time and labor and is more convenient to take.
5. In the rabbits recovered by liranaftate treatment, after the drug is stopped for 15 days, the group 2 and the group 3 have recurrence, but the double-particle-size-distribution emulsion of the invention has no recurrence, and the treatment is thorough.
Claims (3)
1. A liranaftate double-particle size distribution emulsion is characterized in that the active ingredient is liranaftate; the emulsion comprises the following components in percentage by weight: 0.01-5.0% of liranaftate, 0.1-12.0% of oil phase, 0.5-6.0% of first surfactant, 15.0-30.0% of second surfactant, 0.1-8.0% of cosurfactant and the balance of deionized water; the first surfactant is one or a mixture of two of polyoxyethylene 40 hydrogenated castor oil (RH-40), castor oil polyoxyethylene ether 40(EL-40), emulsifier OP-10, Tween 80 and Tween 20; the second surfactant is one or a mixture of two of span-80, span-20, tween-85 and triethanolamine oleate; the oil is selected from one or two of ethyl acetate, soybean oil, ethyl oleate, isopropyl myristate (IPM), corn oil, Medium Chain Triglyceride (MCT) and olive oil; the cosurfactant is one of absolute ethyl alcohol, 1, 2-propylene glycol, polyethylene glycol 200, triethylene glycol, isopropanol and glycerol; the liranaftate double-particle-size-distribution emulsion has a small particle size distribution range of 1-30 nm and a large particle size distribution range of 200-400 nm.
2. The method of preparing a double-size distribution liranaftate emulsion according to claim 1, comprising the steps of:
1) adding liranaftate into an oil phase for dissolving to obtain a system I;
2) dividing a system I into A, B parts according to the proportion of A: B =1 (3-10);
3) adding a first surfactant into the part A, mixing, and adding deionized water with the weight 2 times that of the part A to obtain a system A1; adding a second surfactant into the part B, mixing, and adding deionized water with the weight 2 times that of the part B to obtain a system B1; then, the cosurfactant is distributed according to the proportion of A, B and then is respectively added into the system A1 and the system B1 to be mixed to obtain a system II and a system III;
4) respectively carrying out ultrasonic emulsification on the system II and the system III until the two systems are uniform, transparent and free of layering;
5) mixing the system II and the system III after ultrasonic emulsification at room temperature, and adding the rest deionized water for mixing to obtain the product.
3. The method for preparing liranaftate double-particle size distribution emulsion according to claim 2, wherein in the step 4), the frequency of ultrasonic emulsification is 18KHZ, and the time of ultrasonic emulsification is more than 30 min.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101422434A (en) * | 2008-12-11 | 2009-05-06 | 扬子江药业集团有限公司 | Liranaftate cream preparation method |
| CN102368998A (en) * | 2009-02-05 | 2012-03-07 | 靶向输送技术公司 | Methods of reducing the proliferation and viability of microbial agents |
| CN103446044A (en) * | 2013-09-05 | 2013-12-18 | 江苏中丹制药有限公司 | Liranaftate ointment and preparation method thereof |
| WO2016046786A1 (en) * | 2014-09-26 | 2016-03-31 | Glaxosmithkline Intellectual Property (No.2) Limited | Long acting pharmaceutical compositions |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101422434A (en) * | 2008-12-11 | 2009-05-06 | 扬子江药业集团有限公司 | Liranaftate cream preparation method |
| CN102368998A (en) * | 2009-02-05 | 2012-03-07 | 靶向输送技术公司 | Methods of reducing the proliferation and viability of microbial agents |
| CN103446044A (en) * | 2013-09-05 | 2013-12-18 | 江苏中丹制药有限公司 | Liranaftate ointment and preparation method thereof |
| WO2016046786A1 (en) * | 2014-09-26 | 2016-03-31 | Glaxosmithkline Intellectual Property (No.2) Limited | Long acting pharmaceutical compositions |
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