KR100866979B1 - Microemulsion based hydrogel comprising itraconazole and preparation method thereof - Google Patents

Abstract

The present invention relates to a microemulsion hydrogel in which itraconazole is dissolved in benzyl alcohol, which is an oil phase. The present invention relates to a microemulsion hydrogel having a reduced side effect and a fungal therapeutic effect by applying to the skin, and a preparation method thereof.

Itraconazole, benzyl alcohol, microemulsion, hydrogel

Description

Microemulsion based hydrogel comprising itraconazole and preparation method according to itraconazole

1A and 1B relate to the phase equilibrium of a microemulsion that is the basis of the formation of a microemulsion hydrogel according to the present invention,

Figure 2 shows an embodiment of a microemulsion-based hydrogel manufacturing process chart of the external skin,

3A and 3B relate to transmission electron micrographs showing characteristics and sizes of microemulsions prepared according to an embodiment of the present invention (a: F1 × 25,000, b: F2 × 25,000),

Figure 4 relates to the results of skin permeation measurement after applying the microemulsion or microemulsion hydrogel prepared in one embodiment of the present invention,

Figure 5 relates to the result of measuring the amount of drug deposition in the skin removed from the dead skin, 8 hours after applying the microemulsion or microemulsion hydrogel prepared in one embodiment of the present invention,

6a and 6b shows the results of skin permeation measurement after applying the skin external preparation for each concentration of the preferred composition,

7 shows the results of measuring the amount of drug deposition in the skin from which exfoliation was performed 8 hours after the application of the skin external preparation for each concentration of the preferred composition,

Figure 8 shows the results of measuring the amount of drug deposits in the skin after removing the exfoliation after applying the external application for skin according to the present invention live hairless mice and the like.

The present invention relates to a microemulsion hydrogel that can reduce side effects and increase fungal power by applying itraconazole, which has high fungal power but severe hepatotoxicity and gastrointestinal disorder during oral administration, to topical skin.

Itraconazole is a triazole-based antifungal drug. It is used for the treatment of candidiasis, early fungal disease, and dermatophytosis. It is a very poorly soluble drug and is mainly used as an oral drug in clinical use. Take 3-6 months with / day.

The bioavailability of highly water soluble drugs such as itraconazole during oral administration may be affected by the physicochemical conditions of the small intestine, in combination with foods in the small intestine, and can lead to hepatotoxicity, nausea, diarrhea, Side effects include abdominal pain, indigestion, and headaches. It is mainly metabolized by CYP3A4 in the liver and affects many clinically important drugs such as H ₂ -receptor antagonists, oral contraceptives, astemisol, rifampin, and the like.

Itraconazole oral preparations for the treatment of candidiasis and early fungal disease have long discomfort for maintaining effective drug concentrations on the skin, nails, and the inconvenience of taking them with food to increase bioavailability. There is a need to overcome these drawbacks and to develop topical skin application formulations capable of rapidly delivering an effective amount of drug to a desired site.

The topical application of itraconazole and its high affinity with keratinous tissues make it easy to express the drug due to high transition to skin or nails and long stay. However, it is difficult to develop a formulation due to poor solubility of itraconazole.

The target tissue for topical application is the skin and must be able to transport the drug sufficiently through the stratum corneum without affecting the function of the skin barrier.

Skin is a tissue that acts as a barrier to prevent various substances from entering the body. It is divided into three layers: epidermis, dermis, and subcutaneous tissue.

Of these, the epidermis is the thinnest layer that plays an important role in moisturizing and protecting the skin. From below, the epidermis is divided into the basal layer, the pole layer, the granule layer, and the stratum corneum. In the basal layer, cell division of keratinocytes occurs and the divided cells gradually become Ascending upwards, differentiates and forms keratin layer with keratinized keratinocytes. Since the stratum corneum has a strong protective film function, the drug permeability is unsatisfactory, and there is a limit in the expression of the external effects of the external preparation for skin, which must maintain a local concentration for a certain period of time.

On the other hand, microemulsions have been proposed through many studies to be ideal as a vehicle (vehicle) that can increase the skin transport of water-soluble, poorly soluble drugs. It is composed of lipophilic and hydrophilic parts to increase the solubility of poorly soluble drugs, thereby improving the skin permeability due to the concentration gradient.

Therefore, the present inventors conducted a study of a microemulsion hydrogel for developing a topical formulation of itraconazole, and the o / w microemulsion containing itraconazole is easy to apply to the skin by the water phase of the outer layer, and contains an itraconazole-containing Transcutol (diethylene glycol monoether), used as a surfactant to maintain daily life, is non-toxic and suitable for bioavailability and enhances skin penetration with a strong solubilizer. Phospholipid is one of the skin constituents, and it has the ability to bind to the skin. The present invention has been completed by focusing on the fact that the effect can be enhanced.

Accordingly, an object of the present invention is to provide a microemulsion hydrogel using itraconazole, which can reduce side effects and increase efficacy by applying itraconazole to local skin with high fungal activity but severe liver toxicity and gastrointestinal disorders.

In order to achieve the above object, the present invention provides a microemulsion hydrogel in which itraconazole is dissolved in benzyl alcohol in an oil phase.

The microemulsion hydrogel includes itraconazole, benzyl alcohol, a surfactant, and a gelling agent.

As the surfactant, a mixture of two or more selected from the group consisting of diethylene glycol monoether, ethanol and phospholipid is used. Preferably, diethylene glycol monoether is used as the main surfactant, and ethanol and phospholipid are used together as the auxiliary surfactant.

The gelling agent is preferably 2-propenoic acid (Carbopol®) (hereinafter referred to as 'carbopol') or xanthan gum in which water is dissolved in water.

In addition, the microemulsion hydrogel according to the present invention is itraconazole 0.02-3.0% by weight, benzyl alcohol 5.0-15.0% by weight, diethylene glycol monoether 5.0-20.0% by weight, ethanol 5.0-20.0% by weight, phospholipid 5.0-20.0 Weight percent, 0.5-5.0 weight percent of one compound selected from Carbopol or xanthan gum and the balance of water.

At this time, itraconazole plays the role of an active ingredient exhibiting a pharmacological effect, and if present in excess of the content range, excessive precipitation of itraconazole may occur, and if present in a small amount, transition to skin may not be desired, and thus the desired pharmacological effect may not be obtained. .

In addition, benzyl alcohol serves as a solvent for preparing the active ingredient itraconazole in the oil phase, and when present in excess of the content range, excessive skin irritation may occur, the microemulsion is broken, and the angle for forming the microemulsion Changes in the content of the ingredients are required.

On the other hand, when present in a small amount, it is not sufficient to dissolve itraconazole, and as in the presence of an excessive amount, it is impossible to form a microemulsion and may cause a problem that requires control of each component content to form.

In addition, diethylene glycol monoether is one of the main surfactants used in the present invention, if present in an excessive or small amount outside the above content range, it is impossible to form microemulsions and affects the degree of transition of itraconazole to the pharmacological effect. Problems may arise.

In addition, ethanol is one of the auxiliary surfactants used in the present invention, when present in an excessive or small amount outside the above content range, it is impossible to form microemulsions and affects the solubility of itraconazole to precipitate or affect the degree of skin migration. Problems may arise with the expression of pharmacological effects.

In addition, phospholipid is another co-surfactant used in the present invention, when present in an excess or small amount outside the above content range, it is impossible to form microemulsions and affects the degree of transition of itraconazole to the skin, which causes problems in the expression of pharmacological effects. May be caused.

The diameter of the microemulsion formed in the present invention is 20 to 200 nm, a diameter larger or smaller than the above range may affect the degree of skin transition of itraconazole, which may cause problems in the expression of pharmacological effects.

In addition, carbopol or xanthan gum is a component for formulation in the form of a gel, and if present in an excessive or small amount out of the above content range, the gel formation degree is too weak or too viscous for the formation of the microemulsion-based hydrogel so that skin application is difficult. It is not easy and can cause problems with skin transition of itraconazole.

In addition, the present invention comprises the steps of dissolving itraconazole in benzyl alcohol in the oil phase; Preparing an oil phase by adding a surfactant to the dissolved solution; And it provides a method for producing a microemulsion hydrogel comprising the step of adding a carbopol or xanthan gum to the water phase prepared above.

The oil phase comprises 10-70 parts by weight based on 100 parts by weight of the total microemulsion hydrogel, wherein the oil phase contains 0.02-3.0% by weight of itraconazole, 5.0-15.0% by weight of benzyl alcohol and 82.0-92.0% by weight of surfactant. It is preferable.

At this time, if the oil phase is contained in an excessive or small amount out of the above range may affect the stability of the sufficiently dissolved itraconazole and the possibility of forming the o / w microemulsion system and may cause problems due to the possibility of phase separation when mixed with the water phase, The oil phase is prepared by dissolving itraconazole in benzyl alcohol at room temperature and then adding a surfactant under stirring.

In addition, the aqueous phase is composed of 30 to 90 parts by weight based on 100 parts by weight of the total microemulsion hydrogel, wherein the aqueous phase preferably contains 0.5-5.0% by weight of carbopol or xanthan gum and 95.0-99.5% by weight of water. .

At this time, if the water phase is contained in an excessive or small amount out of the above range, it may affect the stability of the sufficiently dissolved itraconazole and the possibility of forming the o / w microemulsion system, and there is a possibility of phase separation in mixing with the oil phase. The preparation of the aqueous phase may be made to dissolve and uniformly dissolve Carbopol or xanthan gum in water while stirring.

Since the carbopol gels in a weak base, it is necessary to add a weak alkalizing agent such as triethanolamine (pH 7.3 to 8.3), but in the case of xanthan gum, gelation is performed at a relatively wide range of pH, for example, pH 3-12. It is possible to adjust the desired pH without any other alkalizing agent.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the present invention is not limited by these examples.

[Examples 1 to 2] Preparation of Microemulsion

After dissolving itraconazole in benzyl alcohol to prepare an oil phase, a mixture of diethylene glycol monoethyl ether (transcutol ^™ ) and phosphatidylcholine (S ₇₅ PC): EtOH (2: 3) was 0.5: 9.5, 1: 9, and 1.5, respectively. : 8.5, 2: 8, 2.5: 7.5, 3: 7, 3.5: 6.5, 4: 6, 4.5: 5.5, 5: 5, 5.5: 4.5, 6: 4, 6.5: 3.5, 7: 3, 7.5: 2.5 , 8: 2, 8.5: 1.5, 9: 1 and 9.5: 0.5 were added at a weight ratio and stirred at room temperature.

Water was added to the oil phase and the surfactant mixture to identify a region where a uniform microemulsion was formed, and a pseudo-ternary phase diagram such as FIGS. 1A and 1B was formed.

As a result, a stable microemulsion in which no phase separation occurred according to the composition and the ratio as shown in Table 1 was prepared.

Ingredient (%, w / w) Example 1 (F1) Example 2 (F2) Itraconazole 0.02 0.02 Benzyl alcohol 10 10 Transcutol 20 10 ethanol 12 18 Phosphatidylcholine 8 12 water 49.98 49.98

3A and 3B, the properties of the formed microemulsion were confirmed by transmission electron microscope (TEM) (x 25,000), and the diameter of the microemulsion was 20-200 nm.

[Examples 3 to 6] Preparation of skin external preparation (hydrogel) using microemulsion

A skin external preparation which is a gelling agent using the composition of the microemulsion obtained in Examples 1 and 2 was prepared by the preparation method shown in FIG. 2 according to the prescription of Table 2.

Ingredient (%, w / w) Example 3 (F1-1) Example 4 (F1-2) Example 5 (F2-1) Example 6 (F2-2) Itraconazole 0.02 0.02 0.02 0.02 Benzyl alcohol 10 10 10 10 Transcutol 20 20 10 10 Xanthan Gum 0.7 - 0.7 - Cabopol 980 - 0.7 - 0.7 ethanol 12 12 18 18 Phosphatidylcholine 8 8 12 12 Triethanolamine - 0.2 - 0.2 water 49.28 49.02 49.28 49.08

Experimental Example 1 In Vitro Skin Permeation Experiment

Male hairless mice (5-6 weeks old, 18-20 g) were used as experimental animals. The hairless mouse was lethal to the cervical vertebra and the skin was removed from the back area with an area of about 3cm x 3cm, and the subcutaneous fat and tissues were carefully removed so as not to damage the skin.

The amount and rate of itraconazole penetration through the skin were measured using a Franz diffusion cell. The stratum corneum was anchored between the donor phase and the receptor phase to direct the donor phase. Benzyl alcohol, PBS, PEG400 = 3: 8: 4 (v / v / v) mixed solution was used as the receptor phase, and the stirring was continued at 600 rpm while being maintained at 37 ± 0.5 ° C.

The area of skin in contact with the receptor phase was 2.0 cm ² and the dose of the receptor phase was 12 ml. 500 μl of the composition prepared in Examples 1 to 6 was applied to the donor phase to the skin surface, and 1.0 ml of receptor phase was collected at an hourly interval from 3 to 8 hours, and immediately supplemented with the same amount of fresh receptor phase.

1.0 ml of the receptor phase taken every hour was filtered using a membrane filter (0.2 μm) and then the amount of itraconazole was quantified using HPLC analysis. In this case, Capcell pak C ₁₈ (4.6 X 250 mm, Shiseido) was used, and the mobile phase was mixed with acetonitrile and water at 70:30 v / v, to which 0.5 wt% triethylamine was added. (pH 7) was used, the flow rate was 1.0ml / min, the injection amount was 60㎛ and the detection wavelength was measured by a fluorescence detector at excitation 260nm, emission 365nm.

As a result, as shown in FIG. 4, the skin permeation amount during the 8 hours of the composition according to F1-1 of Example 3 and F1-2 of Example 4, which is a gel formulation based on the F1 composition of Example 1 and the F1 composition, was The microemulsion and skin permeability of Example 1 without the gelling agent added were 4.87, 2.60 and 1.50 μg / cm ² , respectively (Examples 1 and 3: p <0.01, Example 1 and Example). 4: p <0.001), there was no significant difference between Example 3 and Example 4 with different kinds of gelling agents.

In addition, the skin permeation amount for 8 hours in F2 composition of Example 2 and F2-1 of Example 5 and F2-2 of Example 6, which are gel preparations based on the F2 composition, was respectively 4.02 as shown in FIG. 4. , 3.81 and 3.98 μg / cm ² showed no difference in skin permeation with or without gelling agent.

As shown in FIG. 6A, in the formulation according to Example 4 (F1-2), skin permeation for 8 hours according to the itraconazole concentration was 1.50, 2.89 and 11.59 μg / at 0.02%, 1% and 1.5% by weight, respectively. Skin permeation increased with increasing concentration in cm ² .

In addition, as shown in Figure 6b in the formulation according to Example 6 (F2-2) for 8 hours according to the itraconazole concentration skin permeation amount was 3.98, 7.72 and 5.94 ㎍ / cm ² there was no significant difference with the increase in concentration.

Experimental Example 2 Intradermal Drug Deposition Experiment

After the skin permeation experiment (8 hours), 2.0 cm ² of skin area was taken, which was washed with methanol to remove the drug remaining on the surface and in contact with the preparation. The taken skin was stripped 20 times with adhesive tape to remove the stratum corneum.

Finely cut the skin from which the stratum corneum was removed, add 2 ml of methanol, pulverize for 5 minutes with a tissue homogenizer, vortex for 6 minutes, centrifuge at 3000 rpm for 5 minutes, take a supernatant, and filter the filtrate with a membrane filter (0.2 μm). Was quantified by HPLC to determine the amount of drug deposited in the skin.

As shown in FIG. 5, the amount of drug deposits in the skin exfoliated in the order of F1 of Example 1, F1-1 of Example 3, and F1-2 of Example 4 was 1.02, 1.00, and 0.47 μg / cm ² , respectively. There was a tendency to decrease as in skin penetration. In addition, in the prescription of F2 of Example 2, F2-1 of Example 5, and F2-2 of Example 6, the amount of drug deposits in the skin having been exfoliated was almost similar to 1.13, 1.13, and 1.45 µg / cm ² , respectively.

In addition, in the formulation of Example 4 (F1-2), the amount of drug in the skin exfoliated according to the concentration was increased as the concentration of itraconazole increased to 0.47, 2.08 and 3.07 µg / cm ² as shown in FIG. In Example 6 (F2-2), it was found that the deposition amount increased to 1.45 and 2.01 ㎍ / cm ² at 0.02 wt% and 1 wt% of itraconazole, respectively, but at 1 wt% at 2.03 ㎍ / cm ² at 1.5 wt%. Did not show a big difference from.

Experimental Example 3 In vivo Transdermal Administration of Formulation

The male hairless mouse (5-6 weeks old, 18-20 g) was fixed and the width of 3.0 cm ² (1.5 cm X 2 cm) was selected as the result of Experimental Example 2 F1-2 ( 1.5% by weight), F2-2 (1.5% by weight) formulation of Example 6 was applied by applying 300μl to the back area.

After 4 hours and 8 hours, it was lethal to the cervical vertebra and treated in the same manner as in Experiment 2 to determine the amount of drug deposited in the exfoliated skin. 0.2-0.3 ml of blood was collected from the heart and centrifuged at 12000 rpm for 10 minutes to obtain 0.1 ml of plasma. It was cut back with 2x methanol and analyzed by HPLC analysis.

As a result of in vivo transdermal administration with two preparations in which the amount of drug deposition in the skin was large in the results of Experiment 2, as shown in FIG. 8, the amount of drug in the skin removed from exfoliation was 4 hours in the case of F1-2 of Example 4. after 8 hours, respectively 7.99㎍ / cm ² and 10.11㎍ / cm ² was carried out for example 6 F2-2 of 4 hours and 8 hours after each 9.83㎍ / cm ^2, and 15.28 μg / cm ² . In contrast, itraconazole was not detected by HPLC in plasma.

As described above, the present invention is prepared by preparing a microemulsion up to 200nm containing a poorly soluble drugs itraconazole, benzyl alcohol, phospholipid, diethylene glycol monoethyl ether and adding a gelling agent to the microemulsion The multi-emulsion hydrogel, which is a microemulsion hydrogel, can not only penetrate and localize itraconazole into the skin well, but also prevent the drug from entering the blood, thereby avoiding systemic side effects, which can be used as an effective itraconazole skin external preparation. Can be.

Claims (6)

It is a microemulsion hydrogel in which itraconazole is dissolved in benzyl alcohol, which is an oil phase. It is 0.02-3.0 wt% of itraconazole, 5.0-15.0 wt% of benzyl alcohol, 5.0-20.0 wt% of diethylene glycol monoether, 5.0-20.0 wt% of ethanol, and phospholipid. 5.0-20.0 wt%, 2-propenoic acid (Carbopol®) or 0.5-5.0 wt% of one compound selected from xanthan gum and the residual amount of water Hydrogel. delete delete delete delete Dissolving itraconazole in benzyl alcohol in the oil phase; Preparing an oil phase by adding a surfactant to the dissolved solution; And Adding an aqueous phase to which 2-propenoic acid (Carbopol®) or xanthan gum was added to the prepared oil phase. Method for producing a microemulsion hydrogel for topical skin treatment according to claim 1 comprising a.

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