PHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION IN POWDER FORMULATION CONTAINING ANTIVIRAL AGENT

Abstract

Provided is a pharmaceutical composition for oral administration in the form of powder obtained by a process including: (a) preparing an emulsion including zanamivir as an active ingredient; triglyceride; acyl glycerol; a nonionic surfactant; a sugar; and water; and (b) lyophilizing the emulsion prepared in the step (a). The pharmaceutical composition according to the presently claimed subject matter can significantly increase in vivo absorption rate of zanamivir. Further, the pharmaceutical composition according to the presently claimed subject matter is in the form of powder, which not only make it easy to store and distribute but also make it possible to avoid the use of functional packaging materials for preventing changes in moisture.

Claims

1. A pharmaceutical composition for oral administration in the form of powder obtained by a process comprising: (a) preparing an emulsion comprising zanamivir as an active ingredient; triglyceride; acyl glycerol; a nonionic surfactant; a sugar; and water, and (b) lyophilizing the emulsion prepared in the step (a).

2. The pharmaceutical composition according to claim 1, wherein the step (a) is carried out by preparing an emulsion including zanamivir in a concentration of 0.5˜5 mg/ml in a mixed solution comprising 1˜6% by weight of triglyceride; 1˜12% by weight of acyl glycerol; 1˜3% by weight of a nonionic surfactant; 5˜27% by weight of a sugar; and 65˜85% by weight of water.

3. The pharmaceutical composition according to claim 1, wherein the step (a) comprises (a1) preparing a syrup including zanamivir in a concentration of 0.5˜5 mg/ml in a mixed solution comprising 1˜20% by weight of triglyceride; 1˜30% by weight of acyl glycerol; 1˜30% by weight of a nonionic surfactant; 40˜50% by weight of a sugar; and 20˜30% by weight of water and (a2) mixing the syrup obtained in the step (a1) with water in a weight ratio of 1:2˜1:5 to prepare an emulsion.

4. The pharmaceutical composition according to claim 1, wherein the triglyceride is one or more selected from the consisting of triacetin, tripropionin, tributyrin, trivalerin, tricaproin, tricaprylin, tricaprin, triheptanoin, trinonanoin, triundecanoin, trilaurin, tridecanoin, trimyristin, tripentadecanoin, tripalmitin, glyceryl triheptadecanoate, and triolein.

5. The pharmaceutical composition according to claim 4, wherein the triglyceride is tricaprylin.

6. The pharmaceutical composition according to claim 1, wherein the acyl glycerol is one or more selected from the group consisting of glyceryl behenate, glyceryl oleate, glyceryl stearate, glyceryl palmitostearate, and a complex thereof.

7. The pharmaceutical composition according to claim 6, wherein the acyl glycerol is an oleoyl glycerol complex having 30 to 65% by weight of monooleoyl glycerol contents; 15 to 50% by weight of dioleoyl glycerol contents; and 2 to 20% by weight of trioleoyl glycerol contents.

8. The pharmaceutical composition according to claim 1, wherein the nonionic surfactant is one or more selected from the group consisting of a polyoxyethylene-polyoxypropylene block copolymer, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, and polyoxyethylene lauryl ether.

9. The pharmaceutical composition according to claim 8, wherein the nonionic surfactant is polyoxyethylene sorbitan monooleate.

10. The pharmaceutical composition according to claim 1, wherein the sugar is one or more selected from the group consisting of sucrose, maltose, lactose, isomaltose, fructooligosaccharide, galactooligosaccharide, isomaltooligosaccharide, maltodextrin, and mannan oligosaccharide.

11. The pharmaceutical composition according to claim 10, wherein the sugar is sucrose or fructooligosaccharide.

12. The pharmaceutical composition according to claim 2, wherein the step (a) is carried out by preparing an emulsion including zanamivir in a concentration of 0.5˜5 mg/ml in a mixed solution comprising 1˜6% by weight of tricaprylin; 1˜12% by weight of an oleoyl glycerol complex; 1˜3% by weight of polyoxyethylene sorbitan monooleate; 5˜27% by weight of sucrose or fructooligosaccharide; and 65˜85% by weight of water.

13. The pharmaceutical composition according to claim 3, wherein the step (a) comprises (a1) preparing a syrup including zanamivir in a concentration of 0.5˜5 mg/ml in a mixed solution comprising 1˜20% by weight of tricaprylin; 1˜30% by weight of an oleoyl glycerol complex; 1˜30% by weight of polyoxyethylene sorbitan monooleate; 40˜50% by weight of sucrose or fructooligosaccharide; and 20˜30% by weight of water and (a2) mixing the syrup obtained in the step (a1) with water in a weight ratio of 1:2˜1:5 to prepare an emulsion.

14. The pharmaceutical composition according to claim 3, wherein the step (a2) is carried out by mixing the syrup obtained in the step (a1) with water in a weight ratio of 1:2.5˜1:4 to prepare an emulsion.

15. The pharmaceutical composition according to claim 14, wherein the step (a2) is carried out by mixing the syrup obtained in the step (a1) with water in a weight ratio of 1:3 to prepare an emulsion.

16. The pharmaceutical composition according to claim 1, wherein the step (b) further comprises freezing the emulsion obtained in the step (a) before said lyophilization.

Description

DESCRIPTION OF DRAWINGS

[0017] FIG. 1 shows the appearance of the syrup prepared in Example 1.

[0018] FIG. 2 shows the appearance of the pharmaceutical composition in the form of powder prepared in Example 2.

[0019] FIG. 3 shows the appearance of the formulation obtained by the reconstitution through adding purified water to the pharmaceutical composition in the form of powder obtained in Example 2.

[0020] FIG. 4 shows the appearance of the product obtained by lyophilizing the syrup obtained in Example 1 as it is (i.e., without mixing with purified water).

[0021] FIG. 5 shows the appearance of the formulation obtained by the reconstitution through adding purified water to the product obtained by lyophilizing the syrup obtained in Example 1 as it is (i.e., without mixing with purified water).

BEST MODE

[0022] As used herein, the term “pharmaceutical composition for oral administration in the form of powder” refers to a formulation for oral administration having a powder form, which is reconstituted into the form of a solution having a clear and transparent appearance by dissolving in water when used; and then taken in the reconstituted form. The “water” used when used includes purified water, distilled water, sterile water, etc. for conventional oral administration. The “reconstitution” refers to preparing a solution having a clear and transparent appearance by adding about 0.2 to 0.3 part by weight of water such as purified water, distilled water, sterile water, etc. based on 1 part by weight of the powder formulation. Accordingly, a pharmaceutical product comprising the pharmaceutical composition of the present invention may include the above-described pharmaceutical composition for oral administration in the form of powder; and water for reconstitution, such as purified water, distilled water, sterile water, etc.

[0023] The present invention provides a pharmaceutical composition for oral administration in the form of powder obtained by a process comprising: (a) preparing an emulsion comprising zanamivir as an active ingredient; triglyceride; acyl glycerol; a nonionic surfactant; a sugar; and water, and (b) lyophilizing the emulsion prepared in the step (a).

[0024] In the pharmaceutical composition of the present invention, zanamivir used as an active ingredient may be used in a therapeutically effective amount. For example, zanamivir may be contained in an amount ranging from 0.1 to 5 mg, preferably from 1 to 5 mg, more preferably from about 1 mg, in the pharmaceutical composition for oral administration in the form of powder of the present invention, but not limited thereto.

[0025] In the pharmaceutical composition of the present invention, the step (a), a step for forming an emulsion, may be carried out by forming an emulsion by including zanamivir in the components of the pharmaceutical composition in the form of syrup disclosed in Korean Patent Application No. 10-2017-0175681, i.e., in a mixed solution comprising triglyceride, acyl glycerol, a nonionic surfactant, a sugar and water. For example, the step (a) may be carried out by preparing an emulsion including zanamivir in a concentration of 0.5˜5 mg/ml in a mixed solution comprising 1˜6% by weight, preferably 1˜4% by weight, of triglyceride; 1˜12% by weight, preferably 2˜8% by weight, of acyl glycerol; 1˜3% by weight, preferably 1˜2% by weight, of a nonionic surfactant; 5˜27% by weight of a sugar; and 65˜85% by weight of water. If necessary, the order of addition of the components in the preparation of the emulsion may be appropriately determined. For example, an emulsion may be prepared by dissolving saccharides in purified water and then dissolving zanamivir, followed by dissolving triglyceride, acyl glycerol, and a nonionic surfactant in sequence.

[0026] In addition, in the pharmaceutical composition of the present invention, the step (a) may be carried out by preparing the pharmaceutical composition in the form of syrup disclosed in Korean Patent Application No. 10-2017-0175681 and then adding water thereto to preparing an emulsion. As described in the following Examples and Experimental Examples, when the pharmaceutical composition in the form of syrup disclosed in Korean Patent Application No. 10-2017-0175681 is dried or lyophilized as it is, a sticky product is obtained and thus a formulation in the form of powder cannot be prepared. Therefore, it is preferable that the step (a) comprises (a1) preparing a syrup including zanamivir in a concentration of 0.5˜5 mg/ml in a mixed solution comprising 1˜20% by weight, preferably 3˜15% by weight, of triglyceride; 1˜30% by weight, preferably 5˜25% by weight, of acyl glycerol; 1˜30% by weight, preferably 2˜25% by weight, of a nonionic surfactant; 40˜50% by weight of a sugar; and 20˜30% by weight of water and (a2) mixing the syrup obtained in the step (a1) with water in a weight ratio of 1:2˜1:5 to prepare an emulsion. If necessary, the order of addition of the components in the preparation of the emulsion in the step (a1) may be appropriately determined. For example, an emulsion may be prepared by dissolving a sugar in purified water, dissolving zanamivir, and then dissolving triglyceride, acyl glycerol, and a nonionic surfactant in sequence, followed by the step (a2).

[0027] The triglyceride may be one or more selected from the consisting of triacetin, tripropionin, tributyrin, trivalerin, tricaproin, tricaprylin, tricaprin, triheptanoin, trinonanoin, triundecanoin, trilaurin, tridecanoin, trimyristin, tripentadecanoin, tripalmitin, glyceryl triheptadecanoate, and triolein, preferably tricaprylin [e.g., Captex™ 8000 (Abitec)].

[0028] The acyl glycerol, unless otherwise indicated, includes monoacyl glycerol, diacyl glycerol, triacyl glycerol, or a complex thereof. For example, the acyl glycerol may be one or more selected from the group consisting of glyceryl behenate, glyceryl oleate, glyceryl stearate, glyceryl palmitostearate, and a complex thereof. Preferably, the acyl glycerol may be an oleoyl glycerol complex having 30 to 65% by weight of monooleoyl glycerol contents; 15 to 50% by weight of dioleoyl glycerol contents; and 2 to 20% by weight of trioleoyl glycerol contents. In an embodiment, the oleoyl glycerol complex may be an oleoyl glycerol complex having 32 to 52% by weight of monooleoyl glycerol contents; 30 to 50% by weight of dioleoyl glycerol contents; and 5 to 20% by weight of trioleoyl glycerol contents [e.g., Peceol™ (Gattefosse)]. In another embodiment, the oleoyl glycerol complex may be an oleoyl glycerol complex having 55 to 65% by weight of monooleoyl glycerol contents; 15 to 35% by weight of dioleoyl glycerol contents; and 2 to 10% by weight of trioleoyl glycerol contents [e.g., CAPMUL™ (Abitec)].

[0029] The nonionic surfactant may be one or more selected from the group consisting of a polyoxyethylene-polyoxypropylene block copolymer, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, and polyoxyethylene lauryl ether, preferably polyoxyethylene sorbitan monooleate [e.g., Tweeen™ 80 (NOF)].

[0030] The sugar may be one or more selected from the group consisting of sucrose, maltose, lactose, isomaltose, fructooligosaccharide, galactooligosaccharide, isomaltooligosaccharide, maltodextrin, and mannan oligosaccharide, preferably sucrose or fructooligosaccharide.

[0031] In an embodiment, the step (a) may be carried out by preparing an emulsion including zanamivir in a concentration of 0.5˜5 mg/ml in a mixed solution comprising 1˜6% by weight of tricaprylin; 1˜12% by weight of an oleoyl glycerol complex; 1˜3% by weight of polyoxyethylene sorbitan monooleate; 5˜27% by weight of sucrose or fructooligosaccharide; and 65˜85% by weight of water.

[0032] In another embodiment, the step (a) may comprise (a1) preparing a syrup including zanamivir in a concentration of 0.5˜5 mg/ml in a mixed solution comprising 1˜20% by weight of tricaprylin; 1˜30% by weight of an oleoyl glycerol complex; 1˜30% by weight of polyoxyethylene sorbitan monooleate; 40˜50% by weight of sucrose or fructooligosaccharide; and 20˜30% by weight of water and (a2) mixing the syrup obtained in the step (a1) with water in a weight ratio of 1:2˜1:5, preferably in a weight ratio of 1:2.5˜1:4, more preferably in a weight ratio of about 1:3, to prepare an emulsion.

[0033] In the pharmaceutical composition of the present invention, the step (b) may further comprise freezing the emulsion obtained in the step (a). That is, the step (b) may be carried out by freezing the emulsion obtained in step (a) and then lyophilizing the resultant. It is preferable that the freezing is performed by rapid freezing, so as to maintain a uniform dispersion state of the emulsion. The lyophilization may be carried out with a lyophilizer according to a method conventionally used in the field of pharmaceutics, for example, at a temperature of about −114° C. or less and at a pressure of 10 mTorr or less for 2 to 8 hours, preferably for about 5 hours.

[0034] The present invention will be described in further detail with reference to the following examples and experimental examples. These examples and experimental examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

EXAMPLE 1: Preparation of a Syrup

[0035] A zanamivir-containing syrup was prepared according to the components and amounts shown in Table 1. Sucrose was dissolved in purified water and then zanamivir was added thereto. The mixture was transparently dissolved by stirring at 1,000 rpm at 25° C. for 2 hours. Captex™ 8000 (Abitec), Peceol™ (Gattefosse) and Tweeen™ 80 (NOF) were sequentially added thereto, followed by stirring at 1,000 rpm to prepare a syrup.

TABLE-US-00001 TABLE 1 Components of Excipients (% by weight) Zanamivir Purified Captex ™ (concentration) Sucrose water 8000 Peceol ™ Tweeen ™ 1 mg/ml 44.78 22.35 9.13 18.27 5.47

[0036] The appearance of the obtained syrup is shown in FIG. 1. As shown in FIG. 1, the resulting syrup exhibited a clear and transparent appearance.

EXAMPLE 2: Preparation of a Pharmaceutical Composition For Oral Administration in the Form of Powder

[0037] The syrup obtained in Example 1 was mixed with purified water in a weight ratio of 1:3 to form an emulsion, rapidly frozen using liquid nitrogen, and then lyophilized at the temperature of −114° C. or less and at the pressure of 10 mTorr or less for about 5 hours to prepare 7.871 g of a pharmaceutical composition in the form of powder.

EXAMPLE 3: Preparation of a Pharmaceutical Composition For Oral Administration in the Form of Powder

[0038] 4.48 g of Sucrose was dissolved in 22.24 g of purified water and then 0.03 g of zanamivir was added thereto. The mixture was transparently dissolved by stirring at 1,000 rpm at 25° C. for 2 hours. 0.91 g of Captex™ 8000 (Abitec), 1.83 g of Peceol™ (Gattefosse) and 0.55 g of Tweeen™ 80 (NOF) were sequentially added thereto, followed by stirring at 1,000 rpm to form an emulsion (30.1 ml). The emulsion was rapidly frozen using liquid nitrogen and then lyophilized at the temperature of −114° C. or less and at the pressure of 10 mTorr or less for about 5 hours to prepare 7.771 g of a pharmaceutical composition in the form of powder.

Experimental Example 1: Absorption Rate Tests of the Syrup

[0039] The syrup prepared in Example 1 was orally administered to ICR mice (6 weeks old, female) at the doses of 50 mg/kg and 100 mg/kg as zanamivir, using a gastric sonde, respectively. After the administrations, blood samples were collected from the orbital vein of each mouse at 0, 30 minutes, 1, 2, and 4 hours and then centrifuged at 8,000×g at 4° C. for 20 minutes to obtain plasma samples, which were stored at −70° C. The plasma samples were melted at room temperature and then stirred for 1 minute with a vortex mixer. 200.0 μL of 70% acetonitrile and 300.0 μL of 60% acetonitrile were added to 100.0 μL of each plasma sample, which was then stirred for 5 minutes at 3,000 rpm using a vortex mixer. After centrifuging each sample at 14,000×g, 4° C. for 20 minutes, 300.0 μL of the supernatant was taken therefrom and then filtered using a syringe filter (PTFE, chromdisc, 13 mm, pore size 0.20 mm). 200.0 μL of the filtrate was taken and then analyzed by HPLC under the following conditions.

[0040] <HPLC Conditions > [0041] Column: 4.6 mm×250 mm, 5 μm, NH2p-50 [0042] Column temperature: 30° C. [0043] Flow rate: 1 ml/min [0044] Detector: UV 234 nm [0045] Injection volume: 60 μl [0046] Mobile phase: acetonitrile: purified water=65:35 (v/v)

[0047] The pharmacokinetic parameters calculated from each blood concentration profile of zanamivir measured as described above are shown in Table 2 below.

TABLE-US-00002 TABLE 2 Dose Cmax (μg/ml) Tmax (hr) AUC.sub.0-4 hr (min .Math. μg/ml) 50 mg/kg 0.36 ± 0.013 0.5 55.8 100 mg/kg 0.71 ± 0.15  0.5 78

[0048] As shown in Table 2, it can be seen that the Cmax and AUC.sub.0-4hr values increase as the oral dose increases.

Experimental Example 2: Stability Tests of the Syrup

[0049] The zanamivir-containing syrup prepared in Example 1 was stored at 25° C. for 0 and 40 days, followed by measuring the appearances and contents thereof. The results are shown in Table 3 below.

TABLE-US-00003 TABLE 3 Storage period Contents of zanamivir (% by weight) 0 Day 97.4 ± 0.18 40 Days 96.6 ± 0.57

[0050] As shown in Table 3, as a result of the content test evaluation of the syrup, it can be confirmed that the content of the syrup was maintained after 40 days of storage, compared to the initial formulation, and thus that the syrup is stable. In addition, phenomena such as layer separation and precipitation were not observed in both the is initial syrup and the syrup after storage, which confirms that the syrup is stable.

Experimental Example 3: Evaluation on the Forming-Abilities of Powder Formulations

[0051] The appearance of the pharmaceutical composition in the form of powder obtained in Example 2 is shown in FIG. 2. In addition, the appearance of the formulation obtained by the reconstitution thereof, i.e., through adding 2.26 ml of purified water to the pharmaceutical composition in the form of powder obtained in Example 2 (7.871 g), is shown in FIG. 3. As can be seen from the results of FIGS. 2 and 3, the pharmaceutical composition obtained according to the present invention was in the form of powder; and provided a clear and transparent syrup when reconstituted with water.

[0052] In addition, the syrup obtained in Example 1 was rapidly frozen using liquid nitrogen as it is (that is, without mixing with purified water) and then lyophilized under the same conditions as in Example 2. The appearance of the resulting product is shown in FIG. 4. In addition, the appearance of the formulation obtained by the reconstitution thereof, i.e., through adding 2.26 ml of purified water to the resulting product (7.74 g), is shown in FIG. 5. As can be seen from the results of FIGS. 4 and 5, when the syrup was lyophilized without an additional treatment (i.e., without mixing with water), it exhibited a sticky paste appearance and provided an opaque syrup when reconstituted with water.

Experimental Example 4: Stability Tests of the Powder Formulation

[0053] The powder formulation prepared in Example 2 was stored at 25° C. for 0 and 40 days, followed by measuring the appearances and contents thereof. The results are shown in Table 4 below.

TABLE-US-00004 TABLE 4 Storage period Contents of zanamivir (% by weight) 0 Day 100.10 ± 0.57 40 Days 100.06 ± 0.36

[0054] As shown in Table 4, as a result of the content test evaluation of the powder formulation, it can be confirmed that the formulation after the storage period of 40 days maintained the content thereof, compared to the initial formulation, which confirms that the formulation is stable.