WO2018159941A1 - Stable pharmaceutical composition comprising zanamivir - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for oral administration comprising zanamivir. Specifically, provided is a pharmaceutical preparation which comprises zanamivir as an active ingredient and which comprises triglycerides, acylglycerol complexes, and additional nonionic surfactants. As such, the pharmaceutical preparation has an excellent absorption rate in a human body, stability, and uniformity of the content, etc.

Description

Stable Pharmaceutical Compositions Containing Janamivir

The present invention relates to a pharmaceutical composition for oral administration comprising an antiviral agent. Specifically, the pharmaceutical composition includes zanamivir as an active ingredient, and further includes triglycerides, acylglycerol compounds, and surfactants to provide excellent pharmaceutical preparations having excellent absorption rate, stability, and uniformity of contents in the body.

First-generation antiviral products, amantadine and rimantadine, are believed to work by blocking the M2-protein ion-channel of influenza A virus. Blocking the influx of H + ions through the M2-protein channel inhibits the release of free ribonucleic acid protein and release into the cytoplasm. This occurs only in type A strains, not in type B strains. Later, the development of the second-generation antiviral products zanamivir and oseltamivir led to the development of hemagglutinin, which is present as a mushroom-shaped bump on the surface of influenza A and B viruses. HA) or the enzyme neuraminidase (NA). These proteins bind to the membrane surface of infected target cells by cleaving sialic acid residues of sialo glycoproteins and glycolipids. In addition, at the end of viral replication neuraminidase is essential for cleaving sialic acid from the receptor to release the virus. Janamivir is the first commercially developed neuraminidase inhibitor and is used for the treatment and prevention of influenza viruses A and B.

Oseltamivir has the structure of Formula I and is commercially available under the trade name Tamiflu. It is widely used as a treatment for swine flu or avian influenza.

[Formula I]

Chemically, zanamivir is 5- (acetylamino) -4-[(aminoiminomethyl) amino] -2,6-anhydro-3,4,5-trideoxy-D-glycero-D-galacto Non-2-enoic acid (Formula II), represented by the following structural formula:

[Formula II]

Janamivir is effective by binding to the conserved region of the influenza neuraminidase enzyme, which catalyzes cleavage of terminal sialic acid attached to glycolipids and glycoproteins, and is marketed under the trade name RELENZA. have.

The bioavailability of zanamivir is known to be about 2%, and it is known to be 4% to 17% when zanamivir is inhaled as a powder. In the case of powdered inhalants, 5 mg doses are given twice daily, twice daily for 5 days. Currently, rerenza is used for the treatment of influenza A and B infections, but should be orally inhaled using a dischaler for respiratory administration. Therefore, an inhalation device for oral inhalation is required separately, and it is difficult to administer a certain amount every time due to inhalation, and the use of the device should be explained to the patient, and in particular, it is difficult to administer in children.

Therefore, the present inventors have attempted to improve the problem of low bioavailability of zanamivir during oral administration, to solve the problems caused by inhalation administration, and to develop oral formulations that are convenient to take and are pharmaceutical.

Despite the excellent antiviral effect of zanamivir, it was difficult to be widely used due to low bioavailability during oral administration. The inventors of the present invention have completed the present invention by administering an additive which can improve the absorption rate of zanamivir while seeking various solutions to solve such problems.

 Accordingly, the present invention is to provide a pharmaceutical composition, preparations and a method for preparing oral administration that is excellent in bioavailability during oral administration, and pharmaceutically good oral administration.

The present inventors have found that by administering zanamivir, which has low bioavailability during oral administration, together with other additives, bioavailability can be increased during oral administration.

That is, the present inventors used triglyceride, acylglycerol complex, or other nonionic surfactant as an additive to increase the absorption rate of zanamivir. When these were used alone or only two types did not show an effect of improving the absorption rate, when all three types were used, it was surprisingly found that the absorption rate is very high.

Accordingly, the present invention provides pharmaceutical compositions comprising zanamivir as an active ingredient and triglycerides, acylglycerol complexes and other nonionic surfactants as additives.

Triglycerides include triacetin, tripropionine, tributyrin, trivalerine, tricaproin, tricapryline (Captex8000), tricaprine, triheptanoin, trinonanoin, triondecanoin, trira We can be selected from one or more of the group consisting of tridecanoin, trimiristin, tripentadecanoin, tripalmitin, glyceryl triheptadecanoate and triolein.

Acylglycerol complex may be selected from one or more of the group consisting of glyceryl behenate, glyceryl monooleate (Peceol), glyceryl stearate and glyceryl palmitostearate.

The nonionic surfactant may be selected from the group consisting of polyoxyethylene-polyoxypropylene copolymer (poloxamer), sorbitan ester (Span), polyoxyethylene sorbitan (Tween) and polyoxyethylene ether (Brij). have.

In addition, the inventors have found that when the triglyceride, acylglycerol complex, acylglycerol complex, and other nonionic surfactants are all included, no phase separation occurs immediately after preparation or after centrifugation, and the content is uniform.

In particular, the inventors have found that pharmaceutical compositions comprising zanamivir, including triglycerides, acylglycerol complexes, and other nonionic surfactants as additives, are convenient in dosage form and are useful in bioavailability, stability and It was confirmed that the content uniformity was all excellent.

In addition, the present inventors provide emulsion or syrup formulations comprising triglycerides, acylglycerol complexes and other nonionic surfactants as additives in the preparation of co-formulations comprising zanamivir and oseltamivir.

The present invention solves the problem that the oral administration of zanamivir has a low bioavailability to use it for inhalation, thereby increasing the convenience of medication through oral administration, and can be applied to patients who have difficulty inhaling. No need for inhalation equipment, such as cost is reduced, and solved the problem that the dosage can be changed during inhalation.

In addition, the present invention provides a pharmaceutical composition or formulation capable of administering zanamivir via oral, as well as having high bioavailability when administered orally, and having excellent pharmaceutical properties such as stability and content uniformity.

In particular, the present invention provides a formulation which is convenient to take by providing an emulsion or syrup formulation comprising zanamivir, and which is excellent in both bioavailability, stability and content uniformity.

The present invention also provides emulsion or syrup formulations with good stability, including zanamivir and oseltamivir.

1 shows the results of water absorption of the compositions of Examples 1-7.

Figure 2 shows the results of phase separation immediately after preparation of the compositions 1 to 13 and after centrifugation.

3 shows bioavailability when zanamivir dissolved in physiological saline was administered intravenously and when the composition of Example 1 was orally administered.

4 shows syrup formulation properties of zanamivir and pharmaceutical compositions comprising zanamivir and oseltamivir.

Figure 5 shows the change in zanamivir concentration in vivo by dosage.

The present invention relates to pharmaceutical compositions comprising antiviral agents, triglycerides, acylglycerol complexes and nonionic surfactants.

The antiviral agent of the present invention is at least one selected from the group consisting of zanamivir, tenofovir disoproxyl, sidofovir, gancyclovir, foscarnet, ribavirin and oseltamivir, and pharmaceutically acceptable salts thereof. It may be, but is not limited thereto.

In particular, the present invention relates to pharmaceutical compositions comprising zanamivir, triglycerides, acylglycerol complexes and additional nonionic surfactants.

Triglycerides include triacetin, tripropionine, tributyrin, trivalerine, tricaproin, tricapryline (Captex8000), tricaprine, triheptanoin, trinonanoin, triondecanoin, trira We can be selected from one or more of the group consisting of tridecanoin, trimyristin, tripentadecanoin, tripalmitin, glyceryl triheptadecanoate and triolein, but are not limited thereto. Most preferably, triglyceride is tricapryline (Captex8000).

Triglycerides are included in an amount of 1 to 20% by weight, more preferably 3 to 15% by weight, based on the weight of zanamivir.

The acylglycerol complex may be selected from one or more of the group consisting of glyceryl behenate, glyceryl monooleate (Peceol), glyceryl stearate and glyceryl palmitostearate, but is not limited thereto. The acylglycerol complex is most preferably glyceryl monooleate (Peceol).

The acylglycerol complex is contained in an amount of 1 to 30% by weight, more preferably 5 to 25% by weight, based on the weight of zanamivir.

The nonionic surfactant may be selected from the group consisting of polyoxyethylene-polyoxypropylene copolymer (poloxamer), sorbitan ester (Span), polyoxyethylene sorbitan (Tween) and polyoxyethylene ether (Brij). It is not limited thereto. Most preferably, the nonionic surfactant is polyoxyethylene sorbitan (Tween).

The nonionic surfactant is included in an amount of 1 to 30% by weight, more preferably 2 to 25% by weight, based on the weight of zanamivir.

The composition of the present invention has high bioavailability when it comprises all of triglycerides, acylglycerol complexes and additional nonionic surfactants.

In particular, the composition comprising zanamivir as an active ingredient, Captex8000, Peceol and Tween80 as an additive increases the bioavailability of zanamivir, and has pharmaceutical properties such as excellent stability and content uniformity.

In addition, the composition of the present invention may further comprise gum.

Gum may be selected from one or more of the group consisting of arabic gum, agar, guar gum, lansan gum, trakans gum and xanthan gum, arabic gum is most preferred.

In addition, the composition of the present invention may further comprise a saccharide. The sugar may be selected from the group consisting of sucrose, maltose, lactose, isomaltose, fructooligosaccharide, galactooligosaccharide, isomaltooligosaccharide, maltodextrin and mannan oligosaccharide.

The present invention includes a pharmaceutical formulation wherein the composition is formulated. The formulations may be formulated for oral administration.

In addition, the composition of the present invention can be used in the form of oral dosage forms, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., respectively, according to a conventional method, preferably emulsion or syrup It may be a formulation.

The present invention relates to emulsion or syrup formulations comprising zanamivir as an active ingredient and triglycerides, acylglycerol complexes as additives and further nonionic surfactants.

Specifically, the present invention relates to an emulsion or syrup formulation comprising zanamivir as an active ingredient and Captex8000, Peceol and Tween80 as additives.

The present invention relates to emulsion or syrup formulations comprising zanamivir and oseltamivir as active ingredients and triglycerides, acylglycerol complexes and further nonionic surfactants as additives.

In particular, the present invention relates to an emulsion or syrup formulation comprising zanamivir and oseltamivir as active ingredients and Captex8000, Peceol and Tween80 as additives.

The present invention

a) mixing triglycerides, acylglycerol complexes and additional nonionic surfactants;

b) adding the mixture to distilled water in which at least one active ingredient selected from the group consisting of zanamivir and oseltamivir is dissolved; And

c) a method of preparing comprising the step of emulsifying the solution obtained above.

The present invention

a) dissolving sucrose in purified water;

b) adding at least one active ingredient selected from the group consisting of zanamivir and oseltamivir to the sucrose solution, followed by stirring; And

c) a process comprising the step of mixing and stirring the triglycerides, acylglycerol complexes and additional nonionic surfactants.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, these examples are only provided for the purpose of illustration in order to facilitate understanding of the present invention, the scope of the present invention is not limited by the following examples.

Example 1

To prepare a pharmaceutical composition for oral administration containing zanamivir according to the ingredients and contents of Table 1 below.

Captex 8000 (Abitec), Peceol (PECEOL ™, Gattefosse) and Tween 80 (tween ™ 80, NOF) were mixed in the ratio shown in Table 1 and added to distilled water in which zanamivir was completely dissolved. did. At this time, the oil phase and the water phase were mixed at a constant ratio, and the solution was stirred at 25 ° C. for 2 hours to obtain an emulsion.

Example 2

In the same manner as in Example 1 using only Captex 8000 to prepare a pharmaceutical composition for oral administration containing zanamivir.

Example 3

In the same manner as in Example 1 using only peseol to prepare a pharmaceutical composition for oral administration containing zanamivir.

Example 4

In the same manner as in Example 1 using only Tween 80 to prepare a pharmaceutical composition for oral administration containing zanamivir.

Example 5

In the same manner as in Example 1 using Captex 8000 and peseol were mixed according to the composition ratio of Table 1, and then added to distilled water in which zanamivir completely dissolved to prepare a pharmaceutical composition for oral administration.

Example 6

Peceol and Tween 80 were mixed in the same manner as in Example 1, followed by mixing according to the composition ratio of Table 1, and then added to distilled water in which zanamivir was completely dissolved to prepare a pharmaceutical composition for oral administration.

Example 7

In the same manner as in Example 1 using the Captex 8000 and Tween 80 was mixed according to the composition ratio of Table 1, and then added to distilled water in which zanamivir completely dissolved to prepare a pharmaceutical composition for oral administration.

Example	Component ratio (v / v,%)
	Captex 8000	Peceol	Tween 80
One	27.78	55.56	16.67
2	100	-	-
3	-	100	-
4	-	-	100
5	50	50	-
6	-	50	50
7	50	-	50

[Examples 8 to 13]

To prepare a pharmaceutical composition for oral administration containing an antiviral agent according to the components and contents of Table 2.

Captex 8000 (Abitec), Peceol (PECEOL ™, Gattefosse) and Tween 80 (tween ™ 80, NOF) were mixed in the ratio shown in Table 2, and then added to distilled water in which the antiviral agent was completely dissolved. . At this time, the oil phase and the water phase were mixed at a constant ratio, and the solution was stirred at 25 ° C. for 2 hours to obtain an emulsion. The antiviral concentrations in the formulations of Examples 8-13 are all 10 mg / mL.

Example	Antiviral agents	Component ratio (v / v,%)
		Captex 8000	Peseol	Twin 80
8	Tenofovir disoproxil	27.78	55.56	16.67
9	Cidofovir
10	Ganciclovir
11	Foscarnet
12	Ribavirin
13	Oseltamivir

Example 14

Preparation of Syrup Formulations

According to the ingredients and contents of Table 3 below, a syrup formulation containing zanamivir was prepared.

A certain amount of sucrose was weighed and then dissolved in purified water. After a certain amount of zanamivir was added to the sucrose solution, the mixture was stirred at 25 ° C. at 1,000 rpm for 2 hours.

After confirming that the completely transparent melted, cap-Tex ^{8000 (captex TM 8000, Abitec)} , page seol (PECEOL ^TM, Gattefosse), after the twin-80 (tween ^TM 80, NOF) were mixed according to the ratio shown in Table 3, 1,000 rpm Stirring to complete the syrup formulation.

Janamivir concentration	Excipient Components (W / W%)
	Sucrose	Purified water	Captex 8000	Peseol	Twin 80
5 mg / ml	40	20	10.4	20.8	6.3

Example 15

Manufacture of zanamivir and oseltamivir

According to the ingredients and contents of Table 4 below, a syrup formulation containing zanamivir and oseltamivir was prepared.

A certain amount of sucrose was weighed and then dissolved in purified water. Janamivir and oseltamivir were added to the sucrose solution, and the mixture was stirred at 1,000 rpm at 25 ° C for 2 hours.

After confirming that the completely transparent melted, cap-Tex ^{8000 (captex TM 8000, Abitec)} , page seol (PECEOL ^TM, Gattefosse), after the twin-80 (tween ^TM 80, NOF) were mixed according to the ratio shown in Table 4, 1,000 rpm Stirring to complete the syrup formulation.

Janamivir concentration	Oseltamivir concentration	Excipient Components (W / W%)
		Sucrose	Purified water	Captex 8000	Peseol	Twin 80
5 mg / ml	10 mg / ml	40	20	10.4	20.8	6.3

[Test Example 1]

Absorption Confirmation Test

ICR mice (6 weeks old, females) were orally administered with gastric sonde at a dose of 50 mg / kg, including oral administration of zanamivir prepared in each example. Blood was collected from the orbital vein of the mouse at 0, 30, 1, 2, 4, 6 and 8 hours after drug administration, and centrifuged at 8,000 × g, 4 ° C. for 20 minutes to obtain a plasma sample. It was stored at -70 ° C.

The plasma sample was dissolved 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 the plasma sample, followed by stirring at 3,000 rpm for 5 minutes. Each sample was centrifuged at 14,000 × g, 4 ° C. for 20 minutes, and 300.0 μL of the supernatant was filtered using a syringe filter (PTFE, chromdisc, 13 mm, pore size 0.20 mm). The filtrate was analyzed by HPLC taking 200.0 μL.

The pharmacokinetic parameters calculated from the blood concentration of zanamivir as measured above are shown in Table 5 below.

Example	C max (μg / ml)	T max (hr)	AUC 0-T (min 占 ㎍ / ml)
One	1.69 ± 0.68	2	508.15
2	0.34 ± 0.06	One	118.32
3	0.15 ± 0.12	0.5	30.81
4	0.29 ± 0.15	6	127.01
5	0.38 ± 0.1	8	148.01
6	0.29 ± 0.01	0.5	120.67
7	0.23 ± 0.04	0.5	94.61

Blood concentration test results are shown in Table 6 and FIG. 1. As shown in Table 6 and Figure 1, it was confirmed that the absorption rate is the best in Example 1. That is, it can be seen that the water absorption of the composition containing all three additives is the best.

Hours (hr)	Example 1	Example 2	Example 3	Example 4	Example 5	Example 6	Example 7
0	0	0	0	0	0	0	0
2	1.69	0.26	0.06	0.27	0.29	0.26	0.18
4	1.01	0.28	0.07	0.26	0.36	0.26	0.21
6	1.27	0.23	0.05	0.29	0.29	0.26	0.21
8	0.63	0.15	0.05	0.27	0.38	0.23	0.22

[Test Example 2]

Absorption confirmatory test of syrup preparation

Using the syrup formulation containing zanamivir prepared in Example 14, the absorption rate was confirmed in the same manner as in Test Example 1.

The dose of zanamivir was set to 50 mg / kg and 100 mg / kg, respectively, and blood was collected at 0, 30 minutes, 1 hour, 2 hours and 4 hours.

The pharmacokinetic parameters calculated from the blood concentration of zanamivir measured as described above are shown in Table 7 below.

Dosage	C max (μg / ml)	T max (hr)	AUC 0-4hr ( minμg / ml)
50 mg / kg	0.36 ± 0.013	0.5	55.8
100 mg / kg	0.71 ± 0.15	0.5	78

As shown in Table 7 and FIG. 5, it was confirmed that the C _max and AUC _0-4hr values increased as the oral dose was increased.

[Test Example 3]

Stability Check Test

After the formulations of Examples 1 to 7 were prepared according to the above-described preparation method to confirm their properties, each formulation was centrifuged at 1,500 × g and 20 ° C. for 15 minutes. Phase stability immediately after centrifugation was confirmed to evaluate the stability of the formulation.

As shown in Figure 2, in Example 1 to 7 immediately after the production does not occur phase separation, in Example 1 after the centrifugation does not occur, but in Example 2 to 7 it was confirmed that the phase separation appears.

As a result, it was confirmed that only Example 1 has stability without phase separation immediately after preparation and after centrifugation.

[Test Example 4]

Content uniformity test

After centrifugation in Test Example 3, the content of zanamivir in the upper, middle, and lower layers of the formulation of Example 1 was analyzed, and the results are shown in Table 8.

Initial zanamivir content (%)	% After centrifugation
	Prize	medium		Ha
100	101.788	97.455	102.655

As shown in Table 8, it was confirmed that even after centrifugation in Example 1, the zanamivir content is uniformly present in the upper, middle, and lower layers.

[Test Example 5]

Stability Test of Syrup Formulations

The syrup formulation comprising zanamivir prepared in Example 14 was stored at 25 ° C. conditions for 0 and 40 days, after which the properties and contents were measured. The results are shown in Table 9 below.

Storage period	Janamivir content (%)
0 days	97.4 ± 0.18
40 days	96.6 ± 0.57

As shown in Table 9, as a result of the content test evaluation of the syrup formulation, the formulation after 40 days of storage period was confirmed that the formulation is stable because the content is maintained compared to the initial formulation.

In addition, the syrup formulation after the initial syrup formulation and storage did not observe a phenomenon such as layer separation and precipitation, it was confirmed that the stability.

[Test Example 6]

Additive Ratio Confirmation Test

As a result of repeating the stability and content uniformity test of Test Examples 3 and 4 according to the ratio of the additive, the ratio of the additive showing excellent stability and content uniformity is shown in Table 10.

% By weight of zanamivir
Captex 8000	Peseol	Twin 80
1-20	1-30	1-30

Regarding the zanamivir weight, it was confirmed that stability and content uniformity were excellent when Captex8000 included 1 to 20 wt%, Peceol 1 to 30 wt%, and Tween80 1 to 30 wt%.

[Test Example 7]

Bioavailability test

Experimental results of orally administering the composition of Example 1 to the mouse in Test Example 1, and experimental results of dissolving zanamivir in physiological saline at a concentration of 10 mg / ml and orally and intravenously administered the solution to the mice, respectively. 11 is shown.

	Dosing method	AUC 0-T (min 占 ㎍ / ml)	C max (μg / ml)	Tmax (hr)	Bioavailability (%)
Example 1 Composition	Oral administration	508.15	1.69 ± 0.68	2	43.13
Janamivir dissolved in physiological saline	Oral administration	-	-	-	-
	Intravenous administration	1178.11	76.35 ± 12.45	0.083	-

The oral administration of zanamivir dissolved in physiological saline did not occur in vivo. In addition, as shown in Figure 3, when the zanamivir dissolved in physiological saline intravenously administered, the bioavailability is sharply reduced, it was confirmed that the bioavailability is excellent when the composition of Example 1 orally administered.

[Test Example 8]

Stability Check Test

After the formulations of Examples 8 to 13 were prepared according to the above-described preparation method to confirm their properties, each formulation was centrifuged at 1,500 × g and 20 ° C. for 15 minutes. Phase stability immediately after centrifugation was confirmed to evaluate the stability of the formulation.

As shown in FIG. 2, phase separation does not occur immediately after manufacture in the formulations of Examples 8 to 13, and phase separation does not occur even after centrifugation in the formulations of Examples 8 to 13 to ensure stability.

[Test Example 9]

Stability Identification Test of Syrup Formulation

As shown in FIG. 4, it was confirmed that the properties of the zanamivir single syrup prepared in Examples 14 and 15, and the zanamivir and oseltamivir complex syrups, respectively, showed clear and transparent properties.

[Test Example 10]

Content uniformity test

After centrifugation in Test Example 6, the contents of Examples 8 to 13 formulations were analyzed in the upper, middle, and lower layers of the Examples 8 to 13 formulations, and the results are shown in Table 12.

Example	Content after centrifugation (%, initial material content 100%)
	Prize	medium		Ha
8	99.89	100.06	101.02
9	100.25	100.98	99.78
10	101.56	100.12	99.87
11	98.45	101.54	100.12
12	100.21	100.57	99.61
13	101.54	99.45	99.63

As shown in Table 12, it was confirmed that even after centrifugation in the formulations of Examples 8 to 13, the zanamivir content is uniformly present in the upper, middle, and lower layers.

Claims (20)

1. A pharmaceutical composition comprising an antiviral agent, a triglyceride, an acylglycerol complex and a nonionic surfactant.
2. The antiviral agent of claim 1 wherein the antiviral agent is selected from the group consisting of zanamivir, tenofovir disoproxyl, sipofovir, gancyclovir, poscarnet, ribavirin and oseltamivir, and pharmaceutically acceptable salts thereof. Wherein at least one pharmaceutical composition is selected.
3. The pharmaceutical composition of claim 2, wherein the antiviral agent is zanamivir or oseltamivir.
4. The triglyceride according to claim 1, wherein the triglyceride is triacetin, tripropionine, tributyrin, trivalerine, tricaproin, tricapryline, tricaprine, triheptanoin, trinonanoin, triondecanoin , Trilaurin, tridecanoin, trimiristin, tripentadecanoin, tripalmitin, glyceryl triheptadecanoate and triolein.
5. The pharmaceutical composition of claim 1, wherein the acylglycerol complex is selected from the group consisting of glyceryl behenate, glyceryl monooleate, glyceryl stearate and glyceryl palmitostearate.
6. The pharmaceutical composition of claim 1, wherein the nonionic surfactant is selected from the group consisting of polyoxyethylene-polyoxypropylene copolymers, sorbitan esters, polyoxyethylene sorbitan and polyoxyethylene ethers.
7. The pharmaceutical composition of claim 4, wherein the triglyceride is tricapryline.
8. 6. The pharmaceutical composition of claim 5, wherein the acylglycerol complex is glyceryl monooleate.
9. The pharmaceutical composition of claim 6, wherein the nonionic surfactant is polyoxyethylene sorbitan.
10. 4. A pharmaceutical composition according to claim 3 comprising 1 to 20% by weight of triglycerides relative to the weight of zanamivir.
11. The pharmaceutical composition according to claim 3, wherein the acylglycerol complex comprises 1 to 30% by weight based on the weight of zanamivir.
12. 4. A pharmaceutical composition according to claim 3 comprising 1 to 30% by weight of nonionic surfactant, based on the weight of zanamivir.
13. The pharmaceutical composition of claim 1 comprising zanamivir, tricapryline, glyceryl monooleate and polyoxyethylene sorbitan.
14. The pharmaceutical composition according to claim 13, comprising 1 to 20% by weight of tricapryline, 1 to 30% by weight of glyceryl monooleate and 1 to 30% by weight of polyoxyethylene sorbitan, based on the weight of zanamivir.
15. The pharmaceutical composition of claim 1 comprising zanamivir, oseltamivir, tricapryline, glyceryl monooleate and polyoxyethylene sorbitan.
16. The pharmaceutical composition of claim 1, further comprising gum or sugars.
17. A pharmaceutical formulation for oral administration wherein the composition according to claim 1 is formulated.
18. 18. The pharmaceutical formulation of claim 17, wherein the pharmaceutical formulation is an emulsion or syrup formulation.
19. a) mixing triglycerides, acylglycerol complexes and nonionic surfactants;

    b) adding the mixture to distilled water in which at least one active ingredient selected from the group consisting of zanamivir and oseltamivir is dissolved; And

    c) emulsifying by stirring the solution obtained above

    Method for producing a pharmaceutical composition for oral administration comprising a.
20. a) dissolving sucrose in purified water;

    b) adding at least one active ingredient selected from the group consisting of zanamivir and oseltamivir to the sucrose solution, followed by stirring; And

    c) A process for preparing a syrup formulation comprising mixing and stirring triglycerides, acylglycerol complexes and additional nonionic surfactants.

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