Patent Application
20200230099
The present invention relates to an oral pharmaceutical composition comprising an antiviral agent. Specifically, the present invention provides a pharmaceutical formulation with improved absorption rate in the body, stability of formulation, and content uniformity, comprising zanamivir as an active ingredient, and further comprising triglyceride, an acylglycerol compound, and a surfactant.
The first generation antivirals such as amantadine or rimantadine are believed to have mechanism blocking M2-protein ion-channel of type A influenza virus. Blocking the influx of H+ ion through the M2-protein channel inhibits viral uncoating and release of free ribonucleoproteins into the cytoplasm. This only occurs in type A strain and not in type B strain. The next antiviral strategy resulted in the development of the second generation antivirals such as zanamivir or oseltamivir, which inhibit either hemagglutinin (HA) or neuraminidase (NA) enzyme forming a mushroom-shaped projection on the surface of influenza A and B viruses. These proteins bind to the membrane surface of a target cell to be infected by cleaving sialic acid residues of sialoglycoprotein and sialoglycolipid. Further, at the end of viral replication, the neuraminidase enzyme is essential for cleaving sialic acid from receptors to allow virus release. Zanamivir is the first neuraminidase inhibitor as commercially available and used for the treatment and prevention of both influenza A and B viruses.
Oseltamivir has chemical structure of formula I below and is commercially available under the trade name of Tamiflu®. It is widely used as a medicine for swine flu and avian influenza.
The chemical name of zanamivir is 5-(acetylamino)-4-[(aminoiminomethyl)amino]-2,6-anhydro-3,4,5-trideoxy-D-glycero-D-galacto-non-2-enonic acid (Formula II), and is represented by the following structure:
Zanamivir binds to a conserved region of neuraminidase enzyme of influenza virus, which catalyses cleavage of sialic acid residues attached to glycolipids or glycoproteins. It is commercially available under the trade name of RELENZA®.
It is known that bioavailability of zanamivir is generally about 2%, and 4% to 17% when administered through inhalation as powder. 5 mg of inhalant powder is twice inhaled, twice a day for 5 days. RELENZA is currently used in treatment of type A and B influenza, while the use of Diskhaler is required for oral inhalation. As such, the medicinal product is disadvantageous in that additional respirator for oral inhalation is required, it is hard to be administered in a fixed amount every time, and explanation to patients on how to use the appliance is needed. Especially, pediatric use is difficult.
Based on the above, the present inventors intended to improve low bioavailability of zanamivir upon oral administration and to solve problems of inhaled administration, so that an oral formulation with easy administration and improved pharmaceutical properties is finally developed.
Despite excellent antiviral effect, zanamivir was difficult to be widely used because of its low bioavailability when orally administered. When trying different solutions to solve the problem, it was found that zanamivir can be administered with additives to improve absorption rate of zanamivir, based on which the present invention was completed.
The present invention is to provide an oral pharmaceutical composition and a formulation with improved bioavailability upon oral administration and good pharmaceutical properties, and a preparation method thereof.
The present inventors found that when administering zanamivir having low bioavailability upon oral administration along with other additives, the bioavailability for oral administration can be increased.
Specifically, the present inventors used triglyceride, an acylglycerol complex or another non-ionic surfactants as additives to increase absorption rate of zanamivir. With just one or two types of the additives, few improvements on absorption rate were found. However, when all three types of the additives were used, surprisingly, it was found that absorption rate is very high.
Accordingly, the present invention provides a pharmaceutical composition comprising zanamivir as an active ingredient and triglyceride, an acylglycerol complex, and another non-ionic surfactant as additives.
Triglyceride may be one or more selected from the group consisting of triacetin, tripropionin, tributyrin, trivalerin, tricaproin, tricaprylin (Captex8000), tricaprin, triheptanoin, trinonanoin, triundecanoin, trilaurin, tridecanoin, trimyristin, tripentadecanoin, tripalmitin, glyceryl triheptadecanoate, and triolein.
The acylglycerol complex may be one or more selected from the group consisting of glyceryl behenate, glyceryl monooleate (Peceol), glyceryl stearate, and glyceryl palmitostearate.
The non-ionic surfactant may be one or more selected from the group consisting of polyoxyethylene-polyoxypropylene copolymer (poloxamer), sorbitan ester (Span), polyoxyethylene sorbitan (Tween), and polyoxyethylene ether (Brij).
The present inventors also discovered that when triglyceride, an acylglycerol complex, and another non-ionic surfactant are all comprised, phase separation does not occur immediately after preparation or after centrifugation and also the content is uniform.
Especially, the present inventors identified when a pharmaceutical composition comprising zanamivir and triglyceride, an acylglycerol complex, and another non-ionic surfactant as additives is prepared into the form of an emulsion or a syrup, administration is convenient and bioavailability, stability, and content uniformity are all improved.
In addition, the present invention provides an emulsion or a syrup comprising triglyceride, acylglycerol complex and another non-ionic surfactant as additives, upon preparation of a combination comprising zanamivir and oseltamivir.
The present invention solves a problem that since bioavailability is low when zanamivir is orally administered, inhalation is the only viable option. As such, drug compliance is increased through oral administration and zanamivir can be applied to patients having problems with inhalation. Further, cost can be reduced as respirator is not required, and a variation problem in administered amount upon inhalation has also been solved.
The present invention also provides a pharmaceutical composition or formulation that has not only high bioavailability upon oral administration, but also good pharmaceutical properties such as stability and content uniformity, so that zanamivir can orally be administered.
Especially, the present invention provides an emulsion or a syrup formulation comprising zanamivir, which results in that administration is convenient and bioavailability, stability, and content uniformity are all improved.
The present invention also provides an emulsion or a syrup formulation with good stability, comprising zanamivir and oseltamivir.
The present invention relates to a pharmaceutical composition comprising an antiviral agent, triglyceride, an acylglycerol complex, and a non-ionic surfactant.
The antiviral agent of the present invention may be, but is not limited to, one or more selected from the group consisting of zanamivir, tenofovir disoproxil, cidofovir, ganciclovir, foscarnet, ribavirin, oseltamivir, and pharmaceutically acceptable salts thereof.
Especially, the present invention relates to a pharmaceutical composition comprising zanamivir, triglyceride, an acylglycerol complex, and additional non-ionic surfactant.
Triglyceride may be, but is not limited to, one or more selected from the group consisting of triacetin, tripropionin, tributyrin, trivalerin, tricaproin, tricaprylin (Captex8000), tricaprin, triheptanoin, trinonanoin, triundecanoin, trilaurin, tridecanoin, trimyristin, tripentadecanoin, tripalmitin, glyceryl triheptadecanoate, and triolein. Most preferably, triglyceride is tricaprylin (Captex8000).
Triglyceride is comprised in an amount of 1-20 wt %, and more preferably 3-15 wt % based on the weight of zanamivir.
The acylglycerol complex may be, but is not limited to, one or more selected from the group consisting of glyceryl behenate, glyceryl monooleate (Peceol), glyceryl stearate, and glyceryl palmitostearate. Most preferably, the acylglycerol complex is glyceryl monooleate (Peceol).
The acylglycerol complex is comprised in an amount of 1-30 wt %, and more preferably, 5-25 wt % based on the weight of zanamivir
The non-ionic surfactant may be, but is not limited to, one or more selected from the group consisting of polyoxyethylene-polyoxypropylene copolymer (poloxamer), sorbitan ester (Span), polyoxyethylene sorbitan (Tween), and polyoxyethylene ether (Brij). Most preferably, the non-ionic surfactant is polyoxyethylene sorbitan (Tween).
The non-ionic surfactant is comprised in an amount of 1-30 wt %, and more pereferably, 2-25 wt % based on the weight of zanamivir
The composition according to the present invention exerts high bioavailability when triglyceride, an acylglycerol complex, and additional non-ionic surfactant are all comprised.
Specifically, the composition comprising zanamivir as an active ingredient, and Captex8000, Peceol, and Tween80 as additives increases bioavailability of zanamivir and exerts pharmaceutical properties such as good stability and content uniformity.
The composition of the present invention may further comprise a gum. The gum may be, but is not limited to, one or more selected from the group consisting of arabic gum, agar, guar gum, rhamsan gum, tragacanth gum, and xanthan gum. Arabic gum is most preferable.
The composition according to the present invention may further comprise a sugar. The sugar may be one or more selected from the group consisting of sucrose, maltose, lactose, isomaltose, fructooligosaccharide, galactooligosaccharide, isomaltooligosaccharide, maltodextrin, and mannan oligosaccharide.
The present invention comprises a pharmaceutical formulation formulated from the composition above. The formulation may be formulated for oral administration.
The composition of the present invention may be formulated into a dosage form for oral administration such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols according to conventional methods. Preferably, it may be an emulsion or a syrup.
The present invention relates to an emulsion or a syrup comprising zanamivir as an active ingredient and triglyceride, an acylglycerol complex, and additional non-ionic surfactant as additives.
Specifically, the present invention relates to an emulsion or a syrup formulation comprising zanamivir as an active ingredient and Captex8000, Peceol, and Tween80 as additives.
The present invention relates to an emulsion or a syrup formulation comprising zanamivir and oseltamivir as active ingredients and triglyceride, an acylglycerol complex, and additional non-ionic surfactant as additives.
Specifically, the present invention relates to an emulsion or a syrup comprising zanamivir and oseltamivir as active ingredients and Captex8000, Peceol, and Tween80 as additives.
The present invention comprises a preparation method comprising the steps of:
a) mixing triglyceride, acylglycerol complex and additional non-ionic surfactant to obtain a mixture;
b) adding the mixture to distilled water in which one or more active ingredients selected from the group consisting of zanamivir and oseltamivir are dissolved, to obtain a solution; and
c) stirring and emulsifying the solution obtained from step b).
The present invention comprises a preparation method comprising the steps of:
a) dissolving sucrose in distilled water to obtain a sucrose solution;
b) adding one or more active ingredients selected from the group consisting of zanamivir and oseltamivir to the sucrose solution, and then stirring; and
c) mixing triglyceride, an acylglycerol complex, and an additional non-ionic surfactant, and then stirring.
Hereinafter, the present invention will be described in more detail through the working examples. However, the examples are provided merely for helping the understanding of the present invention, and the scope of the present invention is not limited to the following examples.
According to the ingredients and amounts in Table 1 below, an oral pharmaceutical composition comprising zanamivir was prepared.
Captex™ 8000 (Abitec), PECEOL™ (Gattefosse), and Tween™ 80 (NOF) were mixed according to the amount in Table 1, followed by adding into a distilled water where zanmivir was completely dissolved. Then, oil phase and water phase were mixed in a certain ratio and stirring at 25□ for 2 hours to obtain an emulsion.
In the same manner as Example 1, an oral pharmaceutical composition comprising zanamivir was prepared using Captex™ 8000 alone.
In the same manner as Example 1, an oral pharmaceutical composition comprising zanamivir was prepared using PECEOL™ alone.
In the same manner as Example 1, an oral pharmaceutical composition comprising zanamivir was prepared using Tween™ 80 alone.
In the same manner as Example 1, an oral pharmaceutical composition was prepared using Captex™ 8000 and PECEOL™ wherein they are mixed in a ratio shown in Table 1, and then adding to a distilled water where zanmivir is completely dissolved.
In the same manner as Example 1, an oral pharmaceutical composition was prepared using PECEOL™ and Tween™ 80 wherein they are mixed in a ratio shown in Table 1, and then adding to a distilled water where zanmivir is completely dissolved.
In the same manner as Example 1, an oral pharmaceutical composition comprising zanamivir was prepared using Captex™ 8000 and Tween™ 80 wherein they are mixed in a ratio shown in Table 1, and then adding to a distilled water where zanmivir is completely dissolved.
According to the ingredients and amounts in Table 2 below, an oral pharmaceutical composition comprising an antiviral agent was prepared.
Captex™ 8000 (Abitec), PECEOL™ (Gattefosse), and Tween™ 80 (NOF) were mixed in the ratio shown in Table 2, followed by adding into a distilled water where an antiviral agent was completely dissolved. Then, oil phase and water phase were mixed in a certain ratio and stirring at 25□ for 2 hours to obtain an emulsion. The concentration of the antiviral agent was 10 mg/mL in all formulations of Examples 8 to 13.
A syrup formulation comprising zanamivir was prepared according the ingredients and amounts in Table 3 below
A certain amount of sucrose was weighed and dissolved in distilled water. A certain amount of zanamivir was added into the sucrose solution, and then stirred for 2 hours at 25□ and 1,000 rpm.
Once it was completely and clearly dissolved, Captex™ 8000 (Abitec), PECEOL™ (Gattefosse), and Tween™ 80 (NOF) were mixed according to the ratio in Table 3, and then stirred at 1,000 rpm to obtain a syrup formulation.
A syrup formulation comprising zanamivir and oseltamivir was prepared according to the ingredients and amounts in Table 4 below.
A certain amount of sucrose was weighed and dissolved in distilled water. Zanamivir and oseltamivir were added into the sucrose solution, and then stirred for 2 hours at 25□ and 1,000 rpm.
Once it was completely and transparently dissolved, Captex™ 8000 (Abitec), PECEOL™ (Gattefosse), and Tween™ 80 (NOF) were mixed according to the ratio in Table 4, and then stirred at 1,000 rpm to obtain a syrup formulation.
An oral pharmaceutical composition comprising zanamivir prepared from each example was orally administered to ICR mice (6-week, female) in dosage of 50 mg/kg and using gastric sonde. At 0 min, 30 min, lhr, 2 hr, 4 hr, 6 hr, and 8 hr after administration of a drug, blood was taken from orbital vein and centrifuged at 8,000×g and 4□ for 20 minutes to obtain a plasma sample, followed by storing at −70□.
After the plasma sample was melted at room temperature, it was stirred using vortex mixer for a minute. 200.0 μL of 70% acetonitrile and 300.0 μL of 60% acetonitrile were put in 100.0 μL of the sample, and stirred using vortex mixer for 5 minutes at 3,000 rpm. Each sample was centrifuged at 14,000×g and 4□ for 20 minutes, and then 300.0 μL of supernatant was taken and filtered using syringe filter (PTFE, chromdisc, 13 mm, pore size 0.20 mm). 200.0 μL of filtrate was taken and analyzed with HPLC.
The pharmacokinetics parameters as calculated based on the blood concentration of zanamivir obtained above are shown in Table 5 below.
The result of blood concentration test is presented in Table 6 and
Using a syrup formulation comprising zanamivir prepared in Example 14, the absorption rate was evaluated in the same manner as Test Example 1.
The dosage of zanamivir was 50 mg/kg or 100 mg/kg. Blood was taken and measured at 0 min, 30 min, 1 hr, 2 hr, and 4 hr.
The pharmacokinetics parameters as calculated based on the blood concentration of zanamivir obtained above are shown in Table 7 below.
As shown in Table 7 above and
The formulations were prepared according to Examples 1 to 7 and examined for their properties, followed by centrifuging at 1,500×g and 20□ for 15 minutes. Immediately after centrifugation, it was examined whether phase separation was observed to evaluate the stability of the formulation.
As shown in
As such, it was confirmed that only Example 1 has stability in showing no phase separation immediately after preparation and after centrifugation.
After centrifugation according to Test Example 3, the formulation of Example 1 was analyzed on the content of zanamivir in the top, middle, and bottom layers. The results are shown in Table 8.
As shown in Table 8, it was confirmed that the content of zanamivir existed uniformly over the top, middle, and bottom layers even after centrifugation of Example 1.
A syrup formulation comprising zanamivir prepared in Example 14 was stored for 0 and 40 days at 25□, and the property and content were analyzed. The results are shown in Table 9 below.
Upon evaluation of the content test of the syrup formulation, as shown in Table 9 above, it was confirmed that the formulation stored for more than 40 days maintained the content compared to the formulation at initial stage, which resulted in that the formulation is stable.
Moreover, phenomenon such as phase separation or precipitation was not observed from the syrup formulation at initial stage as well as after stored. As such, it was confirmed that the formulation is stable.
Evaluation on stability and content uniformity from Test Example 3 and 4 was repeatedly performed on the different ratios of the additives. Table 10 shows the ratio of the additives exerting good stability and content uniformity.
It was confirmed that stability and content uniformity are good when 1-20 wt % of Captex™ 8000, 1-30 wt % of PECEOL™, and 1-30 wt % of Tween™ 80 are comprised based on the weight of zanmivir.
The test result of Test Example 1 obtained from oral administration of the composition of Example 1 to mice, and the results obtained from oral administration and intravenous administration of a solution to mice where 10 mg/ml of zanamivir was dissolved in physiological saline are shown in Table 11.
No absorption in body was found in the oral administration of zanamivir dissolved in physiological saline. Further, as shown in
The formulations were prepared according to Examples 8 to 13 and examined for their properties, followed by centrifuging at 1,500×g and 20□ for 15 minutes. Immediately after centrifugation, it was examined whether phase separation was observed to evaluate the stability of the formulation.
As shown in
As shown in
After centrifugation in Test Example 6, the formulations from Example 8 to 13 were analyzed on the contents in the top, middle, and bottom layers. The results are shown in Table 12.
As shown in Table 12, it was confirmed that the content of zanamivir existed uniformly over the top, middle, and bottom layers even after centrifugation of the formulations of Examples 8 to 13.
| Number | Date | Country | Kind |
|---|---|---|---|
| 10-2017-0027224 | Mar 2017 | KR | national |
| 10-2017-0175681 | Dec 2017 | KR | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/KR2018/001327 | 1/31/2018 | WO | 00 |
