KR20180003413A - An oral solid formulation containing oseltamivir and a process for the preparation thereof - Google Patents

Abstract

The present invention relates to a solid formulation comprising Oseltamivir or pharmaceutically allowable salts thereof, and a pH controller. When the solid formulation is prepared in a liquid formation, pH is 3.0-5.0. When titration for 0.1N HCL 5 ml is performed after 75 mg of the liquid formation is collected as Oseltamivir free base, pH dropping width is 1.5 or less. When titration for 0.1N HCL 10 is performed, pH dropping width is 2.0 or less.

Description

TECHNICAL FIELD The present invention relates to an oral solid preparation containing oseltamivir and a preparation method thereof,

The present invention relates to a solid preparation comprising oseltamivir or a pharmaceutically acceptable salt thereof, and more particularly to a solid preparation comprising oseltamivir or a pharmaceutically acceptable salt thereof. More particularly, the stability of the active ingredient can be maintained for a short period of time, And a solid preparation for ocular administration containing oseltamivir, which can ensure the stability of the active ingredient even in a solid state during storage and can prevent the rapid absorption of oseltamivir in a living body, will be.

Tamiflu ( ^R ), which is commonly used as a treatment for influenza A (H1N1), which is commonly referred to as a new influenza or swine influenza, contains oseltamivir phosphate as a main component (Patent Document 1) and is currently used as a capsule or suspension powder And is commercially available.

It is known that oseltamivir can be orally administered 75 mg (1 capsule) twice a day for 5 days to adult and 13 year olds and older for the treatment of swine flu. However, in the case of pediatric or elderly people, it is often inconvenient to swallow capsules, and in adult cases, it may be difficult to swallow. In this case, when the solid preparation is prepared into a liquid form and administered, for example, a suspension powder or a dry syrup is prepared as a suspending agent or a syrup. In addition, when the dosage of tamiflu unit capsules is excessive as in infants, it is possible to administer the capsules in an appropriate dose by administering a suspension powder or a dry syrup, and in general, it is possible to increase the adherence of medicines to infants whose capsules are difficult to swallow .

However, a suspension powder or a dry syrup product may be prepared by directly administering a suspension or syrup prior to use to a patient, but for convenience of administration, a pharmacist is usually prepared as a suspension or syrup in a pharmacy . In this case, the suspension powder or the dry syrup may be administered as a suspension or a syrup after 4 to 5 days after the preparation, and since the oestamibir is in a liquid form, the stability of oseltamivir is lowered and the content of oseltamivir may decrease . In addition, oseltamivir is a drug that is very rapidly absorbed in vivo. When it is present in liquid form, it is not necessary that the drug disintegrate and dissolve, so that rapid absorption of the drug into the living body may occur.

WO1996-026933

The present invention can maintain the stability of an active ingredient in a solid preparation for a long period of time, such as during distribution and storage, while maintaining the stability of an active ingredient for a short period of time even after preparation into a liquid form, Containing solid preparation for oral administration.

The present invention also provides a process for preparing the oseltamivir-containing oral solid preparation.

One aspect of the present invention is

As solid formulations comprising oseltamivir or a pharmaceutically acceptable salt thereof, and a pH adjusting agent,

When the above solid preparation is formulated into a liquid formulation, the pH is 3.0 to 5.0, and when the amount of the liquid preparation containing 75 mg of oseltamivir free base is taken, the pH drop width upon addition of 5 mL of 0.1 N HCl is 1.5 or less, 0.1 And a pH drop width of 2.0 or less when 10 mL of N HCl is added dropwise.

In another aspect of the present invention,

Simple mixing of oseltamivir or a pharmaceutically acceptable salt thereof, a saccharide, and a pH adjusting agent, and

And a step of formulating the obtained mixture. The present invention also provides a method for producing the oral solid preparation.

The oral solid preparation containing oseltamivir according to one embodiment of the present invention has a pH of about 3.0 to 5.0 when prepared into a liquid form and contains a pH adjusting agent having a pH buffering ability so that the pH of the oseltamivir- Not only the short-term stability can be ensured but also the solid preparation according to the present invention can secure the stability of the active ingredient for a long period of time in the solid preparation state due to the presence of the acidifying agent. In addition, it is possible to provide a solid preparation for ocular administration containing oseltamivir, which is free from the rapid absorption of drugs during administration into a living body, and which is free from side effects.

Hereinafter, the present invention will be described in more detail.

All technical terms used in the present invention are used in the sense that they are generally understood by those of ordinary skill in the relevant field of the present invention unless otherwise defined. In addition, preferred methods or samples are described in this specification, but similar or equivalent ones are also included in the scope of the present invention. Also, the numerical values set forth herein are considered to include the meaning of " about " unless explicitly stated. The contents of all publications referred to in this specification are incorporated herein by reference in their entirety

One aspect of the present invention is

As solid formulations comprising oseltamivir or a pharmaceutically acceptable salt thereof, and a pH adjusting agent,

When the above solid preparation is formulated into a liquid formulation, the pH is about 3.0 to 5.0, and when the amount of the liquid preparation containing 75 mg of oseltamivir free base is taken, the pH drop width is about 1.5 or less when 5 mL of 0.1 N HCl is added And a pH drop width of about 2.0 or less when 10 mL of 0.1 N HCl is added dropwise.

In the present specification, the term "pH adjusting agent" means an amount of 75 mg as the free base of oseltamivir in the liquid formulation when pH of the solid preparation is adjusted to 3.0-5.0 when prepared as a liquid preparation. Means any pH adjusting agent that can exhibit a drop width of 1.5 or less and exhibit a pH drop width of 2.0 or less upon addition of 10 mL of 0.1 N HCl. The pH adjusting agent can act as a stabilizer to increase the stability of oseltamivir in the solid preparation and can adjust the pH of the liquid phase to about 3 to 5 even when the solid preparation is prepared into a liquid phase, And thus can serve as a stabilizer for increasing the stability of oseltamivir.

The pH adjusting agent includes a combination of an inorganic acid or an organic acid, and a conjugated base thereof.

The inorganic acid may be hydrochloric acid, sulfuric acid, phosphoric acid, or any combination thereof, but is not limited thereto.

The organic acid may be any organic compound exhibiting acidity, and specifically includes carboxylic acid, sulfonic acid, sulfinic acid, sulfamic acid, phenol, enol, thiol, phosphonic acid, phosphoric acid, boronic acid, imidic acid, hydrazinic acid, Is a compound having a functional group that exhibits acidity, such as benzoic acid, ascorbic acid, or hydroxamic acid.

The organic acid may be one type or a combination of several kinds of organic acids.

In one embodiment, the pH adjusting agent comprises a conjugate base of an organic acid and its organic acid.

In one embodiment, the organic acid may be an organic acid having a carboxylic acid.

In one embodiment, the organic acid having a carboxylic acid may be an organic acid having 1 to 6 carbon atoms and having at least two carboxylic acid functional groups. More specifically, the organic acid having a carboxylic acid may be an organic acid having 4 to 6 carbon atoms and having at least two carboxylic acid functional groups. More specifically, the organic acid having a carboxylic acid may be an organic acid having 4 to 6 carbon atoms and 2 to 3 carboxylic acid functional groups. The organic acid may be, for example, malonic acid, succinic acid, tartaric acid, fumaric acid, glutaric acid, citric acid, malic acid, or any combination thereof, but is not limited thereto.

Depending on the specific type of organic acid, the stability of the active ingredient may vary. As a result of the test, when the organic acid having 2 to 3 carboxylic acid functional groups having 4 to 6 carbon atoms was present, it was confirmed that the stability of the active ingredient was high when other organic acids were present. The organic acids having 4 to 6 carbon atoms and 2 to 3 carboxylic acid functional groups include malonic acid, succinic acid, tartaric acid, fumaric acid, glutaric acid, citric acid, malic acid, or any combination thereof.

In one embodiment, the organic acid comprises tartaric acid, fumaric acid, succinic acid, malic acid, citric acid, and any combination thereof.

The conjugate base means a substance in which protons are removed from the acid and the remaining anions form salts other than the protons for stabilization. The cation may be any cation known in the art as capable of forming a conjugated base, and may be selected, for example, from Na ⁺ , K ⁺ , Mg ²⁺ , and Ca ²⁺ .

In one embodiment, the pH adjusting agent is an organic acid having 4 to 6 carbon atoms and 2 to 3 carboxylic acid functional groups, and may be malonic acid, succinic acid, tartaric acid, fumaric acid, glutaric acid, citric acid, malic acid, And combinations of salts of cations selected from Na ⁺ , K ⁺ , Mg ^{2 +} , and Ca ²⁺ as their conjugate bases.

In one embodiment, the pH adjusting agent comprises a combination of tartaric acid and sodium tartrate, or a combination of citric acid and sodium citrate.

The amount of the organic acid which can exhibit a pH of about 3 to 5 in the liquid phase depending on the specific constituents of the organic acid can be determined by a person skilled in the art and may vary depending on the specific organic acid. For example, the organic acid may be present in an amount of about 0.3 to 6% by weight relative to the total weight of the solid preparation, and more specifically about 0.5 to 5% by weight based on the total weight of the solid preparation.

The combined base of the organic acid and its organic acid has a pH of from 3.0 to 5.0 when the solid preparation is prepared as a liquid preparation, and the amount of the liquid preparation containing 75 mg of oseltamivir free base is taken, The drop width is less than or equal to 1.5 and the pH drop width at 10 mL of 0.1 N HCl is less than or equal to 2.0, and in one embodiment the organic acid and its organic acid conjugate base can be present in a ratio of from 1: 0.5 to 1: 5 < / RTI > by weight.

The oseltamivir or a pharmaceutically acceptable salt thereof includes oseltamivir free base or oseltamivir phosphate, and may further include any other pharmaceutically acceptable salt.

The oral solid preparation according to the present invention can increase the stability of oseltamivir for a short period of time in a liquid phase by adjusting the pH of the liquid phase to 3 to 5 when prepared into a liquid form (see Test Examples 1 and 7). In addition, it was confirmed that the stability of the active ingredient can be maintained during long-term circulation and storage in a solid preparation state by controlling the formation of a flexible substance for a long period of time by containing the pH adjusting agent even in a solid preparation state (Test Example 6).

Further, the oral solid preparation according to the present invention was prepared by taking 75 mg of the liquid formulation as an oseltamivir free base in an amount of 75 mg, adding a pH drop width of 1.5 or less when 5 mL of 0.1 N HCl was added, adding 10 mL of 0.1 N HCl it was confirmed that the pH buffering effect exhibiting a pH drop width of 2.0 or less results in a change in the pharmacokinetic profile compared to the case of not having such a pH action. As a result of the test, the solid preparation according to one embodiment of the present invention has a Cmax that is comparatively lower than that of the comparative example in which the pH buffering effect is low when administered in vivo, and has a Cmax similar to that of commercially available tamiflu, It was confirmed that the possibility of occurrence of side effects due to absorption was low (Test Example 4). These effects can be said to be a very significant effect in the characteristics of formulations which may cause side effects due to rapid absorption of oseltamivir in solid formulations to be administered after formulation in liquid form upon administration.

As used herein, the term " short term "means a period of about 30 days or less, more specifically about 20 days or less, and" long term "means three or more years that is a conventional shelf life.

In one embodiment, the solid preparation can be a stable oral solid preparation in liquid form, such that it contains at least 99% of the active ingredient at room temperature for up to 20 days when formulated in liquid form.

In one embodiment, the solid formulation is a solid first agent for oral use wherein the solids formulation is about 0.5% or less in content of C when stored for at least six months at accelerations of about 40 +/- 2% and relative humidity of about 75 +/- 5% .

In one embodiment, the solid formulation is stable in liquid form until it contains at least 99% of the active ingredient at room temperature for 20 days at the time of formulation into the liquid phase, and the solid formulation is maintained at a temperature of about 40 +/- 2 DEG C and a relative humidity of about 75 +/- 5% It may be an oral solid for which the content of C is less than 0.5% when stored for more than 6 months under accelerated conditions.

As used herein, the term " softening material C " means the softening material C described in the supplements of the United States Pharmacopeia (USP), OHSLAMIC OXYTAMIVIR PHOSPHATE Capsule.

The oral solid preparations can be any oral solid preparations known in the art. In one embodiment, the oral solid preparation can include, but is not limited to, a dry syrup, a suspending powder, a granule, a powder, a capsule, or a tablet.

In one embodiment, the oral solid preparation can be any oral solid preparation prepared and dispensed in the form of a liquid for use, including, but not limited to, dry syrups or suspending powders.

In one embodiment, the oral solid preparation may be an oral solid preparation containing granules comprising oseltamivir or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive, for example, ≪ / RTI >

The pH adjusting agent may be contained in the preparation of the granules. The fact that it can be contained in the preparation of the granules means that it can be added at any stage of the granulation process and can be prepared in particular in a mixture for the production of granules containing the active ingredient, Liquid, or added after incorporation, or any combination thereof. In addition, according to a specific method for producing granules, a person skilled in the art can appropriately select an additional step of the pH adjusting agent.

The pharmaceutically acceptable additives may vary depending on the kind of the solid preparation, but may be selected from the group consisting of, for example, sugars, flavoring agents, sweeteners, acidifiers, preservatives, and any combination thereof.

The saccharide may be selected from the group consisting of D-sorbitol, D-mannitol, xylitol, erythritol, white sugar, and any combination thereof, but is not limited thereto. As a result of the test of the suitability of the saccharides in the oseltamivir solid preparation, when the total saccharides were present in the presence of the exemplified saccharides under the condition of 60 ° C, all of them did not significantly increase and compatibility with oseltamivir was very excellent (See Test Example 2).

The flavoring agent is selected from the group consisting of strawberry, lemon, melon, mint, banana, peach, orange, cherry, truffle, pineapple, grape, and any combination thereof But is not limited thereto.

The sweetening agent may be selected from the group consisting of sucralose, saccharin, stevioside, acesulfame potassium, aspartame, enzyme-treated stevia, tauromine, and any combination thereof, but is not limited thereto.

The acidic agent may be selected from the group consisting of sodium tartrate, sodium citrate, disodium succinate, sodium ascorbate, sodium chloride, sodium hydrogencarbonate, and any combination thereof, but is not limited thereto.

The preservative may be selected from benzyl alcohol and its derivatives, sorbic acid and its salts, paraoxybenzoic acid methyl, propyl p-oxybenzoate, butyl p-oxybenzoate, benzalkonium salt, benzoic acid salt and any combination thereof, But is not limited thereto.

Alternatively, the pharmaceutically acceptable additive may further comprise a coloring agent and a thickening agent, and examples of the coloring agent include titanium oxide, talc, light silicic anhydride, blue No. 1, or red No. 40, Zero may be xanthan gum, gelatin, gellan gum, carboxymethyl cellulose, povidone, polyethylene glycol, or hypromellose.

In one embodiment, the solid preparation is a solid preparation comprising oseltamivir or a pharmaceutically acceptable salt thereof, and a pH adjusting agent, wherein the solid preparation comprises at least 99% of the active ingredient for 20 days at room temperature when prepared into a liquid form It can be a stable oral solid preparation in liquid form, for example a dry syrup.

In one embodiment, the solid formulation is a solid formulation comprising oseltamivir or a pharmaceutically acceptable salt thereof and a pH adjusting agent, wherein the solid formulation is formulated in liquid form at a temperature of 40 ± 2 ° C and a relative humidity of 75 ± 5% It may be an oral solid for which the content of C is less than 0.5% when stored for more than 6 months under accelerated conditions, for example a dry syrup.

In one embodiment, the solid preparation is a solid preparation comprising oseltamivir or a pharmaceutically acceptable salt thereof, and a pH adjusting agent, wherein the solid preparation comprises at least 99% of the active ingredient for 20 days at room temperature when prepared into a liquid form It is stable in liquid form and can be used as an oral solid for oral administration in which the solid preparation is stored at accelerated conditions of 40 ± 2 ° C and relative humidity of 75 ± 5% For example, it is a dry syrup.

In another aspect of the present invention,

Simple mixing of oseltamivir or a pharmaceutically acceptable salt thereof, a saccharide, and a pH adjusting agent, and

Comprising the step of formulating the resulting mixture

There is provided a method of producing an oral solid preparation according to an aspect of the present invention.

The details of the method for producing the solid preparation can be applied to the oral solid preparation according to one aspect of the present invention as it is.

The formulation step may be any method of formulating the solid formulation.

In one embodiment, the formulation step can be prepared as a dry syrup by simply sieving and mixing the resulting mixture.

In one embodiment, the formulation step comprises

An assembly step of producing granules from the resulting mixture;

A sizing step of sieving the granules;

Mixing the granules with the saccharide, and then mixing the granules with the saccharide.

The granulation step may be prepared according to any granulation method known in the art, and may be prepared by a wet granulation method or a dry granulation method.

In one embodiment, the wet granulation method comprises preparing a mixture comprising oseltamivir or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive in a combined solution, -mill process. For example, the granulation process may be performed by filtering the association product into a sieve, and the process of granulation and granulation may be performed simultaneously by controlling the sludge of the sieve. After the granulation, drying may be performed, and after drying, saccharide and post-mixing may be performed.

The pH adjusting agent may be added to the mixture, the combined solution, and / or the after-mixing. In one embodiment, the pH adjusting agent may be added to the mixture.

The sizing step may be performed so that the residual amount after sieving with a sieve of 30 mesh is 20.0 wt% or less.

In one embodiment, the granulation step and the sizing step can be performed simultaneously using the sieve of 30 mesh in the assembly process.

The drying process is preferably carried out at a temperature which does not exceed about 60 캜, preferably not more than about 50 캜, more preferably not more than about 40 캜, most preferably not more than 20 For example, by air drying, fluid bed drying, oven drying or microwave drying at a temperature of from < RTI ID = 0.0 > 40 C < / RTI >

In the dry granulation method, the pH adjusting agent may be added to the mixture in the mixing and / or post-mixing. In one embodiment, the pH adjusting agent may be added to the mixture.

In one embodiment, the dry granulation method comprises admixing a mixture comprising oseltamivir or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive, such as roller compacting or slugging For example, a roller pressing method can be used. Specifically, roller pressing refers to a method of manufacturing granules through a method in which powder is passed between two rollers while being compressed at a constant pressure. The roller pressing method can be carried out by making a roller-pressed mixture using a roller compactor, and then performing a pulverization process by a fitz-mill as necessary to obtain an appropriate-sized granule .

The granules prepared by the dry granulation method can be subjected to a sizing step by sieving. The sizing step can be performed so that the remaining amount after sieving with a sieve of 30 mesh is 20.0 wt% or less for the purpose of evaluating the granularity of granules.

Additional formulation steps can be carried out according to any method known in the art for the formulation of the solid formulations using the granules so prepared, for example, according to any known method of formulation into tablets or capsules .

Hereinafter, the present invention will be described in detail based on the following examples. However, the following examples are intended to illustrate the present invention, but the scope of the present invention is not limited thereto.

Test Example  One: Osel Tamivier  Stability test of solution by pH

788 mg of oseltamivir phosphate was precisely weighed, placed in a 100-mL volumetric flask, and purified water was added thereto to dissolve the solution. Then, an oseltamivir solution (6 mg / mL) was prepared according to the following table. Then, oseltamivir solutions of about pH 2.0, pH 3.0, pH 4.0, pH 5.0, and pH 6.0 were prepared by adding phosphoric acid and 0.1 M KOH dropwise to each brown glass bottle. The prepared solution was allowed to stand at room temperature for 5 days and at 60 ° C for 5 days, and then the content was calculated according to the content analysis method described in USP 'Oseltamivir phosphate Capsule'.

The results are shown in Table 1 below.

pH Immediately after preparation Room temperature condition 5 days 5 days at 60 ℃ 2.0 100.00% 96.15% 83.64% 3.0 98.41% 95.17% 4.0 99.88% 98.11% 5.0 99.49% 94.38% 6.0 93.34% 84.43%

As shown in Table 1, dissolved oseltamivir showed significantly higher contents of oseltamivir at pH 3.0, pH 4.0 and pH 5.0 than at pH 2.0 and pH 6.0. Therefore, it was confirmed that the oseltamivir in the liquid phase was stably maintained at a pH of about 3.0 to 5.0.

Test Example  2: Oseltamivir  Compatibility with sugars and organic acids

The compatibility test of oseltamivir with saccharides and organic acids was carried out.

1 g of oseltamivir phosphate, 10 g of saccharide (ratio 1:10), 5 g of oseltamivir phosphate main ingredient and 5 g of organic acid (ratio 1: 1) were mixed and mixed in a rotary tablet machine (Sejong, MRC-18) To prepare a flake. Then, the flakes were placed in a brown glass bottle and exposed at 60 ° C for 10 days and 20 days. The flakes were taken out, and the flexible substances were measured according to the flexible substance analysis method described in USP 'Oseltamivir phosphate Capsule' Respectively.

The results are shown in Table 2 below.

Total Flexible Substance (%) Type and ratio 60 ℃ 10 days 60 ℃ 20 days Active ingredient Oseltamivir phosphate 0.26 0.30 sugars
(Main component: saccharide = 1: 10) D-sorbitol 0.27 0.31 D-mannitol 0.29 0.31 Xylitol 0.29 0.33 Erythritol 0.31 0.34 White sugar 0.34 0.36 Organic acid
(Main component: organic acid = 1: 1) Tartaric acid 0.29 0.30 Fumaric acid 0.31 0.32 Suche mountain 0.30 0.33 Malian 0.33 0.37 Citric acid 0.35 0.36 Benzoic acid 0.61 1.15 Erysorbic acid 0.54 1.27

As shown in Table 2, it was confirmed that oseltamivir phosphate was stable even when mixed with any saccharide. On the other hand, oseltamivir phosphate is stable when combined with tartaric acid, fumaric acid, succinic acid, malic acid and citric acid, but when compared with erythorbic acid and benzoic acid, stability is relatively poor. Among organic acids having excellent stability, they have 4 to 6 carbon atoms and two or more carboxyl groups.

Comparative Example  One: Osel Tamivier Dry syrup  Produce

Oseltamivir phosphate, D-sorbitol, tartaric acid, sucralose, and sodium benzoate having the compositions shown in Table 3 below were sieved through 30 mesh sieve and mixed to prepare oseltamivir dry syrup.

Example  One: Osel Tamivier Dry syrup  Produce

Oseltamivir phosphate, D-sorbitol, tartaric acid, sodium tartrate, sucralose, and sodium benzoate having the compositions shown in Table 3 below were sieved with 30 mesh sieve and mixed to prepare oseltamivir dry syrup.

Example  2: Osel Tamivier Dry syrup  Produce

Oseltamivir phosphate, D-sorbitol, citric acid, sodium citrate, sucralose, and sodium benzoate having the compositions shown in Table 3 below were sieved with 30 mesh sieve and mixed to prepare oseltamivir dry syrup.

Constituent Content (mg) Comparative Example 1 Example 1 Example 2 Oseltamivir phosphate 512.2 512.2 512.2 D-sorbitol 12294.8 11560.8 11264.8 Tartaric acid 20 190 - Sodium tartrate - 564 - Citric acid - - 550 Sodium citrate - - 500 Sucralose 160 160 160 Sodium benzoate 13 13 13 total 13000 13000 13000 PH after liquid preparation 3.80 3.80 3.80

Test Example  3: Evaluation of pH change rate

The oseltamivir dry syrup of Comparative Example 1 and Examples 2 and 3 was prepared into liquid syrup and 12.5 mL (corresponding to 75 mg as oseltamivir free base) was measured and the pH change rate was measured using 0.1 N HCl Are shown in Table 4 below.

0.1N HCl approx. 0 mL 5 mL 10 mL 15 mL
pH Comparative Example 1 3.80 1.96 1.61 1.46 Example 1 3.80 2.98 2.36 1.68 Example 2 3.80 3.04 2.35 1.83

As shown in Table 4, when 5 mL of 0.1 N HCl was added dropwise, the pH changes of Examples 1 and 2 were 0.82 and 0.76, respectively, and the rate of change was 1.50 or less. When 10 mL of 0.1 N HCl was added dropwise, Respectively, to 1.44 and 1.45, respectively. On the other hand, in the case of Comparative Example 1 which does not contain a conjugated base, the pH change of Comparative Example 1 at the time of adding 5 mL of 0.1 N HCl was 1.84, and the rate of change was 1.50 or more. appear. Therefore, it was confirmed that Examples 1 and 2 had significantly higher buffering capacity than Comparative Example 1. [

Further, according to the results of Examples 1 and 2, it was confirmed that even if the types of organic acids contained and their conjugate bases are different, they can have the same degree of buffering capacity when controlling the content of each organic acid and its conjugated base.

Test Example  4: Pharmacodynamic  Character rating

12.5 ml (75 mg as oseltamivir) of liquid syrup (pH 3.80) was prepared for the dry syrup of commercially available tamiflu powder, Comparative Example 1, and Examples 1 and 2, and 12 beagles (Dog ), Blood samples were collected at 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after oral administration to the patient. The respective PK profiles including the time of arrival (Tmax) are shown in Table 5 below.

AUC _{0 -24} (ng · hr / mL) C _max (ng / mL) T _max (hr) Tamiflu powder for suspension 7583.5 ± 1470.8 1972.5 ± 877.1 0.8 ± 0.2 Comparative Example 1 7763.3 ± 1438.8 2286.6 + - 666.4 0.7 ± 0.1 Example 1 7650.2 占 1494.2 2047.8 ± 735.3 0.8 ± 0.2 Example 2 7525.3 + 1389.7 2015.7 ± 812.0 0.8 ± 0.1

According to the above Table 5, when comparing the pharmacokinetic profiles in beagle dogs with syrups having the same pH (3.80), it was found that Comparative Example 1, Examples 1 and 2 and Tamiflu suspension powder had similar AUC, _max . < / RTI > Therefore, it was shown that C _max can be varied depending on the pH buffering ability even if the pH is the same, and Examples 1 and 2 having pH buffering ability have a relatively low C _max as compared with Comparative Example 1 having low pH buffering capacity , It has been confirmed that the possibility of side effects due to rapid drug absorption is low, while ensuring the efficacy of the medicament, since it has a C _max similar to that of commercially available tamiflu.

Example  3: Osel Tamivier Dry syrup  Manufacturing (wet granulation)

Oseltamivir phosphate, D-sorbitol, tartaric acid, sodium tartrate, sucralose, and sodium benzoate were mixed with purified water, dried and sieved through a 30-mesh sieve to prepare wet granules.

D-sorbitol was added to the prepared granules and mixed to prepare oseltamivir granules.

Example  4: Osel Tamivier Dry syrup  Manufacturing (dry granule)

After mixing oseltamivir phosphate, D-sorbitol, tartaric acid, sodium tartrate, sucralose, and sodium benzoate with the composition as shown in Table 6 below, granules were formed with a roller compactor and then sieved with a 30 mesh sieve to prepare dry granules Respectively.

D-sorbitol was added to the prepared granules and mixed to prepare oseltamivir granules.

Constituent Content (mg) Example 1 Example 3 Example 4 Primary
mix Oseltamivir phosphate 512.2 512.2 512.2 D-sorbitol 11560.8 2560.8 2560.8 Tartaric acid 190 190 190 Sodium tartrate 564 564 564 Sucralose 160 160 160 Sodium benzoate 13 13 13 Association amount Purified water - (120) - Formulations 30 mesh 30 mesh 30 mesh Secondary
mix D-sorbitol - 9000.0 9000.0 Gross weight 13000.0 13000.0 13000.0 fair Simple mixing Wet granule Dry granule

Test Example  5: Osel Tamivier  Evaluation of uniformity of contents by manufacturing process

Using the solid preparations prepared in Examples 1, 3 and 4, the content uniformity was evaluated by oseltamivir manufacturing process.

The content uniformity was evaluated by the content analysis method of 'Oseltamivir phosphate Capsule' of each USP, and the relative standard deviation was calculated by measuring the content 10 times.

The results are shown in Table 7 below.

Relative standard deviation Example 1 1.57% Example 3 0.91% Example 4 1.12%

As shown in Table 7, it was confirmed that the relative standard deviation of the content uniformity evaluation in Examples 1, 3, and 4 was 2.0% or less.

Test Example  6: Osel Tamivier  By manufacturing process Flexible material  evaluation

Flexible materials were evaluated for each oseltamivir manufacturing process using the solid preparations prepared in Examples 1, 3 and 4.

The evaluation of the soft materials was carried out in 13 g of the solid preparations of Examples 1, 3 and 4 in a brown glass bottle, followed by 3 months and 6 months at room temperature and 40 ° C / 75% relative humidity. The content of C was calculated by measuring the contents of the flexible material according to the method of analysis of the contents of "Phosphate Capsule".

The results are shown in Table 8 below.

Immediately after preparation Room temperature condition 40 ° C / 75% relative humidity conditions 3 months 6 months 3 months 6 months Flexible Substance C Example 1 0.00% 0.03% 0.05% 0.08% 0.19% Example 3 0.00% 0.04% 0.09% 0.11% 0.24% Example 4 0.18% 0.04% 0.08% 0.10% 0.22%

As shown in Table 8, when the solid preparations of Examples 1, 3, and 4 were allowed to stand at room temperature and 40 ° C / 75% relative humidity conditions, It was confirmed that the stability was excellent even when stored in a solid state for a long period of time. (Not more than 0.50% based on C for USP pharmaceuticals).

Test Example  7: Osel Tamivier Of dry syrup Liquefaction  Subsequent stability evaluation

13 g of the granules of Example 1 were placed in a brown glass bottle, and 55 mL of purified water was added thereto. After shaking, the mixture was allowed to stand at room temperature for 10 days and 20 days, and then analyzed according to the content analysis method described in USP's Oseltamivir phosphate Capsule The content was calculated.

The results are shown in Table 9 below.

Immediately after preparation 10 days at room temperature Room temperature condition 20 days Example 1 99.98% 99.59% 99.52%

As shown in Table 9, when the granules of Example 1 were prepared into a liquid form and left at room temperature, it was confirmed that the content of the active ingredient was stably maintained until 20 days (based on USP drug alginate content: 90.0% to 110.0 %).

The present invention has been described with reference to the preferred embodiments. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the above-described embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.

Claims (15)

As solid formulations comprising oseltamivir or a pharmaceutically acceptable salt thereof, and a pH adjusting agent,
When the above solid preparation is formulated into a liquid preparation, the pH is 3.0 to 5.0, and when the amount of the liquid preparation containing 75 mg of oseltamivir free base is taken, the pH drop width upon addition of 5 mL of 0.1 N HCl is 1.5 or less, 0.1 N hydrochloric acid, the pH drop width of 2.0 mL or less when 10 mL of N HCl is added. The oral solid preparation according to claim 1, wherein the pH adjusting agent comprises a congugate base of an organic acid having 4 to 6 carbon atoms and two or more carboxylic acid functional groups and an organic acid thereof. 2. The oral solid preparation according to claim 1, wherein the oseltamivir or a pharmaceutically acceptable salt thereof is an oseltamivir free base or oseltamivir phosphate. 3. The oral solid preparation according to claim 2, wherein the organic acid is selected from the group consisting of tartaric acid, fumaric acid, succinic acid, malic acid, citric acid, and any combination thereof. 3. The oral solid preparation according to claim 2, wherein the congugate base of the organic acid comprises a cation component selected from Na ⁺ , K ⁺ , Mg ^{2 +} , Ca ²⁺ . 3. The oral solid preparation according to claim 2, wherein the organic acid is contained in an amount of 0.3 to 6% by weight based on the total amount of the solid preparation. [Claim 3] The oral solid preparation according to claim 2, wherein the organic acid and the organic base of the organic acid are contained in a weight ratio of 1: 0.5 to 1: 5. The oral solid preparation according to claim 1, wherein the oral solid preparation is a dry syrup, a suspension powder, a granule, or a powder. The oral solid preparation according to claim 1, wherein the solid oral preparation for oral use is prepared in liquid form during use. 2. The oral solid preparation according to claim 1, wherein the oral solid preparation contains granules or a mixture comprising oseltamivir or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive. 11. The oral solid preparation of claim 10, wherein the pharmaceutically acceptable additive is selected from the group consisting of sugars, flavoring agents, sweeteners, preservatives, and any combination thereof. 12. The oral solid preparation according to claim 11, wherein the saccharide is a saccharide selected from the group consisting of D-sorbitol, D-mannitol, xylitol, erythritol, saccharose, and any combination thereof. Simple mixing of oseltamivir or a pharmaceutically acceptable salt thereof, a saccharide, and a pH adjusting agent, and
The method for producing an oral solid preparation according to any one of claims 1 to 12, comprising the step of formulating the obtained mixture. 14. The method of claim 13, wherein the formulation step comprises
An assembly step of producing granules from the simple mixed mixture;
A sizing step of sieving the granules; And
And mixing the sized granules with a saccharide. 15. The manufacturing method according to claim 14, wherein the sizing step is performed in a sieve of 30 mesh.