KR20160082170A - An oral solid formulation containing rivaroxaban - Google Patents

Abstract

The present invention provides an oral solid formulation comprising: rivaroxaban or pharmaceutically acceptable salts thereof as an active ingredient; a polyvinyl caprolactam polyvinyl acetate-polyethylene glycol graft copolymer as a solubilizing agent; and a pharmaceutically acceptable additive, and a producing method thereof.

Description

An oral solid formulation comprising a rivaroxaban,

The present invention relates to an oral solid preparation containing a rivaroxan as an active ingredient, and more particularly to a solid preparation for oral administration containing a rivaroxan which has improved solubility of the rivaroxan and thus increased dissolution rate and bioavailability will be.

Rivaroxaban has a structure represented by the following formula (1) and is currently marketed worldwide under the trade name Xarelto.

 [Chemical Formula 1]

LIVER LAVAZAN is of the opinion that i) reduce the risk of stroke and systemic embolism in patients with atrial fibrillation, ii) treatment of deep vein thrombosis and pulmonary embolism, iii) reduce the risk of recurrence of deep venous thrombosis and pulmonary embolism, iv) (V) prevention of acute coronary syndromes with elevated cardiac biomarkers in patients who have been treated with aspirin or clopidogrel in combination with aspirin, It is known to have an efficacy of reducing the incidence of atherosclerosis (cardiovascular death, myocardial infarction).

Despite this efficacy, it is known that the solubility and bioavailability of the LIVARKAZAN tablet are low.

Patent Document 1 discloses a method for preparing a liposome tablet by a fluidized bed granulation method in order to improve the solubility of the liposome. However, the fluidized bed granulation method has a limitation in improving the solubility of the active ingredient, causing the loss of the active ingredient, and there is a need to develop a new formulation for improving the solubility of the active ingredient.

WO 2005/060940

It is an object of the present invention to provide a solid preparation for oral use of Ribaetraban wherein the solubility of the Ribasulfan is increased and consequently the dissolution rate and the bioavailability are improved.

One aspect of the present invention is

There is provided an oral solid preparation comprising a lipocalic acid or a pharmaceutically acceptable salt thereof, a polyvinylcaprolactam polyvinyl acetate polyethylene glycol graft copolymer as a solubilizing agent, and a pharmaceutically acceptable additive.

In another aspect of the present invention,

A granule preparation step for granulating a mixture comprising LIVARKAZAN or a pharmaceutically acceptable salt thereof, a polyvinylcaprolactam polyvinyl acetate polyethylene glycol graft copolymer as a solubilizing agent, and a pharmaceutically acceptable additive; And

And granulating the granules. The present invention also provides a method for producing the solid preparation for oral use according to the present invention.

The solid preparation for oral administration containing the liposomes according to the present invention is characterized in that the solubility of the liposomes is increased and the dissolution rate and the bioavailability are increased as a result of using the polyvinylcaprolactam polyvinyl acetate polyethylene glycol graft copolymer appear.

In addition, as one specific example of the solid preparation containing the liposome, irrespective of whether the direct compression method or the granular compression method is used in the production of the tablet and whether or not the granule compression method is used, The solubility of the slurry increased, and the dissolution rate and bioavailability were improved. Therefore, the oral solid preparations containing the liposomes according to the present invention have not only remarkably improved bioavailability but also various granulation methods other than the fluidized bed granulation method which may cause the loss of the liposomes There is an advantage that it can be.

FIG. 1 is a graph showing the results of measurement of solubility in supersaturated state in water, pH 1.2 solution, pH 4.0 solution, and pH 6.8 solution for the tablets of Example 1 and Comparative Examples 1 to 5.
Figure 2 shows the results of a dissolution test at 75 rpm in 900 mL of acetate buffer (pH 4.5) + 0.5% sodium lauryl sulfate solution using a sinker in a USP paddle for the tablets of Example 1 and Comparative Examples 1 to 5 Fig.
FIG. 3 is a graph showing the results of measurement of solubility in supersaturated state in water, pH 1.2, pH 4.0, and pH 6.8 for the tablets of Example 2 and Comparative Examples 6 to 10. FIG.
4 is a graph showing the results of measurement of solubility in supersaturated state in water, pH 1.2 solution, pH 4.0 solution, and pH 6.8 solution for the tablets of Examples 1, 3, 4 and 5.
Figure 5 shows the dissolution test for the tablets of Examples 1, 3, 4 and 5 in water at 75 rpm in 900 mL of acetate buffer (pH 4.5) + 0.5% sodium lauryl sulfate solution using a sinker in a USP paddle And FIG.
Figure 6 shows the results of a dissolution test at 75 rpm in 900 mL of acetate buffer (pH 4.5) + 0.5% sodium lauryl sulfate solution using a sinker in a water, USP paddle for the tablets of Examples 1 and 6 Graph.
FIG. 7 is a graph showing the results of measuring the drug blood concentration over time after administering the tablets of Example 1 and Comparative Example 1 to male rats, respectively. FIG.

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. 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

There is provided an oral solid preparation comprising a lipocalic acid or a pharmaceutically acceptable salt thereof, a polyvinylcaprolactam polyvinyl acetate polyethylene glycol graft copolymer as a solubilizing agent, and a pharmaceutically acceptable additive.

The pharmaceutically acceptable salt of the Ribasoxan is an acid addition salt or a base addition salt. The acid addition salt includes a salt with an inorganic acid or an organic acid. Examples of the inorganic acid salt include salts with hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid. Examples of the organic acid salt include acetic acid, trifluoroacetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, , Benzoic acid, or methanesulfonic acid), ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, or naphthalenedisulfonic acid, but is not limited thereto. The base addition salts include, for example, alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, or ammonia salts or organic amine salts such as diethylamine, triethylamine, ethyl And salts with diisopropylamine, procaine, dibenzylamine, N-methylmorpholine, or dihydroabiethylamine.

As used herein, the term " rivaroxan or a pharmaceutically acceptable salt thereof " is to be interpreted as being capable of existing in all its crystalline and amorphous forms, and in the form of its hydrates, solvates, and co-crystals.

The polyvinyl caprolactam polyvinyl acetate polyethyleneglycol graft copolymer is a hydrophilic polymer commercially available under the trade name Soluplus and has a molecular weight of about 90,000 to 140,000 g / mol (hereinafter referred to as " polyvinyl caprolactam- , Also referred to as SolUplus). Soluplus is a material known as a material that can be used as a solubilizer in the preparation of solid dispersions or solid solutions (WO12 / 105767).

The present inventors have experimented with various solubilizing agents known in the art for the purpose of increasing the solubility of the liposomes of the liposome solid preparation. As a result, it was confirmed that SolulPlus can increase the solubility, dissolution rate, and bioavailability of the solid preparation compared to various other hydrophilic polymer solubilizing agents (see Examples 1, 2, and 3).

As a result of the experiment, when the granule was produced as a granule not having a conventional solid dispersion or solid solution but a manufacturing method remarkably simple compared with the granule, or as a tablet by the granule compression method using the granule, Soluble PLUS showed solubility, And bioavailability (see Examples 1, 2, 3, and 7). Regardless of the method by which the granules are produced, by the wet granulation method and the dry granulation method, and by the method of the high-speed blender, the fluidized bed granulator and the spray dryer in the production of the wet granules, It was confirmed that the solubility, dissolution rate, and bioavailability of the quaternary solid preparation can be increased. In addition, it was confirmed that the tablets could be increased in solubility, dissolution rate, and bioavailability by direct compression method instead of granule compression method (see Experimental Examples 4, 5, and 7). Therefore, the solid preparation according to the present invention can be also used for other granulation methods which do not cause the risk of loss of the reabsorban which is a disadvantage of the conventional method (WO 2005/060940) in which the solubility of the reabsorban is improved by the fluidized bed granulation method There is an advantage that it can be manufactured.

The solubles may be present in an amount of about 5 to 100 parts by weight, more specifically about 10 to 50 parts by weight, and more particularly about 15 to 30 parts by weight, based on 100 parts by weight of the active ingredient. If the content is less than the above range, the solubility of the drug of the liposome solid preparation can not be sufficiently increased, and if it is used in an excess amount, the disintegration of the solid preparation may be inhibited and the elution of the drug may be inhibited.

In one embodiment, the ribaviruzane or a pharmaceutically acceptable salt thereof has an average particle size (X ₅₀ ) of less than 30 μm. More specifically, the liposomes or pharmaceutically acceptable salts thereof have an average particle size (X ₅₀ ) of less than 15 μm and an average particle size (X ₉₀ ) of less than 30 μm.

In the present specification, the average particle size (X ₅₀ ) means the average particle size of particles having a particle size of the lower 50% of the total particles, and the average particle size (X ₉₀ ) Mean the average particle size.

As a result of the experiment, the solid preparation according to the present invention showed a significantly higher dissolution rate when the average particle size of the active ingredient, LIVAROCK SABAN, falls within the above range, as compared with the case where the particle size is larger than the above range (see Experimental Example 6).

The solid preparation may be any solid agent including a mixture of Riboxetran or a pharmaceutically acceptable salt thereof, Solulux, and a pharmaceutically acceptable additive. The solid preparation may be formulated into, for example, pellets, capsules, tablets, powders, granules and the like, but is not limited thereto. More specifically, the oral solid preparation may be in the form of a capsule or tablet. When the complex preparation of the present invention is a capsule, the capsule may be in the form of powders, granules, tablets, syrups, pellets and the like.

In one embodiment, the solid preparation is a tablet, which may be a tablet by direct compression method, which is directly tabletting the raw material mixture, or may be a tablet by granule compression method, prepared after granulation of the raw material mixture.

In the granule compression method, granules can be produced by a wet granulation method or a dry granulation method. The wet granulation method may be produced by any method known in the art and may be manufactured, for example, by drying the wet granulate by a high-speed mixer, a fluidized bed granulator, or a spray dryer, no. In one embodiment, the wet granules are wet granules produced by a high speed mixer. When the wet granules are prepared by a high-speed mixer, the flowability is better than that produced by other methods, thereby increasing the tabletting efficiency at the time of tabletting and lowering the possibility of producing poor tableting at the time of tabletting. It is advantageous.

The pharmaceutically acceptable excipients for oral solid preparations according to the present invention may be any excipients typically included in oral solid preparations, for example, solubilizers, diluents, disintegrants, lubricants, And any combination thereof.

Wherein the solubilizing agent is selected from the group consisting of sodium lauryl sulfate (SLS), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sodium carboxymethylcellulose, polybinipyrrolidone, and any combination thereof And in one embodiment, the solubilizing agent is sodium lauryl sulfate. The solubilizing agent may be contained in an amount of 0.1 to 50 parts by weight, specifically about 10 to 30 parts by weight, based on 100 parts by weight of the liposome or a pharmaceutically acceptable salt thereof.

The diluent is selected from the group consisting of lactose, microcrystalline cellulose, mannitol, sucrose, lactose, sorbitol, xylitol, glucose, and any combination thereof, and in one embodiment the diluent is lactose. The diluent may be contained in an amount of 100 to 300 parts by weight, specifically 150 to 250 parts by weight, based on 100 parts by weight of the lipase inhibitor or a pharmaceutically acceptable salt thereof.

The disintegrant is comprised of alginic acid, sodium alginate, sodium carboxymethylcellulose, microcrystalline cellulose, powdered cellulose, croscarmellose sodium, crospovidone, pregelatinized starch, starch glycolate, starch, and any combination thereof , And in one embodiment, the disintegrant is croscarmellose sodium. The disintegrant may be contained in an amount of 10 to 60 parts by weight, specifically 30 to 55 parts by weight, based on 100 parts by weight of the lipase inhibitor or a pharmaceutically acceptable salt thereof.

The lubricant may be selected from the group consisting of calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulphate, sodium stearyl fumarate, zinc stearate, stearic acid, cured vegetable oil, polyethylene glycol, Sodium, talc, and any combination thereof, and in one embodiment the lubricant is calcium stearate. The lubricant may be contained in an amount of 0.5 to 10 parts by weight, specifically 3 to 7 parts by weight, based on 100 parts by weight of the liposomes or pharmaceutically acceptable salts thereof.

In one embodiment, the solid formulation is prepared by using a sinker according to the second law paddle method according to the US Pharmacopoeia (USP) at 37 占 0.5 占 폚, about 900 ml of an aqueous buffer solution at a pH of about 4.5 and about 0.5% Sulfate solution of about 95% by weight or more in the elution test at about 75 rpm for about 60 minutes (see Experimental Examples 2, 5 and 6).

The solid preparation can lower the content of the active ingredient contained per unit dosage form due to the increase in solubility of the liposomes and the resulting increase in dissolution rate and bioavailability. When the content of the active ingredient is low, it is pharmaceutically preferable because it is easy to formulate.

In one embodiment, the solid formulation may contain about 10 to 40 mg of Riboxazan free base per unit dosage form.

In another aspect of the present invention,

A granule preparation step for granulating a mixture comprising LIVARKAZAN or a pharmaceutically acceptable salt thereof, a polyvinylcaprolactam polyvinyl acetate polyethylene glycol graft copolymer as a solubilizing agent, and a pharmaceutically acceptable additive; And

And granulating the granules. The present invention also provides a method for producing the solid preparation for oral use according to the present invention.

The details of the method for preparing the combined preparation may be applied to the combined preparation according to one aspect of the present invention.

The steps of each step involved in the method of manufacturing the composite preparation can be carried out based on the conventional granulation and tablet manufacturing processes performed in the art.

[Example]

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Example 1 and Comparative Example 1-5: Preparation of Riba-Roxan Tablets According to Types of Hydrophilic Polymer Solubilizing Agents

The additives except for the main component and magnesium stearate were wet-granulated using a high-speed mixer (Sejong, Korea; Agitator 126 ± 10 rpm, Chopper 3000 ± 300 rpm, combined time 2 ± 1 min) After drying at a moisture content of 2.0 ± 0.5% using a fluid bed drier (air temperature of 50 ± 10 ° C.), magnesium stearate (S-Mg) was added as a lubricant, and the mixture was treated with a column blender And mixed to obtain granules. Then, the granules containing the liposomes were tableted by using a tablet machine (SF-100, Bosch, Germany).

Experimental Example 1: Evaluation of solubility according to the type of solubilizing agent

The solubilities of the tablets of Example 1 and Comparative Examples 1 to 5 in a supersaturated state in water, pH 1.2, pH 4.0 and pH 6.8 were measured.

<Analysis method>

Approximately 10 mg of the standard Liparol SABANE was taken in a 100 mL volumetric flask, adjusted to the mark with a diluent (acetonitrile: purified water = 80: 20 v / v%) and filtered through a 0.45 ㎛ membrane filter to prepare a standard solution. Separately, the tablets of Example 1 and Comparative Examples 1 to 5 were shaken with an induction pestle to obtain 10 mg of the contents. Four kinds of liquids (purified water, pH 1.2, pH 4.0, pH 6.8 ) To a final volume of 100 mL. After mixing for 12 hours and 1 hour, the supernatant was filtered through a 0.45 ㎛ membrane filter to prepare a sample solution.

The above standard solution and 20 μL of the sample solution were tested according to the liquid chromatographic method under the following conditions.

&Lt; HPLC Measurement Condition >

- Detector: ultraviolet absorption spectrophotometer (measuring wavelength: 249 nm)

- Column: column packed with octadecylsilylated silica gel (25 cm x 4.6 mm, 5 um) or similar column

- Flow rate: 1.2 mL / min

- Column temperature: 40 ° C

- mobile phase: acetonitrile: purified water = 55: 45 v / v%

The solubilities measured from the tablets of Example 1 and Comparative Examples 1 to 5 are shown in Table 2 and FIG.

As shown in Table 2 and FIG. 1, the tablets of Example 1 in which Solurup Plus was contained as a hydrophilic polymer showed higher solubility at all pH conditions than the tablets of Comparative Examples 1 to 5. The results show that the solubility of the liposomes can be improved by using Solutipule as a hydrophilic polymer.

Experimental Example 2: Elution test of tablet according to the type of solubilizing agent

The tablets of Example 1 and Comparative Examples 1 to 5 were subjected to a dissolution test using a sinker in a USP paddle at 75 rpm in 900 mL of acetate buffer (pH 4.5) + 0.5% sodium lauryl sulfate solution. The results are shown in Table 3 and FIG.

As shown in Table 3 and FIG. 2, in Comparative Examples 1 to 5, the dissolution rate was significantly lower than that of Example 1 using Solutol Plus as the hydrophilic polymer. The above results show that it is preferable to use Solutel as a hydrophilic polymer because the solubility increases when the solubility of the rivaroxaban increases.

EXAMPLE 2 and COMPARATIVE EXAMPLES 6 TO 10 Preparation of Ribasol Tablets according to Solubilizing Agent Types

The same procedure as in Example 1 was repeated according to the composition of the following Table 4 to prepare tablets of Example 2 and Comparative Examples 6 to 10.

Experimental Example 3: Evaluation of solubility according to kind of solubilizing agent

The solubilities of the tablets of Example 2 and Comparative Examples 6 to 10 in a supersaturated state in water, pH 1.2, pH 4.0 and pH 6.8 were measured.

The results are shown in Table 5 and FIG.

As shown in Table 5 and FIG. 3, the tablets of Example 2 containing the hydrophilic polymer SolUplus were found to be more stable than the hydrophilic polymer SolUplus at all the pH conditions of Comparative Examples 6 to 10 using different solubilizing agents The solubility was high. The above results show that the solubility of the rivaroxaban can be significantly improved as compared with other solubilizing agents when Soluburus is used as a hydrophilic polymer.

Example 3: Preparation of Ribarox tablets by granulation (1)

To compare the solubility and dissolution according to the granulation method, tablets were prepared according to various granulation methods according to the composition shown in Table 6 below. Concretely, Solut-Plus as a hydrophilic polymer was mixed with a homogenizer (Homogenizer; Sejong, Korea; 1500RPM, cooperating time: 10 minutes) as a hydrophilic polymer as an active ingredient, (S-Mg) was added as a lubricant, and then the mixture was dried in a fluidized bed drier (feed temperature: 50 ± 10 ° C) so as to have a moisture content of 2.0 ± 0.5% (Column Blender) to obtain granules. Then, the granules containing the liposomes were tableted by using a tablet machine (SF-100, Bosch, Germany).

Example 4: Preparation of Ribarox tablets by granulation (2)

To compare the solubility and dissolution according to the granulation method, tablets were prepared according to various granulation methods according to the composition shown in Table 6 below. Specifically, Soluvplus as a hydrophilic polymer was mixed in a purified water with a homogenizer (Alembic, India) as an active ingredient and mixed with a homogenizer (Sejong, Korea, 1500 RPM, combined time 10 min) into a spray dryer (Korea, Agitator 126 ± 10 rpm, Chopper 3000 ± 300 rpm, combined time 2 ± 1 min), and the water content was adjusted to 2.0 ± 0.5% using a fluidized bed dryer (air temperature 50 ± 10 ℃) After drying, magnesium stearate (S-Mg) was added as a lubricant, followed by post-mixing with a column blender to obtain granules. Then, the granules containing the liposomes were tableted by using a tablet machine (SF-100, Bosch, Germany).

Example 5: Preparation of Ribarox tablets by direct tableting method

According to the composition shown in Table 6 below, the main components and additives were mixed in a column blender and tablets were prepared by tabletting using a tableting machine (SF-100, Bosch, Germany).

[Table 6]

Experimental Example 4: Evaluation of solubility according to purification method

The solubilities of the tablets of Examples 1 and 3 to 5 in a supersaturated state in water, pH 1.2, pH 4.0, and pH 6.8 were measured.

The results are shown in Table 7 and FIG.

As shown in Table 7 and FIG. 4, when the hydrophilic polymer contains Solutol Plus, irrespective of the direct compression method or the granular compression method, in the case of the granular compression method, A significant improvement in solubility can be achieved.

Experimental Example 5: Elution test of tablets according to the manufacturing method

For the tablets of Examples 1 and 3 to 5, a dissolution test was performed in a USP paddle with a sinker at 75 rpm in 900 mL of acetate buffer (pH 4.5) + 0.5% sodium lauryl sulfate solution. The results are shown in Table 8 and FIG.

As shown in Table 8 and FIG. 5, when solvolux is contained as the hydrophilic polymer, irrespective of the direct compression method or the granule compression method, in the case of the granule compression method, The dissolution rate was similar.

Example 6: Preparation of tablets using different size granules

Tablets were produced by the same composition and method as in Example 1 except that raw materials having particle sizes about three times larger than the raw materials (X ₅₀ <15 μm, X ₉₀ <30 μm) used in Example 1 were used.

Experimental Example 6: Elution test of tablets according to the particle size of the liposome

Table 9 and FIG. 6 show the results of the dissolution tests performed on the tablets prepared in Examples 1 and 6, respectively, in which the raw materials were prepared in different particle sizes.

As shown in Table 9 and FIG. 6, the dissolution rate was significantly lowered when the raw material of the fine powder (X ₅₀ <15 μm, X ₉₀ <30 μm) was not used. The results show that the particle size of the main component is preferably in terms of dissolution rate in the range of X ₅₀ <15 μm and X ₉₀ <30 μm as measured by HELOS (Alembic Pharmaceuticals Ltd., India).

EXPERIMENTAL EXAMPLE 7: Comparison of Ribaroxaban Pharmacokinetics

Male rats (Sprague-Dawley, Sprague-Dawley, USA) (n = 4) were divided into two groups, followed by administration of the tablets of Example 1 to the first group with the double blind method, Tablets were administered. After analyzing the drug concentration in the blood, the pharmacokinetic parameter was calculated using Phoenix's WinNonlin program using the drug concentration over time, and the results are shown in Table 10 and FIG. 7, respectively .

As shown in Table 10 and Fig. 7, the AUC was about 1.7 times higher and the Cmax about 1.6 times higher than that of Soluto Plus. Therefore, the use of SoluPlus improves the solubility and maximizes the drug concentration in a specific organ, thereby increasing the bioavailability of the drug and thus maximizing the therapeutic effect of the drug.

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 (11)

A solid oral preparation for oral administration comprising: a lipocalazine or a pharmaceutically acceptable salt thereof as an active ingredient; a polyvinylcaprolactam polyvinyl acetate polyethylene glycol graft copolymer as a solubilizing agent; and a pharmaceutically acceptable additive. The oral solid preparation according to claim 1, wherein the polyvinylcaprolactam polyvinyl acetate polyethylene glycol graft copolymer is present in an amount of 10 to 100 parts by weight based on 100 parts by weight of the active ingredient. 2. The oral solid preparation according to claim 1, wherein the Ribasulfan or a pharmaceutically acceptable salt thereof has an average particle size (X ₅₀ ) of less than 30 μm. The oral solid preparation according to claim 1, which is a tablet produced by the direct compression method or the granular compression method. 5. The oral solid preparation according to claim 4, wherein the granule is compressed by a wet granulation method or a dry granulation method. 6. The oral solid preparation according to claim 5, wherein the wet granulation method is a drying method after the production of wet granules by a high-speed mixer, a fluidized bed granulator, or a spray dryer. 2. The oral solid preparation of claim 1, wherein the pharmaceutically acceptable additive is selected from the group consisting of solubilizers, diluents, disintegrants, lubricants, and any combination thereof. 8. The method of claim 7,
The solubilizing agent is selected from the group consisting of sodium lauryl sulfate (SLS), hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sodium carboxymethylcellulose, polybinipyrrolidone, and any combination thereof Selected,
Wherein the diluent is selected from the group consisting of lactose, microcrystalline cellulose, mannitol, sucrose, lactose, sorbitol, xylitol, glucose and any combination thereof,
The disintegrant is comprised of alginic acid, sodium alginate, sodium carboxymethylcellulose, microcrystalline cellulose, powdered cellulose, croscarmellose sodium, crospovidone, pregelatinized starch, starch glycolic acid sodium, starch, and any combination thereof &Lt; / RTI &gt;
The lubricant may be selected from the group consisting of calcium stearate, glyceryl monostearate glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, hardened vegetable oil, polyethylene glycol, sodium benzoate , Talc, and any combination thereof. The method according to claim 1, which comprises using a sinker according to the second law paddle method according to the USP (USP), adding 75 mL of a mixture of a solution of a pH 4.5 aqueous solution and a 0.5 wt.% Sodium lauryl sulfate solution rpm exhibited a dissolution rate of 95% or more by weight of the lipopolysaccharide for 60 minutes. 2. The oral solid preparation according to claim 1, wherein the Ribasol sac is contained in an amount of 2.5-20 mg per unit dosage form as Ribasol sacin free base. A granule preparation step for granulating a mixture comprising LIVARKAZAN or a pharmaceutically acceptable salt thereof, a polyvinylcaprolactam polyvinyl acetate polyethylene glycol graft copolymer as a solubilizing agent, and a pharmaceutically acceptable additive; And
The method according to any one of claims 1 to 10, comprising the step of tableting the granules.

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