HK1235301B - Pharmaceutical compositions comprising lobeglitazone for oral administration - Google Patents

Description

Pharmaceutical composition for oral administration comprising lobemidone

[ field of technology ]

The present invention relates to pharmaceutical compositions for oral administration comprising lobemidone having improved solubility and dissolution rate.

[ background Art ]

Lobemidone is one of the series of glitazones developed by Chong Kun Dang Pharmaceutical corp and is approved as a 20 th new drug in korea. Lobemidone is used as an orally administered antidiabetic agent with an activity of improving insulin resistance. In particular, lobelidone is used as a medicament for type 2 diabetes. Furthermore, lobemidone can be very useful for obese diabetics because lobemidone has no cardiovascular side effects that are controversial on existing drugs of the glitazone series, particularly on GSK's rosiglitazone.

Lobemidone has a 2, 4-thiazolidinedione moiety, as illustrated in formula I below, and N-methylaminoethoxy benzyl is conjugated to the 2, 4-thiazolidinedione moiety as a linker. Lobemidone is a white or pale yellow powder and has little odor.

[ I ]

Meanwhile, lobemidone was originally developed as a sulfate salt, but lobemidone sulfate is water-insoluble, and a phenomenon of intermolecular aggregation was found, and there was a problem in that solubility was lowered when lobemidone sulfate was dissolved and recrystallized. Subsequently, the problem of decreasing the solubility of lobemidone sulfate arises when lobemidone sulfate is formulated as an active ingredient.

The dissolution rate of a drug is closely related to the solubility of the drug, and it is generally known that if the solubility of a drug is low, the dissolution rate of the drug is also low.

As explained above, when the drug dissolves out of the pharmaceutical dosage form too slowly, the drug concentration in the blood does not reach an effective level and the intended therapeutic effect cannot be achieved. Therefore, a certain level of dissolution rate and dissolution pattern that can maximize the drug effect is a very important issue in the formulation.

Thus, development of dosage forms for oral administration requires an increase in dissolution rate to rapidly exhibit efficacy. The following methods may be used to increase the dissolution rate of orally administered formulations: 1) Reducing particle size by grinding the active ingredient; 2) Adding a surfactant or a solubilizer; 3) Nanocrystallization; and 4) using a solid dispersion. The first of the above 4 methods is the simplest method of increasing the dissolution rate and is most widely used.

In increasing the dissolution rate of a drug for oral administration by decreasing the particle size of an active ingredient, in particular, it is general that the dissolution rate increases when the particle size of the active ingredient is small. However, there is a problem of decreasing the stability of orally administered drugs because the surface area is increased by decreasing the particle size of the active ingredient, resulting in an increased chance of reacting with other additives contained in the formulation.

Korean publication No. 10-2005-0084316 discloses that the dissolution rate is improved by using a water-soluble additive such as d-mannitol instead of lactose, and korean publication No. 10-2007-0093259 discloses that the dissolution rate can be improved by using a specific polymer such as a methacrylate-methacrylate copolymer. However, it is not significant to prepare a solid dispersion by using an excessive amount of polymer or using an excessive amount of surfactant to increase the dissolution rate result because the effect is significantly reduced due to the reduced ratio of the amount of poorly soluble drug dissolved to the dosage of surfactant.

Further, stability can be ensured with a pH control agent by allowing a drug that is decomposed at a certain pH level to exist in a stable pH range in which the drug cannot be decomposed, but its utility is very limited when various pH levels of the human body are considered, and its application is mainly limited to liquid formulations.

The inventors of the present invention, in studying a method of maintaining the solubility and target dissolution rate of lobemidone, confirmed that when a therapeutically effective amount of lobemidone or a pharmaceutically acceptable salt thereof is wet granulated by using water as a binding solvent and using a cellulose derivative as an excipient, the solubility is maintained and the dissolution rate is significantly improved, thus completing the present invention.

[ invention ]

[ problem ]

The present invention provides pharmaceutical compositions for oral administration comprising lobemidone or a pharmaceutically acceptable salt thereof, having improved solubility and dissolution rate. In particular, the present invention provides a pharmaceutical composition for oral administration, which exhibits rapid efficacy by wet granulating lobelide or a pharmaceutically acceptable salt thereof having low solubility with purified water to maintain solubility and to increase dissolution rate in combination with a solvent and using a cellulose derivative as an excipient.

[ technical solution ]

The present invention provides pharmaceutical compositions for oral administration of lobemidone or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of the present invention maintains the solubility of the active ingredient (i.e., lobelia or a pharmaceutically acceptable salt thereof) and exhibits an increased dissolution rate.

The pharmaceutical composition of the present invention may include 0.1 to 10.0 parts by weight of lobemidone or a pharmaceutically acceptable salt thereof and 10.0 to 40.0 parts by weight of a cellulose derivative.

Regarding the pharmaceutical composition of the present invention, for the lobemidone or a pharmaceutically acceptable salt thereof, lobemidone free base or any pharmaceutically acceptable salt may be used. Preferably, for the lobemidone or a pharmaceutically acceptable salt thereof, lobemidone sulfate may be used. In addition, lobemidone or a pharmaceutically acceptable salt thereof may be prepared as disclosed in korean patent No. 10-0450700.

Furthermore, a pharmacologically effective amount of said lobemidone or a pharmaceutically acceptable salt thereof may be administered. Specifically, it may comprise 0.1 to 1000mg, preferably 0.1 to 500mg, and most preferably 0.1 to 250mg of said lobemidone or a pharmaceutically acceptable salt thereof.

Further, the cellulose derivative means a derivative formed by converting one or more hydroxyl groups present in one or more anhydrous glucose repeating units of a cellulose polymer to provide one or more conjugate groups on the cellulose polymer, such as cellulose acetate, cellulose ether, cellulose ester, and the like.

In one embodiment of the invention, the cellulose ether is a "suitable ether conjugated group which may be present on the anhydrous glucose repeat unit of the cellulose polymer" and which comprises a moiety which is optionally conjugated with a moiety selected from the group consisting of hydroxyl, carboxyl, (C) ₁ -C ₄ ) Alkoxy and hydroxy (C) ₁ -C ₄ ) Of alkoxy groupsSubstituted by one or more substituents (C ₁ -C ₄ ) An alkyl group. For example, the "cellulose ether" includes (C ₁ -C ₄ ) Alkyl groups such as methyl or ethyl, etc.; hydroxy (C) ₁ -C ₄ ) Alkyl groups such as 2-hydroxyethyl, 2-hydroxypropyl, or 3-hydroxypropyl, etc.; (C) ₁ -C ₄ ) Alkoxy (C) ₁ -C ₄ ) Alkyl groups such as 2-methoxyethyl, 3-methoxypropyl, 2-methoxypropyl, or 2-ethoxyethyl, etc.; hydroxy (C) ₁ -C ₄ ) Alkoxy (C) ₁ -C ₄ ) Alkyl groups such as 2- (2-hydroxyethoxy) ethyl or 2- (2-hydroxypropoxy) propyl, etc.; carboxyl (C) ₁ -C ₄ ) Alkyl groups such as carboxymethyl and the like; or H- [ O- (C) ₁ -C ₄ ) Alkyl-)] _m (m is an integer in the range of 1 to 5, e.g. 1, 2 or 3), e.g. H- [ O-CH (CH) ₃ )CH ₂ -] _m Or H- [ O-CH ₂ CH ₂ -] _m Etc. For clarity of explanation, the term "ether conjugated group" means one or more of the functional groups conjugated to the cellulose polymer through an oxygen atom. For example, when the ether conjugated group is methyl, one or more hydroxyl groups of the anhydrous glucose repeat unit are converted to methoxy groups.

Moreover, the cellulose ether may comprise the same ether conjugated groups, e.g. methylcellulose may comprise methyl groups. Alternatively, the cellulose ether may comprise a plurality of different ether conjugated groups. For example, hydroxypropyl methylcellulose refers to cellulose that contains methyl groups and hydroxypropyl (e.g., 2-hydroxypropyl) ether conjugated groups.

Regarding the pharmaceutical composition of the present invention, as the cellulose derivative, a water-soluble cellulose ether or an ester of a water-soluble cellulose ether is preferably used. The water-soluble cellulose ether or the ester of a water-soluble cellulose ether may be present in the composition in an amount sufficient to inhibit the rate of precipitation of the drug from the solution in vivo as the drug passes from the acidic environment of the stomach to the gastrointestinal tract where absorption of the drug is expected (e.g., the high pH region of the upper intestine). In detail, 0.1 to 90 parts by weight, preferably 1 to 80 parts by weight, more preferably 5 to 75 parts by weight, and most preferably 10 to 40 parts by weight of the water-soluble cellulose ether or the ester of the water-soluble cellulose ether may be contained in the composition, per 0.1 to 10 parts by weight of lobemidone or a pharmaceutically acceptable salt thereof (i.e., active ingredient).

Regarding the pharmaceutical composition of the present invention, the preferred water-soluble cellulose ether may be selected from methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose, hydroxybutyl methyl cellulose, hydroxyethylethyl cellulose, salts of carboxymethyl cellulose (e.g., sodium carboxymethyl cellulose), salts of carboxymethyl hydroxyethyl cellulose (e.g., sodium carboxymethyl hydroxyethyl cellulose), and the like. More preferably, the water-soluble cellulose ether may be selected from hydroxyethyl cellulose, hydroxypropyl methylcellulose, and salts of carboxymethyl cellulose (e.g., sodium carboxymethyl cellulose), and the like.

Further, in an embodiment of the present invention, the water-soluble cellulose ether may be selected from hydroxyethyl cellulose and hydroxypropyl cellulose. When the water-soluble cellulose ether is hydroxypropyl cellulose, the content of the hydroxypropoxyl group may be 16.0wt% or more, preferably 20wt% to 40wt%. Also, it is preferred that the hydroxypropyl cellulose has a kinematic viscosity of 100 to 600cP (e.g., 150 to 450 cP), and at this point the viscosity is measured with a 2% w/v solution of hydroxypropyl cellulose at 25 ℃. Alternatively, low substituted hydroxypropyl cellulose, wherein the hydroxypropoxyl content is from about 5 to about 16 weight percent, may be used as the hydroxypropyl cellulose. The low substituted hydroxypropylcellulose generally appears to be water insoluble, but it was found that the low substituted hydroxypropylcellulose is sufficiently hydrophilic for the composition of the invention to prevent precipitation of the drug from solution, and that the low substituted hydroxypropylcellulose is one of the water-soluble cellulose derivatives of the invention. Preferably, the low substituted hydroxypropyl cellulose has a degree of substitution of about 0.1 to about 1.0, such as 0.2 to 0.4 (e.g., about 0.2), and the term "degree of substitution" refers to the average number of hydroxypropyl groups per anhydrous glucose ring of cellulose. Further, the content of hydroxypropoxyl groups may be from about 5wt% to about 16wt%, and preferably from 9wt% to 13wt%, according to the low substituted hydroxypropylcellulose. Also, it is preferable that the low-substituted hydroxypropylcellulose has an average particle diameter of 10 to 75 μm, and more preferably 50 to 60 μm.

In addition, the pharmaceutical compositions of the present invention may further comprise one or more pharmaceutically acceptable excipients. Diluents, binders, disintegrants and/or lubricants may be used as the additive.

For the present invention, as the diluent, a water-soluble diluent is preferably used. The water-soluble diluents may be sugars (e.g., lactose, sucrose, and glucose), polysaccharides (e.g., dextrates and maltodextrins), polyols (e.g., mannitol, xylitol, and sorbitol), and cyclodextrins, modified starches (e.g., hydrolyzed or pregelatinized starches that can be modified by heating, mechanical, or chemical), microcrystalline starches, mannitol, sorbitol, trehalose, maltose, inorganic salts (e.g., calcium carbonate, magnesium carbonate, calcium hydrogen phosphate (anhydrous/dihydrate), tricalcium phosphate), cellulose, microcrystalline cellulose, calcium sulfate, xylitol, and lactitol, and the like, without limitation. With respect to the present invention, a sufficient volume of the water-soluble diluent is provided to the formulation, and the water-soluble diluent may be present in the formulation in an amount sufficient for tablet preparation. The water-soluble diluent of the present invention may be contained in the composition in an amount of 1 to 25 parts by weight, preferably 1 to 20 parts by weight, and more preferably 2 to 15 parts by weight, based on 0.1 to 10 parts by weight of lobemidone or a pharmaceutically acceptable salt thereof.

In the present invention, as the adhesive, a hydrophilic adhesive is preferably used. The hydrophilic binder is provided in an amount sufficient to support lobemidone or a pharmaceutically acceptable salt thereof (i.e., the active ingredient) along with other excipients in the composition. The hydrophilic binder facilitates the preparation and handling of the particles and improves the stability of the active ingredient. Suitable hydrophilic binders for use in the present invention may be selected from polyvinylpyrrolidone (e.g. povidone K25-32, in particular K29-32, the value "K" being the range of average molecular weights obtained by Fikentscher's equation), lactose (which may be present in the form of a dehydrate or hydrate, e.g. lactose monohydrate), starch, modified starch, sugar, gum arabic, gum tragacanth, guar gum, pectin, wax binders, microcrystalline cellulose, copovidone, gelatin and alginates (e.g. sodium alginate) and the like. Preferably, the hydrophilic binder of the present invention may be selected from polyvinylpyrrolidone, starch, modified starch and microcrystalline cellulose. The hydrophilic binder of the present invention may be contained in the composition in an amount of 1 to 20 parts by weight, preferably 1 to 10 parts by weight, and more preferably 2 to 8 parts by weight, based on 0.1 to 10 parts by weight of lobemidone or a pharmaceutically acceptable salt thereof.

The disintegrant of the present invention may be selected from croscarmellose sodium, crospovidone, polyvinylpyrrolidone, sodium starch glycolate, starch, alginic acid and the like, and croscarmellose sodium or crospovidone is preferably used. The disintegrant of the present invention may be contained in the composition in an amount of 0.1 to 20 parts by weight, preferably 0.1 to 10 parts by weight, and more preferably 1 to 10 parts by weight, based on 0.1 to 10 parts by weight of lobemidone or a pharmaceutically acceptable salt thereof.

Suitable lubricants of the present invention represent pharmaceutically acceptable additives commonly used in the art as lubricants or slip modifiers (slip modifiers) for preparing solid formulations. The lubricant may be selected from talc, magnesium stearate, calcium stearate, colloidal dioxide, calcium silicate, starch, mineral oil, wax, glyceryl behenate, polyethylene glycol, sodium benzoate, sodium acetate, sodium stearyl fumarate, and hydrogenated vegetable oil, without limitation. Preferably, the lubricant is selected from magnesium stearate, sodium stearyl fumarate and stearic acid, and most preferably, the lubricant is magnesium stearate. It is preferred to provide a sufficient amount of lubricant because it reduces die wall friction when the preparation is compressed into tablets. In addition, the lubricant facilitates handling of the dry powder of the preparation. Preferably, the lubricant of the present invention is contained in the composition in an amount of 0.1 to 2 parts by weight, based on 0.1 to 10 parts by weight of lobemidone or a pharmaceutically acceptable salt thereof.

According to a preferred embodiment of the present invention, the pharmaceutical composition comprises:

(a) 0.1 to 10 parts by weight of lobemidone or a sulfate thereof;

(b) 10 to 40 parts by weight of a cellulose derivative selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl methylcellulose, and salts of carboxymethyl cellulose;

(c) 2 to 15 parts by weight of one or more water-soluble diluents selected from lactose (in particular, lactose monohydrate), mannitol and microcrystalline cellulose;

(d) 2 to 8 parts by weight of one or more hydrophilic binders selected from polyvinylpyrrolidone (e.g. povidone K25-32, in particular K29-32), starch, modified starch, sugar and hydroxypropyl methylcellulose;

(e) 1 to 10 parts by weight of one or more disintegrants selected from croscarmellose sodium or crospovidone; and

(f) 0.1 to 2.0 parts by weight of one or more lubricants (e.g. magnesium stearate), and

the total of the components (a) + (b) + (c) + (d) + (e) + (f) is 100 parts by weight.

Additional excipients that may be added to the pharmaceutical composition of the present invention are preservatives, stabilizers, antioxidants, silica flowability modifiers, adhesion inhibitors, and the like, and appropriate amounts of additional random ingredients (e.g., colorants or fragrances) may be mixed into the formulation, which do not adversely affect the tablets or powders prepared by using the preparation and do not adversely affect the intended function.

The pharmaceutical compositions of the present invention may be administered by a variety of suitable routes including oral, ocular, transdermal, subcutaneous, intravenous or intramuscular, and the like. Depending on the route of administration selected, the pharmaceutical compositions of the present invention may be formulated for oral or parenteral administration, but oral administration is most preferred.

As formulations for oral administration, the pharmaceutical compositions of the present invention may be formulated into the form of powders, granules, tablets, pills, dragees, capsules, liquid preparations, gel preparations, slurry preparations, suspensions and the like by methods known in the art. For example, in the case of formulations for oral administration, tablets or coated tablets may be obtained by: mixing the active ingredient and solid excipients and then grinding and mixing, adding sufficient additives and then processing into a particulate mixture.

The formulations for oral administration of the present invention may be prepared by various methods known in the art. Examples of such methods are: drying, grinding and tabletting after wet granulation, with or without film coating; grinding and tabletting after dry granulation, with or without film coating; tabletting after dry mixing, with or without film coating; forming a tablet; wet granulating, drying and filling the granules into gelatin capsules; filling gelatin capsules with dry mix; or filling the suspension or solution into gelatin capsules or the like. In general, the marking agents are distinguished by depressions or impressions on their surface.

Preferably, the pharmaceutical composition of the present invention may be prepared by a preparation method comprising: (S1) mixing lobemidone or a pharmaceutically acceptable salt thereof, a diluent, a binder and a disintegrant and processing by wet granulation, and (S2) mixing the wet granulated product, cellulose derivative, binder, disintegrant and lubricant.

Furthermore, it is most preferable to use purified water as a solvent for wet granulation in step (S1).

The pharmaceutical composition of the present invention prepared by the method of the present invention has excellent physical stability (hardness or friability) and exhibits remarkably excellent dissolution rate.

[ beneficial effects of the invention ]

The pharmaceutical composition of the present invention can exhibit immediate pharmacological efficacy by increasing the dissolution rate while maintaining the solubility of lobemidone or a pharmaceutically acceptable salt thereof.

[ description of the drawings ]

FIG. 1 shows the results of dissolution rate comparisons between tablets prepared by using cellulose derivatives (low substituted hydroxypropylcellulose) having 5wt% (comparative example 2), 10wt% (example 1), 15wt% (example 2), 32wt% (example 3), 40wt% (example 4), 50wt% (comparative example 3) and 63wt% (comparative example 4), respectively.

Fig. 2 shows the result of comparison of dissolution rates between tablets prepared by using the composition, wherein the solvents of the binding solution used in the wet granulation process were purified water (example 3), purified water: absolute ethanol=1:1 mixed solution (comparative example 5), purified water: dichloromethane=4:1 mixed solution (comparative example 6), purified water: dichloromethane=1:4 mixed solution (comparative example 7), purified water: isopropanol=4:1 mixed solution (comparative example 8), and purified water: isopropanol=1:4 mixed solution (comparative example 9), respectively.

[ detailed description ] of the invention

The present invention will be described more fully hereinafter with reference to the accompanying examples, comparative examples, and experimental examples. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein.

Examples 1-4 and comparative examples 1-4: preparation of the tablet comprising lobemidone sulfate of the present invention

Pharmaceutical compositions comprising lobemidone sulfate were prepared with the compositions of table 1 below.

1)Development of active ingredients

Lobemidone sulfate was developed by using lactose hydrate (spray-dried) and mixed with croscarmellose sodium (Ac-di-sol, DMV-Fonterra Excipients GmBH, germany).

2)Preparation of the binding solution

Blue dye No. 2 was added to purified water and ground and stirred by a homogenizer (HG-150,Daihan Scientific). Povidone K-30 (DaebongLS, korea) was added thereto, and the mixture was stirred and dissolved. The binding solution was then prepared by screening through a 350 mesh screen.

3)Preparation of granules

The mixture of 1) above and the binding solution of 2) above were placed in a high speed mixer (LFS-GS-2J,Fukae Powtec,Japan) and mixed and granulated with the high speed mixer. The granules were then dried by using a fluid bed dryer (FBCG-1,Cheongjin Technology Industry,Korea). After drying, the particles were broken up by Co-mil (U3, quadro, canada).

4)Finally mixing and tabletting

The dried granules of 3) were placed in a mixer and a first mixing was performed by adding croscarmellose sodium, microcrystalline cellulose (Avicel PH 102,FMC BioPolymer,U.S.A.) and low substituted hydroxypropyl cellulose (LH-11, shin-Etsu, japan). After the first mixing was completed, a second mixing was performed by putting magnesium stearate screened through a 30-mesh sieve, to prepare a final mixture. Tablets were obtained by tabletting using an automatic tablet press (XP 1, korsch, germany).

TABLE 1

(amount of ingredients: mg/tablet;

ex.: examples are given; ex: comparative examples; )

Experimental example 1: measurement of hardness and friability of the prepared tablets

The hardness, friability and angle of repose of the tablets obtained from examples 1 to 4 and comparative examples 1 to 4 of the present invention were measured by the following methods, and the measurement results are shown in table 2 below.

[ measurement of hardness ]

-a durometer: BH-225 (Pharmatest Apparatebau, gmbH, germany)

-measuring method: calculating the average of 10 cycle measurements

[ measurement of friability ]

Friability determinator: SVM-102 (Pharmatest Apparatebau, gmbH, germany)

-measuring method: 20 tablets, friability measured after 100 rotations

TABLE 2

As shown in table 2, when 10wt% or more of the water-soluble cellulose derivative was contained, the prepared tablets had high hardness and low friability. Comparative example 1 proved to be inadequate for orally administered compositions, as insufficient intra-granular adhesive strength resulted in non-formation of tablets and thus no measurement. Furthermore, comparative example 2 exhibited a low hardness of 5kp and a high friability of 0.7%. However, examples 1 to 4 or comparative examples 3 and 4 containing 10wt% or more of the water-soluble cellulose derivative exhibited significantly improved hardness and friability of 10kp or more and 0.1% or less, respectively.

Experimental example 2: dissolution test

The formulations obtained from examples 1 to 4 and comparative examples 2 to 4 were tested for dissolution according to the second method (paddle) of dissolution test specified in korean pharmacopoeia (10 th edition) and analyzed by the following method. The results of the dissolution test are shown in table 3 and fig. 1.

[ method of dissolution test ]

-means for: hanson SR 8 (Hanson Research, U.S. A.)

-dissolution medium: PH 1.2 Medium 900mL

Temperature of the dissolution medium: 37+ -0.5 DEG C

-rotational speed: 50rpm

Amount of sample: one sheet per container

[ analytical method: conditions of HPLC liquid chromatography ]

-a detector: ultraviolet-visible spectrometer (wavelength measured: 250 nm)

-column: X-Terra RP 18 (4.6X105 mm,5 μm) or equivalent

-mobile phase: 50mM ammonium nitrate (pH 5.0) buffer solution: acetonitrile=55:45

Injection volume: 100 mu L

-flow rate: 1.5mL/min

Column temperature: 40 DEG C

TABLE 3

As shown in table 3 and fig. 1, for examples 1 to 4 and comparative examples 3 and 4, in which hardness and friability sufficient for forming tablets were ensured, examples 1 to 4 exhibited a dissolution rate of 95% only within 30 minutes, while comparative examples 3 and 4 exhibited significantly low dissolution rates of 70% or less even within 45 minutes. Thus, the present invention demonstrates that the lobelidone-containing composition exhibits suitable dissolution behavior for the pharmacokinetics of lobelidone sulfate, and that the arrival time to reach the maximum blood concentration is 1 hour or less when the lobelidone-containing composition contains 10wt% to 40wt% of the cellulose derivative.

Example 3 and comparative examples 5-9: preparation of the tablet comprising lobemidone sulfate of the present invention

Based on example 3 showing a dissolution behavior of sufficient pharmacokinetics, example 3 and comparative examples 5 to 9 were prepared with the compositions illustrated in table 4 below by changing the binding solution.

TABLE 4

(amount of ingredients: mg/tablet;

ex.: examples are given; ex: comparative examples; )

Experimental example 3: dissolution test

The formulations obtained from example 3 and comparative examples 5 to 9 were tested for dissolution according to the second method (paddle) of dissolution test specified in korean pharmacopoeia (10 th edition) and analyzed by the following method. The results of the dissolution test are shown in table 5 and fig. 2.

[ method of dissolution test ]

-means for: hanson SR 8 (Hanson Research, U.S. A.)

-dissolution medium: pH 4.0 Medium 900mL

Temperature of the dissolution medium: 37+ -0.5 DEG C

-rotational speed: 50rpm

Amount of sample: one sheet per container

[ analytical method: conditions of HPLC liquid chromatography ]

-a detector: ultraviolet-visible spectrometer (wavelength measured: 250 nm)

-column: X-Terra RP 18 (4.6X105 mm,5 μm) or equivalent

-mobile phase: 50mM ammonium nitrate (pH 5.0) buffer solution: acetonitrile=55:45

Injection volume: 100 mu L

-flow rate: 1.5mL/min

Column temperature: 40 DEG C

TABLE 5

The dissolution rate was not significantly different between the various binding solvents during wet granulation when tested in a medium at pH 1.2, but example 3, in which purified water alone was used as the binding solvent, showed a dissolution rate of 97% in 45 minutes when the dissolution test was performed with a medium at pH 4.0, as shown in table 5 and fig. 2. However, comparative examples 5 to 9, in which an organic solvent, or a purified water-organic solvent mixture was used as the binding solvent, exhibited significantly reduced dissolution rates of 60 to 70%. It was thus confirmed that the dissolution rate was significantly reduced when using purified water-organic solvent mixtures as binding solvents, as compared to wet granulation with purified water alone. The present invention has been confirmed by the above experimental examples that the solubility and dissolution rate due to the poor solubility of lobemidone are significantly improved when wet granulation is performed by using only purified water as a binding solvent.

[ Industrial Applicability ]

The pharmaceutical composition of the present invention can exhibit rapid pharmacological efficacy by increasing the dissolution rate while maintaining the solubility of lobemidone or a pharmaceutically acceptable salt thereof. As such, the pharmaceutical compositions of the present invention may be used as pharmaceutical formulations for oral administration.

Claims (12)

1. A pharmaceutical composition for oral administration comprising 0.1 to 10 parts by weight of lobemidone or a pharmaceutically acceptable salt thereof, 10 to 40 parts by weight of a cellulose derivative, 2 to 8 parts by weight of a hydrophilic binder and 1 to 10 parts by weight of a disintegrant,

wherein the pharmaceutical composition for oral administration comprises 32 to 40wt% of the cellulose derivative based on the total weight of the composition,

wherein the cellulose derivative is a low-substituted hydroxypropylcellulose, wherein the content of hydroxypropoxyl groups in the low-substituted hydroxypropylcellulose is 5.0wt% to 16.0wt%,

wherein the hydrophilic binder is polyvinylpyrrolidone and pregelatinized starch,

wherein the disintegrant is croscarmellose sodium,

wherein purified water is used as solvent in wet granulation.

2. The pharmaceutical composition for oral administration of claim 1, wherein the lobemidone or pharmaceutically acceptable salt thereof is lobemidone sulfate.

3. The pharmaceutical composition for oral administration of claim 1, wherein the content of hydroxypropoxyl groups in the low-substituted hydroxypropylcellulose is 9.0wt% to 13.0wt%.

4. The pharmaceutical composition for oral administration of claim 1, wherein the low-substituted hydroxypropylcellulose has an average particle size of 10 to 75 μm.

5. The pharmaceutical composition for oral administration according to claim 4, wherein the low-substituted hydroxypropylcellulose has an average particle size of 50 to 60 μm.

6. The pharmaceutical composition for oral administration of claim 1, further comprising 2 to 15 parts by weight of a water-soluble diluent and 0.1 to 2 parts by weight of a lubricant.

7. The pharmaceutical composition for oral administration of claim 6, wherein the water-soluble diluent is selected from the group consisting of sugars, polysaccharides, polyols, cyclodextrins, and mixtures thereof.

8. The pharmaceutical composition for oral administration of claim 6, wherein the lubricant is selected from the group consisting of talc, magnesium stearate, calcium stearate, stearic acid, colloidal dioxide, calcium silicate, mineral oil, wax, glyceryl behenate, polyethylene glycol, sodium benzoate, sodium acetate, sodium stearyl fumarate, and mixtures thereof.

9. The pharmaceutical composition for oral administration of claim 6, wherein the composition is in the form of a tablet.

10. The pharmaceutical composition for oral administration of claim 9, wherein the lobemidone and pharmaceutically acceptable salts thereof are contained in a first composition for wet granulation and the cellulose derivative is contained in a second composition for post-mixing (post-mixing) with the product of the wet granulation.

11. The pharmaceutical composition for oral administration of claim 10, wherein the solvent for the wet granulation is purified water.

12. The pharmaceutical composition for oral administration of claim 10, wherein the composition is prepared by a process comprising:

mixing the lobemidone or pharmaceutically acceptable salt thereof, a water-soluble diluent, a hydrophilic binder and a disintegrant, and processing by wet granulation; and

mixing the wet granulated product, a cellulose derivative, a hydrophilic binder, a disintegrant and a lubricant.