WO2019004776A2

WO2019004776A2 - Composite chewable tablet including levocetirizine and montelukast with improved stability and drug compliance, and method of preparing the same

Info

Publication number: WO2019004776A2
Application number: PCT/KR2018/007402
Authority: WO
Inventors: Taek Kwan Kwon; Kwang Young Lee; Ho Taek IM; Youg Il KIM
Original assignee: Hanmi Pharmaceutical Co Ltd; Hanmi Pharmaceutical Industries Co Ltd
Current assignee: Hanmi Pharmaceutical Co Ltd; Hanmi Pharmaceutical Industries Co Ltd
Priority date: 2017-06-30
Filing date: 2018-06-29
Publication date: 2019-01-03
Anticipated expiration: 2019-12-30
Also published as: WO2019004776A3

Abstract

Provided are a composite chewable tablet including levocetirizine and montelukast while having improved stability and improved drug compliance by masking a bitter taste, and a method of preparing the same.

Description

COMPOSITE CHEWABLE TABLET INCLUDING LEVOCETIRIZINE AND MONTELUKAST WITH IMPROVED STABILITY AND DRUG COMPLIANCE, AND METHOD OF PREPARING THE SAME

The present disclosure relates to a composite chewable tablet including levocetirizine and montelukast with improved stability and drug compliance, and a method of preparing the composite chewable tablet, and more particularly, to an improved composite chewable tablet including levocetirizine or a pharmaceutically acceptable salt thereof and montelukast or a pharmaceutically acceptable salt thereof while having improved stability and masking a bitter taste, and a method of preparing the composite chewable tablet.

It is estimated that about 300 million people worldwide suffer from asthma. Although it is not easy to compare prevalence rates between different regions, the global prevalence of asthma ranges from 1% to 18% of the population in different countries, according to an investigation conducted on children and adults using a standard investigative method. Asthma is a chronic, allergic inflammatory disease of the airways in which many cells and various mediators are involved. The inflammation of the airways is related with hyperreactivity of the airways, causing symptoms such as recurrent wheezing, difficulty in breathing, chest discomfort, coughing, etc. Asthma can be defined by its clinical, physiological, and pathological characteristics. According to its clinical definition, asthma is a disease that comes with repeated breathing problems, recurrent wheezing, and coughing; according to its physiological definition, asthma is a hyperresponsiveness of the airways and partially reversible airway obstruction; and according to its pathological definition, asthma is a chronic, allergic inflammation of the airways.

Allergic rhinitis refers to a symptomatic disorder of the nose induced by IgE-mediated inflammation after exposure of the membrane of the nose to allergens. Symptoms of allergic rhinitis include rhinorrhea, nasal obstruction, nasal itching, sneezing, ocular pruritis, etc.

Allergic rhinitis and asthma can develop separately. However, there is a study showing that 58% of patients with allergic rhinitis have asthma and 85% to 95% of patients with asthma also suffer from allergic rhinitis, with high rates of complications between these two patient groups. Thus, there is a need to develop a composite formulation having improved stability and efficacy for the simultaneous treatment of these two conditions.

Cetirizine is (2-(4-((4-chlorophenyl)phenylmethyl)-1-piperazinyl)ethoxy)acetic acid, and its levorotatory and dextrorotatory mirror image enantiomers are known as levocetirizine and dextrocetirizine, respectively.

Patent Document 1 discloses a method of treating seasonal and perennial allergic rhinitis using Levocetirizine. Levocetirizine can be obtained via breakdown or asymmetric synthesis from a racemic mixture of cetirizine, e.g., common methods such as described in GB Patent No. 2,225,321 or yeast biocatalytic hydrolysis as described in US Patent Nos. 4,800,162 and 5,057,427. Levocetirizine possesses antihistaminic properties, and hence is useful as an anti-allergic agent, an antihistaminic agent, a bronchodilator, and an anticonvulsant. Also, levocetirizine dihydrochloride has been approved for treatment of allergic rhinitis and is sold under the name Xyzal (Yuhan Corporation).

However, levocetirizine is unstable in terms of physicochemical properties, and it is difficult to maintain its stability over time. There are related compounds of levocetirizine which may be produced during storage: related compound A (Formula I), related compound B (Formula II), and related compound E (Formula III). Related compounds A and B are created via hydrolysis of levocetirizine.

[Formula 1]

[Formula 2]

[Formula 3]

Meanwhile, montelukast is an antagonist for cysteinyl leukotriene type 1 (CysLT1) receptor which is used for the prevention and treatment of leukotriene-mediated diseases and disorders. In addition, montelukast is useful in the treatment of allergic rhinitis, atopic dermatitis, chronic urticaria, sinusitis, nasal polyps, chronic obstructive pulmonary disease, conjunctivitis including nasal conjunctivitis, migraines, cystic fibrosis, viral bronchiolitis, and the like (Non-Patent Document 1).

However, it is also not easy to secure stability of montelukast over time. For example, montelukast in a solid or liquid state is known to be unstable when exposed to light, moisture, and heat, and yields related compounds such as montelukast sulfoxide (Formula 4) and montelukast cis-isomer (Formula 5) (Non-Patent Document 2).

Further, it has been reported that when the commercially available chewable tablet, Singulair, containing a montelukast sodium salt as a main ingredient was exposed to sunlight, the amount of montelukast sulfoxide was increased by 2.4% after 3 weeks, and when montelukast in a 0.1 M hydrochloric acid solution was exposed to a sodium vapor lamp for 6 hours, the amount of montelukast cis-isomer was increased by 14.6%.

[Formula 4]

[Formula 5]

Therefore, in order to develop a composite formulation including levocetirizine and montelukast, it is necessary to improve stability of the drugs which are physicochemically unstable.

Meanwhile, levocetirizine hydrochloride and levocetirizine drugs have a drawback in that they have a bitter taste which lowers drug compliance. In particular, children and the elderly often take allergic rhinitis and asthma medications, and in this case, to increase compliance, it is common to consume the medication in a liquid formulation, or to orally consume the medication in as a mixture of a crushed tablet with water or syrup. In this regard, the bitter taste of drugs is a more serious problem.

However, due to the nature of medicinal products, substances added to mask a bitter taste are subject to restrictions that should not affect the quality control of the medicinal products. Accordingly, it is necessary to develop a formulation that reduces a bitter taste specific to a drug and improves patients' drug compliance while being excellent in terms of quality control of medicinal products.

[Prior Art Documents]

[Patent Document]

(Patent Document 1) International Patent Publication No. WO 94/06429

[Non-Patent Document]

(Non-Patent Document 1) S. E. Dahlen, Eur. J. Pharmacol., 533(1-3), 40-56, 2006

(Non-Patent Document 2) M. M. Al Omari et al., J. Pharm. and Biomed. Anal., 45, 465-471, 2007

Provided is a composite chewable tablet including levocetirizine and montelukast while having improved stability and improved drug compliance by masking a bitter taste.

Further, provided is a method of preparing the composite chewable tablet.

An aspect provides a composite chewable tablet including a first tablet layer including levocetirizine or a pharmaceutically acceptable salt thereof, cyclodextrin or a derivative thereof, and an alkalinizing agent; and a second tablet layer including montelukast or a pharmaceutically acceptable salt thereof.

Another aspect provides a method of preparing the composite chewable tablet, the method including:

preparing a first levocetirizine tablet layer by mixing and granulating levocetirizine or a pharmaceutically acceptable salt thereof, cyclodextrin or a derivative thereof, and an alkalinizing agent;

preparing a second montelukast tablet layer by granulating montelukast or a pharmaceutically acceptable salt thereof; and

stacking one of the first levocetirizine tablet layer and the second montelukast tablet layer on the other of the first levocetirizine tablet layer and the second montelukast tablet layer, followed by tableting.

A composite chewable tablet according to one specific embodiment may minimize a contact between main ingredients by improving stability and may effectively prevent production of related compounds during long-term storage, and may improve patient's compliance by masking the bitter taste. Further, the composite chewable tablet according to one specific embodiment may be excellent in terms of quality control because there is no peak interference at the time of analyzing degradation products for quality control of medicinal products.

These and/or other aspects will become apparent and more readily appreciated from the following description of the embodiments, taken in conjunction with the accompanying drawings in which:

FIG. 1 shows a specificity test under analysis conditions of levocetirizine related compounds, which was performed with respect to Examples 11 and 14, and Comparative Examples 12 and 13, each including strawberry flavor powder, cider flavor powder, cherry flavor powder, or orange flavor powder as a flavoring agent (X axis unit: time(min), Y axis unit: mAU);

FIG. 2 shows mean values of sensory evaluation for bilayer composite chewable tablets of Examples 1 to 10 and Comparative Examples 1 to 10;

FIG. 3 shows mean values of sensory evaluation for bilayer composite chewable tablets of Examples 11 to 20 and Comparative Examples 11 to 19;

FIG. 4 shows levocetirizine dissolution rates of the bilayer composite chewable tablets of Examples 1 to 7 and Comparative Examples 1 to 7;

FIG. 5 shows montelukast dissolution rates of the bilayer composite chewable tablets of Examples 1 to 7 and Comparative Examples 1 to 7;

FIG. 6 shows a dissolution rate (%) of a levocetirizine tablet layer which is a first tablet layer in each of the bilayer composite chewable tablets of Examples 11 to 13, 16, 18 and 20, and Comparative Examples 11, 12, 15, 17, and 19, at different time points; and

FIG. 7 shows a dissolution rate (%) of a montelukast tablet layer which is a second tablet layer in each of the bilayer composite chewable tablets of Examples 11 to 13, 16, 18 and 20, and Comparative Examples 11, 12, 15, 17, and 19, at different time points.

Hereinafter, the present invention will be described in detail.

Unless defined otherwise, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although preferred methods or materials are described, any methods or materials similar or equivalent to those described herein may be also included in the scope of the present disclosure. Further, the numerical values described herein are considered to include the meaning of “approximately”although not specified herein. The contents of all publications referred to herein are incorporated herein by reference in their entirety.

An aspect relates to a composite chewable tablet including levocetirizine and montelukast while having improved stability and improved drug compliance by masking a bitter taste, in which cyclodextrin is used to mask the bitter taste and unpleasant flavor of levocetirizine and to block a contact between the two drugs of levocetirizine and montelukast, thereby improving stability, and an alkalinizing agent is used to set an optimum pH range of the composite formulation including levocetirizine and montelukast, and the chewable tablet provides convenience for the elderly or young children who are difficult to swallow a pill.

An aspect provides a composite chewable tablet including a first tablet layer including levocetirizine or a pharmaceutically acceptable salt thereof; and a second tablet layer including montelukast or a pharmaceutically acceptable salt thereof.

Hereinafter, the composite formulation will be described in more detail with a specific embodiment.

A. First Tablet Layer

(1) Levocetirizine or Pharmaceutically Acceptable Salt Thereof

Levocetirizine or the pharmaceutically acceptable salt thereof used as an active ingredient of the first tablet layer in the composite formulation may be, for example, those disclosed in EP Patent Nos. 0,058,146, 0,601,028 and 0,801,064, GB Patent Nos. 2,225,320 and 2,225,321, US Patent No. 5,478,941 and WO 97/37982. Examples of the pharmaceutically acceptable salt of levocetirizine may include pharmaceutically acceptable non-toxic, organic and inorganic acid addition salts of acetic acid, citric acid, maleic acid, succinic acid, ascorbic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc., metal salts thereof (e.g., sodium salt or potassium salt), ammonium salts, amine salts, amino acid salts, etc., and in a specific embodiment, the pharmaceutically acceptable salt of levocetirizine may be a levocetirizine dihydrochloride salt. The daily dosage amount of levocetirizine or the pharmaceutically acceptable salt thereof may be 0.4 mg to 100 mg, for example, 1 mg to 50 mg, and for example, 2.5 mg to 20 mg.

(2) Cyclodextrin or Derivative Thereof

In order to mask the bitter taste of levocetirizine, levocetirizine may be enclosed in an inclusion compound, for example, cyclodextrin.

Cyclodextrin is an oligosugar obtained by applying an enzyme to a starch, which is a monomolecular host which forms an inclusion complex by inserting a guest molecule or atom to a cavity inside a molecule. By such inclusion, physiochemical properties of a guest molecule may be altered, resulting in increase of its solubility.

Further, cyclodextrin is a cyclic substance composed of 6 to 12 D-glucose units connected via α-1,4-glucosidic linkages to form a cylindrically shaped compound. Cyclodextrin may include alpha(α)-cyclodextrin in which 6 glucose molecules are linked, beta(β)-cyclodextrin in which 7 glucose molecules are linked, gamma(γ)-cyclodextrin in which 8 glucose molecules are linked, delta(δ)-cyclodextrin in which 9 glucose molecules are linked, upsilon(ε)-cyclodextrin in which 10 glucose molecules are linked, and zeta(ζ)-cyclodextrin in which 11 glucose molecules are linked, and other cyclodextrins in which 12 or more glucose molecules are linked.

Secondary hydroxyl groups of C2―OH and C3―OH are located on the side of wider mouth part of a cylindrical structure of cyclodextrin, and primary hydroxyl groups of C6―OH may be found on the other side of smaller mouth part. The outer side of the cylindrical structure is hydrophilic, whereas the inner side of the cylindrical structure shows hydrophobic character due to the presence of hydrogen atoms. Therefore, cyclodextrin may enclose small hydrophobic compounds inside thereof, thereby being used to improve the water solubility of hydrophobic compounds in the fields of medicine, food, cosmetics and the like.

In a specific embodiment, as an inclusion compound capable of masking the bitter tastes and unpleasant flavor of the drug, cyclodextrin such as α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin may be used, larger δ-cyclodextrin, ε-cyclodextrin, or ζ- cyclodextrin may be used, and other cyclodextrins having 12 or more glucose molecules may also be used.

In a specific embodiment, α-, β-, γ-cyclodextrin or α-, β-, γ-cyclodextrin derivative may be used as the cyclodextrin, and for example, hydroxymethyl α-, β-, γ-cyclodextrin, hydroxyethyl α-, β-, γ-cyclodextrin, or hydroxypropyl α-, β-, γ-cyclodextrin may be used. In a specific embodiment, the cyclodextrin may be any one selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, and any combinations thereof. The α-, β-, and γ-cyclodextrins may not have undesirable effects on the content, related compounds, and dissolution analysis for quality control of the composite formulation according to a specific embodiment. The α-, β-, and γ-cyclodextrins may be different from each other in cavity, and among them, β-cyclodextrin which is a medium size of α- and γ-cyclodextrins may be preferred. In a specific embodiment, the cyclodextrin may be β-cyclodextrin. In a specific embodiment, the β-cyclodextrin may be hydroxypropyl β-cyclodextrin.

The cyclodextrin may be used in an amount of 1.0 to 3.0 equivalent weight, for example, 1.0 equivalent weight, 1.2 equivalent weight, 1.4 equivalent weight, 1.6 equivalent weight, 1.8 equivalent weight, 2.0 equivalent weight, 2.2 equivalent weight, 2.4 equivalent weight, 2.6 equivalent weight, 2.8 equivalent weight, or 3.0 equivalent weight with respect to 1 equivalent weight of levocetirizine. When the cyclodextrin may be used in an amount of 1.0 to 3.0 equivalent weight with respect to levocetirizine, an inclusion reaction may be maximized to form an inclusion complex in a homogeneous stable state. When the amount of the cyclodextrin is more than 3.0 equivalent weight, the amount of the cyclodextrin is too large, as compared with levocetirizine having a pharmacological activity, and thus it is apprehended that the total volume is increased during granule preparation, and the preparation thereof is difficult. When the amount of the cyclodextrin is less than 1.0 equivalent weight, it is apprehended that inclusion reactivity is reduced, and thus it is difficult to obtain the inclusion complex in a stable state.

The cyclodextrin may be included in an amount of 3.0% by weight to 30.0% by weight, for example, 3.0% by weight, 5.0% by weight, 5.5% by weight, 6.0% by weight, 6.5% by weight, 7.0% by weight, more than 7.0% by weight, 7.5% by weight, 8.0% by weight, 10.0% by weight, 15.0% by weight, 16.0% by weight, 16.5% by weight, 17.0% by weight, 17.5% by weight, 18.0% by weight, 19.0% by weight, 20.0% by weight, 25.0% by weight, 27.0% by weight, 30.0% by weight, based on the total weight of the first tablet layer, or may be included in the range from the lower limit thereof to the upper limit thereof. The cyclodextrin may be included, for example, in an amount of 3.0% by weight to 30.0% by weight, 5% by weight to 28% by weight, 6% by weight to 30% by weight, 7% by weight to 27% by weight, 8% by weight to 30% by weight, 8% by weight to 27% by weight, or 10% by weight to 25% by weight, based on the total weight of the first tablet layer. Use of the cyclodextrin in the above content range may be effective for the improvement of the bitter taste, dissolution rate, and stability. Further, when the cyclodextrin is used in an amount of 3.0% by weight to 30.0% by weight, based on the total weight of the first tablet layer, the bitter taste may be effectively masked and stability may be improved. The composite formulation including cyclodextrin in the above range may exhibit a levocetirizine dissolution rate of 85% or more at a time point of 30 minutes. However, the content of cyclodextrin is more than 30.0% by weight, based on the total weight of the first tablet layer, the dissolution rate was lowered due to a long disintegration pattern of a core tablet during dissolution. Further, when the content of cyclodextrin is less than 3.0% by weight, based on the total weight of the first tablet layer, the bitter taste was still felt.

(3) Alkalinizing Agent

To set an optimal pH range of the composite formulation including levocetirizine and montelukast, the first tablet layer may include an alkalinizing agent. In the formulation according to one specific embodiment, the first tablet layer may include the alkalinizing agent as a stabilizing agent (or pH regulator). The alkalinizing agent functions to improve stabilities of the drugs by maintaining the inside of granules at a neutral or basic condition. The alkalinizing agent may be meglumine, sodium bicarbonate, sodium carbonate monohydrate, ammonia water, sodium hydroxide, sodium citrate, dried sodium carbonate, or any mixture thereof. In one specific embodiment, the alkalinizing agent may include meglumine.

The alkalinizing agent may be included in an amount of 0.1% by weight to 6.5% by weight, for example, 0.1% by weight to 6.0% by weight, for example, 0.1% by weight to 5.0% by weight, for example, 0.1% by weight, 0.2% by weight, 0.4% by weight, 0.8% by weight, 1% by weight, 1.5% by weight, 1.8% by weight, 2% by weight, 2.5% by weight, 3% by weight, 3.5% by weight, 4% by weight, 4.5% by weight, 5.0% by weight, 5.5% by weight, 6.0% by weight, 6.5% by weight, based on the total weight of the first tablet layer.

In one specific embodiment, the alkalinizing agent may be included in an amount of 1.5% by weight to 6.5% by weight, based on the total weight of the first tablet layer. When the alkalinizing agent is used in an amount of 1.5% by weight to 6.5% by weight, based on the total weight of the first tablet layer, the bitter taste may be effectively masked and stability may be improved. However, when the amount of the alkalinizing agent is more than 6.5% by weight based on the total weight of the first tablet layer, the bitter taste was increased, and thus the taste became strong, and amounts of related compounds were increased by affecting the stability. Further, when the amount of the alkalinizing agent is less than 1.5% by weight based on the total weight of the first tablet layer, the production amounts of the related compounds were increased to reduce the stability.

(4) Flavoring Agent

A flavoring agent in the formulation according to one specific embodiment may be included in the first tablet layer including levocetirizine or the pharmaceutically acceptable salt thereof, cyclodextrin or the derivative thereof, and the alkalinizing agent. The flavoring agent refers to a substance that improves drug compliance by allowing a flavor to be felt when a composition for oral administration is taken. The flavoring agent may be a natural flavoring agent, an artificial flavoring agent, or a mixture thereof. The natural flavoring agent may be an extract from plant leaves, flowers, fruits, etc., plant oil, etc. The plant oil may include spearmint oil, cinnamon oil, peppermint oil, lemon oil, clove oil, bay oil, thyme oil, cedar leaf oil, nutmeg oil, sage oil, almond oil, etc. The artificial flavoring agent may include artificial synthetic fruit flavors of fruits such as lemon, orange, grape, lime, strawberry, etc., artificial synthetic flavors such as vanilla, chocolate, coffee, cocoa, cider, pine leaf, ginseng, red ginseng, and citrus. In one specific embodiment, the flavoring agent may be a strawberry flavor or a cider flavor in powder form, or a combination thereof.

In general, the flavoring agent may be used by dissolving and mixing a volatile aromatic oil in alcohol. The volatile aromatic oil commonly refers to a volatile substance of an oil component that emits a variety of fragrances, such as essential oils of herbs including menthol, lavender, rosemary, sage, thyme, or peppermint. Aroma, which represents a major fragrance, is an aromatic compound, and shows many peaks during analysis in a general analysis equipment, and therefore, the peaks overlap with peaks of related compounds derived from montelukast and levocetirizine, causing peak interference. Thus, accurate analysis of related compounds is difficult.

In order to solve this problem, the present inventors conducted studies on screening for a variety of flavoring agents, and as a result, they found that when a strawberry flavor or a cider flavor or a combination of thereof is used as the flavoring agent, there was no peak interference caused by levocetirizine-derived related compounds and excellent results were obtained in a sensory evaluation. In one specific embodiment, the flavoring agent may be a strawberry flavor in powder form, a cider flavor in powder form, or a combination of thereof. In one specific embodiment, the flavoring agent may be a strawberry flavor powder, and may be used in an amount of 0.1% by weight to 10% by weight, based on the total weight of a granular part of the first tablet layer. In one specific embodiment, the flavoring agent may be used in an amount of 0.1% by weight to 3% by weight, for example, 0.1% by weight to 3.0% by weight, for example, 0.1% by weight, 0.2% by weight. 0.4% by weight, 0.8% by weight, 1% by weight, 1.5% by weight, 1.8% by weight, 2% by weight, 2.4% by weight, 2.5% by weight, 3.0% by weight, based on the total weight of the first tablet layer. In one specific embodiment, the flavoring agent may be a strawberry flavor, a cider flavor, or a combination thereof, and may be used in an amount of 0.1% by weight to 3.0% by weight, for example, 0.5% by weight, 1.0% by weight, 1.1% by weight, 1.2% by weight, 1.25% by weight, 1.3% by weight, 1.35% by weight, 1.5% by weight, 2.0% by weight, 2.4% by weight, 2.5% by weight, 3.0% by weight, based on the total weight of the first tablet layer.

In one specific embodiment, the flavoring agent may be a strawberry flavor, a cider flavor, or a combination thereof. The strawberry flavoring agent may be a composition including the strawberry flavor, and a specific example thereof may be a powder containing a strawberry flavor base, dextrin, lactose, pectin, and ethyl maltol. Further, the cider flavoring agent may be a composition including the cider flavor, and a specific example thereof may be a powder containing a cider base, fermented liquor, propylene glycol, silicon dioxide, and dextrin. In a specific embodiment, the flavoring agent may be a powder having the following composition and composition ratio.

(5) Other Pharmaceutically Acceptable Additive

The first tablet layer of the formulation according to one specific embodiment may further include a pharmaceutically acceptable additive. The additive may be a diluent, a sweetener, a colorant, a binder, a disintegrating agent, a lubricant, or a mixture thereof.

The diluent may be selected from the group consisting of microcrystalline cellulose, lactose, ludipress, mannitol, calcium dihydrogen phosphate, starch, low-substituted hydroxypropyl cellulose, and a mixture thereof. The diluent may be used in an amount of 1% by weight to 99% by weight, preferably 5% by weight to 95% by weight, based on the total weight of the first tablet layer.

The sweetener may be selected from the group consisting of aspartame, acesulfame salt, acesulfame potassium, sucralose, saccharin salt, neotame, cyclamate, thaumatin, LuoHan Guo extract, glycyrrhizin extract, steviten light (at least 98% stevioside), steviten rich (100% enzymatically modified stevia), sugar, glucose, maltose, oligosaccharide, dextrin, invert sugar, fructose, lactose, galactose, corn syrup, sorbitol, maltitol, xylitol, erythritol, hydrogenated corn syrup, trehalose, and mixtures thereof. The sweetener may be selected from the group consisting of acesulfame potassium, sucralose, thaumatin, steviten light (at least 98% stevioside), aspartame, and any combination thereof. In one specific embodiment, the sweetener may be selected from the group consisting of acesulfame potassium, sucralose, thaumatin, steviten light (at least 98% stevioside), and any combination thereof.

The sweetener may be used in an amount of 0.1% by weight to 10% by weight, based on the total weight of the first tablet layer. For example, the sweetener may be used in an amount of 0.1% by weight to 10% by weight, for example, 0.5% by weight to 9.0% by weight, 1% by weight to 8.0% by weight, 2.0% by weight to 8.0% by weight, or 4.0% by weight to 7.0% by weight, based on the total weight of the first tablet layer or the second tablet layer. For example, the sweetener may be used in an amount of 3.0% by weight to 9.0% by weight, for example, 4.0% by weight to 7.0% by weight, based on the total weight of the first tablet layer. For example, the sweetener may be used in an amount of 0.5% by weight to 4.0% by weight, for example, 1.0% by weight to 2.0% by weight, based on the total weight of the second tablet layer.

The colorant may include Food Yellow No. 5, Food blue No. 2, a food lake dye, titanium oxide, yellow iron oxide, red iron oxide, mixtures thereof, etc.

The binder may be selected from the group consisting of hydroxypropyl cellulose, hypromellose, polyvinyl pyrrolidone, copovidone, macrogol, light anhydrous silicic acid, silicate derivatives such as synthetic aluminum silicate, calcium silicate, or magnesium metasilicate aluminate, phosphate salts such as calcium phosphate dibasic, carbonate salts such as calcium carbonate, and mixtures thereof. The binder may be used in an amount of 1% by weight to 30% by weight, for example, 2% by weight to 20% by weight, based on the total weight of the first tablet layer.

The disintegrating agent may be selected from the group consisting of croscarmellose, croscarmellose sodium, carboxymethyl cellulose sodium, crospovidone, and mixtures thereof.

The lubricant or the tabletting aid may be selected from the group consisting of silicon dioxide, silicic acid, colloidal silica, magnesium stearate, talc, and mixtures thereof.

B. Second Tablet Layer

(1) Montelukast or Pharmaceutically Acceptable Salt Thereof

Examples of montelukast or the pharmaceutically acceptable salt thereof used as an active ingredient of the second tablet layer in the composite formulation may include pharmaceutically acceptable non-toxic, organic and inorganic acid addition salts of acetic acid, citric acid, maleic acid, succinic acid, ascorbic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc., metal salts thereof (e.g., sodium salt or potassium salt), ammonium salts, amine salts, amino acid salts, etc., and montelukast sodium salts may be preferred. The daily dosage amount of montelukast or the pharmaceutically acceptable salt thereof may be 0.4 mg to 100 mg, preferably, 1 mg to 50 mg, and more preferably, 2.5 mg to 20 mg.

(2) Other Pharmaceutically Acceptable Additives

The pharmaceutically acceptable additives which may be additionally used in the second tablet layer according to one specific embodiment and amounts thereof are the same as described in the first tablet layer. Further, the second tablet layer may further include a flavoring agent, as needed, and a kind and content of the flavoring agent are the same as described in the first tablet layer.

The composite formulation including the first tablet layer and second tablet layer described in one specific embodiment may be in a multilayer tablet form such as a single layer tablet, a bilayer tablet, or a three layer tablet or in a capsule form such as a soft capsule or a hard capsule, and for example, the composite formulation may be in a bilayer tablet form.

The tablet may be a chewable tablet taken by chewing. In one specific embodiment, the formulation may be a composite chewable tablet in a bilayer tablet form. In one specific embodiment, the chewable tablet may be prepared in various forms such as a round or triangle form.

In one specific embodiment, the composite chewable tablet may further include a coating layer. The chewable tablet may be prepared in various forms such as a round or triangle form, and it may be convenient for the elderly or young children who are difficult to swallow pills.

In one specific embodiment, when one tablet of the composite chewable tablet may be dissolved in about 300 mL of purified water, pH of the dispersion may be 7.0 to 9.0. For example, the pH may be 7.0 to 9.0, 7.5 to 8.5, or 7.7 to 8.0.

According to one specific embodiment, provided is the composite chewable tablet, in which levocetirizine is enclosed in cyclodextrin to mask its bitter taste and the alkalinizing agent is used to set the optimal pH of the bilayer composite chewable tablet including the levocetirizine and montelukast, thereby improving stability of levocetirizine and montelukast.

The composite chewable tablet according to one specific embodiment exhibits a levocetirizine dissolution rate of 85% or more at a time point of 30 minutes and a montelukast dissolution rate of 85% or more at a time point of 20 minutes, indicating no reduction in the dissolution rate and excellent dissolution rate.

The composite chewable tablet according to one specific embodiment may minimize a contact between the main ingredients to improve stability, may effectively prevent production of related compounds during long-term storage, and may improve children and elderly patient's compliance by masking the bitter taste. Further, the composite chewable tablet according to one specific embodiment may further include the flavoring agent to further reduce the bitter taste while being excellent in terms of quality control of medicinal products because there is no peak interference at the time of analyzing related compounds. Further, the bilayer composite chewable tablet according to one specific embodiment may enclose levocetirizine in cyclodextrin and may use the alkalinizing agent to prevent a contact between the active ingredients, thereby minimizing reactivity between the active ingredients and showing excellent stability and therapeutic effects. Further, the bitter taste may be masked by enclosing levocetirizine in cyclodextrin, thereby improving patient's, especially, children and elderly's compliance.

In one specific embodiment, the composite chewable tablet may include a first tablet layer including levocetirizine or the pharmaceutically acceptable salt thereof, cyclodextrin or the derivative thereof, the alkalinizing agent, and the flavoring agent; and a second tablet layer including montelukast or the pharmaceutically acceptable salt thereof.

In one specific embodiment, the composite chewable tablet may include a first tablet layer including levocetirizine or the pharmaceutically acceptable salt thereof, cyclodextrin or the derivative thereof, the alkalinizing agent, and the sweetener; and a second tablet layer including montelukast or the pharmaceutically acceptable salt thereof.

In one specific embodiment, the composite chewable tablet may be used in the prevention or treatment of allergic rhinitis and asthma, and the allergic rhinitis may be selected from the group consisting of rhinorrhea, nasal obstruction, nasal itching, sneezing, and ocular pruritis.

Levocetirizine and montelukast each exhibits different therapeutic mechanisms, and they together may bring about a synergistic effect in the treatment of allergic rhinitis or asthma. The composite chewable tablet according to one specific embodiment employs an antihistamine agent levocetirizine as a first active ingredient to effectively reduce early responses of allergic rhinitis or asthma, and an anti-leukotriene agent montelukast as a second active ingredient for the treatment or prevention of asthma and one of the major symptoms of late allergic rhinitis, i.e., nasal obstruction.

In one specific embodiment, the composite chewable tablet may be packaged so as to be protected from light and moisture. Examples of suitable packaging materials may include foil (e.g., aluminum) pouch or sachet. The foil may be stacked with a polyester film, which protects children (from biting and tearing the package), on its outer surface. Linear low-density polyethylene film may act as a heat-sealable layer for pouch.

Another aspect provides a method of preparing the composite chewable tablet, the method including preparing a first levocetirizine tablet layer by mixing and granulating levocetirizine or the pharmaceutically acceptable salt thereof, cyclodextrin or the derivative thereof, and the alkalinizing agent; preparing a second montelukast tablet layer by granulating montelukast or the pharmaceutically acceptable salt thereof; and stacking one of the first levocetirizine tablet layer and the second montelukast tablet layer on the other of the first levocetirizine tablet layer and the second montelukast tablet layer, followed by tableting.

In one specific embodiment, the preparation method may include preparing a first levocetirizine tablet layer by dissolving levocetirizine or the pharmaceutically acceptable salt thereof, cyclodextrin or the derivative thereof, and the alkalinizing agent, mixing the solution with a pharmaceutically acceptable additive, and granulating the mixture; preparing a second montelukast tablet layer by dissolving montelukast or the pharmaceutically acceptable salt thereof, mixing the solution with a pharmaceutically acceptable additive, and granulating the mixture; and stacking one of the first levocetirizine tablet layer and the second montelukast tablet layer on the other of the first levocetirizine tablet layer and the second montelukast tablet layer, followed by tableting.

In one specific embodiment, the preparation method may include preparing a first levocetirizine tablet layer by dissolving cyclodextrin in purified water, dissolving levocetirizine or the pharmaceutically acceptable salt thereof, the alkalinizing agent, the sweetener, and the binder therein to prepare a binding solution, mixing and granulating the solution together with a pharmaceutically acceptable additive; preparing a second montelukast tablet layer by dissolving and dispersing the binder and the colorant, dissolving montelukast or the pharmaceutically acceptable salt thereof therein, and mixing and granulating the solution together with a pharmaceutically acceptable additive; and stacking one of the first levocetirizine tablet layer and the second montelukast tablet layer on the other of the first levocetirizine tablet layer and the second montelukast tablet layer, followed by tableting.

In one specific embodiment, the preparation method may further include using the flavoring agent in the preparation of the first levocetirizine tablet layer.

Reference will now be made in detail to embodiments, examples of which are illustrated in the accompanying drawings, wherein like reference numerals refer to like elements throughout. In this regard, the present embodiments may have different forms and should not be construed as being limited to the descriptions set forth herein. Accordingly, the embodiments are merely described below, by referring to the figures, to explain aspects of the present description. As used herein, the term “and/or” includes any and all combinations of one or more of the associated listed items. Expressions such as “at least one of” when preceding a list of elements, modify the entire list of elements and do not modify the individual elements of the list.

Hereinafter, the present invention will be described in more detail with reference to the following Examples. However, these Examples are for illustrative purposes only, and the scope of the present disclosure is not intended to be limited by these Examples.

Example 1: Preparation of composite formulation

Hydroxypropyl β-cyclodextrin was dissolved in purified water, and then meglumine, levocetirizine dihyhydrochloride, sucralose, and hydroxypropylcellulose were dissolved to prepare a levocetirizine binding solution. The binding solution was mixed with D-mannitol, croscarmellose sodium, and microcrystalline cellulose to form granules, which were then dried and sieved to obtain a levocetirizine granular part. The formed granules were mixed with croscarmellose sodium, sucralose, colloidal silica, and magnesium stearate to prepare a final mixture of a levocetirizine tablet part.

Further, hydroxypropylcellulose and red iron oxide were dissolved in purified water to prepare a binding solution. The binding solution was mixed with montelukast, D-mannitol, croscarmellose sodium, and microcrystalline cellulose to form granules, which were then dried and sieved to obtain a montelukast granular part. The formed granules were mixed with croscarmellose sodium, aspartame, colloidal silica, and magnesium stearate to prepare a final mixture of a montelukast tablet part.

The above two granular parts were used in respective corresponding amounts to prepare a bilayer composite tablet by using a bilayer tableting machine.

Specific components and composition of Example 1 are as shown in the following Tables 1a and 1b.

[Table 1a]

[Table 1b]

Examples 2 to 4: Preparation of composite formulations

Bilayer composite chewable tablets of Examples 2 to 4 were prepared in the same manner as in Example 1, except that the content of the alkalinizing agent of the levocetirizine tablet part was changed.

Specific components and compositions of the levocetirizine tablet parts according to Examples 2 to 4 are as shown in the following Table 2. The composition of the montelukast tablet part is as shown in the above Table 1b of Example 1.

[Table 2]

Examples 5 to 7: Preparation of composite formulations

Bilayer composite chewable tablets of Examples 5 to 7 were prepared in the same manner as in Example 1, except that the content of hydroxypropyl β-cyclodextrin of the levocetirizine tablet part was changed.

Specific components and compositions of the levocetirizine tablet parts according to Examples 5 to 7 are as shown in the following Table 3. The composition of the montelukast tablet part is as shown in the above Table 1b of Example 1.

[Table 3]

Examples 8 to 10: Preparation of composite formulations

Bilayer composite chewable tablets of Examples 8 to 10 were prepared in the same manner as in Example 1, except that the ingredient of the sweetener of the levocetirizine tablet part was changed.

Specific components and compositions of the levocetirizine tablet parts according to Examples 8 to 10 are as shown in the following Table 4. The composition of the montelukast tablet part is as shown in the above Table 1b of Example 1.

[Table 4]

Example 11: Preparation of composite formulation

A bilayer composite chewable tablet of Example 11 was prepared by preparing the montelukast tablet part and the levocetirizine tablet part using the same components and composition as in Example 1, except that strawberry flavor powder (4.5 mg) was further included as the flavoring agent of the levocetirizine tablet part such that the total weight of the components was 184.5 mg.

Examples 12 to 14: Preparation of composite formulations

Bilayer composite chewable tablets of Examples 12 to 13 were prepared in the same manner as in Example 11, except that hydroxypropyl β-cyclodextrin of the levocetirizine tablet part was changed to hydroxypropyl α, γ-cyclodextrin. Further, Example 14 was prepared by changing only the kind of the flavoring agent in Example 11.

Specific components and compositions of the levocetirizine tablet parts according to Examples 12 to 14 are as shown in the following Table 5. The composition of the montelukast tablet part is as shown in the above Table 1b of Example 1.

[Table 5]

Examples 15 to 20: Preparation of composite formulations

Bilayer composite chewable tablets of Examples 15 to 20 were prepared in the same manner as in Example 11, except that the contents of hydroxypropyl α-, β-, γ-cyclodextrin and the flavoring agent of the levocetirizine tablet part were changed.

Specific components and compositions of the levocetirizine tablet parts according to Examples 15 to 20 are as shown in the following Table 6. The composition of the montelukast tablet part is as shown in the above Table 1b of Example 1.

[Table 6]

Comparative Examples 1 to 5: Preparation of composite formulations

Bilayer composite chewable tablets of Comparative Examples 1 to 5 were prepared in the same manner as in Example 1, except that the presence or absence of the alkalinizing agent of the levocetirizine tablet part was changed or the component or content of the stabilizer or pH regulator was changed.

Specific components and compositions of the levocetirizine tablet parts according to Comparative Examples 1 to 5 are as shown in the following Table 7a.

[Table 7a]

The compositions of the montelukast tablet parts according to Comparative Examples 1 to 5 are common as shown in the following Table 7b.

[Table 7b]

Comparative Examples 6 and 7: Preparation of composite formulations

Bilayer composite chewable tablets of Comparative Examples 6 and 7 were prepared in the same manner as in Example 1, except that the content of hydroxypropyl β-cyclodextrin of the levocetirizine tablet part was changed.

Specific components and compositions of the levocetirizine tablet parts according to Comparative Examples 6 and 7 are as shown in the following Table 8. The composition of the montelukast tablet part is as shown in the above Table 7b of Comparative Example 1.

[Table 8]

Comparative Examples 8 to 10: Preparation of composite formulations

Bilayer composite chewable tablets of Comparative Examples 8 to 10 were prepared in the same manner as in Example 1, except that the component of the sweetener of the levocetirizine tablet part was changed.

Specific components and compositions of the levocetirizine tablet parts according to Comparative Examples 8 to 10 are as shown in the following Table 9. The composition of the montelukast tablet part is as shown in the above Table 7b of Comparative Example 1.

[Table 9]

Comparative Examples 11 to 13: Preparation of composite formulations

Bilayer composite chewable tablets of Comparative Examples 11 to 13 were prepared in the same manner as in Example 11, except that hydroxypropyl β-cyclodextrin was excluded from the components of the levocetirizine tablet part, or the kind and content of the flavoring agent were changed or the content of the alkalinizing agent was changed.

Specific components and compositions of the levocetirizine tablet parts according to Comparative Examples 11 to 13 are as shown in the following Table 10. The composition of the montelukast tablet part is as shown in the above Table 7b of Comparative Example 1.

[Table 10]

Comparative Examples 14 to 19: Preparation of composite formulations

Bilayer composite chewable tablets of Comparative Examples 14 to 19 were prepared in the same manner as in Example 11, except that the grade or content of hydroxypropyl cyclodextrin of the levocetirizine tablet part was changed.

Specific components and compositions of the levocetirizine tablet parts according to Comparative Examples 14 to 19 are as shown in the following Table 11. The composition of the montelukast tablet part is as shown in the above Table 7b of Comparative Example 1.

[Table 11]

Experimental Example 1: Stability Test Under Stress Storage Conditions

The bilayer composite chewable tablets of Examples 1 to 20, and Comparative Examples 1 to 19 were stored under stress conditions as follows, and then production of related compounds of levocetirizine and montelukast was evaluated under the following conditions to compare stability.

< Stress Storage Test Conditions>

Storage conditions: packaged in HDPE bottle at 60℃ and relative humidity of 75%

Test duration: Initial and 4 weeks

Analysis target: Related compounds of levocetirizine and montelukast

Column: stainless steel column with an inner diameter of about 4.6 mm and a length of about 25 cm packed with octadecyl silylated silica gel with a particle diameter of 5 μm for liquid chromatography (Symmetry Shield RP18, Waters)

Mobile phase:

A-purified water:acetonitrile:10% trifluoroacetic acid= 69:30:1(v/v/v)

B-purified water:acetonitrile:10% trifluoroacetic acid= 29:70:1(v/v/v)

[Table 12]

Detector: ultraviolet absorption spectrophotometer (measurement wavelength: 230 nm)

Flow rate: 1.0 mL/min

Column temperature: 30℃

Column: stainless steel column with an inner diameter of about 4.6 mm and a length of about 25 cm packed with diisopropyl phenethyl silica gel with a particle diameter of 5 μm for liquid chromatography (Zorbax SB-Phenyl, Agilent Zorbax)

Mobile phase:

A-0.1% trifluoroacetic acid-containing purified water

B-0.1% trifluoroacetic acid-containing acetonitrile solution

[Table 13]

Detector: ultraviolet absorption spectrophotometer (measurement wavelength: 238 nm)

Flow rate: 1.5 mL/min

Column temperature: 25℃

Changes in the content of unknown related compound of levocetirizine are shown in the following Table 14, and changes in the content of montelukast sulfoxide which is a related compound of montelukast are shown in the following Table 15.

[Table 14]

[Table 15]

As shown in Tables 14 and 15, it was confirmed that the bilayer composite chewable tablets of Examples 1 to 10 including both the alkalinizing agent and cyclodextrin satisfied related compound standards which were predetermined with respect to each of the active ingredients, under the stress conditions for 4 weeks. However, the bilayer composite chewable tablets of Comparative Examples 1 to 3 and Comparative Examples 5 to 6 including no alkalinizing agent and/or no cyclodextrin or including the alkalinizing agent and/or cyclodextrin in an amount out of the predetermined range produced about 3 times to about 10 times larger amounts of related compounds under stress storage conditions, as compared with the composite tablet formulations of Examples 1 to 10. In particular, the bilayer composite chewable tablet of Comparative Example 3 including the excessive amount of the alkalinizing agent influenced stability of montelukast to produce a relatively large amount of sulfoxide. Further, the bilayer composite chewable tablets of Comparative Examples 8 to 10 prepared by varying the kind of the sweetener showed reduced stability. These results indicate that stability of levocetirizine and montelukast in the bilayer composite chewable tablet may be improved by enclosing the active ingredient in cyclodextrin and by using the alkalinizing agent.

Further, as shown in Tables 14 and 15, it was confirmed that the bilayer composite chewable tablets of Examples 11 to 20 prepared by varying the grade and content of cyclodextrin satisfied related compound standards which were predetermined with respect to each of the active ingredients, under the stress conditions for 4 weeks. It was also confirmed that there was no difference in the stability according to addition and change of the flavoring agent. Further, the bilayer composite chewable tablets of Comparative Example 11, 14, 16, and 18 including no cyclodextrin or including cyclodextrin in a small amount out of the predetermined range, as compared with Examples, showed increased production of the related compounds under the stress conditions for 4 weeks, as compared with those of Examples. However, Comparative Examples 15, 17, and 19 including the excessive amount of cyclodextrin showed similar stability to Example 11 irrespective of the grade of cyclodextrin.

These results indicate that stability of levocetirizine and montelukast in the bilayer composite chewable tablet may be improved by enclosing the active ingredient in cyclodextrin.

Experimental Example 2: Test of Related Compound Specificity

With respect to the flavoring agents added to the bilayer composite chewable tablets of Examples 11 and 14, and Comparative Examples 12 and 13, specificity of related compounds was tested under the following analysis conditions to compare the presence or absence of peak interference. A test sample prepared by excluding the flavoring agent from the composition of Example 11 was used as a control example. The measurement results are shown in the following Table 17 and FIG. 1.

Mobile phase:

A-purified water:acetonitrile:10% trifluoroacetic acid= 69:30:1(v/v/v)

B-purified water:acetonitrile:10% trifluoroacetic acid= 29:70:1(v/v/v)

[Table 16]

Flow rate: 1.0 mL/min

Column temperature: 30℃

[Table 17]

FIG. 1 shows a specificity test under analysis conditions of levocetirizine related compounds, which was performed with respect to Examples 11 and 14, and Comparative Examples 12 and 13, each including strawberry flavor powder, cider flavor powder, cherry flavor powder, or orange flavor powder as the flavoring agent (X axis unit: time(min), Y axis unit: mAU).

As shown in Table 17 and FIG. 1, the results of comparing the test sample (Control Example) without the flavoring agent and Examples and Comparative Example including the flavoring agent showed that the strawberry flavor powder or the cider flavor powder used in Example 11 or 14 showed no particular peaks in chromatogram analysis. However, the cherry flavor powder or the orange flavor powder used in Comparative Example 12 or 13 showed peaks which overlapped with the peaks of levocetirizine related compounds. These results indicate that the cherry flavor powder or the orange flavor powder included in the composite chewable tablets causes peak interference and thus accurate analysis of related compounds is difficult. It was also confirmed that the strawberry flavor powder or the cider flavor powder is suitable as the flavoring agent for masking the bitter taste of the composite chewable tablet.

Experimental Example 3: pH measurement

Since montelukast is stable under alkaline conditions and levocetirizine is stable under acidic conditions, pH was measured for the stability test of bilayer composite tablet formulation. pH was measured with respect to the bilayer composite chewable tablets of Examples 1 to 10 and Comparative Examples 1 to 10, as dispersed in purified water. In detail, one tablet of the composite tablet was dispersed in 300 mL of purified water, and pH thereof was measured using a pH meter. The measured values are shown in the following Tables 18 and 19.

[Table 18]

[Table 19]

As shown in Tables 18 and 19, pH of the bilayer composite chewable tablet dispersions of Examples 1 to 10 was in the range from 7.0 to 8.7. It was confirmed that pH of Comparative Examples 1 to 5 prepared by varying the presence or absence, ingredient, or content of the alkalinizing agent was out of the range to which pH of Examples belonged.

Experimental Example 4: Sensory Evaluation

Thirty healthy adult males were given one dose of the bilayer composite chewable tablet (taken once a day), and the bitter taste was evaluated immediately after taking and 1 minute after taking. The taste evaluation was measured in accordance with the criteria of the following Table 20 and respective evaluation values were averaged and shown in Table 21. The results are shown in FIGS. 2 and 3.

[Table 20]

[Table 21]

As shown in Table 21 and FIG. 2, all samples of Examples including the alkalinizing agent and cyclodextrin together with the sweetener showed excellent drug compliance. However, Comparative Example 3 including the excessive amount of meglumine and Comparative Example 4 to 5 including citric acid or arginine were strongly bitter due to the bitter taste and acrid taste of the stabilizer itself. In Comparative Example 6 including the small amount of cyclodextrin, the bitter taste of levocetirizine remained intact because the amount of cyclodextrin capable of enclosing levocetirizine was small. However, Comparative Example 7 including cyclodextrin in an amount sufficient to enclose levocetirizine and the sweetener samples showed bitterness similar to those of Examples.

As shown in Table 21 and FIG. 3, there was no great difference in the sensory evaluation according to the grade of cyclodextrin, and all of them showed excellent drug compliance. Further, cherry flavor powder and orange flavor powder samples (Comparative Examples 12 and 13) showed excellent tastes. However, there was a difference in the taste evaluation according to reduction of the cyclodextrin content, which seems to be due to the lack of masking of bitter taste because of incomplete inclusion of levocetirizine which tastes bitter.

Experimental Example 5: Dissolution Test of Bilayer Composite Chewable Tablet

Examples 1 to 7 and Comparative Examples 1 to 7, and Examples 11 to 13, 16, 18 and 20, and Comparative Examples 11, 12, 15, 17, and 19 were subjected to a FDA-recommended dissolution test.

With regard to the montelukast tablet layer, 900 mL of 0.5% sodium lauryl sulfate solution was used as an eluent, and a paddle method was used at a temperature of the eluent of 37±5℃, and a stirring rate of 50 rpm. Subsequently, with regard to the levocetirizine tablet layer, 900 mL of purified water was used as an eluent, and a paddle method was used at a temperature of the eluent of 37±5℃, and a stirring rate of 50 rpm. 5, 10, 15, 20, 30, and 45 minutes after the dissolution test, 3 mL of samples were taken and equal amount of the eluent was added thereto. Then, the solutions acquired at the dissolution test were filtrated with 0.45 μm membrane filter, and dissolution rates of montelukast and levocetirizine were analyzed by liquid chromatography of the following conditions.

Instrument: HPLC (Hitachi 2000 series, Japan)

Detector: ultraviolet absorption spectrophotometer (measurement wavelength: 225 nm)

Column: stainless steel column with an inner diameter of about 4.6 mm and a length of about 15 cm packed with cyanized silica gel with a particle diameter of 5 μm for liquid chromatography (Inertsil C8, 4.6 mm X 150 mm, 5 μm)

Mobile phase: 0.025 mol/L Potassium dihydrogen phosphate solution (pH 6.6, 10 mol/L sodium hydroxide solution) : acetonitrile = 4 : 6 (v/v)

Flow rate: 1.0 mL/min.

Column temperature: 45℃

The dissolution test results of levocetirizine and montelukast which were measured under the above analysis conditions are shown in Tables 22 and 23.

[Table 22]

[Table 23]

FIG. 4 shows a dissolution rate (%) of the levocetirizine tablet layer which is the first tablet layer in each of the bilayer composite chewable tablets of Examples 1 to 7, and Comparative Examples 1 to 7 at different time points.

FIG. 5 shows a dissolution rate (%) of the montelukast tablet layer which is the second tablet layer in each of the bilayer composite chewable tablets of Examples 1 to 7, and Comparative Examples 1 to 7 at different time points.

FIG. 6 shows a dissolution rate (%) of the levocetirizine tablet layer which is the first tablet layer in each of the bilayer composite chewable tablets of Examples 11 to 13, 16, 18 and 20, and Comparative Examples 11, 12, 15, 17, and 19 at different time points.

FIG. 7 shows a dissolution rate (%) of the montelukast tablet layer which is the second tablet layer in each of the bilayer composite chewable tablets of Examples 11 to 13, 16, 18 and 20, and Comparative Examples 11, 12, 15, 17, and 19 at different time points.

As shown in the dissolution results of Tables 22 and 23 and FIGS. 4 to 7, Examples 1 to 7, Examples 11 to 13, and Examples 16, 18, and 20, and Comparative Examples 1 to 6 and Comparative Examples 11 to 12 showed similar levocetirizine dissolution rates without delay of dissolution. However, Comparative Example 7, 15, 17, and 19 including the excessive amount of cyclodextrin showed a disintegration pattern in which cyclodextrin acts as a binder, and thus the tablet core remained long during dissolution.

It should be understood that embodiments described herein should be considered in a descriptive sense only and not for purposes of limitation. Descriptions of features or aspects within each embodiment should typically be considered as available for other similar features or aspects in other embodiments.

While one or more embodiments have been described with reference to the figures, it will be understood by those of ordinary skill in the art that various changes in form and details may be made therein without departing from the spirit and scope of the disclosure as defined by the following claims.

Claims

A composite chewable tablet comprising:

a first tablet layer comprising levocetirizine or a pharmaceutically acceptable salt thereof, cyclodextrin or a derivative thereof, and an alkalinizing agent; and

a second tablet layer comprising montelukast or a pharmaceutically acceptable salt thereof.
The composite chewable tablet of claim 1, wherein the alkalinizing agent is any one selected from the group consisting of meglumine, sodium bicarbonate, sodium carbonate monohydrate, ammonia water, sodium hydroxide, sodium citrate, dried sodium carbonate, and any mixture thereof.
The composite chewable tablet of claim 2, wherein the alkalinizing agent comprises meglumine.
The composite chewable tablet of claim 1, wherein the alkalinizing agent is comprised in the first tablet layer in an amount of about 0.1% by weight to about 6.5% by weight, based on the total weight of the first tablet layer.
The composite chewable tablet of claim 1, wherein the cyclodextrin is any one selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, and any combination thereof.
The composite chewable tablet of claim 1, wherein the cyclodextrin is comprised in the first tablet layer in an amount of about 1.0 to about 3.0 equivalent weight, based on 1 equivalent weight of levocetirizine.
The composite chewable tablet of claim 1, wherein the first tablet layer further comprises a flavoring agent.
The composite chewable tablet of claim 7, wherein the flavoring agent is any one selected from the group consisting of a strawberry flavor in powder form, a cider flavor in powder form, and a combination thereof.
The composite chewable tablet of claim 1, wherein any one of the first tablet layer and the second tablet layer further comprises a pharmaceutically acceptable additive.
The composite chewable tablet of claim 9, wherein the pharmaceutically acceptable additive is selected from the group consisting of a diluent, a sweetener, a colorant, a binder, a disintegrating agent, a lubricant, and any mixture thereof.
The composite chewable tablet of claim 10, wherein the sweetener is any one selected from the group consisting of aspartame, acesulfame salt, acesulfame potassium, sucralose, neotame, cyclamate, thaumatin, LuoHan Guo extract, glycyrrhizin extract, steviten light (98% or more stevioside), steviten rich (100% enzymatically modified stevia), sugar, maltose, oligosaccharide, dextrin, invert sugar, fructose, lactose, galactose, corn syrup, maltitol, xylitol, erythritol, hydrogenated corn syrup, trehalose, and any combination thereof.
The composite chewable tablet of claim 11, wherein the sweetener is any one selected from the group consisting of acesulfame potassium, sucralose, thaumatin, steviten light (98% or more stevioside), aspartame, and any combination thereof.
The composite chewable tablet of claim 10, wherein the sweetener is comprised an amount of about 0.1% by weight to about 10% by weight, based on the total weight of the first tablet layer or the second tablet layer.
The composite chewable tablet of claim 1, wherein the composite chewable tablet is in a bilayer tablet.
The composite chewable tablet of claim 1, further comprising a coating layer.
The composite chewable tablet of claim 1, wherein a dispersion prepared by dissolving one tablet the composite chewable tablet in 300 mL of purified water has a pH of about 7.0 to about 9.0.
The composite chewable tablet of claim 1, wherein the composite chewable tablet is used for prevention or treatment of allergic rhinitis or asthma.
A method of preparing the composite chewable tablet of claim 1, the method comprising:

preparing a first levocetirizine tablet layer by mixing and granulating levocetirizine or a pharmaceutically acceptable salt thereof, cyclodextrin or a derivative thereof, and an alkalinizing agent;

preparing a second montelukast tablet layer by granulating montelukast or a pharmaceutically acceptable salt thereof; and

stacking one of the first levocetirizine tablet layer and the second montelukast tablet layer on the other of the first levocetirizine tablet layer and the second montelukast tablet layer, followed by tableting.