HK1200337B

HK1200337B - Stable pharmaceutical formulation for oral administration comprising levocetirizine or a pharmaceutically acceptable salt thereof, and montelukast or a pharmaceutically acceptable salt thereof

Info

Publication number: HK1200337B
Application number: HK15100824.5A
Authority: HK
Inventors: Taek Kwan Kwon; Dong Ho Kim; Kyeong Soo Kim; Yong Il Kim; Jae Hyun Park; Jong Soo Woo
Original assignee: Hanmi Pharm. Co., Ltd.
Priority date: 2012-01-06
Filing date: 2013-01-04
Publication date: 2018-04-20

Description

Stable pharmaceutical formulation for oral administration comprising levocetirizine or a pharmaceutically acceptable salt thereof and montelukast or a pharmaceutically acceptable salt thereof

Technical Field

The present invention relates to a pharmaceutical preparation (pharmaceutical dosage form) for oral administration for preventing or treating allergic rhinitis or asthma, which comprises: (a) a first particulate fraction comprising levocetirizine or a pharmaceutically acceptable salt thereof and an organic acid; and (b) a second particulate portion comprising montelukast or a pharmaceutically acceptable salt thereof.

Background

"allergic rhinitis" refers to a symptomatic disorder of the nose induced by IgE-mediated inflammation following allergen exposure of the nasal mucosa. Allergic rhinitis includes such symptoms as rhinorrhea, nasal obstruction, nasal itching, sneezing, ocular itching, etc.

"asthma" refers to disorders in which inflammation of the respiratory tract causes swelling of the bronchial mucosa and muscle spasms occur in the bronchi, which restrict the entry and exit of airflow in the lungs. Asthma can cause symptoms such as dyspnea, severe coughing, and in severe cases, the persistence of asthma can even lead to death.

Allergic rhinitis and asthma can develop separately, however, studies have shown that nearly 58% of patients with allergic rhinitis also suffer from asthma and 85-95% of patients with asthma also suffer from allergic rhinitis, which studies show a high incidence of complications between the two patient populations. Therefore, there is a need to develop a combination composition having improved stability and therapeutic efficacy for treating both of the conditions.

Meanwhile, cetirizine is (2- (4- ((4-chlorophenyl) phenylmethyl) -1-piperazinyl) ethoxy) acetic acid, and its levorotatory and dextrorotatory enantiomers are disclosed as "levocetirizine" and "dextrocetirizine", respectively.

Levocetirizine can be obtained by isolation from a racemic mixture of cetirizine, or by asymmetric synthesis, such as the conventional methods disclosed in british patent No. 2225321 or the enzymatic biocatalytic hydrolysis disclosed in U.S. patent nos. 4800162 and 5057427. Levocetirizine has the properties of an antihistamine and is therefore useful as an agent for antiallergic and antihistamine agents as well as anticonvulsants and bronchodilators. Similarly, levocetirizine hydrochloride has been approved for the treatment of allergic rhinitis and is commercially available in xyzal (yuhan corporation).

Montelukast is an antagonist that inhibits the cysteine leukotriene I (CysLT1) receptor, which is useful for the prevention and treatment of leukotriene-mediated diseases. In particular, montelukast has been reported to be effective in treating allergic rhinitis, atopic dermatitis, chronic urticaria, sinusitis, nasal polyps, chronic obstructive pulmonary disease, conjunctivitis, including rhinoconjunctivitis, migraine, cystic fibrosis, viral bronchiolitis, and the like [ see, e.g., s.e.dahlen, eur.j.pharmacol, 533(1-3), 40-56(2006) ]. Furthermore, cis-trinin (MSD) containing montelukast sodium is approved for more than two years for the treatment of asthma in adult and pediatric patients and is currently available on the market.

There are reports relating to pharmaceutical compositions in the form of bilayer tablets comprising montelukast sodium, which is stable under basic conditions, and levocetirizine hydrochloride, which is stable under acidic conditions. [ R.T.Rathod, J.Indian. Assic., 107(8), 562-564(2009) ]. In preparing the composition in the form of a tablet, it is difficult to completely separate montelukast and levocetirizine from each other. Even in the case of forming a bilayer tablet, it is not possible to completely separate each active ingredient mechanically. Moreover, a bi-layer tablet press is required in order to manufacture such tablets.

Furthermore, levocetirizine is also unstable in physicochemical properties and it is difficult to prepare a stable product for aging resistance. There are 3 major degradation products of levocetirizine including related substance a of formula (I), related substance B of formula (II), and related substance F of formula (III). Related substances a and B are produced by hydrolysis of levocetirizine, and related substance F is produced by side reaction of levocetirizine with excipients or release agents for hard capsules. In fact, levocetirizine shows an increased rate of formation of the related substances A, B and F under accelerated storage conditions, and thus does not readily provide stability during the manufacture of the capsule formulation.

Formula (I)

Formula (II)

Formula (III)

Montelukast is known to be unstable when exposed to light, heat, or moisture, and produces such degradation products as montelukast sulfoxide of formula (IV) and the cis isomer of montelukast of formula (V). According to the reference [ see m.m. alomari et al, j.pharm.and biomed.anal, 45, 465-471(2007) ], when a commercially available cis-tronic chewable tablet is exposed to sunlight, the amount of montelukast sulfoxide is increased by 2.4% after 3 weeks; and when montelukast in a 0.1M hydrochloric acid solution was exposed to a sodium lamp for 6h, the amount of the cis-isomer of montelukast increased by 14.6%. As reported, it is not easy to prepare a stable montelukast product that is resistant to aging.

Formula (IV)

Formula (V)

During the manufacture of hard capsules, capsule materials and excipients are used to maintain the capsule shape and make the capsule surface smooth. Examples of the capsule material include gelatin, pullulan (pullulan ), hydroxypropylmethylcellulose (hydroxypropylmethyl cellulose ), polyvinyl alcohol, and the like; and examples of the excipient include diacetylated monoglyceride, sucrose fatty acid ester, sodium lauryl sulfate and the like. Also, a releasing agent such as mineral oil, lecithin, etc. is used to easily release the capsule from a mold which forms the shape of the capsule.

The inventors of the present invention have studied a combined preparation (combined preparation) comprising levocetirizine or a pharmaceutically acceptable salt thereof and montelukast or a pharmaceutically acceptable salt thereof as active ingredients. It has been found that when levocetirizine and montelukast are prepared in separate tablets and then filled into hard capsules, the amount of the relevant substances rises more rapidly than in a composition in the form of a tablet of the active ingredient alone due to the materials from the excipients and the release agents and the moist content (moisture content) present in the capsule, and thus the stability of the active ingredient deteriorates. Accordingly, the present inventors have made an effort to solve the problems and have found that when an organic acid such as citric acid is used in a granule part containing levocetirizine, the production of levocetirizine and montelukast-related substances can be effectively inhibited and thus have good long-term storage stability even after the active ingredient is filled into a hard capsule.

Disclosure of Invention

Accordingly, it is an object of the present invention to provide a pharmaceutical formulation for oral administration comprising levocetirizine or a pharmaceutically acceptable salt thereof and montelukast and a pharmaceutically acceptable salt thereof, in which the active ingredient is filled in a hard capsule for good long-term storage stability, for the prevention or treatment of allergic rhinitis or asthma.

It is another object of the present invention to provide a process for preparing the above pharmaceutical formulation for oral administration.

According to an object of the present invention, there is provided a pharmaceutical preparation for oral administration for preventing or treating allergic rhinitis or asthma, comprising:

(a) a first particulate fraction comprising levocetirizine or a pharmaceutically acceptable salt thereof and an organic acid; and

(b) a second particulate portion comprising montelukast or a pharmaceutically acceptable salt thereof.

According to another object of the present invention, there is provided a method for preparing the pharmaceutical formulation, comprising the steps of:

(i) mixing levocetirizine or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable additive and an organic acid, and tableting the mixture, wherein the organic acid is used in an amount of 40 to 1000 parts by weight based on 100 parts of levocetirizine.

(ii) Mixing montelukast or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive and tableting the mixture; and

(iii) (iii) filling the levocetirizine tablet obtained in step (i) and the montelukast tablet obtained in step (ii) into a hard capsule.

According to still another object of the present invention, there is provided a capsule preparation prepared by the above method.

Drawings

The above and other objects and features of the present invention will become apparent from the following description of the present invention when taken in conjunction with the accompanying drawings.

Fig. 1 shows the amount of levocetirizine-related substance used for the capsule formulations obtained in examples 1 to 6 and comparative example 1 under accelerated storage conditions (40 ℃/75% RH) for 6 months;

fig. 2 shows the amounts of montelukast-related substances for the capsule formulations obtained in examples 1 to 6 and comparative example 1 under accelerated storage conditions (40 ℃/75% RH) for 6 months;

fig. 3 shows a schematic view of a capsule formulation of the present invention.

Detailed Description

The present invention will be described in detail below.

The present invention provides a pharmaceutical formulation for preventing or treating allergic rhinitis or asthma, which comprises (a) a first granule part comprising levocetirizine or a pharmaceutically acceptable salt thereof; and (b) a second particulate portion comprising montelukast or a pharmaceutically acceptable salt thereof.

The pharmaceutical formulation of the present invention uses an antihistamine agent, levocetirizine, as a first active ingredient to reduce early allergic rhinitis and asthma reactions, and an anti-leukotriene agent, montelukast, as a second active ingredient to treat and prevent one of the major symptoms of late rhinitis, i.e., nasal congestion and asthma.

Levocetirizine or a pharmaceutically acceptable salt thereof contained in the first granule portion in the present invention is disclosed in, for example, european patent application nos. 0058146, 0601028 and 0801064, british patent nos. 2225320 and 2225321, U.S. patent No. 5478941, and international patent publication No. WO 97/37982. Pharmaceutically acceptable salts of levocetirizine may include, but are not limited to, pharmaceutically acceptable non-toxic acid addition salts of organic or inorganic acids, such as salts of acetic, citric, maleic, succinic, ascorbic, hydrochloric, hydrobromic, sulfuric, phosphoric, and the like; metal salts (e.g., sodium or potassium salts), ammonium salts, amine salts, and amino acid salts, preferably levocetirizine dihydrochloride. The daily dose of levocetirizine or a pharmaceutically acceptable salt thereof is 0.4 to 100mg, preferably 1 to 50mg, more preferably 2.5 to 20mg per unit dosage form.

The montelukast or pharmaceutically acceptable salt thereof contained in the second granule part in the present invention is preferably montelukast sodium. The daily dose of montelukast or its pharmaceutically acceptable salts is 0.4 to 100mg, preferably 1 to 50mg, more preferably 2.5 to 20mg per unit dosage form.

The pharmaceutical preparation of the present invention comprises an organic acid as a stabilizer in an amount of 40 to 1000 parts by weight, preferably 50 to 500 parts by weight, based on 100 parts of levocetirizine.

The organic acid can reduce the production of the produced levocetirizine-related substance and montelukast-related substance due to excipients and release agents of the capsule. If the amount of the organic acid is less than 40 parts by weight, the effect on the stability of levocetirizine and montelukast becomes insignificant; meanwhile, when administered to the body, an amount of organic acid exceeding 1000 parts by weight may cause irritation and unnecessary organic acid may be inhaled into the body system.

Examples of the organic acid may be selected from the group consisting of: citric acid, tartaric acid, succinic acid, glutamic acid, aspartic acid, oxalic acid, malic acid, acetic acid, sorbic acid, ascorbic acid, alginic acid, fumaric acid, lactic acid, and mixtures thereof.

The pharmaceutical formulation of the present invention may be prepared in the form of an oral solid pharmaceutical formulation selected from the group consisting of powder, granules, pellets, tablets and capsules, preferably in the form of capsules.

In one embodiment of the present invention, the pharmaceutical formulation of the present invention is a capsule formulation comprising (a) a first particulate fraction comprising levocetirizine or a pharmaceutically acceptable salt thereof and an organic acid; and (b) a second granular portion comprising montelukast or a pharmaceutically acceptable salt thereof, wherein the granular portions are physically filled separately and into a capsule.

The first or second particulate fraction may be in the form of a tablet, preferably a mini-tablet.

The first or second particulate fraction may each further comprise a pharmaceutically acceptable additive. The pharmaceutically acceptable additive may be selected from the group consisting of: diluents, disintegrants, binders, lubricants, and mixtures thereof.

Suitable examples of the diluent may include microcrystalline cellulose, lactose, ludipress, mannitol, monocalcium phosphate, starch, low-substituted hydroxypropylcellulose, and a mixture thereof. The diluent may be used in an amount ranging from 1 to 99% by weight, preferably 5 to 95% by weight, based on the total weight of the tablet.

Examples of disintegrants may include any material that exhibits stable disintegration in a liquid environment selected from the group consisting of: crospovidone, sodium starch glycolate, croscarmellose sodium, low substituted hydroxypropyl cellulose, starch, alginates or sodium salts thereof, and mixtures thereof. Preferably, the disintegrant may be crospovidone, sodium starch glycolate, croscarmellose sodium, low substituted hydroxypropylcellulose, or a mixture thereof. The amount of the disintegrant may range from 1 to 30% by weight, preferably 2 to 20% by weight, based on the total weight of the tablet.

Examples of the binder may include hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, copovidone, polyethylene glycol, light anhydrous silicic acid, synthetic aluminum silicate, silicate derivatives such as calcium silicate or magnesium silicate, phosphates such as calcium hydrogen phosphate, carbonates such as calcium carbonate, and mixtures thereof. The binder may be used in an amount ranging from 1 to 30% by weight, preferably 2 to 20% by weight, based on the total weight of the tablet.

Examples of the lubricant may include stearic acid, metal salts of stearic acid, such as calcium stearate or magnesium stearate, talc, colloidal silicon dioxide, sucrose fatty acid esters, hydrogenated vegetable oils, high melting point waxes, glycerin fatty acid esters, glycerin behenate, and mixtures thereof. The lubricant may be used in an amount ranging from 0.3 to 5% by weight, preferably 0.5 to 3% by weight, based on the total weight of the tablet.

In addition, each tablet comprising the first or second particle fraction may further comprise a coating layer. The coating layer may be formed on at least one surface selected from the tablet to completely separate montelukast and levocetirizine.

In the present invention, the coating substrate for the coating layer may be a conventional polymer compound. Examples of the coating base may include hydroxypropylmethylcellulose (hypromellose), hydroxypropylcellulose, methylcellulose, ethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, hydroxyethylcellulose, but are not limited thereto. The amount of the coating base is preferably maintained at a minimum to improve manufacturing efficiency and provide a formulation of optimal size for administration. Thus, the amount of the coating base may range from 0.5 to 50% by weight, preferably 1 to 10% by weight, based on the total weight of the tablet.

In the capsule formulation of the present invention, the capsule may be any conventional hard capsule, which is generally used for the preparation of a medicament. For the hairSaid hard capsule matrix of the invention may be selected from the group consisting of: gelatin, pullulan (NPcaps)^TMEtc.; capsugel), hydroxypropyl methylcellulose, and polyvinyl alcohol.

In the present invention, the hard capsule may have any conventional capsule size used for pharmaceutical preparation. The internal volume of the hard capsules varies with their size: no.00(0.95mL), No.0(0.68mL), No.1(0.47mL), No.2(0.37mL), No.3(0.27mL) and No.4(0.20mL) (Suheung Capsule Co, Korea). The size of the capsule may preferably be small for the convenience of the patient; however, the size of the capsule used in the present invention may include No.0, No.1, No.2, No.3, and No.4, preferably No.1, No.2, and No.3, due to the mass limitation of the contents filled into the capsule.

The pharmaceutical formulation of the present invention may be used for preventing or treating allergic rhinitis or asthma, and the allergic rhinitis may be selected from the group consisting of symptoms such as rhinorrhea, nasal obstruction, nasal itching, sneezing, and ocular itching.

Furthermore, the present invention provides a process for the preparation of a pharmaceutical formulation comprising the steps of: (i) mixing levocetirizine or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable additive and an organic acid, and tableting the mixture, wherein the organic acid is used in an amount of 40 to 1000 parts by weight based on 100 parts of levocetirizine. (ii) Mixing montelukast or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive and tableting the mixture; and (iii) filling the levocetirizine tablet obtained in step (i) and the montelukast tablet obtained in step (ii) into a hard capsule.

The method may further comprise the step of coating the tablets produced in step (i) or (ii). The capsule preparation prepared in the present invention may be administered by oral route and the like.

Further, the present invention provides a capsule preparation prepared by the above method.

The capsule formulation of the present invention comprises montelukast and levocetirizine physically separated in the hard capsule, and thus completely separates the two total active ingredients. Thus, reactivity between the two active ingredients can be minimized and the stability of the formulation enhanced, thereby optimizing therapeutic efficacy. It is also advantageous that pre-existing analytical methods for the evaluation of the time-independent stability of a single formulation can also be used for the formulation of the invention, instead of developing new analytical methods. Furthermore, the organic acid contained in the first granule fraction may not only enhance the stability of levocetirizine but also stabilize montelukast.

The following examples are intended to further illustrate the invention without limiting its scope.

Example 1: preparation of Combined preparation I

Levocetirizine hydrochloride, ludipress (basf), microcrystalline cellulose, citric acid, croscarmellose sodium, light anhydrous silicic acid and magnesium stearate were sieved and mixed, and the mixture was compressed into tablets using a circular punch having a diameter of 5.5mm to obtain levocetirizine tablets. The levocetirizine tablets were then coated with a coating solution prepared by dissolving Opadry White (Y-1-7000, Colorcon) in distilled water.

Meanwhile, montelukast sodium, D-mannitol, microcrystalline cellulose, light anhydrous silicic acid, hydroxypropylcellulose, sodium starch glycolate and magnesium stearate were sieved and mixed, and the mixture was compressed into tablets using a circular punch having a diameter of 5.5mm to obtain montelukast tablets. Then, the montelukast tablet is coated with a coating solution prepared by dissolving hydroxypropylmethylcellulose, hydroxypropylcellulose, titanium dioxide, yellow iron oxide, red iron oxide in distilled water.

Finally, the two tablets thus obtained were filled into a No.1 hard capsule mainly composed of gelatin to obtain a capsule formulation comprising 10mg of montelukast and 5mg of levocetirizine.

Example 2: preparation of Combined preparation II

The procedure of example 1 was repeated except that a hard capsule mainly composed of pullulan was used to obtain a capsule formulation comprising 10mg of montelukast sodium and 5mg of levocetirizine.

Example 3: preparation of Combined preparation III

The procedure of example 1 was repeated except that a hard capsule mainly composed of hydroxypropylmethylcellulose was used to obtain a capsule formulation comprising 10mg of montelukast sodium and 5mg of levocetirizine.

Example 4: preparation of Combined preparation IV

Levocetirizine hydrochloride, ludipress, microcrystalline cellulose, tartaric acid, croscarmellose sodium, light anhydrous silicic acid, and magnesium stearate were sieved and mixed, and the mixture was compressed into tablets using a circular punch having a diameter of 5.5mm to obtain levocetirizine tablets. The levocetirizine tablets were then coated with a coating solution prepared by dissolving Opadry White (Y-1-7000) in distilled water.

Example 5: preparation of Combined preparation V

Levocetirizine hydrochloride, ludipress, microcrystalline cellulose, succinic acid, croscarmellose sodium, light anhydrous silicic acid, and magnesium stearate were sieved and mixed, and the mixture was compressed into tablets using a circular punch having a diameter of 5.5mm to obtain levocetirizine tablets. The levocetirizine tablets were then coated with a coating solution prepared by dissolving Opadry White (Y-1-7000) in distilled water.

Example 6: preparation of Combined preparation VI

Levocetirizine hydrochloride, ludipress, microcrystalline cellulose, ascorbic acid, croscarmellose sodium, light anhydrous silicic acid and magnesium stearate were sieved and mixed, and the mixture was compressed into tablets using a circular punch having a diameter of 5.5mm to obtain levocetirizine tablets. The levocetirizine tablets were then coated with a coating solution prepared by dissolving Opadry White (Y-1-7000) in distilled water.

Comparative example 1: preparation of Combined preparation VII

Levocetirizine hydrochloride, ludipress, microcrystalline cellulose, croscarmellose sodium, light anhydrous silicic acid, and magnesium stearate were sieved and mixed, and the mixture was compressed into tablets using a circular punch having a diameter of 5.5mm to obtain levocetirizine tablets. The levocetirizine tablets were then coated with a coating solution prepared by dissolving Opadry White (Y-1-7000) in distilled water.

Comparative example 2: preparation of Combined preparation VIII

The procedure of comparative example 1 was repeated except that a hard capsule mainly composed of pullulan was used to obtain a capsule formulation comprising 10mg of montelukast sodium and 5mg of levocetirizine.

Comparative example 3: preparation of combination preparation IX

The procedure of comparative example 1 was repeated except that a hard capsule mainly composed of hydroxypropylmethylcellulose was used to obtain a capsule formulation comprising 10mg of montelukast sodium and 5mg of levocetirizine.

Comparative example 4: preparation of Combined preparation X

Levocetirizine hydrochloride, ludipress, microcrystalline cellulose, croscarmellose sodium, light anhydrous silicic acid, and magnesium stearate were sieved and mixed, and phosphoric acid was added, and the mixture was compressed into tablets using a circular punch having a diameter of 5.5mm to obtain levocetirizine tablets. The levocetirizine tablets were then coated with a coating solution prepared by dissolving Opadry White (Y-1-7000) in distilled water.

Comparative example 5: preparation of Combined preparation XI

Levocetirizine hydrochloride, ludipress, microcrystalline cellulose, sodium hydroxide, croscarmellose sodium, light anhydrous silicic acid, and magnesium stearate were sieved and mixed, and the mixture was compressed into tablets using a circular punch having a diameter of 5.5mm to obtain levocetirizine tablets. The levocetirizine tablets were then coated with a coating solution prepared by dissolving Opadry White (Y-1-7000) in distilled water.

Comparative example 6: preparation of levocetirizine tablets (single tablets)

Experimental example 1: stability testing under accelerated conditions

The combined capsule formulation comprising levocetirizine and montelukast prepared in examples 1 to 6 and comparative examples 1 to 5 and a single tablet of levocetirizine prepared in comparative example 6 was stored under the following accelerated storage conditions. The amounts of the related substances (impurities) of levocetirizine and montelukast were determined to compare the stability of the formulations. The results are shown in tables 3 and 4 and fig. 1 and 2.

< accelerated storage conditions >

Storage conditions were as follows: including HDPE bottles at 40 ℃, 75% RH.

Duration of the test: initial and 6 months

Analyzing a target: levocetirizine and levocetirizine related substances, and montelukast related substances.

Column: a Symmetry Shield RP18 column with a stainless tube (4.6mm inner diameter. times.25 cm length) was packed with octadecylsilyl silica gel (particle size: 5 μm) for HPLC (Waters).

And (3) eluate: A-Distilled Water (DW) acetonitrile 10% trifluoroacetic acid (TFA) 69:30:1(v/v/v)

B-DW acetonitrile 10% TFA 29:70:1(v/v/v)

[ Table 1]

Washing out conditions

Time (min)	A(％)	B(％)
			0	100	0
2	100	0
			30	25	75
40	100	0
			50	100	0

A detector: UV-absorption detector (absorption at 230 nm)

Flow rate: 1.2mL/min

Column temperature: 30 deg.C

Column: a Zorbax SB-Phenyl column (Agilent Zorbax) with a stainless tube (4.6mm internal diameter. times.25 cm length) was packed with diisopropylphenethyl silica gel (particle size: 5 μm) for HPLC (Waters).

And (3) eluate: a-distilled water containing 0.1% TFA

B-acetonitrile containing 0.1% TFA

[ Table 2]

Washing out conditions

Time (min)	A(％)	B(％)
			0	60	40
20	10	90
			30	10	90
31	60	40
			35	60	40

A detector: UV-absorption detector (absorption at 230 nm)

Flow rate: 1.5mL/min

Column temperature: 25 deg.C

The change in the content of levocetirizine-related substance A, B, F is shown in table 3, and the change in the montelukast-related substances, i.e., montelukast sulfoxide and montelukast cis-isomer, is shown in table 4.

[ Table 3]

Changes in levocetirizine related substances

[ Table 4]

Changes in Montelukast related substances

As shown in tables 3 and 4 and fig. 1 and 2, the combined capsule formulation of levocetirizine and montelukast using an organic acid as a stabilizer according to examples 1 to 6 and the single tablet according to comparative example 6 resulted in no significant change after 6 months under the accelerated storage conditions and thus exhibited particularly good storage stability.

In contrast, the combined capsule formulation of levocetirizine and montelukast having no organic acids according to comparative examples 1 to 3 showed an increase of related substances by nearly 2 to 10 times, compared to the inventive capsule formulations of examples 1 to 6, after 6 months under accelerated storage conditions. And, the combined capsule formulation comprising inorganic acid, comparative example 4, and the basifying agent, comparative example 5, exhibited increased levels of the related substances, compared to the sample comprising organic acid. In particular, it is evident that the samples with organic acids according to examples 1 to 6 only allow negligible amounts of the levocetirizine related substance F compared to the other samples. Accordingly, it has been found that an organic acid as a stabilizer can be added to the capsule formulation comprising levocetirizine and montelukast for improving the overall stability of the formulation.

Although the invention has been described with respect to the specific embodiments described above, it will be appreciated that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.

Claims

1. A pharmaceutical formulation for oral administration for preventing or treating allergic rhinitis or asthma, comprising:

(a) a first particulate fraction comprising levocetirizine, or a pharmaceutically acceptable salt thereof, and an organic acid selected from the group consisting of: citric acid, tartaric acid, succinic acid, and ascorbic acid; and

(b) a second particulate portion comprising montelukast or a pharmaceutically acceptable salt thereof,

wherein the formulation is a capsule formulation in which,

the first and second particulate portions are physically separated in the capsule; and is

The pharmaceutical formulation comprises the organic acid in an amount of 50 to 500 parts by weight, based on 100 parts of levocetirizine or a pharmaceutically acceptable salt thereof;

wherein the capsule is a hard capsule,

wherein the capsule is made of a material selected from the group consisting of gelatin, pullulan, and hydroxypropylmethylcellulose.

2. The pharmaceutical formulation for oral administration of claim 1, wherein the first or second particulate fraction is in the form of a mini-tablet.

3. The pharmaceutical formulation for oral administration of claim 1, wherein said first and second particulate portions each independently further comprise a pharmaceutically acceptable additive selected from the group consisting of diluents, disintegrants, binders, lubricants and mixtures thereof.

4. The pharmaceutical formulation for oral administration of claim 2, wherein said mini-tablet further comprises a coating layer.

5. The pharmaceutical formulation for oral administration of claim 1, wherein said allergic rhinitis is selected from the group consisting of rhinorrhea, nasal obstruction, nasal itching, sneezing and ocular itching.

6. A method for preparing a capsule formulation, the method comprising the steps of:

(i) mixing levocetirizine or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable additive and an organic acid in an amount of 50 to 500 parts by weight based on 100 parts of levocetirizine or a pharmaceutically acceptable salt thereof, and tableting the mixture,

wherein the organic acid is selected from the group consisting of: citric acid, tartaric acid, succinic acid, and ascorbic acid;

(iii) (iii) filling the levocetirizine tablet obtained in step (i) and the montelukast tablet obtained in step (ii) into a hard capsule,

7. The method of claim 6, further comprising coating the tablet prepared in step (i) or (ii).

8. A capsule formulation prepared by the method of claim 6.