WO2013154347A1

WO2013154347A1 - Liquid formulation for oral administration comprising ambroxol, levodropropizine and buffering agent, and method for preparing the same

Info

Publication number: WO2013154347A1
Application number: PCT/KR2013/002999
Authority: WO
Inventors: Yong Il Kim; Jin Cheul Kim; Jae Ho Kim; Yo Han Kim; Jae Hyun Park; Jong Soo Woo
Original assignee: Hanmi Pharm. Co., Ltd.
Priority date: 2012-04-10
Filing date: 2013-04-10
Publication date: 2013-10-17
Also published as: KR20130114948A; TW201345563A; TWI589305B; KR101915056B1

Abstract

A liquid formulation for oral administration comprising ambroxol, levodropropizine and a buffering agent, and a method for preparing such formulation are provided. This liquid formulation shows enhanced storage stability over time and improved patient compliance, and thus can be safely used for the treatment of acute and chronic cough.

Description

DESCRIPTION

LIQUID FORMULATION FOR ORAL ADMINISTRATION COMPRISING AMBROXOL, LEVODROPROPIZINE AND BUFFERING AGENT, AND METHOD FOR PREPARING THE

SAME

FIELD OF THE INVENTION

The present invention relates to a liquid formulation for oral administration comprising ambroxol, levodropropizine and a buffering agent, and a method for preparing the same.

BACKGROUND OF THE INVENTION

Ambroxol, as shown below, is a compound clinically proven to be effective in the treatment of acute and chronic respiratory diseases associated with viscid or excessive mucus, e.g., acute and chronic bronchitis, asthmatic bronchitis, sinusitis, rhinitis sicca, and the like, and is currently available under the brand names Mucopect (Boehringer Ingelheim) and Wooridul Ambroxol Syr. (Wooridul Pharm):

Ambroxol is a metabolite of bromhexine which stimulates mucus secretion and promotes a normalization of mucus viscosity. In recent studies, ambroxol is shown to have secretolytic activity, anti-inflammatory and antioxidant activity, a local anaesthetic effect, etc. (Malerba M. et al., Expert Opin Drug Metab Toxicol, 2008 Aug, 4(8): 1 1 19-29). Also, ambroxol is used for the treatment of acute sore throat owing to its analgesic effect, and it is generally prepared into a syrup formulation so that it acts fast and has a long lasting analgesic effect of at least 3 hours (de Mey C. et al., Arzneimittelforschung., 2008, 58(1 1): 557-558). In 4 out of 5 studies, groups administered with a syrup formulation containing 20 mg of ambroxol showed a significant reduction in pain, as well as fast (30 minutes after the administration) and a long lasting analgesic effect (at least 3 hours).

Levodropropizine, as shown below, is the levo isomer of dropropizine as an antitussive that peripherally suppresses afferent pathway related with the cough reflex:

Levodropropizine only acts in the peripheral nervous system with no action in the central nervous system, and hence, it has differentiated mechanism causing no side effects such as constipation or respiratory depression which can be produced by opioid antitussives such as codeine and the like. Also, it demonstrates significantly reduced occurrence of central nervous system adverse effect (drowsiness); suppresses inflammation, bronchoconstriction, and mucus hypersecretion; and is also known as a safe drug because it does not interact with other drugs such as beta blockers, methylxanthines, mucoregulators, corticosteroids, antibiotics, antihistamines, etc. In Korea, levodropropizine is currently available under the brand names Levotuss by Hyundai Pharm., Lebrocol Syr. by Hamni Pharm Co., Ltd., and other 17 other syrup preparations, and is used for the treatment of cough caused by acute and chronic bronchitis. Thus, an enhancement effect can be expected by developing a complex liquid formulation using ambroxol, which can reduce viscosity and show expectorant activity, and levodropropizine, a peripheral antitussive. Accordingly, there have been a number of cases where ambroxol and levodropropizine were prescribed in a combination formulation. However, each said syrup preparation had to be taken three times a day, and thus, there has been an inconvenience that patients were required to take a relatively large amount of syrup per dose.

The present inventors have endeavored to develop a complex liquid formulation comprising ambroxol and levodropropizine having the same efficacy even in a small quantity, e.g., 10 mL or less, for improving patient compliance. However, there have been found that when said two ingredients exist in a liquid formulation together, an increase in the amount of related substances of ambroxol and levodropropizine was observed.

Impurities in drug substance may cause adverse side effects in a patient, and hence the purity of an active ingredient is one of the most important factors in providing safe and effective pharmaceutical formulation. Such impurities not only include compounds which can be completely removed during the manufacturing process of the active ingredients, but also the breakdown products which can be produced by various environmental factors, e.g., temperature, moisture, and light, even after the final product was prepared.

Therefore, the present inventors have studied on the factors that promote the production of related substances when liquid formulation comprising ambroxol and levodropropizine is in a stored condition; and have found that the stability of the active ingredient in an aqueous solution can only be secured in a specific pH condition. Thus, the present invention is accomplished by using a buffering agent to regulate the pH condition of the formulation.

SUMMARY OF THE INVENTION

Therefore, it is an object of the present invention to provide a liquid formulation for oral administration comprising ambroxol or a pharmaceutically acceptable salt thereof, and levodropropizine or a pharmaceutically acceptable salt thereof having improved stability.

It is further object of the present invention to provide a method for preparing the liquid formulation for oral administration.

In accordance with one aspect of the present invention, there is provided a liquid formulation for oral administration comprising ambroxol or a pharmaceutically acceptable salt thereof, levodropropizine or a pharmaceutically acceptable salt thereof, and a buffering agent in an aqueous medium having a pH value of 4.5 to 5.5.

In accordance with another aspect of the present invention, there is provided a method for preparing the liquid formulation for oral administration, which comprises the steps of:

(1) dissolving a pharmaceutically acceptable excipient in an aqueous medium;

(2) adjusting the pH of the mixture prepared in step (1) to a pH in the range of 4.5 to 5.5 by using a buffering agent;

(3) dissolving ambroxol or a pharmaceutically acceptable salt thereof, and levodropropizine or a pharmaceutically acceptable salt thereof in the mixture prepared in step (2); and

(4) adding an aqueous medium to the mixture prepared in step (3).

The liquid formulation of the present invention prepared by employing ambroxol and levodropropizine having different drug action mechanisms shows improved patient compliance and enhanced storage stability over time, and thus can be safely used for the treatment of acute and chronic cough.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is the result of stability test of the inventive liquid formulation at 60 °C according to its pH value, showing the maximum amount of unknown related substances of ambroxol hydrochloride produced.

FIG. 2 is the result of stability test of the inventive liquid formulation at 60 °C according to its pH value, showing the maximum amount of unknown related substances of levodropropizine produced.

DETAILED DESCRIPTION OF THE INVENTION Embodiments of the present invention are explained in detail hereinafter.

The present invention provides a liquid formulation for oral administration having a pH value of 4.5 to 5.5 comprising ambroxol or a pharmaceutically acceptable salt thereof, levodropropizine or a pharmaceutically acceptable salt thereof, and a buffering agent in an aqueous medium.

The present invention is characterized in adjusting the pH of the liquid formulation to 4.5-5.5 by using a buffering agent in the preparation of the complex liquid formulation comprising ambroxol and levodropropizine. In the said range, the production of unknown substances that are derived from ambroxol and levodropropizine can be inhibited effectively, and thereby improving the storage stability significantly.

The pharmaceutically acceptable salt in accordance with the present invention includes any salt prepared by conventional methods known in the art. Examples of such salts are acid addition salts formed by inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, nitric acid, carbonic acid, and the like; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gentisic acid, fumaric acid, lactobionic acid, salicylic acid, acetylsalicylic (aspirin), and the like; amino acid such as glycine, alanine, valine, isoleucine, serine, cysteine, cystine, aspartate, glutamine, lysine, arginine, tyrosine and proline; sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, and the like; metal salts formed by alkali metals such as sodium, potassium, and the like; and a salt formed by an ammonium ion and the like.

In the present invention, active ingredients employed are ambroxol or a pharmaceutically acceptable salt thereof, and levodropropizine or a pharmaceutically acceptable salt thereof, preferably ambroxol hydrochloride and levodropropizine, respectively.

In one embodiment of the present invention, the formulation comprises ambroxol or a pharmaceutically acceptable salt thereof in an amount of 100 mg to 1,000 mg (e.g., 300 mg) per 100 mL of the liquid formulation, and levodropropizine or a pharmaceutically acceptable salt thereof in an amount of 300 mg to 1 ,500 mg (e.g., 600 mg) per 100 mL of the liquid formulation.

In the present invention, the buffering agent is employed in an amount for adjusting the pH of the liquid formulation to 4.5 ~ 5.5. In one embodiment of the present invention, the formulation comprises the buffering agent in an amount of 100 mg to 1,000 mg (e.g., 300 mg to 600 mg) per 100 mL of the liquid formulation.

The buffering agent in the present invention is selected from the group consisting of citric acid, sodium citrate hydrate, potassium citrate, acetic acid, sodium acetate, sodium carbonate, calcium carbonate, calcium phosphate tribasic, calcium lactate, glycine, maleic acid, malic acid, sodium glutamate, monosodium glutamate, sodium lactate, sodium phosphate and a mixture thereof.

In the present invention, the buffering agent is preferably selected from the group consisting of citric acid, sodium citrate hydrate, potassium citrate, acetic acid, sodium acetate, malic acid, sodium glutamate, glycine, sodium carbonate, maleic acid, sodium lactate and a mixture thereof; more preferably selected from the group consisting of a mixture of citric acid and sodium citrate hydrate, a mixture of citric acid and potassium citrate, a mixture of acetic acid and sodium acetate, a mixture of malic acid and sodium glutamate, a mixture of glycine and sodium carbonate, and a mixture of maleic acid and sodium lactate; and most preferably a mixture of citric acid and sodium citrate hydrate.

In the present invention, the aqueous medium is selected from the group consisting of purified water, ethanol and a mixture thereof, preferably purified water. The liquid formulation in accordance with the present invention may further comprise a pharmaceutically acceptable excipient, and the pharmaceutically acceptable excipient is selected from the group consisting of antioxidants, sweetening agents, preservatives, viscosity modifying agents and a mixture thereof.

The antioxidant of the present invention is selected from the group consisting of sodium pyrosulfite, ascorbic acid, erythorbic acid and a mixture thereof. The amount of the antioxidant is employed in an amount of 0.1 to 100 mg, preferably 1 to 10 mg per 100 mL of the liquid formulation.

The sweetening agent of the present invention is selected from the group consisting of white sugar, potassium acesulfame, saccharine, dextrose and a mixture thereof. The amount of the sweetening agent is employed in an amount of 5 to 100,000 mg, preferably 10 to 50,000 mg per 100 mL of the liquid formulation.

The preservative of the present invention is selected from the group consisting of methyl paraoxybenzoic acid, ethyl paraoxybenzoic acid, isopropyl paraoxybenzoic acid, sorbic acid, potassium sorbate, sodium sorbate and a mixture thereof. The amount of the preservative is employed in an amount of 5 to 200 mg, preferably 10 to 100 mg per 100 mL of the liquid formulation.

The viscosity modifying agent of the present invention is selected from the group consisting of concentrated glycerin, polyvinylpyrrolidone, ethyl cellulose, sodium carboxymethylcellulose and a mixture thereof. The amount of the viscosity modifying agent is employed in an amount of 100 to 20,000 mg, preferably 200 to 10,000 mg per 100 mL of the liquid formulation. The liquid formulation in accordance with the present invention is used for prevention or treatment of acute and chronic respiratory diseases selected from the group consisting of acute and chronic bronchitis, asthmatic bronchitis, sinusitis, rhinitis sicca and acute sore throat. The present invention provides a method for preparing the liquid formulation for oral administration, which comprises the steps of: (1) dissolving a pharmaceutically acceptable excipient in an aqueous medium; (2) adjusting the pH of the mixture prepared in step (1) to 4.5 to 5.5 by using a buffering agent; (3) dissolving ambroxol or a pharmaceutically acceptable salt thereof, and levodropropizine or a pharmaceutically acceptable salt thereof in the mixture prepared in step (2); and (4) adding an aqueous medium to the mixture prepared in step (3).

The complex liquid formulation prepared in accordance with the present invention employs ambroxol and levodropropizine having different drug action mechanisms in one liquid formulation, and thus reduces the dose required and improves patient compliance by increasing patient convenience. In addition, the production of unknown substances that is derived from ambroxol and levodropropizine can be inhibited effectively by adjusting the pH value in the range of 4.5 to 5.5, and thereby improving the storage stability of the liquid formulation. Therefore, the liquid formulation prepared in accordance with the present invention is effective even in a small quantity, e.g., 10 mL or less, and useful for prevention or treatment of acute and chronic respiratory diseases.

Hereinafter, the present invention is described more specifically by the following examples, but these are provided only for illustration purposes and the present invention is not limited thereto.

Examples 1 to 3: Preparation of liquid formulations In accordance with the composition and the amount (mg/100 mL) described in Table 1 below, liquid formulations of Examples 1 to 3 were prepared by using ambroxol hydrochloride (Hwail Pharm., Korea) and levodropropizine (Sungwoo Chemical, Korea), concentrated glycerin (Seojin Chemical), white sugar (CheilJedang), D-sorbitol solution (Roquette), potassium acesulfame (Nutrinova), sodium pyrosulfite (Riedel-de Haen), citric acid (DSM Nutritional), sodium citrate hydrate (Jungbunzlauer), paraoxybenzoic acid methyl (Sanfu Chemical), and paraoxybenzoic acid propyl (Sanfu Chemical).

Specifically, purified water, paraoxybenzoic acid methyl, paraoxybenzoic acid propyl, potassium acesulfame and sodium pyrosulfite were placed in a manufacturing tank, and the mixture was completely dissolved by stirring for 30 min at 95 °C to completely dissolve the mixture. The resulting solution was cooled down to 50 °C, added with white sugar, D-sorbitol solution, citric acid and sodium citrate hydrate sequentially, and stirred for 60 min to completely dissolve the mixture. The pH value of each solution was adjusted according to Table 1 below. The temperature of the manufacturing tank was lowered to 35 to 40 °C, and ambroxol hydrochloride and levodropropizine were added thereto, followed by stirring to completely dissolve the mixture. The temperature of the manufacturing tank was lowered to 30 °C or less, and sterile purified water at room temperature was added to bring the level to a meniscus, followed by stirring for 20 min. The final mixture was filtered through a 1 μιη filter, and stored in a storage tank or a suitable container.

[Table 1]

Paraoxybenzoic acid methyl 80 80 80

Paraoxybenzoic acid propyl 16 16 16

Citric acid 300 320 300

Sodium citrate hydrate 110 0 230

purified water a.a a.a a.a

pH 5.0 4.5 5.5

* a.a: appropriate amount

Comparative Examples 1 to 3: Preparation of liquid formulations In accordance with the composition and the amount (mg/100 mL) described in Table 2 below, liquid formulations of Comparative Examples 1 to 3 were prepared by repeating the procedures of Example 1, using ambroxol hydrochloride and levodropropizine, concentrated glycerin, white sugar, D-sorbitol solution, potassium acesulfame, sodium pyrosulfite, citric acid, sodium citrate hydrate, paraoxybenzoic acid methyl, and paraoxybenzoic acid propyl.

[Table 2]

* a.a: appropriate amount Examples 4 to 8: Preparation of liquid formulations In accordance with the composition and the amount (mg/100 mL) described in Table 3 below, Liquid formulations of Examples 4 to 8 were prepared by repeating the procedures of Example 1 , using ambroxol hydrochloride and levodropropizine, concentrated glycerin, white sugar, D-sorbitol solution, potassium acesulfame, sodium pyrosulfite, paraoxybenzoic acid methyl, paraoxybenzoic acid propyl and a buffer.

[Table 3]

* a.a: appropriate amount

Test Example: Evaluation of the related substance produced

A test was performed on the liquid formulations prepared in Exampli and Comparative Examples 1 to 3 in order to evaluate storage stability over time.

Specifically, each liquid formulation was contained in a HDPE bottle, and stored in a chamber under accelerated conditions at 60 °C. After 4 weeks later, the maximum amounts of unknown related substances of ambroxol hydrochloride and levodropropizine from each breakdown products thereof were evaluated according to the following condition using HPLC method. The results are shown in Tables 4 and 5, and Figs. 1 and 2.

Absorbance: 248 nm

Column: stainless steel column (inner diameter: approximately 4.6 mm; length: approximately 250 mm) packed with 5 μηι CI 8

Eluents: Acetonitrile and phosphate buffer (5 : 5 (v/v%))

Absorbance: 254 nm

Column: stainless steel column (inner diameter: approximately 4.6 mm; length: approximately 150 mm) packed with 5 μηι C8

Eluents: Methanol and phosphate buffer (4 : 6 (v/v%))

[Table 4] Breakdown products of ambroxol hydrochloride

[Table 5] Breakdown products of levodropropizine

Also, according to 'Guidance for Industry; Stability Testing of Drug Substances and Drug Products' issued by FDA, the liquid formulations prepared in accordance with Example 1 and Comparative Example 1 were tested under accelerated conditions. The accelerated test was performed by placing each of the liquid formulation in separate HDPE bottle and storing the containers at 40 °C with a relative humidity of 75%. After 1 and 3 months, samples were withdrawn and investigated for any significant changes. The results are shown in Table 6 below.

[Table 6]

As shown in Tables 4 to 6, and Figs. 1 and 2, when pH value of the complex liquid formulations, comprising ambroxol hydrochloride and levodropropizine as main ingredients, were kept in the range of 4.5 to 5.5 by using a buffering agent, the production of unknown substances that are derived from the main ingredients was inhibited effectively. In particular, the production of ambroxol hydrochloride-related substances was reduced approximately 12- to 15-fold (max) under accelerated conditions, and the production of levodropropizine was reduced approximately 25- to 35-fold or more. Therefore, the results indicate that the storage stability of the liquid formulation of the present invention is significantly enhanced.

Also, according to the specification of International Conference on Harmonisation (ICH), there should be not more than 0.2% and 0.5% by weight for unknown and known impurities, respectively. The inventive liquid formulation of Example 1 showed satisfactory result of less than 0.5% at 40 °C accelerated condition even until 3 months after the initial period. In contrast, the liquid formulation of Comparative Example 1, which did not employ a buffering agent for adjusting the pH to 4.5 to 5.5, far exceeded the predetermined limits of ICH guideline even from 1 month after the initial period.

Claims

What is claimed is:

1. A liquid formulation for oral administration having a pH value of 4.5 to 5.5 comprising ambroxol or a pharmaceutically acceptable salt thereof; levodropropizine or a pharmaceutically acceptable salt thereof; and a buffering agent in an aqueous medium.

2. The liquid formulation for oral administration of claim 1, wherein the buffering agent is selected from the group consisting of citric acid; sodium citrate hydrate; potassium citrate; acetic acid; sodium acetate; sodium carbonate; calcium carbonate; calcium phosphate tribasic; calcium lactate; glycine; maleic acid; malic acid, sodium glutamate, monosodium glutamate, sodium lactate, sodium phosphate and a mixture thereof.

3. The liquid formulation for oral administration of claim 2, wherein the buffering agent is selected from the group consisting of citric acid, sodium citrate hydrate, potassium citrate, acetic acid, sodium acetate, malic acid, sodium glutamate, glycine, sodium carbonate, maleic acid, sodium lactate and a mixture thereof.

4. The liquid formulation for oral administration of claim 2, wherein the buffering agent is a mixture of citric acid and sodium citrate hydrate.

5. The liquid formulation for oral administration of claim 1, wherein the aqueous medium is selected from the group consisting of purified water, ethanol and a mixture thereof.

6. The liquid formulation for oral administration of claim 1, wherein the ambroxol or the pharmaceutically acceptable salt thereof is employed in an amount of 100 mg to 1,000 mg per 100 mL of the liquid formulation.

7. The liquid formulation for oral administration of claim 1, wherein the levodropropizine or the pharmaceutically acceptable salt thereof is employed in an amount of 300 mg to 1,500 mg per 100 mL of the liquid formulation.

8. The liquid formulation for oral administration of claim 1, which further comprises a pharmaceutically acceptable excipient selected from the group consisting of an antioxidant, a sweetening agent, a preservative, a viscosity modifying agent and a mixture thereof.

9. A method for preparing the liquid formulation for oral administration of claim 1, comprising the steps of:

(1) dissolving a pharmaceutically acceptable excipient in an aqueous medium; (2) adjusting the pH of the mixture prepared in step (1) to 4.5 to 5.5 by using a buffering agent;

(4) adding an aqueous medium to the mixture prepared in step (3).