TW201345563A - Liquid formulation for oral administration comprising ambroxol, levodropropizine and buffering agent, and method for preparing the same - Google Patents

Abstract

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

Liquid formulation containing ampso, levodoxe piperazine and buffer for oral administration and method for preparing same Field of invention

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

Background of the invention

Ampsol, as shown below, is a compound that is clinically proven to be effective in the treatment of acute and chronic respiratory diseases associated with viscous or excessive mucus, such as acute and chronic bronchitis, asthmatic bronchitis, sinus Inflammation, dry rhinitis, and the like, and recently available under the brand Mucopect (Boehringer Ingelheim) and Wooridul Ambroxol Syr. (Wooridul Pharm):

Ampso is a metabolite of bromhexine, which It stimulates mucus secretion and promotes the normalization of mucus viscosity. In a recent study, the Ambrosia line showed sterolytic activity, anti-inflammatory and antioxidant activity, local anesthetic effects, etc. (Malerba M. et al., "Expert Opin Drug Metab Toxicol." , 2008 Aug, 4(8): 1119-29"). Also, due to its analgesic effect, Ambrosia is used to treat acute sore throat and is generally prepared as a syrup formulation whereby it acts rapidly and has a sustained analgesic effect of at least 3 hours (de Mey) C. et al., "Arzneimittelforschung., 2008, 58(11): 557-558"). In 4 of the 5 studies, the group containing the 20 mg ambleo syrup formulation showed a significant reduction in pain, as well as rapid (30 minutes after administration) and prolonged analgesic effect (at least 3 hours).

L-Hydroxypiperazine, as shown below, is a left-handed isomer of hydroxypropionazine as an antitussive agent that inhibits the incoming pathway of cough reflexes around it:

L-Hydroxypiperazine acts only in the peripheral nervous system and has no effect in the central nervous system. Therefore, it has a mechanism of differentiation that does not cause side effects, such as constipation or respiratory depression, which can be caused by, for example, codeine and the like. Opiate antitussives are produced. Also, it demonstrates a significant reduction in central nervous system adverse events (drowsiness); inhibition of inflammation, bronchoconstriction, and excessive mucus secretion; and is also known as a safe drug because it does not interact with other drugs, such as beta-resistance Broken agent, methylxanthine, mucus Mucoregulators, glucocorticoids, antibiotics, antihistamines, etc. In Korea, L-hydroxypropionazine is currently available under Leventus, Hyundai Pharm, Lebrocol Syr. from Hamni Pharm Ltd., and 17 other brands of other syrups, and is used to treat acute and chronic bronchitis. cough.

Thus, by developing a complex liquid formulation using abuxophone and levodropropizine, the former can reduce viscosity and exhibit sputum activity, the latter being a peripheral antitussive, and an enhanced effect can be expected. Accordingly, there have been many instances where ampsol and levodropropizine are formulated in a combined formulation. However, each of these syrup preparations must be taken three times a day, and thus it is inconvenient that the patient is required to take a relatively large amount of syrup per dose.

The present inventors have been working on the development of a complex liquid formulation comprising ampsol and levodropropizine, which has the same therapeutic effect, even in a small amount, for example 10 mL or less, for improving patient compliance. Sex. However, it has been found that when the two components are present together in a liquid formulation, an increase in the amount of related substances in amblomole and levodropropizine is observed.

Impurities in the drug substance may cause undesirable side effects in the patient, and therefore, the purity of the active ingredient is one of the most important factors in providing a safe and effective drug formulation. Such impurities include not only compounds which can be completely removed during the preparation of the active ingredient, but also decomposition products which are produced by various environmental factors such as temperature, moisture and light even after the preparation of the final product.

Therefore, the inventors have studied factors which promote the production of related substances when a liquid formulation comprising abuxope and levoprofenil is used in a storage condition; and it has been found that the active ingredient is in an aqueous solution. Stability can only be ensured under specific pH conditions. Thus, the present invention is achieved by using a buffer to adjust the pH conditions of the formulation.

Summary of invention

Accordingly, it is an object of the present invention to provide a liquid formulation for oral administration comprising Ambaxol or one of its pharmaceutically acceptable salts and L-hydroxypiperazine or one of its pharmaceutically acceptable salts And has improved stability.

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

According to one aspect of the present invention, there is provided a liquid formulation for oral administration comprising Ambrosol or one of its pharmaceutically acceptable salts, L-hydroxypiperazine or one of its pharmacological agents Accepts salts, and one of the buffers in aqueous media, and has a pH of 4.5 to 5.5.

According to another aspect of the present invention, there is provided a method for preparing the orally administered liquid formulation, the method comprising the steps of: (1) dissolving a pharmaceutically acceptable excipient in an aqueous medium; (2) adjusting the pH of the mixture prepared in the step (1) to a pH in the range of 4.5 to 5.5 by using a buffer; (3) amblomer or one of the pharmaceutically acceptable salts thereof, And L-hydroxypiperazine or one of its pharmaceutically acceptable salts is dissolved in the step (2) The mixture; and (4) an aqueous medium is added to the mixture prepared in step (3).

The liquid formulation prepared by using ampoule and levodropropizine having different pharmacokinetic mechanisms of the present invention exhibits improved patient compliance and enhanced storage stability over time, and thus can be safe It is used to treat acute and chronic cough.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph showing the results of a stability test of a liquid formulation of the present invention at a pH of 60 ° C, which shows the maximum amount of unknown related substances produced by Amber's hydrochloric acid.

Figure 2 is a graph showing the results of a stability test of the liquid formulation of the present invention at a pH of 60 ° C, which shows the maximum amount of unknown related substances produced by L-hydroxypropipetazine.

Detailed description of the preferred embodiment

Embodiments of the invention are explained in detail below.

The present invention provides a liquid formulation for oral administration having a pH of from 4.5 to 5.5, comprising Ambazoxone or one of its pharmaceutically acceptable salts, L-hydroxypiperazine or one of them Pharmaceutically acceptable salts, and buffers in an aqueous medium.

The present invention is characterized in that the liquid formulation is adjusted to a pH of 4.5 to 5.5 by using a buffer in the preparation of the composite liquid formulation comprising amblomole and levodropiperazine. In this range, derived from Abuso and The production of an unknown substance of L-hydroxypiperazine can be effectively inhibited, and thus the storage stability is remarkably improved.

The pharmaceutically acceptable salts according to the invention include 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; 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, acetyl salicylic acid (aspirin), and the like; formed by amino acids, such as glycine, alanine, lysine, isoleucine , serine, cysteine, cystine, aspartic acid, glutamic acid, lysine, arginine, tyrosine, and valine; by sulfonic acid formers, such as methanesulfonic acid And ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like; metal salts formed by alkali metals such as sodium, potassium and the like, and salts formed by ammonium ions and the like.

In the present invention, the active ingredient used is ambroxol or one of its pharmaceutically acceptable salts, and levodoxe piperazine or one of its pharmaceutically acceptable salts, preferably Abuxo Hydrochloride and L-hydroxypropionazine.

In one embodiment of the invention, the formulation comprises Ambrosol or a pharmaceutically acceptable salt thereof in an amount of from 100 mg to 1,000 mg (eg, 300 mg) per 100 mL of the liquid formulation, and L-hydroxypropyl Piperazine or one of its pharmaceutically acceptable salts in 100 mL of the liquid formulation, One of 300 mg to 1,500 mg (for example, 600 mg).

In the present invention, the buffer is used in an amount to adjust the pH of the liquid formulation to one of 4.5 to 5.5. In one embodiment of the invention, the formulation comprises the buffer in an amount of from 100 mg to 1,000 mg (eg, from 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, tricalcium phosphate, calcium lactate, A mixture of glycine, maleic acid, malic acid, sodium glutamate, monosodium glutamate, sodium lactate, sodium phosphate, and the like.

In the present invention, the buffer is preferably selected from the group consisting of citric acid, sodium citrate hydrate, potassium citrate, acetic acid, sodium acetate, malic acid, sodium glutamate, glycine a mixture of sodium carbonate, maleic acid, sodium lactate, and the like; 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 optimally citric acid and citric acid a mixture of sodium hydrates.

In the present invention, the aqueous medium is selected from the group consisting of pure water, ethanol, and the like, preferably pure water.

The liquid formulation according to the present invention may further comprise a pharmaceutically acceptable excipient, and the pharmaceutically acceptable excipient is selected from the group consisting of antioxidants, sweeteners, preservatives, viscosity modifiers and One of the others The group consisting of the mixture.

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

The sweetener of the present invention is selected from the group consisting of white sugar, potassium acesulfame, saccharin, dextrose, and the like. The amount of the sweetener is employed in an amount of from 5 to 100,000 mg per 100 mL of the liquid formulation, preferably from 10 to 50,000 mg.

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

The viscosity modifier of the present invention is selected from the group consisting of concentrated glycerin, polyvinylpyrrolidone, ethylcellulose, sodium carboxymethylcellulose, and the like. The amount of the viscosity modifying agent is employed in an amount of from 100 to 20,000 mg per 100 mL of the liquid formulation, preferably from 20 to 10,000 mg.

The liquid formulation according to the present invention is for use in the prevention or treatment of acute and chronic respiratory diseases selected from acute and chronic bronchial tubes This group consisting of inflammation, asthmatic bronchitis, sinusitis, dry rhinitis and acute sore throat.

The present invention provides a method for preparing the orally administered liquid formulation, the method comprising the steps of: (1) dissolving a pharmaceutically acceptable excipient in an aqueous medium; (2) using one The buffer adjusts the pH of the mixture prepared in the step (1) to 4.5 to 5.5; (3) amblomer or one of the pharmaceutically acceptable salts thereof, and levonippromazine or one of the pharmacological agents thereof An acceptable salt is dissolved in the mixture prepared in step (2); and (4) an aqueous medium is added to the mixture prepared in step (3).

The composite liquid formulation prepared according to the present invention employs ampoule and levodropropizine having different pharmacokinetic mechanisms in a liquid formulation, and thus reduces the required dose, and by improving patient convenience Improve patient compliance. Furthermore, the production of an unknown substance derived from amblomole and levodropiprazine can be effectively inhibited by adjusting the pH in the range of 4.5 to 5.5, and thereby improving the storage stability of the liquid formulation. Therefore, the liquid formulation prepared according to the present invention is effective even in a small amount, for example, 10 mL or less, and can be used for preventing or treating acute and chronic respiratory diseases.

In the following, the present invention is more specifically illustrated by the following examples, but these are provided for the purpose of illustration only, and the invention is not limited thereto.

Examples 1 to 3: Preparation of liquid formulations

The liquid formulations of Examples 1 to 3 were prepared by using Ambleo according to the composition and quantity (mg/100 mL) described in Table 1 below. Hydrochloride (Hwail Pharm., Korea) and Lung Hydroxy Piperazine (Sungwoo Chemical, Korea), concentrated glycerin (Seojin Chemical), white sugar (CheilJedang), D-sorbitol solution (Roquette), potassium sulfonate ( Nutrinova), Riedel-de Haen, citric acid (DSM Nutritional), sodium citrate hydrate (Jungbunzlauer), methyl p-hydroxybenzoic acid (Sanfu Chemical) and ethyl p-hydroxybenzoic acid (Sanfu Chemical) Prepared.

Specifically, pure water, methyl p-hydroxybenzoic acid, propyl p-hydroxybenzoic acid, potassium sulfonate and sodium metabisulfite are placed in a manufacturing tank, and the mixture is completely dissolved by stirring at 95 ° C for 30 minutes. To completely dissolve the mixture. The resulting solution was cooled to 50 ° C, and white sugar, D-sorbitol solution, citric acid, and sodium citrate hydrate were sequentially added thereto, and stirred for 60 minutes to completely dissolve the mixture. The pH 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 levodropiperazine were added thereto, followed by stirring to completely dissolve the mixture. The temperature of the manufacturing tank was lowered to 30 ° C or below, and a sterile pure water system at room temperature was added to make the level into a meniscus, followed by stirring for 20 minutes. The final mixture is filtered through a 1 μm filter and stored in a storage tank or a suitable container.

Comparative Examples 1 to 3: Preparation of Liquid Formulations

The liquid formulations of Comparative Examples 1 to 3 were prepared by repeating the procedure of Example 1 using ambroxol hydrochloride and L-hydroxypropyl, according to the composition and quantity (mg/100 mL) described in Table 2 below. Piperazine, concentrated glycerin, white sugar, D-sorbitol solution, potassium sulfonate, sodium metabisulfite, citric acid, sodium citrate hydrate, methyl p-hydroxybenzoic acid and propyl p-hydroxybenzoic acid.

^* aa: the right amount

Examples 4 to 8: Preparation of Liquid Formulations According to the composition and amount (mg/100 mL) described in Table 3 below, the liquid formulations of Examples 4 to 8 were prepared by repeating the procedure of Example 1, using Anbu Hydrochloride and L-hydroxypropipetazine, concentrated glycerin, white sugar, D-sorbitol solution, potassium sulfamate, sodium metabisulfite, methyl p-hydroxybenzoic acid, propyl p-hydroxybenzoic acid and a buffer.

^* aa: the right amount

Experimental example: evaluation of the relevant substances produced

To assess storage stability over time, a test was performed on the liquid formulations prepared in Examples 1 to 3 and Comparative Examples 1 to 3.

Specifically, each liquid formulation was contained in a high density polyethylene (HDPE) bottle and stored in a chamber at 60 ° C acceleration. After 4 weeks, the highest amount of unknown related substances of abuxophone hydrochloride and levo-hydroxypropionazine derived from each of the decomposition products thereof was evaluated using the HPLC method according to the following conditions. These results are shown in Tables 4 and 5, and in Figures 1 and 2.

<HPLC conditions - Ambseal hydrochloride>

Absorption: 248nm

Column: stainless steel column (inner diameter: about 4.6mm; length: about 250mm) filled with 5μm C18

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

<HPLC conditions - L-hydroxypropipetazine>

Absorption: 254nm

Pipe column: stainless steel pipe column (inner diameter: about 4.6mm; length: about 150mm) filled with 5μm C8

Eluent: methanol and phosphate buffer (4:6 (v/v%))

Also, according to the 'Industry Guide; Stability Test of Drug Substance and Pharmaceutical Products' issued by the FDA, the liquid formulations prepared according to Example 1 and Comparative Example 1 were tested under accelerated conditions. The accelerated test was carried out in a separate HDPE bottle by placing each liquid formulation and stored in a container at 40 ° C and a relative humidity of 75%. After 1 month and 3 months, the samples were taken and any significant changes were investigated. These results are shown in Table 6 below.

As shown in Tables 4 to 6 and Figures 1 and 2, the pH of the composite liquid formulation containing ambroxol hydrochloride and levodropropizine as a main component was maintained at 4.5 by using a buffer. When it is in the range of 5.5, the generation of an unknown substance derived from the main component is effectively suppressed. In particular, under accelerated conditions, the production of ambroxol hydrochloride-related substances is reduced. It is about 12 to 15 times (maximum), and the production of the levospiro piperazine is reduced by about 25 to 35 times or more. Therefore, these results indicate that the storage stability of the liquid formulation of the present invention is significantly enhanced.

Also, according to the specifications of the International Federation of Pharmaceutical Regulations (ICH), they should not exceed 0.2% and 0.5% by weight of unknown and known impurities, respectively. The liquid formulation of Example 1 of the present invention exhibited less than 0.5% satisfactory results at 40 °C accelerated conditions, even up to 3 months after the initial period. Conversely, the liquid formulation of Example 1 was compared, which did not employ a buffer for adjusting the pH to 4.5 to 5.5, far exceeding the limits pre-determined by the ICH guidelines, even one month after the initial period. Rear.

Claims (9)

An orally administered liquid formulation having a pH of from 4.5 to 5.5 comprising: ambroxol or a pharmaceutically acceptable salt thereof; levodropropizine or its pharmaceutically acceptable form An acceptable salt; and a buffer in an aqueous medium. The liquid formulation for oral administration according to claim 1, wherein the buffer is selected from the group consisting of citric acid; sodium citrate hydrate; potassium citrate; acetic acid; sodium acetate; sodium carbonate Calcium carbonate; tricalcium phosphate; calcium lactate; glycine; maleic acid; malic acid; sodium glutamate; monosodium glutamate; sodium lactate; sodium phosphate and mixtures thereof. The liquid formulation for oral administration according to claim 2, wherein the buffer is selected from the group consisting of citric acid; sodium citrate hydrate; potassium citrate; acetic acid; sodium acetate; Sodium glutamate; glycine; sodium carbonate; maleic acid; sodium lactate and mixtures thereof. A liquid formulation for oral administration according to claim 2, wherein the buffer is a mixture of citric acid and sodium citrate hydrate. The liquid formulation for oral administration according to claim 1, wherein the aqueous medium is selected from the group consisting of pure water, ethanol, and the like. A liquid formulation for oral administration according to claim 1 wherein the ampoule or a pharmaceutically acceptable salt thereof is present in an amount of from 100 mg to 1,000 mg per 100 mL of the liquid formulation. A liquid formulation for oral administration according to item 1 of the patent application, wherein The L-hydroxypropylpiperazine or a pharmaceutically acceptable salt thereof is present in an amount of from 300 mg to 1,500 mg per 100 mL of the liquid formulation. The liquid preparation for oral administration according to claim 1, further comprising a pharmaceutically acceptable excipient selected from the group consisting of an antioxidant, a sweetener, a preservative, a viscosity modifier, and the like a group of mixtures. A method for preparing the orally administered liquid formulation according to claim 1 of the patent application, 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 buffer; (3) using Ambazoline or a pharmaceutically acceptable salt thereof, and L-hydroxypropionazine Or a pharmaceutically acceptable salt thereof is dissolved in the mixture obtained in the step (2); and (4) an aqueous medium is added to the mixture obtained in the step (3).