WO2017091165A1

WO2017091165A1 - Liquid formulation of levodropropizine and method for preparation thereof

Info

Publication number: WO2017091165A1
Application number: PCT/TR2015/050201
Authority: WO
Inventors: Ersin Yildirim; Başak ACAR KARAKÖY; Sevinç KAHRAMAN; Tolga Ramazan KARASU; Sumit ABNAWE; Fatih Cengiz Aygül
Original assignee: Pharmactive Ilac San Ve Tic AS
Current assignee: Pharmactive Ilac San Ve Tic AS
Priority date: 2015-11-26
Filing date: 2015-11-26
Publication date: 2017-06-01
Anticipated expiration: 2018-05-26

Abstract

The present invention relates to a liquid formulation for oral administration having reduced amount of N-oxide impurity comprising levodropropizine and sugar.

Description

LIQUID FORMULATION OF LEVODROPROPIZINE AND METHOD FOR PREPARATION THEREOF

FIELD OF THE INVENTION

The present invention relates to a liquid formulation for oral administration having reduced amount of impurity comprising levodropropizine and sugar.

BACKGROUND OF THE INVENTION

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.

Levodropropizine is marketed under various brand names around worldwide. Levodropropizine is marketed under brand names Lavenil, Levopront, Levosol and Azinex in Turkey.

None of the prior art discloses the use of sugar to reduce the oxidation impurities in the levodropropizine composition.

The present inventors have tried to develop a liquid formulation comprising levodropropizine and sugar in various concentrations and it is observed that at low sugar concentration the amount of related substances of levodropropizine increases.

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 factors, e.g., temperature, moisture, airand light, even after the final product was prepared. The present inventors have found that the stability of liquid formulation comprising levodropropizine can be secured by using specific sugar concentration. Thus, the present invention is accomplished by using a sugar in a specific concentration to render the composition stable.

SUMMARY OF THE INVENTION

The present invention relates to a liquid pharmaceutical formulation for oral administration comprising levodropropizine or a pharmaceutically acceptable salt thereof and sugar, wherein oxidation impurity is within the acceptable limit.

The present invention is also related to a liquid pharmaceutical formulation for oral administration comprising levodropropizine or a pharmaceutically acceptable salt thereof, sugar in a concentration of 60-90% and preservative, wherein oxidation impurity is within the acceptable limit. DETAILED DESCRIPTION OF THE INVENTION

An object of the present invention is to provide a liquid formulation of levodropropizine or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a syrup formulation comprising levodropropizine or a pharmaceutically acceptable salt thereof and sugar concentration in the range of 60-90% of the total composition by weight.

The term "oxidation impurity" as used herein refers to the impurity generated by oxidation of active agent in the presence of oxygen.

The term "acceptable limit" as used herein refers to the limit within which parameter passes the test.

The present invention provides a liquid pharmaceutical formulation for oral administration comprising levodropropizine or a pharmaceutically acceptable salt thereof and 60-90% of sugar.

The present invention is characterized in using higher concentration of sugar in the preparation of the liquid formulation comprising levodropropizine. In the said concentration, the production of unwanted substances that are derived from 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 acids such as glycine, alanine, valine, isoleucine, serine, cysteine, cystine, aspartate, glutamine, lysine, arginine, tyrosine and proline; sulfonic acids such as methanesulfonic acid, ethane sulfonic acid, benzene sulfonic acid, toluene sulfonic 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.

The presence of oxygen in the liquid dosage form can interact with the active drug and lead to the oxidative degradation. This interaction generates impurities in the dosage form which may be harmful for consumption. In an embodiment of the present invention, higher concentration of the sugar is used to prevent such interaction and to avoid production of impurities. Liquid dosage form of present invention does not require further additional antioxidant to prevent the oxidation of active drug.

In one another embodiment, the present invention provides a liquid dosage form comprising levodropropizine and a sugar in the concentration of 60-90% of the total composition by weight.

In one another embodiment, the present invention provides a liquid dosage form comprising levodropropizine and sucrose in the concentration of 60-90% of the total composition by weight.

In one another embodiment, the present invention provides a liquid dosage form comprising levodropropizine and sucrose in the concentration of 60-90%, more preferably 70-80% of the total composition.

In one another embodiment, the present invention provides syrup comprising levodropropizine and sucrose in the concentration of 60-90%, preferably 70-80% of the total composition by weight.

In one another embodiment, the present invention provides a syrup comprising levodropropizine, sucrose in the concentration of 60-90%, preferably 70-80% of the total composition by weight and preservative agents. Presence of preservative in the composition does not significantly affect the generation of oxidation impurity but affects the concentration of active agent in the composition. It is therefore observed that in presence of specific concentration of sugar and preservative agent, the assay of active agent and the amount of oxidation impurity remains within the acceptable limits. It is also observed that assay of active agent falls outside the acceptable limit in absence of preservative agent in the composition however at the same time amount of oxidation impurity is within the allowable limit.In an aspect of the embodiment, the oxidation impurity is N-oxide impurity.

The composition of the present invention can be present in the liquid dosage form selected from but not limited to a syrup and solution.

In one another embodiment, the present invention further comprises pharmaceutically acceptable excipient(s) selected from the group consisting of an antioxidant, flavoring agent, preservative agent, viscosity modifying agent and a mixture thereof.

The antioxidant of the present invention is selected from the group consisting of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, sodium pyrosulfite, ascorbic acid, erythorbic acid and a mixture thereof. These examples in no way limit the choices for the addition of antioxidant agents, which can be any of many agents known in the art.

The sweetening agent of the present invention is selected from the group consisting of sugar such as brown sugar, white sugar, sucrose, lactose, lactulose, maltose,trehalose, saccharine and dextrose, potassium acesulfame, and a mixture thereof. These examples in no way limit the choices for the addition of sweetening agents, which can be any of many agents known in the art. The amount of the sweetening agent is employed in an amount of 80 to 130g, preferably 90 to 120g per 150 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. These examples in no way limit the choices for the addition of preservative agents, which can be any of many agents known in the art.The amount of the preservative agent is employed in an amount of 0.1 to 0.4g, preferably 0.15 to 0.3g per 150 mL of the liquid formulation.

The flavoring agent of the present invention is selected from the group consisting of raspberry, apple and rosemary. These examples in no way limit the choices for the addition of flavoring agents, which can be any of many agents known in the art. The amount of the flavoring agent is employed in an amount of 0.3 to 0.5g, preferably 0.35 to 0.45g per 150 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. These examples in no way limit the choices for the addition of flavoring agents, which can be any of many agents known in the art. The buffering agent of the present invention is selected from the group consisting of citric acid, sodium citrate hydrate, sodium hydroxide, potassium citrate, acetic acid, sodium acetate, malic acid, sodium glutamate, glycine, sodium carbonate, maleic acid, sodium lactate and a mixture thereof. These examples in no way limit the choices for the addition of buffering agents, which can be any of many agents known in the art. The amount of the buffering agent is employed in an amount of 0.5 to 5 g, preferably 1 to 3 g per 150 mL of the liquid formulation.

Examples

The present invention will be described in more detail by way of the following examples, but scope of the present invention is not limited thereto.

Examples 1-6:

Manufacturing process:

1. Purified water was heated up to 70-90 °C, optionally preservatives were added and stirred for 10-15 minutes.

2. Sugar was added at 80°C under stirring and cooled down to 40°C temperature. 3. Buffering agent was added at 40°C temperature and stirred for 5-10 minutes.

4. Active agent was added and mixed for 10-15 minutes until all get dissolved.

5. Flavor was added and stirred for 5-10 minutes.

6. Buffer solution was prepared another with purified water and buffering agent

(10%w/v). Papered buffer solution was added to step 5 for 5-10 min to get pH 5.5-6.5 (~4.5ml-10%w/v solution equivalent to 0.15g/150ml).

7. The volume of the Bulk product is adjusted with purified water.

8. Filtered by 100-200 micron filter under vacuum.

9. Final product was filled into the suitable container.

Stability data

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 to 6 were tested under stability conditions. The accelerated test was performed by placing each of the liquid formulation in separate glass bottle and storing the containers at 40 °C with a relative humidity of 75%. After 6 months, samples were withdrawn and investigated for any significant changes. The results are shown in Table 1 below.

Table l.Six month stability data of examples 1-6

Levodropropizine Assay (mg/5mL) Impurity-N-oxide (%)

Examples Limit: 30.00 mg/5 mL + % 5 Limit: Maximum 0.50%

(28.50 mg/ 5 mL - 31.50 mg/ 5ml)

Initial 25°C + 30°C 40°C+ Initial 25°C + 30°C 40°C +

60%RH 65%RH %75RH 60%RH 65%RH %75RH

Example 1 30.37 30.60 30.19 29.67 N.D* 0.06 0.12 0.48

Example 2 28.10 28.07 28.03 27.86 N.D* 0.06 0.12 0.47

Example 3 32.65 32.50 32.58 32.08 N.D* 0.11 0.21 0.90

Example 4 30.67 30.43 30.53 30.13 N.D* 0.12 0.24 0.93

Example 5 30.55 30.40 30.16 29.98 N.D* 0.09 0.18 0.63

Example 6 31.25 30.02 30.07 30.90 N.D* 0.09 0.17 0.60

* N.D = Not ] Detected Also, according to the specification of International Conference on Harmonization (ICH), there should be not more than 0.5% of the theoretical amount of active substance by weight for known impurities. According to these criteria, the amount of the N-oxide impurity is not more than 0.5% of the theoretical amount of levodropropizine in the composition by weight. The liquid formulation of Example 1 showed satisfactory result of less than 0.5% of N-oxide impurity at 40°C accelerated condition at 6 months after the initial period. Example 2 shows satisfactory results of impurity level but fails to maintain drug assay within acceptable limit. In contrast, the liquid formulation of Comparative Example 3-6, which did not employ a 70- 80% of sucrose, far exceeded the predetermined limits of ICH guideline.

Claims

1. A liquid pharmaceutical formulation for oral administration comprising levodropropizine or a pharmaceutically acceptable salt thereof, wherein it comprises the sugar in the concentration of 60-90% of total composition by weight.

2. The liquid pharmaceutical formulation for oral administration as claimed in claim 1 wherein sugar is present in the concentration of 70-80% of total composition by weight.

3. The liquid pharmaceutical formulation for oral administration as claimed in claim 1 wherein sugar is selected from brown sugar, white sugar, sucrose, lactose, lactulose, maltose, trehalose, saccharine and dextrose.

4. The liquid pharmaceutical formulation for oral administration as claimed in claim 3 wherein sugar is sucrose.

5. The liquid pharmaceutical formulation for oral administration as claimed in claim 1 further comprises a pharmaceutically acceptable excipients selected from the group consisting of an antioxidant, a flavoring agent, a preservative, viscosity modifying agent and a mixture thereof.

6. The liquid pharmaceutical formulation for oral administration as claimed in claim 5 wherein preservative 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.

7. The liquid pharmaceutical formulation for oral administration as claimed in claim 1 wherein the amount of the N-oxide impurity is not more than 0.5% of the theoretical amount of levodropropizine in the composition by weight.