A stable oral liquid composition comprising terbutaline & guaifenesin

Abstract

The present invention relates to a stable oral liquid composition comprising Terbutaline or its pharmaceutically acceptable salt, Guaifenesin, a chelating agent, sodium metabisulfite and at least one more pharmaceutically acceptable excipient. The invention further relates to a preparation of said composition and used thereof to relieve symptoms such as wheezing, shortness of breath, chest tightness, breathing difficulties, coughing, etc. associated with asthma by reducing bronchoconstriction.

Description

[0001] A STABLE ORAL LIQUID COMPOSITION COMPRISING TERBUTALINE & GUAIFENESIN

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a stable oral liquid composition comprising Terbutaline or its pharmaceutically acceptable salt, Guaifenesin, a chelating agent, sodium metabisulfite and at least one more pharmaceutically acceptable excipient. The invention further relates to a preparation of said composition and used thereof to relieve symptoms such as wheezing, shortness of breath, chest tightness, breathing difficulties, coughing, etc. associated with asthma by reducing bronchoconstriction.

[0004] BACKGROUND OF THE INVENTION

[0005] Terbutaline is chemically 5-[2-(tert-butylamino)-1 -hydroxyethyl] benzene-1 ,3-diol as shown in formula (I):

[0006] Terbutaline is a (32 adrenergic receptor agonist. Agonism of these receptors in bronchioles activates adenylyl cyclase, increasing intracellular cyclic adenosine monophosphate (cAMP), thus increased cAMP decreases intracellular calcium, activating protein kinase A, inactivating myosin light-chain kinase, activating myosin light-chain phosphatase, and finally relaxing smooth muscle in the bronchiole. Terbutaline is used as a “reliever” inhaler in the management of asthma symptoms as mentioned here in above. Guaifenesin is 3-(2-methoxyphenoxy) propane-1 ,2-diol as shown in formula (II):

[0007] It is an expectorant commonly used for the symptomatic relief from congested chests and coughs associated with cold, bronchitis, and / or other breathing illnesses. Guaifenesin acts as an expectorant by increasing the volume and reducing the viscosity of secretions in the trachea and bronchi in order to increase the efficiency of the cough reflex and facilitate removal of the secretions. Additionally, Guaifenesin has muscle relaxant and anticonvulsant properties and may act as an NMDA receptor antagonist. It is generally used in combination with other medications and is more effective particularly when taken by mouth.

[0008] The combination of Terbutaline (as a sulfate salt) and Guaifenesin is well known combination and marketed under the tradename of Bricanyl Expectorant® syrup for relieving cough by softening phlegm in the respiratory tract, widens the airway and facilitates breathing in patients with asthma or other similar diseases. Bricanyl Expectorant® can be taken for three times (10-15 ml) in one day in adult population. The dosage of Bricanyl Expectorant® should be adjusted by the total weight of the body in children and it should not be used in children less than 6 years. Since, it is used in children older than 6 years, the effectiveness and stability are significantly important.

[0009] Bricanyl Expectorant® is a syrup that contains sorbitol, glycerin, citric acid, sodium hydroxide, sodium benzoate, disodium edetate, sodium saccharine, ethanol, methanol, raspberry flavor and deionized water.

[0010] US 3937838 firstly discloses Terbutaline compound and its processes for preparation, pharmaceutical compositions and use thereof in the treatment of lung diseases such as bronchial asthma, chronic bronchitis, acute bronchospasm, asthma, bronchospasm prophylaxis and chronic obstructive pulmonary disease. US 4390732 firstly discloses Guaifenesin compound and its processes for preparation with good yield and purity.

[0011] TR 2017 / 20846 discloses the pharmaceutical syrup composition comprising Terbutaline sulfate in an amount of 0.01 % - 0.1 % and Guaifenesin in an amount of 0.1 - 8 % by the total weight of the composition and its manufacturing process.

[0012] TR 2017 / 20845 discloses the pharmaceutical syrup composition comprising Terbutaline sulfate in an amount of 0.01 % - 0.1 % by the weight of the total composition and its manufacturing process.

[0013] WO 2003068206 A1 discloses a pharmaceutical composition comprising a combination of a bronchodilator selected from salbutamol and terbutaline, or a pharmaceutically acceptable salt or derivative thereof, and guaifenesin, or a pharmaceutically acceptable salt or derivative thereof, as active ingredients.

[0014] Without binding to any theory, it is believed that use of preservative and chelating agent in marketed composition of Bricanyl Expectorant® is to control the degradation impurity, particularly oxidation impurity, which arises from the oxidation Terbutaline. However, when we have checked the impurity level of innovator’s marketed composition along with other equivalent products available in market, we observed that level of said oxidation impurity, which is coming at RRT 0.88, is out of expected limit set by ICH.

[0015] Thus, there still exist a need of getting a stable and efficient composition without compromising the efficacy and potency of the said composition.

[0016] To overcome this problem, the inventors of the present invention have done the series of experiments and checked different agents, which are allowed to use in oral solution, to control the said oxidation impurity during the stability and surprisingly identified that Sodium metabisulfite has ability to control the said oxidation impurity that too without compromising the efficacy and potency of oral solution comprising Terbutaline and Guaifenesin. While selecting the suitable antioxidant, many trials have been performed by using known antioxidants including but not limited to Butylated Hydroxy Toluene, Butylated Hydroxy Anisole, etc. but satisfactory results have not been obtained.

[0017] OBJECT OF THE INVENTION

[0018] A main object of the present invention is to provide a stable oral liquid composition comprising Terbutaline or its pharmaceutically acceptable salt and Guaifenesin, which has superior stability over the equivalent compositions known in the market.

[0019] Another object of the present invention is to provide a stable oral liquid composition comprising Terbutaline or its pharmaceutically acceptable salt and Guaifenesin, which contains acceptable amount of oxidation impurity as per ICH guideline.

[0020] Yet another object of the present invention is to provide a stable oral liquid composition comprising Terbutaline or its pharmaceutically acceptable salt and Guaifenesin, in which amount of oxidation impurity remains within specification over the period as per the ICH guideline.

[0021] Yet another object of the present invention is to provide a stable oral liquid composition comprising Terbutaline or its pharmaceutically acceptable salt and Guaifenesin, in which the use of Sodium metabisulfite doesn’t decrease the potency and efficacy of said composition.

[0022] Yet another object of the present invention is to provide a stable oral liquid composition comprising Terbutaline or its pharmaceutically acceptable salt and Guaifenesin, which overcomes the problems of the prior art.

[0023] Yet another object of the invention is to provide a commercially scalable, cost effective, environment friendly and robust process for the preparation of oral liquid composition comprising Terbutaline or its pharmaceutically acceptable salt and Guaifenesin. SUMMARY OF THE INVENTION

[0024] In one aspect, the present invention provides a stable oral liquid composition comprising Terbutaline or its pharmaceutically acceptable salt, Guaifenesin, a chelating agent, sodium metabisulfite and at least one more pharmaceutically acceptable excipient.

[0025] In another aspect, the present invention provides a stable oral liquid composition comprising Terbutaline, which is present in the composition as a sulfate salt.

[0026] In yet another aspect, the present invention provides a stable oral liquid composition comprising Terbutaline sulfate, which is present in an amount of 0.03% to 0.08% by weight of the total volume of the composition.

[0027] In yet another aspect, the present invention provides a stable oral liquid composition comprising Guaifenesin, which is present in an amount of 0.5% to 3.0% by weight of the total volume of the composition.

[0028] In yet another aspect, the present invention provides a stable oral liquid composition comprising Sodium metabisulfite, which is present in an amount of 0.03% to 0.07% by weight of the total volume of the composition.

[0029] In yet another aspect, the present invention provides a stable oral liquid composition comprising the chelating agent is disodium EDTA.

[0030] In yet another aspect, the present invention provides a stable oral liquid composition comprising at least one more pharmaceutically acceptable excipient is selected from preservative, sweetening agent, viscosity agent and pH adjusting agent.

[0031] In yet another aspect, the present invention provides a stable oral liquid composition, which is used to relieve symptoms such as wheezing, shortness of breath, chest tightness, breathing difficulties, coughing, etc. associated with asthma by reducing bronchoconstriction.

[0032] The details of one or more embodiments of the present invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description.

[0033] DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0034] The present invention will now be more specifically illustrated as hereunder.

[0035] In the present invention, unless indicated otherwise, all ingredient concentrations are presented in units of % weight / volume (% w / v).

[0036] The term "about" can indicate a difference of 10 percent of the value specified. Numerical ranges as used herein are meant to include every number and subset of numbers enclosed within that range, whether particularly disclosed or not. Further, these numerical ranges should be construed as providing support for a claim directed to any number or subset of numbers in that range.

[0037] The term “oral liquid composition” as used in the present invention means a pharmaceutical composition which are homogeneous liquid preparations, usually consisting of a solution, an emulsion, or a suspension, of one or more active ingredients in a suitable liquid base. They are prepared for oral administration either as such or after dilution.

[0038] The term “Terbutaline” as used in the present invention includes, but is not limited to, Terbutaline per se, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof, and also its various crystalline and amorphous forms. The term “Guaifenesin” as used in the present invention includes, but is not limited to, Guaifenesin per se, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof, and also its various crystalline and amorphous forms.

[0039] The term “stable” as used herein is intended to mean that a composition of a pharmaceutical product or a method of the present invention does not substantially decompose to form one or more degradation products when stored as per the ICH guideline for stability. For example, there is not more than 0.3% oxidation impurity comes at RRT 0.88, more preferably less than 0.2% oxidation impurity (comes at RRT 0.88) and more preferably less than 0.1 % oxidation impurity (comes at RRT 0.88) identified when the composition of the present invention is stored as per the ICH guideline for stability.

[0040] The term “RRT” refers to Relative Retention Time. Generally, impurities are identified spectroscopically and / or with another physical method, and then are associated with a peak position, such as that in a chromatogram, or with a spot on a TLC plate. Thereafter, the impurity can be identified, e.g., by its relative position in the chromatogram, where the position in a chromatogram is measured in minutes between injection of the sample on the column and elution of the particular component through the detector. The relative position in the chromatogram is known as the “retention time” (RT).

[0041] Retention time can vary about a mean value based upon the condition of the instrumentation as well as many other factors. To mitigate the effects such variations have upon accurate identification of an impurity, those skilled in the art use the “relative retention time” (RRT) to identify impurities. The RRT of an impurity is its retention time divided by the retention time of a reference marker. The term “ICH guideline” refers to International Conference on Harmonization guidelines. The impurity levels in any drug product are described as per its biological or toxicological data. It is quite important for “regulatory” aspect of drug approval also to provide limitation of “impurities.” Therefore, it is necessary to study the impurity profile of any formulation and control it during the manufacturing of a formulation. According to ICH guideline, the liquid formulation, even when stored with an inert surface (e.g., glass or canister) begins to deteriorate (i.e., formation of an oxidized impurity) when subjected to accelerated storage conditions (e.g., 40° C., 75% relative humidity for 3 months), indicating unsuitability of the product. Although present in small amounts, the level of oxidized impurity (after long-term storage) exceeds the qualification threshold and identification threshold calculated based on the maximum daily dosage. (See, ICH Guidance for Industry Q3B® Impurities in New Drug Products, November, 2003).

[0042] The inventors of the present invention have observed that amount of oxidation impurity, derived from the oxidation of Terbutaline compound comes at RRT 0.88, is out of the specification in innovator’s marketed composition as well as equivalent compositions. To overcome the problem associated with increased amount of said oxidation impurity generated during the manufacturing and stability, the inventors of the present invention have surprisingly identified that sodium metabisulfite effectively controlled the said oxidation impurity as compared to other antioxidant such as Butylated Hydroxy Toluene (BHT), Butylated Hydroxy Anisole (BHA), etc.

[0043] Besides that it has also been observed that due to the low solubility of BHT & BHA, precipitation occurred in the solution after the adding BHT & BHA into the composition separately. In contrast, while the addition of sodium metabisulfite to the solution don’t allow solution to be precipitated and provided a clear solution.

[0044] Shortly, it has been surprisingly found that while sodium metabisulfite has been used as an antioxidant at a specific concentration in the liquid composition of the present invention provides a syrup with better stability results and desired impurity profile as compared to reference product (Bricanyl Expectorant®). In general embodiment, the present invention provides a stable oral liquid composition comprising Terbutaline or its pharmaceutically acceptable salt, Guaifenesin, a chelating agent, sodium metabisulfite and at least one more pharmaceutically acceptable excipient.

[0045] In embodiments, a stable oral liquid composition of the present invention comprises Terbutaline as a sulfate salt.

[0046] In embodiments, a stable oral liquid composition of the present invention comprises Terbutaline in an amount of 0.03 % to 0.08 %, more preferably 0.06 % by weight of the total volume of the composition.

[0047] In embodiments, an oral liquid composition of the present invention comprises Guaifenesin in an amount of 0.5 % to 3.0 %, more preferably 1 .3 % by weight of the total volume of the composition.

[0048] In embodiments, an oral liquid composition of the present invention comprises sodium metabisulfite in an amount of 0.03% to 0.07%, more preferably 0.05 % by weight of the total volume of the composition.

[0049] In embodiments, an oral liquid composition of the present invention comprises chelating agent which is disodium EDTA.

[0050] Chelating agents are chemical compounds that react with metal ions to form a stable, water-soluble complex. They are also known as chelates, chelators, or sequestering agents. Chelating agents includes but are not limited to, ethylenediaminetetraacetic acid (EDTA), 2,3-dimercaptopropanesulfonic acid (DMPS), and thiamine tetrahydrofurfuryl disulfide (TTFD). The chelating agent can be used in amount from 0.1 % to 0.5% by weight of the total volume of the composition. In the present invention, EDTA is preferred chelating agent. In embodiments, an oral liquid composition of the present invention comprises at least one more pharmaceutically acceptable excipient is selected from preservative, sweetening agent, viscosity agent and pH adjusting agent.

[0051] Preservative includes but are not limited to, sodium benzoate, cresol, ethylparaben, glycerin, hexetidine, imidurea, methylparaben, monothioglycerol, phenol, phenoxyethanol, phenylmercuric acetate, potassium benzoate, propionic acid, propylene glycol, sodium ethyl paraben, sodium propyl paraben and benzalkonium chloride. The preservative can be used in amount from 0.01 % to 0.2% by weight of the total volume of the composition. In the present invention, preferably sodium benzoate is used as preservative.

[0052] Sweetening agents includes but are not limited to, acesulfame K, aspartame, dextrose, fructose, galactose, inulin, maltitol, maltose, mannitol, saccharin, sodium cyclamate, sorbitol, sucralose, sucrose, trehalose, xylitol. The sweetening agent can be used in amount from 20% to 30-% by weight of the total volume of the composition. In the present invention, preferably sodium saccharine is used as sweetening agent.

[0053] Viscosity agents includes but are not limited to, glycerin, carboxymethylcellulose sodium NF, dextrin, gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium aluminum silicate, poloxamer, polyethylene Oxide, polyvinyl Alcohol, povidone, propylene glycol alginate, silicon dioxide, sodium alginate. The viscosity agent can be used in amount from 15% to 25% by weight of the total volume of the composition. In the present invention, preferably glycerin is used as viscosity agent. pH adjusting agents includes but are not limited to acetic acid, hydrobromic acid, citric acid, gluconic acid, potassium acetate, sodium hydroxide, hydrochloric acid, sulfuric acid, potassium sulfate, barium carbonate. The pH adjusting agent can be used in enough amount until pH reaches 4.0-5.0. In the present invention, preferably sodium hydroxide is used as pH adjusting agent. The oral liquid composition of the present invention is prepared by dissolving of Terbutaline sulfate and Guaifenesin in water by heating and then excipients are added into the solution in suitable manner.

[0054] The oral liquid composition of the present invention is intended for oral use and it is in the form of syrup.

[0055] The oral liquid composition of the present invention is used as a medicament for relieving cough by softening phlegm in the respiratory tract, widens the airway and facilitates breathing in patients with asthma or other similar diseases.

[0056] The following examples are intended to illustrate the scope of the present invention but not to limit it thereto.

[0057] Examples:

[0058] Example 1 : An oral liquid composition comprising Terbutaline sulfate and Guaifenesin

[0059] Table-1 Manufacturing Process:

[0060] 1. Water up to 50% of the production batch was transferred into the production tank and heated to 30-35°C. 5% of water out of the total quantity was kept reserved for washing.

[0061] 2. Guaifenesin was added to water and mixed until it dissolved. Heating process was terminated after the dissolution process was completed.

[0062] 3. EDTA was added and mixed until dissolved.

[0063] 4. Added sodium metabisulfite and mixed until dissolved.

[0064] 5. Terbutaline was added and mixed until dissolved.

[0065] 6. Then Sorbitol, glycerol, sodium saccharin, sodium benzoate and citric acid monohydrate were added in sequential manner and mixed until dissolved.

[0066] 7. Menthol and strawberry flavor were dissolved in alcohol and added to the production tank and mixed.

[0067] 8. Rest of the amount of water was added to complete the volume and the product was mixed for at least 15 minutes. (pH is controlled and final pH should be between 4.1 -4.3)

[0068] The impurity profiles of the composition of table-1 have been checked at below mentioned conditions.

[0069] Table 2

[0070] It is evident from the table-2 that level of oxidation impurity at RRT 0.88 is more than 0.2% at initial stage and increased over the time when composition has been prepared without using an antioxidant like sodium metabisulfite. Example-2: Preparation of an oral liquid composition comprising Terbutaline sulfate and Guaifenesin by nitrogen purging

[0071] Table 3

[0072] Manufacturing Process:

[0073] 1. Water up to 50% of the production batch was transferred into the production tank and heated to 30-35°C. 5% of water out of the total quantity was kept reserved for washing.

[0074] 2. Guaifenesin was added to water and mixed until it dissolved. Heating process was terminated after the dissolution process was completed.

[0075] 3. EDTA was added and mixed until dissolved.

[0076] 4. Added sodium metabisulfite and mixed until dissolved.

[0077] 5. Terbutaline was added and mixed until dissolved.

[0078] 6. Sorbitol, glycerol, sodium saccharin, sodium benzoate and citric acid monohydrate were added and mixed until dissolved. 7. Menthol and strawberry flavor were dissolved in alcohol and added to the production tank and mixed.

[0079] 8. Rest of the amount of water was added to complete the volume and the product was mixed for at least 15 minutes. (pH is controlled and final pH should be between 4.1 -4.3)

[0080] The impurity profiles of the composition of table-3 have been checked at below mentioned conditions.

[0081] Table 4

[0082] As per the conventional approach, the inventors of the present invention produced an oral liquid composition under the nitrogen gas to control the oxidation impurity comes at RRT 0.88. However, it is evident that the said oxidation impurity has been increased after 7 days when stored under normal condition and that too out of set specification.

[0083] Example-3: An oral liquid composition comprising Terbutaline sulfate, Guaifenesin and sodium metabisulfite

[0084] Table 5

[0085] Manufacturing Process:

[0086] 1. Water up to 50% of the production batch was transferred into the production tank and heated to 30-35°C. 5% of water was kept reserved for washing.

[0087] 2. Guaifenesin was added to water and mixed until it dissolved. Heating process was terminated after the dissolution process was completed.

[0088] 3. EDTA was added and mixed until dissolved.

[0089] 4. Added sodium metabisulfite and mixed until dissolved.

[0090] 5. Terbutaline was added and mixed until dissolved.

[0091] 6. Sorbitol was added and mixed until dissolved.

[0092] 7. Glycerol was added and mixed until dissolved.

[0093] 8. Sodium Saccharin was added and mixed until dissolved.

[0094] 9. Sodium Benzoate was added and mixed until dissolved.

[0095] 10. Citric acid Monohydrate was added and mixed until dissolved.

[0096] 11. Menthol and strawberry flavor were dissolved in alcohol and added to the production tank and mixed.

[0097] 12. Rest of the amount of water was added to complete the volume and the product was mixed for at least 15 minutes. (pH is controlled and final pH should be between 4.1 -4.3)

[0098] The oral liquid composition of the present invention has been produced under the nitrogen gas during manufacturing process with sodium metabisulfite in an amount of 0.05 % by weight of the total weight of the composition. Then impurity profiles has been checked at initial stage and after 6 days. Table 6

[0099] It is evident from Table 6 that use of sodium metabisulfite effectively control the oxidation impurity comes at RRT 0.88.

[0100] Example-4: Stability of oral liquid composition of Example-3

[0101] An oral liquid composition prepared as per the example-3 has also been checked under the forced degradation condition i.e. with 3% H2O2 for 4 hour and with %30 H2O2 for 2 hours to see the anti-oxidant effects of sodium metabisulfite over the generation of oxidation impurity comes at RRT 0.88. It can be seen from Table 8, there is no oxidation impurity (comes at RRT 0.88) detected even after the treatment of 30% H2O2.

[0102] Table 8

[0103] Example-5: Comparative Stability analysis of oral liquid composition of Example-3

[0104] An impurity profile of the present invention (at initial stage) has been analyzed and compared with along with innovator’s marketed composition and other equivalent compositions, which are provided here in below table-7. Table 7

Claims

CLAIMS1. An oral liquid composition comprising Terbutaline or its pharmaceutically acceptable salt, Guaifenesin, a chelating agent, sodium metabisulfite and at least one more pharmaceutically acceptable excipient.

2. An oral liquid composition according to claim 1 , wherein Terbutaline is present in the composition as sulfate salt.

3. An oral liquid composition according to claim 1 , wherein Terbutaline sulfate is present in an amount of 0.03 % to 0.08% by weight of the total volume of the composition.

4. An oral liquid composition according to claim 1 , wherein Guaifenesin is present in an amount of 0.5% to 3.0% by weight of the total volume of the composition.

5. An oral liquid composition according to claim 1 , wherein sodium metabisulfite is present in an amount of 0.03% to 0.07% by weight of the total volume of the composition.

6. An oral liquid composition according to claim 1 or claim 5, wherein sodium metabisulfite is present in an amount of 0.05% by weight of the total volume of the composition.

7. An oral liquid composition according to claim 1 , wherein the chelating agent is disodium EDTA.

8. An oral liquid composition according to claim 1 , wherein at least one more pharmaceutically acceptable excipient is selected from preservative, sweetening agent, viscosity agent and pH adjusting agent.

9. An oral liquid composition according to claim 1 is used to relieve symptoms such as wheezing, shortness of breath, chest tightness, breathing difficulties, coughing, etc. associated with asthma by reducing bronchoconstriction.O.An oral liquid composition according to claim 1 comprising an oxidation impurity comes at RRT 0.88 less than 0.3%.

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