EP3600275A1 - Stabilized pharmaceutical syrup composition comprising terbutaline sulphate and ambroxol hydrochloride - Google Patents

Stabilized pharmaceutical syrup composition comprising terbutaline sulphate and ambroxol hydrochloride

Info

Publication number
EP3600275A1
EP3600275A1 EP17721224.8A EP17721224A EP3600275A1 EP 3600275 A1 EP3600275 A1 EP 3600275A1 EP 17721224 A EP17721224 A EP 17721224A EP 3600275 A1 EP3600275 A1 EP 3600275A1
Authority
EP
European Patent Office
Prior art keywords
ambroxol
terbutaline
syrup
pharmaceutical
syrup composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP17721224.8A
Other languages
German (de)
French (fr)
Inventor
Hatice Öncel
Yilmaz Çapan
Onur Pinarbasli
Feristah BILGIN
Nagehan Sarraçoglu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ilko Ilac Sanayi ve Ticaret AS
Original Assignee
Ilko Ilac Sanayi ve Ticaret AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ilko Ilac Sanayi ve Ticaret AS filed Critical Ilko Ilac Sanayi ve Ticaret AS
Publication of EP3600275A1 publication Critical patent/EP3600275A1/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • the present invention relates to combined use of terbutaline or a pharmacologically acceptable salt thereof, which is a B2-adrenergic receptor agonist; and ambroxol or a pharmacologically acceptable salt thereof which is a mucolytic agent; and to pharmaceutical compositions of syrup form comprising this combination and to the fields of use thereof.
  • the pharmaceutical syrup formulation of the present invention is stabilized against degradation of the active ingredients.
  • Terbutaline is a B 2 -adrenergic receptor agonist with a molecular formula of C 12 H 19 N0 3 , chemical name of which is (RS-5-[2-(tert)-butylamino)-l-hydroxyethyl] benzene- 1 , 3 -diol. It is marketed under the trade name Bricanyl® (AstraZeneca).
  • Bricanyl® AstraZeneca
  • Terbutaline is a synthetic sympathomimetic agent which basically acts as a B 2 -agonist. It belongs to Biopharmaceutics classification system (BCS) class II drugs which is widely used in treatment of bronchial asthma. The plasma half-life of about 3- 4 hours, also the drug undergoes first pass metabolism and has poor bioavailability (Gobade NG et al., 2012).
  • Terbutaline is an adrenergic agonist which provides relaxation of bronchial smooth muscles basically by stimulating B 2 -receptors; inhibition of endogenous spasmogenic secretion; inhibition of edema caused by endogenous mediators; increase in mucociliary clearance; and relaxation of uterus muscle. It has the following pharmacological effects: l i) In the lung: bronchodilation; increase in mucociliary clearance; suppression of edema and anti-allergic effects.
  • skeletal muscle stimulates Na7K + transport and also causes depression of subtetanic contractions in slow-contracting muscle.
  • Terbutaline was firstly described in the patent numbered BE 704932.
  • This patent comprises processes for preparation of terbutaline; pharmaceutical compositions comprising terbutaline; and use of terbutaline in the treatment of lung diseases such as bronchial asthma, chronic bronchitis, acute bronchospasm, asthma, bronchospasm prophylaxis and chronic obstructive pulmonary disease.
  • lung diseases such as bronchial asthma, chronic bronchitis, acute bronchospasm, asthma, bronchospasm prophylaxis and chronic obstructive pulmonary disease.
  • terbutaline or a pharmacologically acceptable salt is used, preferably terbutaline sulphate is used.
  • Ambroxol is a metabolite of bromhexine (Bisolvon ®), which is itself derived from vasicine, a plant extract from the Malabar nut plant.
  • Bisolvon ® bromhexine
  • ambroxol hydrochloride is used.
  • other acid addition salt including hydrobromate, oxalate, nitrate, sulphonate, fumarate, maleate, sulfate phosphate, and the like or freebase can also be used.
  • Chemical name of ambroxol hydrochloride is trans-4-[2-amino-3,5-dibromobenzyl] amino] cyclohexanol hydrochloride.
  • the structural formula is represented below (Formula II):
  • Ambroxol is an active substance with a local analgesic, mucolytic and antiinflammatory effect which is used to treat sore throats and respiratory diseases accompanied by viscous mucus formation, e.g. in acute aggravations of chronic bronchitis, asthmatic bronchitis and bronchial asthma. It is currently available under the brand names Mucosolvan® (Boehringer Ingelheim).
  • Ambroxol is usually present in medicaments in the form of ambroxol hydrochloride. It belongs to Biopharmaceutics classification system (BCS) class II drugs used as an expectorant, mucolytic agent to treat acute and chronic diseases. It has short plasma half-life 4 hours require frequent daily dosing (2-3 times) (Md. Mizanur Rahman Moghal et al., 2012). It is commercially available, in the form of suckable lozenges, capsules, as an inhalation solution, syrup and linctus.
  • BCS Biopharmaceutics classification system
  • 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 (deMey C. et al., Arzneistoffforschung., 2008, 58(1 1 ): 557558).
  • 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).
  • asthma reactions are characterized by symptoms such as streaming, itching and reddening of the eyes (allergic conjunctivitis); nasal flow, itching and blockage (allergic rhinitis); allergic sinusitis in sinuses; itching, reddening and eruption of the skin (urticaria); nuisance, distension, vomiting and diarrhea in gastrointestinal system; feeling of blockage, ache, hearing disorders associated with dysfunction of Eustachian tube in ears; snooze, cough, bronchoconstriction, shortness of breath, sniffling, asthma attacks and constriction of respiratory tract associated with edema (angioedema) in respiratory tract. Allergies can also trigger asthma attacks. Asthma is a reversible airway constriction characterized in short breath and sniffle occurring as attacks. Asthma is one of the few chronic diseases most frequently seen in children and adults.
  • US2003/0171391 discloses a pharmaceutical composition containing ambroxol or an acceptable salt thereof for the treatment of diseases which are based on powerful activation of voltage-dependent sodium channels, particularly for the treatment of chronic pain.
  • US/391 discloses an aqueous solution comprising an acid addition salt of ambroxol, wherein the ambroxol content is ranging from 0.1 % to 7% (w/v), and the total content of polyalcohols selected from polyols and/or polyalkyleneglycols is at least 20% (w/v), the total content of alcohols is lower than 1 % (w/v).
  • CN105287367 A discloses a pharmaceutical preparation, and in particular relates to an oral liquid preparation of ambroxol hydrochloride as well as a preparation method and application of the oral liquid preparation.
  • EP 1417961 A1 relates to novel pharmaceutical compositions comprising as pharmacologically active compounds a combination of an expectorant-effective amount of bromhexine or ambroxol or a pharmacologically acceptable salt thereof and a parasympatholytic (anticholinergic)-effective amount of isopropamide iodide.
  • WO 2013/154347 relates a liquid formulation for oral administration comprising ambroxol, levodropropizine and a buffering agent, and a method for preparing such formulation are provided.
  • WO 2013/081565 relates to combined use of roflumilast, which is a selective phosphodiesterase-4 (PDE-4) enzyme inhibitor, and terbutaline, which is a ⁇ 2 adrenergic receptor agonist; and to drug compositions comprising this pharmaceutical combination that can be used in the allergic and inflammatory diseases of skin or upper and lower respiratory tracts.
  • PDE-4 selective phosphodiesterase-4
  • 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.
  • ambroxol hydrochloride impurity B trans-4-(6,8-dibromo-1 ,4- dihydroquinazolin-3(2H)-yl)cyclohexanol.
  • This is a well-known compound, reported on European Pharmacopoeia as possible impurity of the active ingredient, due to the interaction between ambroxol with formaldehyde.
  • Other possible impurities due to oxidation reactions are impurity A [(2-amino-3,5-dibromophenyl) methanol] and impurity E (2amino3,5dibromo benzaldeyde).
  • WO 2015/177147 presents a cough syrup containing ambroxol hydrochloride with giving a solution to stability problem of ambroxol hydrochloride in liquid form.
  • This problem is solved formulating a cough syrup containing ambroxol hydrochloride with substantially free from glycerol and sugar alcohol.
  • the product contains less than 1 g and particularly preferably less than 0.5 g glycerol and similarly less than 5 g and particularly preferably less than 1 g sugar alcohol based in each case on 100 ml_ of the cough syrup.
  • ambroxol hydrochloride impurity B originated by degradation of the active ingredient is a common problem of drug products and in particular of liquid forms. Of course, it must be regarded as a negative aspect which may limit the stability of the product. However, under certain storage conditions involving contact with the air, stability problems can still occur. Therefore, there still exists a need for new stable syrup formulations.
  • a stable, liquid formulation comprising terbutaline sulphate and ambroxol hydrochloride is studied.
  • This combination has the same efficacy with each pharmaceutical composition separately even in a small quantity, e.g., 10 mL or less, for improving patient compliance.
  • the present invention relates to a unit-dose combination formulation for the combined delivery of terbutaline sulphate and ambroxol hydrochloride.
  • a chemically and physically stable dosage form which can provide therapeutic levels of terbutaline sulphate and ambroxol hydrochloride from the same unit-dose formulation in a fashion similar to each of the separate products available commercially would be extremely beneficial in the treatment of bronchial asthma for patients.
  • the combination of terbutaline sulphate and ambroxol hydrochloride product is not available in the market. Hence there is a need for patient compliant combination of terbutaline sulphate and ambroxol hydrochloride for treatment of bronchial asthma in order to eliminate taking each drug three times a day.
  • compositions of the invention are prepared by formulating the active agents together with at least one pharmaceutically acceptable excipient and combining them in a single dosage form.
  • the aim of the present invention was to develop, formulate and evaluation of terbutaline sulphate and ambroxol hydrochloride syrup formulation for maintenance treatment of lung diseases that have emerged as a secretion complication of asthma and bronchospasm.
  • Another aim of the present invention was to provide an oral pharmaceutical syrup composition comprising terbutaline sulphate and ambroxol hydrochloride wherein a significantly improved pharmaceutical stability.
  • an oral pharmaceutical syrup composition wherein the pH of the composition is optimized within a range for solubility of the active ingredients.
  • a sugar-free oral pharmaceutical syrup composition with a pleasant taste.
  • pharmaceutical composition of the present invention has a pleasant taste that permits it to be administrated to children without any reluctance.
  • terbutaline and “ambroxol” used in the present invention refers to free bases or pharmaceutically acceptable salts, enantiomers, racemates, solvates, hydrates, various polymorphic forms, amorphous and crystalline forms of said active agents or combinations thereof.
  • terbutaline sulphate and ambroxol hydrochloride were used.
  • terbutaline sulphate and ambroxol hydrochloride are considered to cooperate favorable in the treatment of bronchial asthma.
  • Terbutaline sulphate is a B2-adrenergic receptor agonist used to provide relaxation of bronchial smooth muscles;
  • ambroxol hydrochloride is a mucolytic agent used to treat respiratory diseases associated with viscid or excessive mucus accumulated in respiratory track. Therefore this product is used for maintenance treatment of lung diseases that have emerged as a secretion complication of asthma and bronchospasm.
  • An even further object of the present invention is to obtain a combination formulation wherein the product may provide a better advantage to the patients by improving therapeutic activity compared to monotherapy.
  • compositions of this invention are used as liquid preparations of oral administration as syrup.
  • thickening agent of the present invention is selected from the group comprising, but not limited to, cellulose derivatives which can be cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, methyl cellulose, microcrystalline cellulose and the like or combination thereof.
  • cellulose derivatives which can be cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, methyl cellulose, microcrystalline cellulose and the like or combination thereof.
  • HEC hydroxyethyl cellulose
  • preservatives like alcohols, benzoates, sorbates, and parabens is common in liquid formulations. Preservatives are effective in controlling mold, inhibiting yeast growth and protecting against bacterial proliferation, thus, finally, to allow compliance with the European Pharmacopoeia microbiological specifications (Ph. Eur. 6.7, 5.1 .4) for "aqueous preparations for oral use” or "aqueous preparations for oromucosal use”. The use of preservatives is particularly recommended in aqueous compositions, wherein microorganisms can find favorable conditions for their propagation.
  • the solution of this invention preferably comprises a taste masking agent.
  • acesulfam potassium was used both as sweetener and bitter taste masking agent.
  • the oral pharmaceutical syrup composition has a pH range of between 2.5-4.5 values with using a pH adjustment agent namely citric acid monohydrate.
  • the oral liquid pharmaceutical composition can also contain other excipients commonly found in pharmaceutical compositions such as diluent and flavoring agent.
  • compositions of this invention are detailed below showing examples. However, pharmaceutical compounds of this invention are not restricted to the following examples.
  • Total of 150 ml syrup was manufactured by dissolving the following ingredients in distilled water.
  • Citric Acid Monohydrate q.s.
  • Terbutaline sulphate and ambroxol hydrochloride which are active in the formulation, completely dissolve in water to form a clear solution. Additions should be made taking into account the water solubility and properties of the active substances and auxiliary substances.
  • HEC hydroxyethyl cellulose
  • the pH of the syrup was adjusted to 2.1 with using required amount of citric acid monohydrate. All ingredients were dissolved in adequate amount of deionized water to prepare 150 mL total syrup.
  • Example 2 hydroxyethyl cellulose
  • Total of 150 ml syrup was manufactured by dissolving the following ingredients in distilled water.
  • Terbutaline sulphate and ambroxol hydrochloride which are active in the formulation, completely dissolve in water to form a clear solution. Additions should be made taking into account the water solubility and properties of the active substances and auxiliary substances.
  • HEC hydroxyethyl cellulose
  • all excipients were mixed without using citric acid monohydrate as pH adjustment agent. Therefore final pH of syrup was 5.00 without any adjustment.
  • Total of 150 ml syrup was manufactured by dissolving the following ingredients in distilled water.
  • Citric Acid Monohydrate q.s.
  • Terbutaline sulphate and ambroxol hydrochloride which are active in the formulation, completely dissolve in water to form a clear solution. Additions should be made taking into account the water solubility and properties of the active substances and auxiliary substances.
  • HEC hydroxyethyl cellulose
  • the pH of the syrup was adjusted to between 2.5-4.5 with using required amount of citric acid monohydrate. All ingredients were dissolved in adequate amount of deionized water to prepare 150 mL total syrup.
  • Total of 150 ml syrup was manufactured by dissolving the following ingredients in distilled water.
  • Citric Acid Monohydrate q.s.
  • Terbutaline sulphate and ambroxol hydrochloride which are active in the formulation, completely dissolve in water to form a clear solution. Additions should be made taking into account the water solubility and properties of the active substances and auxiliary substances.
  • HEC hydroxyethyl cellulose
  • the pH of the syrup was adjusted to between 2.5-4.5 with using required amount of citric acid monohydrate. All ingredients were dissolved in adequate amount of deionized water to prepare 150 mL total syrup.
  • Example 1 Example 2 Example 3 Example 4
  • ambroxol impurity B should not exceed 0.2% (w/w) limit.
  • the amount of impurity B was lower than ICH impurity limit when compared with example 1 -2 and 4 at initial conditions.
  • HEC hydroxyethyl cellulose
  • pH of the syrup are critical parameters for the impurity profile. Both the change in the hydroxyethyl cellulose (HEC) amount and the change in the pH value cause an increase in the amount of ambroxol impurity B. Therefore in this invention these two parameters were fixed in order to have stable syrup formulation.
  • the stability of a drug substance is an important factor in the manufacture of safe and effective pharmaceutical products. Stability studies are required to be submitted by any applicant seeking approval for a new pharmaceutical product.
  • the rules in force e.g. "Note for Guidance on Impurities in New Drug Products” CPMP/ICH/2738/99, issued by EMEA, European Medicines Agency) provide strict limitations for impurities, nevertheless it is better to prevent or reduce as possible the degradation to avoid the exposure of patients to substances.
  • Accelerated stability tests are performed by storing a product in stress conditions. These tests allow predicting the shelf life of the product over the years when it will be stored in normal storage conditions.
  • the accelerated stability test in this case was performed according to the EMEA Guideline on Stability Testing (CPMP/QWP/122/02, rev 1 ), i.e. by maintaining the product in its container at a temperature of 40 °C ⁇ 2°C and 75% ⁇ 5 %RH (Relative Humidity) for six months.

Abstract

The invention relates to develop a stable, combination of terbutaline sulphate and ambroxol hydrochloride pharmaceutical compositions of syrup for treatment of bronchial asthma. This syrup is stabilized against degradation of the active ingredients by formulating with specific amount of thickening agent in unit dose (w/v %) and adjusting the final pH value of the product into a specific range. Also, this product is used for the treatment of bronchial asthma with maintenance treatment of lung diseases that have emerged as a secretion complication of asthma and bronchospasm.

Description

STABILIZED PHARMACEUTICAL SYRUP COMPOSITION COMPRISING TERBUTALINE SULPHATE AND AMBROXOL HYDROCHLORIDE
DESCRIPTION
Technical field:
The present invention relates to combined use of terbutaline or a pharmacologically acceptable salt thereof, which is a B2-adrenergic receptor agonist; and ambroxol or a pharmacologically acceptable salt thereof which is a mucolytic agent; and to pharmaceutical compositions of syrup form comprising this combination and to the fields of use thereof. The pharmaceutical syrup formulation of the present invention is stabilized against degradation of the active ingredients.
Prior Art:
Terbutaline is a B2-adrenergic receptor agonist with a molecular formula of C12H19N03, chemical name of which is (RS-5-[2-(tert)-butylamino)-l-hydroxyethyl] benzene- 1 , 3 -diol. It is marketed under the trade name Bricanyl® (AstraZeneca). The structural formula terbutaline is represented below (Formula I):
Formula (I) Terbutaline is a synthetic sympathomimetic agent which basically acts as a B2-agonist. It belongs to Biopharmaceutics classification system (BCS) class II drugs which is widely used in treatment of bronchial asthma. The plasma half-life of about 3- 4 hours, also the drug undergoes first pass metabolism and has poor bioavailability (Gobade NG et al., 2012). Terbutaline is an adrenergic agonist which provides relaxation of bronchial smooth muscles basically by stimulating B2-receptors; inhibition of endogenous spasmogenic secretion; inhibition of edema caused by endogenous mediators; increase in mucociliary clearance; and relaxation of uterus muscle. It has the following pharmacological effects: l i) In the lung: bronchodilation; increase in mucociliary clearance; suppression of edema and anti-allergic effects.
ii) In skeletal muscle: stimulates Na7K+ transport and also causes depression of subtetanic contractions in slow-contracting muscle.
iii) In uterine muscle: inhibition of uterine contractions.
iv) In the CNS: low penetration into the blood-brain barrier at therapeutic doses, due to the highly hydrophilic nature of the molecule.
v) In the CVS: administration of terbutaline results in cardiovascular effects mediated through β2-ΓβοβρίθΓ5 in the peripheral arteries and in the heart e.g. in healthy subjects, 0.25 - 0.5 mg injected s.c is associated with an increase in cardiac output (up to 85% over controls) due to an increase in heart rate and a larger stroke volume.
Terbutaline was firstly described in the patent numbered BE 704932. This patent comprises processes for preparation of terbutaline; pharmaceutical compositions comprising terbutaline; and use of terbutaline in the treatment of lung diseases such as bronchial asthma, chronic bronchitis, acute bronchospasm, asthma, bronchospasm prophylaxis and chronic obstructive pulmonary disease. In the present invention, terbutaline or a pharmacologically acceptable salt is used, preferably terbutaline sulphate is used.
Ambroxol is a metabolite of bromhexine (Bisolvon ®), which is itself derived from vasicine, a plant extract from the Malabar nut plant. In the present invention, preferably ambroxol hydrochloride is used. However, other acid addition salt including hydrobromate, oxalate, nitrate, sulphonate, fumarate, maleate, sulfate phosphate, and the like or freebase can also be used. Chemical name of ambroxol hydrochloride is trans-4-[2-amino-3,5-dibromobenzyl] amino] cyclohexanol hydrochloride. The structural formula is represented below (Formula II):
Ambroxol is an active substance with a local analgesic, mucolytic and antiinflammatory effect which is used to treat sore throats and respiratory diseases accompanied by viscous mucus formation, e.g. in acute aggravations of chronic bronchitis, asthmatic bronchitis and bronchial asthma. It is currently available under the brand names Mucosolvan® (Boehringer Ingelheim).
Ambroxol is usually present in medicaments in the form of ambroxol hydrochloride. It belongs to Biopharmaceutics classification system (BCS) class II drugs used as an expectorant, mucolytic agent to treat acute and chronic diseases. It has short plasma half-life 4 hours require frequent daily dosing (2-3 times) (Md. Mizanur Rahman Moghal et al., 2012). It is commercially available, in the form of suckable lozenges, capsules, as an inhalation solution, syrup and linctus.
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 (deMey C. et al., Arzneimittelforschung., 2008, 58(1 1 ): 557558). 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).
Many allergic reactions are characterized by symptoms such as streaming, itching and reddening of the eyes (allergic conjunctivitis); nasal flow, itching and blockage (allergic rhinitis); allergic sinusitis in sinuses; itching, reddening and eruption of the skin (urticaria); nuisance, distension, vomiting and diarrhea in gastrointestinal system; feeling of blockage, ache, hearing disorders associated with dysfunction of Eustachian tube in ears; snooze, cough, bronchoconstriction, shortness of breath, sniffling, asthma attacks and constriction of respiratory tract associated with edema (angioedema) in respiratory tract. Allergies can also trigger asthma attacks. Asthma is a reversible airway constriction characterized in short breath and sniffle occurring as attacks. Asthma is one of the few chronic diseases most frequently seen in children and adults.
US2003/0171391 discloses a pharmaceutical composition containing ambroxol or an acceptable salt thereof for the treatment of diseases which are based on powerful activation of voltage-dependent sodium channels, particularly for the treatment of chronic pain. US/391 discloses an aqueous solution comprising an acid addition salt of ambroxol, wherein the ambroxol content is ranging from 0.1 % to 7% (w/v), and the total content of polyalcohols selected from polyols and/or polyalkyleneglycols is at least 20% (w/v), the total content of alcohols is lower than 1 % (w/v). CN105287367 A discloses a pharmaceutical preparation, and in particular relates to an oral liquid preparation of ambroxol hydrochloride as well as a preparation method and application of the oral liquid preparation.
EP 1417961 A1 relates to novel pharmaceutical compositions comprising as pharmacologically active compounds a combination of an expectorant-effective amount of bromhexine or ambroxol or a pharmacologically acceptable salt thereof and a parasympatholytic (anticholinergic)-effective amount of isopropamide iodide.
WO 2013/154347 relates a liquid formulation for oral administration comprising ambroxol, levodropropizine and a buffering agent, and a method for preparing such formulation are provided.
WO 2013/081565 relates to combined use of roflumilast, which is a selective phosphodiesterase-4 (PDE-4) enzyme inhibitor, and terbutaline, which is a β2 adrenergic receptor agonist; and to drug compositions comprising this pharmaceutical combination that can be used in the allergic and inflammatory diseases of skin or upper and lower respiratory tracts.
In a combination study conducted by Kimbahune R. (Volume 8, Issue 2, May - June 201 1 ; Article-004), ambroxol HCI, guaifenesin and terbutaline sulphate in syrup form is indicated for clinical relief of cough associated with bronchitis, bronchial asthma, emphysema and other bronchopulmonary disorders where bronchospasm, mucous plugging and problems of expectoration co-exist.
However, there have been found that an increase in the amount of related substances of ambroxol is observed in a liquid formulation of ambroxol. In the prior art there is a drawback of the formulations containing ambroxol, both at low and at high concentration, which is the formation of several degradation impurities, both during storage and stability studies.
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.
One of the main impurities produced during the storage of the product, according to EP1543826, is the ambroxol hydrochloride impurity B [trans-4-(6,8-dibromo-1 ,4- dihydroquinazolin-3(2H)-yl)cyclohexanol]. This is a well-known compound, reported on European Pharmacopoeia as possible impurity of the active ingredient, due to the interaction between ambroxol with formaldehyde. Other possible impurities due to oxidation reactions are impurity A [(2-amino-3,5-dibromophenyl) methanol] and impurity E (2amino3,5dibromo benzaldeyde).
WO 2015/177147 presents a cough syrup containing ambroxol hydrochloride with giving a solution to stability problem of ambroxol hydrochloride in liquid form. This problem is solved formulating a cough syrup containing ambroxol hydrochloride with substantially free from glycerol and sugar alcohol. Indeed, the product contains less than 1 g and particularly preferably less than 0.5 g glycerol and similarly less than 5 g and particularly preferably less than 1 g sugar alcohol based in each case on 100 ml_ of the cough syrup.
The formation of ambroxol hydrochloride impurity B originated by degradation of the active ingredient is a common problem of drug products and in particular of liquid forms. Of course, it must be regarded as a negative aspect which may limit the stability of the product. However, under certain storage conditions involving contact with the air, stability problems can still occur. Therefore, there still exists a need for new stable syrup formulations.
Guruprasad P. et al. (2014) studied on interaction between terbutaline sulphate and ambroxol hydrochloride by FTIR study. From the spectra of terbutaline sulphate and ambroxol hydrochloride, physical mixture of terbutaline sulphate and ambroxol hydrochloride and excipients, it was observed that all the characteristic peak of terbutaline sulphate and ambroxol hydrochloride were present in the combination spectrum, thus indicating compatibility of terbutaline sulphate and ambroxol hydrochloride with excipients.
Also, according to clinical studies applied in China (ZHANG Yihua Department of Pharmacy) show that terbutaline combined with ambroxol hydrochloride is fairly effective, safe and reliable and can improve the treatment effective rate and accelerate the disappearance of clinical symptoms in the treatment of bronchial asthma.
In the present invention a stable, liquid formulation comprising terbutaline sulphate and ambroxol hydrochloride is studied. This combination has the same efficacy with each pharmaceutical composition separately even in a small quantity, e.g., 10 mL or less, for improving patient compliance.
The present invention relates to a unit-dose combination formulation for the combined delivery of terbutaline sulphate and ambroxol hydrochloride. A chemically and physically stable dosage form which can provide therapeutic levels of terbutaline sulphate and ambroxol hydrochloride from the same unit-dose formulation in a fashion similar to each of the separate products available commercially would be extremely beneficial in the treatment of bronchial asthma for patients. However, the combination of terbutaline sulphate and ambroxol hydrochloride product is not available in the market. Hence there is a need for patient compliant combination of terbutaline sulphate and ambroxol hydrochloride for treatment of bronchial asthma in order to eliminate taking each drug three times a day.
Description of the Invention:
The characteristic of the pharmaceutical compositions of the invention is that said compositions are prepared by formulating the active agents together with at least one pharmaceutically acceptable excipient and combining them in a single dosage form.
The aim of the present invention was to develop, formulate and evaluation of terbutaline sulphate and ambroxol hydrochloride syrup formulation for maintenance treatment of lung diseases that have emerged as a secretion complication of asthma and bronchospasm.
Another aim of the present invention was to provide an oral pharmaceutical syrup composition comprising terbutaline sulphate and ambroxol hydrochloride wherein a significantly improved pharmaceutical stability.
There is also provided an oral pharmaceutical syrup composition wherein the pH of the composition is optimized within a range for solubility of the active ingredients. There is also provided a sugar-free oral pharmaceutical syrup composition with a pleasant taste. Thus, pharmaceutical composition of the present invention has a pleasant taste that permits it to be administrated to children without any reluctance.
The terms "terbutaline" and "ambroxol" used in the present invention refers to free bases or pharmaceutically acceptable salts, enantiomers, racemates, solvates, hydrates, various polymorphic forms, amorphous and crystalline forms of said active agents or combinations thereof. In this invention, terbutaline sulphate and ambroxol hydrochloride were used.
The mechanisms of action of terbutaline sulphate and ambroxol hydrochloride are considered to cooperate favorable in the treatment of bronchial asthma. Terbutaline sulphate is a B2-adrenergic receptor agonist used to provide relaxation of bronchial smooth muscles; ambroxol hydrochloride is a mucolytic agent used to treat respiratory diseases associated with viscid or excessive mucus accumulated in respiratory track. Therefore this product is used for maintenance treatment of lung diseases that have emerged as a secretion complication of asthma and bronchospasm. An even further object of the present invention is to obtain a combination formulation wherein the product may provide a better advantage to the patients by improving therapeutic activity compared to monotherapy.
Pharmaceutical compositions of this invention are used as liquid preparations of oral administration as syrup.
According to an embodiment, thickening agent of the present invention is selected from the group comprising, but not limited to, cellulose derivatives which can be cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, methyl cellulose, microcrystalline cellulose and the like or combination thereof. In this invention hydroxyethyl cellulose (HEC) is used as thickening agent with an amount of lower than 0.4% (w/v).
The use of preservatives, like alcohols, benzoates, sorbates, and parabens is common in liquid formulations. Preservatives are effective in controlling mold, inhibiting yeast growth and protecting against bacterial proliferation, thus, finally, to allow compliance with the European Pharmacopoeia microbiological specifications (Ph. Eur. 6.7, 5.1 .4) for "aqueous preparations for oral use" or "aqueous preparations for oromucosal use". The use of preservatives is particularly recommended in aqueous compositions, wherein microorganisms can find favorable conditions for their propagation.
As it is well known, ambroxol is characterized by a particularly bitter aftertaste; therefore, it is particularly difficult to mask the aftertaste of ambroxol even when the excipients present in the solution. Accordingly, the solution of this invention preferably comprises a taste masking agent. In this invention, acesulfam potassium was used both as sweetener and bitter taste masking agent.
According to an embodiment of the present invention, the oral pharmaceutical syrup composition has a pH range of between 2.5-4.5 values with using a pH adjustment agent namely citric acid monohydrate.
According to an embodiment of the present invention, the oral liquid pharmaceutical composition can also contain other excipients commonly found in pharmaceutical compositions such as diluent and flavoring agent. Compositions of this invention are detailed below showing examples. However, pharmaceutical compounds of this invention are not restricted to the following examples.
Example 1.
Total of 150 ml syrup was manufactured by dissolving the following ingredients in distilled water.
Terbutalin Sulphate - % amount in unit Ambroxol HCI Syrup dose (%w/v)
Terbutaline Sulphate 0.01 -0.15
Ambroxol HCI 0.20-0.70
Sorbitol 20.0-35.0
Glycerin 3.0-10.0
Sodium Benzoate 0.02-0.5
Acesulfam K 0.50-3.0
Citric Acid Monohydrate q.s.
Hydroxyethyl cellulose <0.4
Strawberry Flavor q.s.
Vanilla Flavor q.s.
Deionized Water q.s.
Terbutaline sulphate and ambroxol hydrochloride, which are active in the formulation, completely dissolve in water to form a clear solution. Additions should be made taking into account the water solubility and properties of the active substances and auxiliary substances. In this formulation, when hydroxyethyl cellulose (HEC) is used with an amount of lower than 0.4% (w/v), the pH of the syrup was adjusted to 2.1 with using required amount of citric acid monohydrate. All ingredients were dissolved in adequate amount of deionized water to prepare 150 mL total syrup. Example 2.
Total of 150 ml syrup was manufactured by dissolving the following ingredients in distilled water.
Terbutalin Sulphate - % amount in unit
Ambroxol HCI Syrup dose (%w/v)
Terbutaline Sulphate 0.01 -0.15
Ambroxol HCI 0.20-0.70
Sorbitol 20.0-35.0
Glycerin 3.0-10.0
Sodium Benzoate 0.02-0.5
Acesulfam K 0.50-3.0
Hydroxyethyl cellulose <0.4
Strawberry Flavor q.s.
Vanilla Flavor q.s.
Deionized Water q.s.
Terbutaline sulphate and ambroxol hydrochloride, which are active in the formulation, completely dissolve in water to form a clear solution. Additions should be made taking into account the water solubility and properties of the active substances and auxiliary substances. In this formulation, when hydroxyethyl cellulose (HEC) is used with an amount of lower than 0.4% (w/v), all excipients were mixed without using citric acid monohydrate as pH adjustment agent. Therefore final pH of syrup was 5.00 without any adjustment. Example 3.
Total of 150 ml syrup was manufactured by dissolving the following ingredients in distilled water.
Terbutalin Sulphate - % amount in unit
Ambroxol HCI Syrup dose (%w/v)
Terbutaline Sulphate 0.01 -0.15
AmbroxolHCI 0.20-0.70
Sorbitol 20.0-35.0
Glycerin 3.0-10.0
Sodium Benzoate 0.02-0.5
Acesulfam K 0.50-3.0
Citric Acid Monohydrate q.s.
Hydroxyethyl cellulose <0.4
Strawberry Flavor q.s.
Vanilla Flavor q.s.
Deionized Water q.s.
Terbutaline sulphate and ambroxol hydrochloride, which are active in the formulation, completely dissolve in water to form a clear solution. Additions should be made taking into account the water solubility and properties of the active substances and auxiliary substances. In this formulation, when hydroxyethyl cellulose (HEC) is used with an amount of lower than 0.4% (w/v), the pH of the syrup was adjusted to between 2.5-4.5 with using required amount of citric acid monohydrate. All ingredients were dissolved in adequate amount of deionized water to prepare 150 mL total syrup. Example 4.
Total of 150 ml syrup was manufactured by dissolving the following ingredients in distilled water.
Terbutalin Sulphate - % amount in unit
Ambroxol HCI Syrup dose (%w/v)
Terbutaline Sulphate 0.01 -0.15
AmbroxolHCI 0.20-0.70
Sorbitol 20.0-35.0
Glycerin 3.0-10.0
Sodium Benzoate 0.02-0.5
Acesulfam K 0.50-3.0
Citric Acid Monohydrate q.s.
Hydroxyethyl cellulose 0.5
Strawberry Flavor q.s.
Vanilla Flavor q.s.
Deionized Water q.s.
Terbutaline sulphate and ambroxol hydrochloride, which are active in the formulation, completely dissolve in water to form a clear solution. Additions should be made taking into account the water solubility and properties of the active substances and auxiliary substances. In this formulation, when hydroxyethyl cellulose (HEC) is used with an amount of 0.5% (w/v), the pH of the syrup was adjusted to between 2.5-4.5 with using required amount of citric acid monohydrate. All ingredients were dissolved in adequate amount of deionized water to prepare 150 mL total syrup.
An in-house HPLC analysis was performed to quantify terbutaline sulphate, ambroxol HCI and impurities in the formulations. The HPLC Assay (%) analyses were performed for all experiments at T0 time (initial condition). The assay (%) results are summarized in the Table 1 . Table 1. Initial condition assay (%) data of studied formulations
Assay (%) at Initial Condition (t0)
Example 1 Example 2 Example 3 Example 4
HEC<0,4% (w/v) HEC<0,4% (w/v) HEC<0,4% (w/v) HEC 0,5% (w/v) pH 2.1 pH 5.0 pH 2.5-4.5 pH 2.5-4.5
Terbutaline
100,8 100,1 101 ,6 99,8
Sulphate
Ambroxol HCI 99,4 100,5 98,4 98,7
Ambroxol
0,42 0,43 0,09 0,53
Impurity B
Terbutaline
ND* ND* ND* ND*
Impurity C
*ND: Not detected.
According to ICH guidelines Impurities in New Drug products. (Q3B), ambroxol impurity B should not exceed 0.2% (w/w) limit. The results demonstrated that in example 3, according to the present invention, the amount of impurity B was lower than ICH impurity limit when compared with example 1 -2 and 4 at initial conditions. This situation shows that in example 3 amount of hydroxyethyl cellulose (HEC) and pH of the syrup are critical parameters for the impurity profile. Both the change in the hydroxyethyl cellulose (HEC) amount and the change in the pH value cause an increase in the amount of ambroxol impurity B. Therefore in this invention these two parameters were fixed in order to have stable syrup formulation.
Stability Studies
The stability of a drug substance is an important factor in the manufacture of safe and effective pharmaceutical products. Stability studies are required to be submitted by any applicant seeking approval for a new pharmaceutical product. The rules in force (e.g. "Note for Guidance on Impurities in New Drug Products" CPMP/ICH/2738/99, issued by EMEA, European Medicines Agency) provide strict limitations for impurities, nevertheless it is better to prevent or reduce as possible the degradation to avoid the exposure of patients to substances.
It is known that many drugs exhibit poor or modest shelf stability. The presence of degradation products of these drugs can give rise to efficacy or toxicity issues, but even if they do not, the diminution of the concentration of a drug as a result of its degradation is inherently undesirable, as it make therapy with the drug less certain. Stability issues can be caused by environmental factors such as humidity, temperature and the like. However, degradation may result from, or be accelerated by, interactions of drug substances with pharmaceutical excipients such as fillers, binders, lubricants, glidants and disintegrating agents or impurities contained in any of these excipients.
Accelerated stability tests are performed by storing a product in stress conditions. These tests allow predicting the shelf life of the product over the years when it will be stored in normal storage conditions. The accelerated stability test in this case was performed according to the EMEA Guideline on Stability Testing (CPMP/QWP/122/02, rev 1 ), i.e. by maintaining the product in its container at a temperature of 40 °C ± 2°C and 75% ± 5 %RH (Relative Humidity) for six months.
Thus, in the development of terbutaline sulphate and ambroxol hydrochloride combination syrup form, the applicant carried out accelerated stability studies on the drug at a temperature of 40°C ± 2°C and 75 % ± 5°C RH for up to 6 months.
The syrup formulations were packed into the dark glass containers and such containers were further packed into the cartoons, and cartoons were charged on to the stability cabinets. Samples were taken out at each stability stage interval and submitted for analysis. The results are summarized in the following Table 2.
Table 2. Stability data of Example 3 formulation over 6 months period and 40°C ± 2°C and 75 % ± 5°C RH humidity
Assay (%) of Example 3 formulation
Initial (t0) 1st month 3rd month 6th month
Terbutaline
101 ,6 102,0 99,6 100,2
Sulphate
AmbroxolHCI 98,4 97,4 97,0 96,4
Ambroxol
0,09 0,1 1 0,14 0,16
Impurity B
Terbutaline
ND* ND* ND* ND*
Impurity C
*Not detected The stability results showed that during six months of storage in accelerated stability conditions, Impurity B in the present invention was increased much less than expected when subjected to 40°±2°C temperature and 75±5 % RH humidity. Also no degradation products were observed or levels of degradation product were below the limits of quantification according to the analytical method adopted. The present inventors during development of combined formulation of terbutaline sulphate and ambroxol hydrochloride syrup compositions encountered problem of raising ambroxol impurity B during stability and is crossing ICH limits in 6 months of accelerated condition. Also results show that the combination of invention have no impact on the degradation profile of terbutaline sulphate. The applicant has surprisingly found that the present invention which is a combination liquid dosage form is stabilized in terms of degradation. Developed formulation content and production technique allowed keeping the ambroxol impurity B of product in the limits defined in ICH guidelines during their shelf life.

Claims

1 . A pharmaceutical syrup composition, characterized in that said composition comprises a combination of ambroxol or a pharmacologically acceptable salt and terbutaline or a pharmacologically acceptable salt thereof as active agents wherein the amount of thickening agent in unit dose is lower than 0.4% (w/v) and the syrup composition has a pH range between 2.5-4.5.
2. The pharmaceutical syrup composition according to claim 1 comprising ambroxol hydrochloride and terbutaline sulphate.
3. The pharmaceutical syrup composition according to claim 1 wherein the thickening agent is selected from the group comprising cellulose derivatives which can be cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, methyl cellulose, microcrystalline cellulose or combination thereof.
4. The pharmaceutical syrup composition according to claim 3, wherein the cellulose derivative is hydroxyethyl cellulose.
5. The pharmaceutical syrup composition according to preceding claims, characterized in that the composition comprises terbutaline sulphate in a concentration of 0.3 mg/mL to 0.9 mg/mL.
6. The pharmaceutical syrup composition according to preceding claims, characterized in that the composition comprises ambroxol hydrochloride in a concentration of 3 mg/mL to 6 mg/mL.
7. The pharmaceutical syrup formulation according to preceding claims, in which after storage at 40 °C ± 2°C and 75% + 5 %RH for at least 6 months, at least 95% of the active compound remains.
8. The pharmaceutical syrup composition according to preceding claims, having less than 0.2 % (w/w) of ambroxol Impurity B after 6 months at 40 °C ± 2°C and 75% + 5
%RH.
9. The pharmaceutical syrup composition according to preceding claims for use in the maintenance treatment of lung diseases that have emerged as a secretion complication of asthma and bronchospasm.
EP17721224.8A 2017-03-27 2017-03-27 Stabilized pharmaceutical syrup composition comprising terbutaline sulphate and ambroxol hydrochloride Withdrawn EP3600275A1 (en)

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