Digisha J. Ahir*, Hasumati A. Raj, Vinit C. Jain

BAMIFYLLINE HCl: A REVIEW OF ANALYTICAL METHODS FOR ITS DETERMINATION IN PHARMACEUTICAL DOSAGE FORMS AND BIOLOGICAL SAMPLES

Digisha J. Ahir*, Hasumati A. Raj, Vinit C. Jain

Department of Quality Assurance,

Shree Dhanvantary Pharmacy College,Kim,Gujarat

*Email:

*Address of correspondence:

Department of Quality Assurance

Shree Dhanvantary Pharmacy College,

Near Railway Station, Kudsad Road,

At: Kim (E),Ta:Olpad,

Dist. Surat, Gujarat (India)

Pin Code-394110

Ph. no. 7600273848

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ABSTRACT:

BamifyllineHCl is a drug of the xanthine chemical class used in asthma and Chronic Obstructive Pulmonary Disease(COPD).It acts as a selective adenosine A1 receptor antagonist.It is a bronchodilator that dilates the bronchi and used in the management of reversible airways obstruction.It is also Non-selective phosphodiesterase inhibitor. BamifyllineHCl is obtained by bisubstitution of theophylline and also known as benzetamophylline with reduced disadvantages as compared to theophylline.The clinical and pharmaceutical analysis of this drug requires effective analytical procedures for quality control and pharmacodynamic and pharmacokinetic studies as well as stability study. An extensive survey of the literature published in various analytical and pharmaceutical chemistry related journals has been conducted and the instrumental analytical methods which were developed and used for determination of Bamifylline in bulk drugs,formulations and biological fluids have been reviewed including chromatographic methods HPTLC, Impurity profiling RP-HPLC, Bioanalytical RP-HPLC,Ion selective electrode determination based on ion pair formation.This review also covers clinical trial studies of BamifyllineHCl. The application of these methods for the determination of BamifyllineHCl in pharmaceutical formulations and biological samples has been also discussed. This article also reviews the significance and pharmacological aspects of this novel xanthinederivative antiasthmatic drug, BamifyllineHCl.

KEY WORDS:BamifyllineHCl, Antiasthmatic agent, Xanthine derivative

INTRODUCTION:

Bronchial Asthma is characterized by hyperresponsiveness of tracheobronchial smooth muscle to a variety of stimuli, resulting in narrowing of air tubes, often accompanied by increased secretion, mucosal edema and mucus plugging[1].Chronic Obstructive Pulmonary Disease(COPD) is a progressive disease with emphysema(alveolar destruction) and bronchiolar fibrosis in variable proportions[1].Asthma is an inflammatory disease of the airways in which the mucous membrane and muscle layers of the bronchi become thickened and the mucous glands enlarge, reducing airflow in the lower respiratory tract.During an asthmatic attack spasmodic contraction of bronchial muscle (bronchospasm)constricts the airway and there is excessive secretion of thick sticky mucus which further reduces the airway. Inspiration is normal but only partial expiration is achieved, so the lungs become hyperinflated and there is severe dyspnoea and wheezing. The duration of attacks usually varies from a few minutes to hours, and very occasionally, days (statusasthmaticus).In severe acute attacks the bronchi may be obstructed by mucus plugs, leading to acute respiratory failure, hypoxia and possibly death.Non-specific factors that may precipitate asthma attacks include:cold air,cigarette smoking, air pollution,upper respiratory tract infection,emotional stress,strenuous exercise[2].

There are many approaches for the treatment of these diseases.

CLASSES OF ANTIASTHMATIC DRUGS[1]:

1. Bronchodilators:

1. β2Sympathomimetics: Salbutamol, Terbutaline, Bambuterol, Salmeterol, Formeterol, Ephedrine.
2. Methyl Xanthines: Theophylline,Aminophylline,Cholinetheophylline, Hydroxyethyltheophylline, TheophyllineEthanolate of piperazine, Doxophylline.
3. Anticholinergics: Ipratopium Bromide, Tiotropium Bromide.

1. Leucotriene antagonists: Montelukast, Zafirlukast.

1. Mast cell stabilizers: Sodium cromoglycate, Ketotifen.

1. Corticosteroides:

1. Systemic: Hydrocortisone, Prednisolone and others
2. Inhalational: Beclomethasonedipropionate, Fluticasonedipropionate, Flunisonide, Ciclesonide.

1. Anti-IgE antibody: Omalizumab

BAMIFYLLINE HCl:

BamifyllineHCl is a class of xanthine derivative[3].It is also known as benzetamophylline, retains a broad spectrum of pharmacological properties of theophylline with reduced disadvantages, principally the well known stimulating effect on the central nervous system, obtained by bisubstitution of theophylline[4].BamifyllineHCl has been investigated extensively in preclinical studies.Tablet containing 600mg,900mg,1200mg of BamifyllineHCl is patented from European Patent Office with patent no. EP 0 324 981 A1 on 21stApril1989[5].In recommendations of the NDAC(Pulmonary) held on 28th January 2012 by FDC,committee opined that BamifyllineHCl seems to be safe and effective as an additional bronchodilator. The committee recommended for granting permission to conduct the proposed clinical trial as per the protocol submitted in India[6]. Respiratory drug condensation aerosols and methods of making and using them containing BamifyllineHCl is patented from United States Patent and Trademark Office with patent no. US 8,506,935 on 13thAugust, 2013[7].This review focuses on the role of BamifyllineHCl, a novel antiasthmaticagent which distinguishes it from the other currently available xanthine derivatives that are used in asthma.

PHYSICOCHEMICAL PROPERTIES[3][4][8]:

Molecular formula: C20H27N5O3

IUPAC Name: 8-benzyl-7-[2-[ethyl(2-Hydroxyethyl) amino]ethyl]-1, 3-dimethylpurine-2, 6- dione

Structure:

Molecular weight : 385.46008 gm/mole

Melting point : 184˚C to 188˚C

Characteristics : A white to almost white crystalline powder

Solubility: Freely soluble in methanol andwater.Slightly soluble in acetone

MECHANISM OF ACTION[9]:

Bamifylline is a drug of the xanthine chemical class which acts as a selective adenosine A1 receptor antagonist.It is a bronchodilator. It dilates the bronchi and used in the management of rerversible airways obstruction.

PHARMACOKINETICS[10]:

Distribution volumes of Bamifylline are three to ten times larger than those of Theophylline. The half-life of Bamifylline plasma concentrations ranges from 1.5 hours to 2.0 hours, which is appreciably shorter than that of Theophylline which exceeds four hours. Bamifylline is catabolized into several closely related compounds and into sulpho- and glucurono-conjugates of anhydroxylated derivative. Its metabolites are rapidly and extensively excreted via the kidneys and the liver. Only the unchanged Bamifylline has been recorded in the blood following administration of the radio-labelled parent compound. Bamifylline achieves peak plasma levels more rapidly than Theophylline. When administered intravenously, bioavailability is 100%, as with all intravenously administered drugs, if taken orally, taking the drug late in the evening may slow the absorption process, without affecting the bioavailability.

DOSE AND PRECAUTIONS[8][9]:

Adult: 600 or 900 mg daily, given in 2-3 divided doses. Bamifylline should be administered with caution in patients with severe heart failure, serious hypertension, hepatic and renal insufficiency, gastric ulcer and hyperthyroidism. Bamifylline is contraindicated in conditions like Hyperthyroidism, Myocardial infarction, Gastric ulcer, Hypersensitivity. Drug should not be given to pregnant and lactating mothers.

DRUG INTERACTIONS[9]:

Bamifylline is known to interact with other drugs like Allopurinol, Cimetidine (HCl), Clindamycin, Erythromycin, Lincomycin (HCl), Phenytoin (Na), Propranolol (HCl).

USES[8][9]:

Asthma,COPD preparations.

ADVERSE EFFECTS[9]:

The symptomatic adverse reactions produced by Bamifylline are more or less tolerable and if they become severe, they can be treated symptomatically, these include Headache, Nausea, Rashes, Urticaria, Itching, Dermatitis, Slight distal tremors, Gastralgia.

ADVANTAGES[4][9]:

BamifyllineHCl is more potent and has reduced side effects as compared to other xanthine derivative drugs.Distribution volumes of Bamifylline are three to ten times larger than those of Theophylline. The half-life of Bamifylline plasma concentrations ranges from 1.5 hours to 2.0 hours, which is appreciably shorter than that of Theophylline which exceeds four hours.

CLINICAL TRIALS:

Pharmacological Activity of Bamifylline on Lung Anaphylaxis: In Vitro Studies

Bamifylline, a 7-8 disubstitutedtheophylline derivative, reduces in a dose dependent way (1 X 10 _ 5 M, 1 X 10 -4 M and 1 X 10 _ 3 M) the release of histamine, TXB2 (measured also as TXA2-like material) and SRS-A (as LID4 like material) during the immunological challenge of actively sensitized guinea-pig lungs perfused in vitro. Theophylline was significantly less potent than bamifylline and particularly, at the higher concentrations used (1 X 10 - ' M), bamifylline was 2 . 7 times more potent than theophylline in reducing the immunological release of histamine and 1 .6 and 1 .5 times more potent in inhibiting the production of TXB 2 and SRS-A, respectively. These data suggest that the ability of the two xanthine derivatives to control the immunological release of histamine represents an important point in understanding the mechanism of their anti-anaphylactic activity[4].

Selective Activity of Bamifylline on Adenosine A1-Receptors in Rat Brain:

The activity of the xanthine derivative bamifylline on central adenosine A1andA2 receptors has been evaluated with radio-receptor binding in rat brain in comparison with other structure-related compounds.3 Bamifylline displaced H-Cycle-hexyl-adenosine and 3 H-Diethyl-8-phenyl xanthine with a potency similar to that of 8-phenyl-theophylline, suggesting a high activity on Al-receptor subtype.3In contrast, when H-N-Ethyl-carboxamido adenosine was used to label A2 adenosine receptors in rat striatum, bamifylline displayed a lower activity comparable to that of enprofylline, an alkyl- xanthine considered a very weak antagonist of adenosine receptors.

By calculating for each xanthine derivative its relative potency at A1 and A2receptors (A2/~1 ratio), bamifylline turned out being the most selective A 1 adenosine receptor antagonist so far tested[11].

Bronchial and Cardiac effects of Bamifylline in comparison with theophylline in vitro and in vivo studies[12].

ANALYTICAL METHODS:

A New HPTLC Method For Estimation Of Bamifylline: Development And Validation Consideration[13]:

The HPTLC separation was achieved on an Aluminum backed layer of silica gel 60F254 using Methanol: toluene (2.5 : 7.5 v/v) as mobile phase. Quantitation was achieved by densitometric analysis at 277 nm over the concentration range of 100–600 ng/spot. The method was found to give compact spot for the drug (Rf= 0.51 ± 0.01). The linear regression analysis data for the calibration plots showed good linear relationship with r2 = 0.9995. The method was validated for precision, recovery, repeatability, and robustness as per the ICH guidelines . The minimum detectable amount was found to be 7.65 ng/spot, whereas the limit of quantitation was found to be 23.19 ng/spot.

High-Performance Liquid Chromatographic Method for the Determination of Bamifylline and its Three Metabolites in Human Plasma[14]:

Stationary phase : reversed-phase ion-pair system with Hypersil ODS 3 µm,Detection wavelength : 275 nm,Column packing: Nucleosil C18 (5 µm), Nucleosil NH2 (5 µm) and Hypersil ODS (3 µm);

Gradient Elution:-

Normal Phase:Pump A : Isooctane : methylene chloride(20:80 v/v),Pump B : Isopropanol.

IsocraticElution:-Reversed phase ion pair chromatography.

Determination of Bamifylline Hydrochloride Impurities in Bulk material and Pharmaceutical forms Using Liquid Chromatography with UltravioletDetection[15]:

Column : 5 µm Erbasil ODS connected to a disposable 20 x 4.6 mm i.d.Pelliguard pre-column (40 µm),Mobile phase: methanol-tetrahydrofuran-potassium dihydrogenphosphate (60:4:40, v/v/v),Flow-rate:1.0 ml/min,Detection wavelength : 278 nm.

PVC Membrane Ion-Selective Electrode for the Determination of BamifyllineHCl in Pure Solution and in Pharmaceutical Preparations[16]:

A new Bamifylline(Bf) ion-selective PVC membrane electrode based on the ion-pair complex of Bamifylline hydrochloride (Bf-HCl) with sodium tetraphenylborate (TPB) was prepared and its performance characteristics were studied. The electrode membrane which made of 8.0% (w/w) of ion pair Bf-TPB, 46% (w/w) of tricresyl phosphate (TCP) and 46% (w/w) of poly vinyl chloride (PVC) is used, slope was 57.82 mV per concentration decade, at 250C; usable concentration range 1.00×10-5-1.00×10-2M Bamifylline; the limit detection is 4.58×10-6. Response time is less then or equals to 10sec. The changes in pH did not affect the electrode performance within the range 3.0-/7.5.

CONCLUSION:

The presented review highlights on various analytical methods published on BamifyllineHCl in terms of sensitivity, accuracy, precision, advantages and disadvantages.HPLC methods were found to be most sensitive for BamifyllineHCl. In this way various analytical methods for the estimation of BamifyllineHClin bulk or in various matrixes like blood, serum, plasma or in pharmaceutical dosage forms is discussed. The presented information is useful for the researchers especially those involved in the formulation development and quality control of BamifyllineHCl and combination with other drug.

REFERENCES AND NOTES:

1)K.D.Tripathi,Essentials of Medical Pharmacology,Ed. 6th,Jaypee Brothers Medical Publishers(P)Ltd,pp.216-217.

2)Ross and Wilson,Anatomy and Physiology, Ed. 9th, Harcourt Publishers Limited 2001,pp.260-261.

3)F. Tomai,F. Crea,A. Gaspardone et al.,“Effects of A1 Adenosine Receptor Blockade by Bamiphylline on Ischaemic Preconditioning during Coronary Angioplasty”,European Heart Journal,1996,Vol.17 (6), pp.846–53.

4)F. Berti,F. Magni,G. Rossoni et al.,“Pharmacological Activity of Bamifylline on Lung Anaphylaxis: In Vitro Studies”,Pharmacological Research,1990,Vol. 22(2),pp.143-150.

5)Rotini,L. Gabriele,“NewGalenic Formulation with Programmed Release”,European Patent EP 0324 981 A1, July 89.

6)Recommendations of the NDAC(Pulmonary),New Drugs FDC,Delhi, January 2012.

7)Hale,L. Ron,M. Peter et al.,“Respiratory Drug Condensation Aerosols and Methods of Making and Using Them”,U.S.Patent 8,506,935,August 2013.

8)“Bamifylline Full Prescribing Information, Dosage and Side Effects, CIMS India”, 2013,

9)Mustafa Hamid Enterprises, “A Comprehensive Online Drug Reference Guide, Pharma Drug Reference”, 2011,

10)M. Whirl-Carrillo,E. McDonagh,J. Hebert et al.,“Pharmacogenomics-Knowedge for Personalized Medicine”,Clinical Pharmacology & Therapeutics,2012,Vol.9(4),pp.414-417.

11)M. Abbracchio,F. Cattabeni,Selective Activity of Bahifylline on Adenosine A1-Receptors in Rat Brain,Pharmacological Research Communications,1987,Vol. 19(8),pp.537-545.

12)S. Bongrani,P. Sochintarelli,R. Razetti, Bronchial and Cardiac effects of Bamifylline in comparison with theophylline in vitro and in vivo studies, Pharmacological Research Communications,1988,Vol. 20(2),pp.51.S.

13)R. Patel,M. Patel,T. Goswami,“A New HPTLC method for estimation of Bamifylline:Development and validation consideration”,International Journal of Advances in Pharmaceutical Analysis,2012,Vol.2(4),pp.83-87.

14)G. Nicot,G. Lachatre,C. Gonnet et al.,“High-performance liquid chromatographic method for the determination of Bamifylline and its three metabolites in human plasma”,Journal of chromatography,1983,Vol.277,pp.239-249.

15)G. Arlucci,A. Colanzi,P. Mazzeo,“Determination of Bamifylline hydrochloride impurities in bulk material and pharmaceutical forms using liquid chromatography with ultraviolet detection”,Journal of Pharmaceutical & Biomedical Analysis,1990,Vol.8(Nos 8-12),pp.1067-1069.

16)M. Abou-Dan,Y. Ahmed,A. Kurdi,“PVC Membrane Ion-selective Electrode for the Determination of BamifyllineHCl in Pure Solution and in Pharmaceutical Preparations”,Journal of Natural Sciences and Mathematics Qassim University, 2010,Vol. 4(2),pp.135-148.

ACKNOWLEDGMENTS:

The authors are greatly thankful to Shree Dhanvantarypharmacy college, for providing all the facilities to carry out the work.

ABBREVIATIONS:

HPLC, high-performance liquid chromatography; RP-HPLC, reversed phase high-performance liquid chromatography; LC, liquid chromatography; UV, ultraviolet; λ, wavelength; ABS, absorbance; LOD, limit of detection; LOQ, limit of quantitation; mol l−1, concentration; SD, standard deviation; RSD, relative standard deviation

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