International Journal of Biological Macromolecules

Published by: Elsevier

Published by

Elsevier

Highlights

  • Gellan gum & HPMC impart mucoadhesion; NaHCO3 aids in in-vivo buoyancy for >6 h.
  • Water diffusion, polymer swelling, hydrogel formation: leads to anomalous drug release.
  • Hydrophilic polymers enhance bioavailability, solubility & dissolution of cilnidipine.
  • Floating & mucoadhesion improve drug absorption in human volunteers.

Abstract

Cilnidipine, a fourth-generation both L-and N-type calcium channel blocker (CCB) is safe and effective in lowering blood-pressure without reflex tachycardia compared to other dihydropyridine CCBs. However, its low solubility coupled with extensive first-pass metabolism results in very low oral bioavailability. Thus the study aimed to improve oral bioavailability of Cilnidipine by increasing its gastrointestinal transit-time and mucoadhesion. Gastroretentive tablets were prepared by direct-compression technique using gellan gum as hydrogel forming polymer and sodium bicarbonate as gas-generating agent. Statistical optimization was carried out by design approach which showed that gellan gum has significant impact on floating lag time, mucoadhesive strength, % drug release at 1 h and time to release 90% of drug. Drug release study revealed that optimized tablets prolonged drug release for 12 h and followed anomalous-diffusion indicating drug release is by coupling of both diffusion and erosion mechanism. Intragastric behaviour of formulation in human volunteers revealed that radio-opaque tablets remain buoyant in stomach for more than 6 h with sufficient mucoadhesion. Comparative pharmacokinetic profiling in human subjects revealed that relative bioavailability of Cilnidipine GR tablets was enhanced compared to reference tablets. Thus concluded that gastroretentive tablets to be promising strategy for improved oral bioavailability of Cilnidipine for effective treatment of hypertension.

Keywords

Gastroretentive tablet
;
Cilnidipine
;
Gellan gum
;
Central composite design
;
Scanning electron microscopy
;
Roentgenography study
;
in-vivo bioavailability

Introduction

Hypertension or high blood pressure as identified by World Health Organization is a multifactorial, multifaceted disease and is a leading cause of morbidity and mortality worldwide [1]. It is a “silent killer” accountable for deaths of approximately nine million people globally each year [2]. Clinically, it is defined as systolic blood pressure equal to or above 140 mmHg and/or diastolic blood pressure equal to or above 90 mmHg [2,3]. Although it remains asymptomatic in early stages but if left uncontrolled it is liable for development of further complications leading to heart attack, heart failure, stroke and kidney failure [1,2].
Blood is the vital fluid of the body; it is carried from the heart to all parts of the body. Each time the heart beats, it pumps blood into the vessels. The force by which blood is pushed against the walls of the arteries creates a pressure which is nothing but the blood pressure [4]. Viscosity of blood is known to play an important role in the development of various cardiovascular diseases [5,6]. It has been reported that alteration in blood rheology is responsible for elevation of blood pressure and thereby development of hypertension [[7], [8], [9], [10], [11]]. This increase in blood viscosity during hypertension may be due to increased red blood cell aggregability [12]. Thus the present study aims to determine morphological changes or abnormalities of the erythrocytes in hypertensive patients in comparison with normotensive and treated individuals.
Though hypertensive state converges into severe complications, preventive option imparting the use of various antihypertensives for prolong duration remains a key factor for its long term control [2]. Currently, various classes of antihypertensive agents including, diuretics, α-blockers, β-blockers, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, and calcium channel blockers are being clinically used for the treatment of hypertension and various heart diseases [[13], [14], [15], [16]]. However, for lifelong treatment of such chronic illness, sustained release dosage form for prolong period of time is desirable. Nowadays, gastroretentive drug delivery system (GRDDS) has been evolved as a preferred option for improved sustained delivery of orally administered drugs [17]. These low density systems remain buoyant in the gastric region for prolong duration thereby providing continuous release of drug and thus enhancing the oral bioavailability [18]. Various ways have been suggested for development of GRDDS including, floating, bioadhesive, swellable, high density system and other delayed release gastric devices [18]. Amongst them, this paper reports a combination of floating and mucoadhesive system for the formulation of effervescent gastric tablets of cilnidipine to prolong its gastric residence time.
Cilnidipine, a recently developed novel dihydropyridine calcium channel blocker was selected as a model drug for the formulation of floating gastroretentive tablets. It is a fourth-generation antihypertensive agent which possesses both L- and N-type calcium channels blocking activity [19]. It is known to be safe and effective in lowering blood pressure without reflex tachycardia compared to other dihydropyridine calcium channel blockers [20] and also been confirmed to have neuroprotective, cardioprotective and renoprotective effects [19,21] in clinical and animal models. It is a highly lipophilic, Biopharmaceutics Classification System (BCS) class II drug having very low water solubility [22] which is rapidly absorbed following oral administration with maximum peak concentration attained after 2 h [23]. However, it is rapidly metabolised by CYP3A isoenzymes [24] present in the intestinal lining and liver resulting in very low oral bioavailability of approximately 13% [25] and a very short half-life of about 20.4 min [26]. Due to these characteristics, there is a need to modify cilnidipine formulation to a more effective gastroretentive dosage form. With this thought in mind the present study focused on formulation design of cilnidipine floating gastroretentive tablets using gellan gum as bioadhesive polymer.
Gellan gum is a hydrophilic, linear anionic heteropolysaccharide obtained from Pseudomonas elodea [27,28] with a tetrasaccharide repeating unit of glucuronic acid, rhamnose and glucose residues [[29], [30], [31]]. It is a food additive [32] but due to its characteristic property of undergoing ionic gelation in presence of mono- and divalent cations this novel polymer [33] is now being widely used in pharmaceuticals [34] including oral [[35], [36], [37], [38]], ophthalmic [[39], [40], [41], [42], [43], [44]], nasal [[45], [46], [47], [48]] and transdermal [[49], [50], [51]] applications as in-situ gelling agent [52], mucoadhesive agent [53,54] and as sustained or controlled release matrix polymer [[55], [56], [57]]. Considering its innumerable applications, gellan gum was employed as swellable hydrophilic mucoadhesive polymer in the present study.
Accordingly, the aim of present study was to formulate cilnidipine gastroretentive tablets using gellan gum, HPMC K4M and sodium bicarbonate as formulation variables and to systematically evaluate their impact on drug release, mucoadhesive strength and buoyancy properties along with its in-vivo pharmacokinetic and pharmacodynamic evaluation in human volunteers.

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Section snippets

Material

Cilnidipine was gratis sample from J. B. Chemicals, Mumbai, India. Low acyl gellan gum (KELCOGEL® CG-LA) was a generous gift from CP Kelco Mumbai, India. HPMC K4M was kindly provided as gift sample by Colorcon Private Ltd., Goa, India. Microcrystalline Cellulose 102 (MCC 102) was supplied by Ankit Pulp and Boards Pvt. Ltd., Nagpur, India. Sodium bicarbonate was obtained from HiMedia Laboratories Pvt. Ltd., Mumbai, India. Barium sulfate, Leishman's stain, Cedar wood oil, Magnesium Stearate and

Drug-excipient compatibility study

The drug-excipient interaction study was carried out by using Fourier Transform Infrared (FTIR) spectroscopy and Differential Scanning Calorimetry (DSC). For that, pure cilnidipine alone and in combination with excipients were stored in stability chamber (REMI Instruments, Mumbai) maintained at 40 °C and 75% RH (accelerated stability condition) for a period of three months in a sealed amber coloured glass vial secured via rubber stopper and were characterized by FTIR and DSC for drug-excipient

FTIR

FTIR spectroscopy was performed to investigate the possibility of molecular interaction between drug and excipients which were used to formulate gastroretentive floating tablets of cilnidipine. The FTIR spectra of cilnidipine, cilnidipine in combination with polymers (HPMC K4M and gellan gum) and optimized CGRO formulation are presented in (Fig. 1). It was observed that cilnidipine showed characteristic FTIR absorption peaks at 3288.63 cm−1 due to Nsingle bondH stretching vibration, a carbonyl group Cdouble bondO

Conclusion

In the present study, a combination of floating and mucoadhesion technique was used to prolong the gastric residence time of cilnidipine thereby improving its therapeutic effect. The combination offers advantage that the tablet remain buoyant in the gastric fluid even in presence of food whereas mucoadhesion helps in adhesion of tablet to gastric mucosa even during gastric emptying, with this hypothesis cilnidipine gastroretentive tablets containing gellan gum and HPMC K4M as rate-retarding,

Ethics statement

The study protocol have been reviewed and approved by Institutional Ethics Committee (IEC) of Dalvi Memorial Hospital and Research Centre, Nagpur, India (Protocol no. IEC/DMRC/15/49). Written informed consent was obtained from each volunteer before commencement of study.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of competing interest

The authors have no competing interests to declare.

Acknowledgement

The authors would like to express their hearty gratitude to Dalvi Memorial Hospital and Research Centre, Nagpur for their support during the research work. The authors sincerely thank J. B. Chemicals, Mumbai, for providing gift sample of Cilnidipine. The authors are also thankful to CP Kelco Mumbai, Colorcon Private Ltd., Goa and Ankit Pulp and Boards Pvt. Ltd., Nagpur, for providing gift samples of polymers and excipient for research work.

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