Pharmacokinetic Evaluation of Telmisartan Chronotherapeutic Press Coated Tablets

Bharathi Arigela¹*, D. Chandra Sekhar Naik², Kovida Chanumolu³, Yamini Durga Talaparthi³

¹Professor, Department of Pharmaceutics and Biotechnology, KVSR Siddhartha College of Pharmaceutical Sciences, Vijayawada, Andhra Pradesh, India.

²Professor, Department of Pharmaceutics, Nimra College of Pharmacy, Vijayawada, Andhra Pradesh, India.

³Students, KVSR Siddhartha College of Pharmaceutical Sciences, Vijayawada, Andhra Pradesh, India.

*Corresponding Author E-mail: bharathi.arigela004@gmail.com

ABSTRACT:

Ocimum gratissimum mucilage isolated from Ocimum gratissimum seeds at raised temperatures was a white crystalline powder. The modified mucilage derived from Ocimum gratissimum exhibits remarkable flow properties and exhibits insolubility in water and aqueous solutions across a range of alkaline and acidic buffers. It likewise showed excellent water edema (90%) as well. When cooked to 100°C for 30 minutes in water, it does not gel. It was tested as a disintegrant in tablet forms and is thought to be a promising disintegrant. Telmisartan tablets were tested after being manufactured using a direct compression method with 0-10% Ocimum Gratissimum mucilage as a novel super disintegrant. The level of independent factors (sodium starch glycolate, croscarmellose sodium, and Ocimum Gratissimum mucilage) on dependent variables (disintegration time, water absorption, wetting time, and percent release in 5 minutes) in the formulations were optimised using a 2x3 factorial design. After that, the enhanced recipe was press-coated in various ratios with naturally occurring time-released polymers such Gardenia Gummifera and Anogeissus latifolia gum. Based on post-compression properties, the best formulation was selected, and dissolution data underwent three months of accelerated stability testing of the ten coating formulations. Impressive outcomes were observed with F2CC6, with a maximum cumulative medication release of 99.54% in a 12hour period. Due to its release pattern and capacity to administer the medication at the proper time, location, and dosage, the suggested delivery technique exhibits significant promise for hypertensive patients.

KEYWORDS: Ocimum Gratissimum mucilage, Disintegrate, Tablets, Telmisartan.

INTRODUCTION: 

A pharmaceutical regimen based on the circadian cycles known as Chronopharmacotherapy regulates a number of human physiological processes, including hormone synthesis, metabolic processes, biological functioning, behaviour, and timing of sleep¹.

Humans differ significantly in their biochemical and physiologic variability across 24hours due to the presence of many circadian rhythms. Various diseases, such as bronchial asthma, have been linked to increased airway reactivity and a decrease in lung function when assessed across a 24hour cycle, with the highest point occurring in the afternoon and early morning. Both blood pressure and cardiac activity have a strong diurnal rhythm; blood pressure dual sum readings frequently peak in the early morning and then decline in the late afternoon.² It was discovered that the amount of gastric acidity increased during the course of the night and decreased in the early morning. Morning pain is more common in rheumatoid arthritis patients, suggesting a circadian variation that requires time-varying medication administration for best results³. For example, in the early hours of Day 3, there was an increase in discomfort accompanied by morning stiffness in the body, asthma, and a cardiac event. A circadian cycle disruptions have been recorded in children with attention deficit hyperactivity disorder and sleep onset insomnia. The motive of the study reports whether natural time-released polymers can used in press coating to formulate tablets afford to the maximum in vitro percentage drug release within 12hours after the evening dose.⁴ The primary objective of the design is to analyse the effect of core and coating on lag time drug release from the direct compression method.⁵

MATERIAL AND METHODS:

Telmisartan is a pure medication obtained from Yarrow Chemicals, Mumbai. Mannitol was procured from Yarrow Chemicals and Products in Mumbai. Qualigens Fine Chemicals, located in Mumbai, supplied the microcrystalline cellulose. Talc and magnesium stearate were procured from Molychem in Mumbai.

METHODS:

Preparation of Chronotherapeutic Press Coated Tablets:

The compression coating of preparations was used to develop Chronotherapeutic press-coated tablet formulations.⁶ Tables 1 and 2 illustrate the composition of batches with varied amounts of natural time-released polymers (Anogeissus latifolia gum and Gardenia gummifera gum) and natural super disintegratent (Ocimum gratissimum).⁷ The tablets were compressed or press coated by incorporating half of the compression coat mixture in die cavity and manually insert core tablet in the centre of a powder bed. From above, the remainder of the compression coating material is poured into the die's cavity. The tablet is then squashed on the tablet compressing machine.

Table: 1 Formulae of Optimized Telmisartan Core Tablet Employing Ocimum Gratissimum Mucilage

Ingredient(Mg/tablet)	F2
Telmisartan	40
Ocimum Gratissimum	20
Sodium Starch Glycolate	---
Crospovidone	---
Mannitol	20
Micro Crystalline Cellulose	112
Talc	4
Magnesium Stearate	4
Total weight	200

Table: 2 Formulae of Telmisartan Chronotherapeutic Press Coated Tablets:

Formula code	Anogeissus Latifolia gum (mg)	Gardenia Gummifera gum (mg)
F2CC1	200	0
F2CC2	150	50
F2CC3	100	100
F2CC4	50	150
F2CC5	0	200
F2CC6	0	300
F2CC7	200	100
F2CC8	150	150
F2CC9	100	200
F2CC10	300	0

The following products have been tested for in vivo pharmacokinetics in rats.⁸

(i)     Telmisartan tablets at a dose of 2mg /kg.

(ii)    Telmisartan Chronotherapeutic press coated tablets formulated employing Ocimum gratissimum mucilage as a super disintegrant and Gardinea gummifera mucilage as Chronotherapeutic polymer (F2CC6) each containing 2mg of Telmisartan (dose: 1 tablet/rat)⁹

Pharmacokinetic Studies:

An overnight-fasted rats have been separated into three independent groups (n=3) and handled in the following way:

GroupI: Pure Telmisartan (2mg/kg) in 0.5% CMC.

GroupII: Powdered formulated chronotherapeutic press coated tablet of Telmisartan employing Ocimum gratissimum mucilage as a super disintegrant and Gardinea gummifera mucilage as chronotherapeutic polymer (2mg/kg) in 0.5% CMC.¹⁰ The spontaneously hypersensitive rats with systolic blood pressure greater than 200mmHg and diastolic bold pressure 150mmHg and blood samples (0.2ml) were withdrawn by puncture of retro-orbital sinus simultaneously at 0 (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 48, 72 and 96h in micro-centrifuge tube in which 6mg  EDTA was introduced. Obtained blood is thoroughly combined with EDTA and centrifuged at 5000rpm for 25 minutes to separate the plasma. The extracted plasma was maintained at -20⁰C until the medication was analyzed by high-performance liquid chromatography (HPLC) method.¹¹

The method used:

Reported validated HPLC method with slight modifications.

HPLC system (Shimadzu Class VP series having Class VP 6.12 version software¹²

Conditions used:

A pair of pumps (LC-10AT VP), an adjustable wavelength programmed UV/VIS detector (SPD-10A VP), an array controller (SCL-10A VP), and an RP C-18 column (Hypersil BDS C18; 250cm × 4.6mm; 5µ) were employed. Rheodyne injector fitted with 20µl loop software was used for analysis. The mobile phase has acetonitrile-5mmol/L ammonium acetate (50:50v/v). The phase of mobility was administered at an evacuation rate of 0.2ml/ minute. The detected wavelength is 271 nm. The injection volume is 20µl. The amounts of uncertain plasma specimens were calculated by drawing a calibration curve between Telmisartan peak area ratios to IS and Telmisartan concentrations.

RESULTS AND DISCUSSION:

Table 3: Plasma Concentrations of Telmisartan followed by Oral Administration of Telmisartan Tablets (A) and its chronotherapeutic press coated tablets employing Ocimum gratissimum¹³ mucilage as super disintegrant and Gardinea gummifera mucilage as chronotherapeutic polymer (B) in Rats

Time (h)	Plasma Concentration of Telmisartan (ng/ml) (x ± s.d)
	A	B
0.5	10.12 ± 0.01	0.12 ± 0.21
1.0	16.34± 0.21	0.26 ± 0.11
2.0	25.45± 0.24	1.12± 0.23
3.0	42.36± 0.41	1.91 ± 0.12
4.0	63.89 ± 0.11	2.17 ± 0.31
5.0	115.47 ± 0.13	3.64 ± 0.55
6.0	217.68± 0.27	4.42 ± 0.17
8.0	173.89 ± 0.26	215.84 ± 0.52
12.0 24.0 48.0 72.0 96.0	142.97 ± 0.74 74.86 ± 0.25 50.12 ± 0.16 26.31 ± 0.11 9.04 ± 0.17	165.12 ± 0.64 121.18 ± 0.19 63.14 ± 0.16 31.17 ± 0.12 11.07 ± 0.22

A: Telmisartan Tablets B: Telmisartan chronotherapeutic press coated tablets F2CC6.

Fig.1 Time vs plasma concentration profiles of Telmisartan after an oral treatment of Telmisartan(A) and its chronotherapeutic press coated tablets employing Ocimum gratissimum mucilage as super disintegrant and Gardinea gummifera mucilage as chronotherapeutic polymer (B) in Rats.

Fig.2 A Time Vs Log Percent drug unabsorbed Plot of Telmisartan upon oral administration of Telmisartan (A) and its chronotherapeutic press coated tablets Ocimum gratissimum mucilage as a super disintegrant and Gardinea gummifera mucilage as a chronotherapeutic polymer (B) in Rats.

Table 4: An outline of pharmacokinetic criteria measured upon oral ingestion of Telmisartan and chronotherapeutic press-coated tablets made using Ocimum gratissimum mucilage as super disintegrant and Gardinea gummifera mucilage as chronotherapeutic polymer.

Pharmacokinetic Parameter	Telmisartan Tablet	Chronotherapeutic Press Coated Tablets of Telmisartan
Cmax (ng/ml)	217.68	215.84
Tmax (h)	6.0	8.0
AUC0-96h (ng.h/ml)	5546.69	5308.17
AUC0-¥ (ng.h/ml)	5827.43	5570.17
RBA (%)	100	95.58
Ka (h^-1)	0.115	0.0064
Kel (h^-1)	0.0322	0.0423
MRT (h)	0.271	17.70

A Pharmacokinetic evaluation was performed on chronotherapeutic press coated tablets of Telmisartan employing Ocimum gratissimum mucilage as a super disintegrant and Gardinea gummifera mucilage as the chronotherapeutic polymer in comparison to Telmisartan to evaluate timed-release of drug In vivo¹⁴. Table 4 provides An outline of pharmacokinetic criteria determined after oral ingestion of the tested Telmisartan products¹⁵.

The mean residence time (MRT) of Telmisartan was found 0.0271h. The absorption rate constant (K_a) of pure Telmisartan is 0.115h^-1. A C_max of 217.68± 0.27ng/ml was detected six hours after oral delivery of Telmisartan pure medication.

When chronotherapeutic press coated tablets of Telmisartan formulated employing Ocimum gratissimum mucilage as a super disintegrant and Gardinea gummifera mucilage as chronotherapeutic polymer was administered orally at same dose (2 mg/rat), the plasma concentrations were found to be timed release than those observed with Telmisartan pure medication, suggesting fast absorption of Telmisartan from Chronotherapeutic Press Coated tablets. A C_max of 215.84±0.52ng/ml was observed at 8 hours of continuation of oral administration of chronotherapeutic press coated tablets.( K_a) was obtained at 0.0064h^-1. Relative bioavailability of Telmisartan chronotherapeutic press coated tablets was 95.58%.

The pharmacokinetic evaluation indicates that Telmisartan from chronotherapeutic press coated tablets formulated employing Ocimum gratissimum mucilage as super disintegrant and Gardinea gummifera mucilage as chronotherapeutic polymer was timed release in vivo resulting in slower absorption and timely absorption of the drug.

REFERENCES:

1. Tamilanban. T, Mohamedmajeed. A, Chitra. V. Overview of Chronopharmacology. Research J. Pharm. and Tech. 2020; 13(9):4457-4463. doi: 10.5958/0974-360X.2020.00787.8

2. Indrajeet S. Patil, Omkar A. Patil, Girish Chandra R. Mandake, Manoj M. Nitalikar. Development and Evaluation of Telmisartan Pulsatile Drug Delivery by using Response Surface Methodology. Asian J. Pharm. Res. 2018; 8(4): 205-214. doi: 10.5958/2231-5691.2018.00035.7

3. V. Indra. Effective Pain Management to Improve Patient Satisfaction – A Review. Int. J. Nur. Edu. and Research. 2019; 7(4): 613-615.

4. Bhaskar Bangar, Namdeo Shinde, Sunil Deshmukh, Birudev Kale. Natural Polymers in Drug Delivery Development. Res. J. Pharm. Dosage Form. & Tech. 2014; 6(1): 54-57.

5. Debjit Bhowmik, Rishab Bhanot, Darsh Gautam, Parshuram Rai, K.P. Sampath Kumar. Formulation and Evaluation of Telmisartan Fast Dissolving Tablets by Direct Compression Method. Res. J. Pharm. Dosage Form. & Tech. 2017; 9(3): 131-139. doi: 10.5958/0975-4377.2017.00022.2

6. Jatin Patel, Dipen Patel, Savan Vachhani, ST Prajapati, CN Patel. Current Status of Technologies and Devices for Chronotherapeutic Drug Delivery Systems. Research J. Pharm. and Tech. 2010; 3(2): 344-352.

7. Akunneh -Wariso C, Aduema W. Comparative Hypoglycemic effects of aqueous leaf extracts of Vernonia amygdalina, Ocimum gratissimum, Phyllanthus amarus, Gongronema latifolum, Piper nigrum and Solanum melongena on Blood Glucose Level of Alloxan-Induced Diabetic Guinea Pigs. Res. J. Pharmacology and Pharmacodynamics. 2019; 11(2): 55-61. doi: 10.5958/2321-5836.2019.00010.7

8. Saema, Tabassum Wasim Ahmed, Peeyush Kumar Sharma, Imran Khan Pathan, Mamta Bhatia, Marhaba Khan. In vivo and In vitro Model for Evaluation of Anti-microbial activity: A Review. Asian Journal of Pharmaceutical Research. 2023; 13(3): 169-4.

9. Nuha Rasheed, Abdul Saleem Mohammad, Seema Farheen, Shaik Zubair. Simultaneous Formulation Development, Evaluation and Estimation of Innovative Controlled Release Tablets of Bosentan Formulated with Varied Polymers. Asian J. Pharm. Ana. 2016; 6(4): 235-245..

10. S.Kumara Swamy, G. Arun, Bethi Srinivas, Agaiah Goud B. Effect of Various Super Disintegrants on the Drug Release Profile of Orally Disintegrating Tablets. Asian J. Pharm. Tech. 2016; 6(2): 99-105. doi: 10.5958/2231-5713.2016.00014.3

11. Monika A, Rana, Hasumati A. Raj. Development and Validation of High Performance Liquid Chromatography Method for Levosulpiride and its Intermediate in Synthetic Mixture. Asian J. Pharm. Tech. 2015; 5(2): 97-106. doi: 10.5958/2231-5713.2015.00015.X

12. Archana B. Gore, Manojkumar K. Munde, Nikita B. Rukhe, Nilesh S. Kulkarni. A Review on HPLC Method Development and Validation for Gliptin Class: New Oral Antidiabetic Agents. Research Journal of Pharmaceutical Dosage Forms and Technology. 2022; 14(1): 79-6. Doi: 10.52711/0975-4377.2022.00013

13. Ugbogu OC, Emmanuel O, Agi GO, Ibe C, Ekweogu CN, Ude VC, Uche ME, Nnanna RO, Ugbogu EA. A review on the traditional uses, phytochemistry, and pharmacological activities of clove basil (Ocimum gratissimum L.). Heliyon. 2021; Nov 25; 7(11): e08404. doi: 10.1016/j.heliyon.2021.e08404. PMID: 34901489; PMCID: PMC8642617.

14. Gaur PK, Mishra S, Bajpai M. Formulation and evaluation of controlled-release of telmisartan microspheres: In vitro/in vivo study. J Food Drug Anal. 2014; 22(4): 542-548. doi: 10.1016/j.jfda.2014.05.001. Epub 2014 Aug 8. PMID: 28911472; PMCID: PMC9354994.

15. Stangier J, Su CA, Roth W. Pharmacokinetics of orally and intravenously administered telmisartan in healthy young and elderly volunteers and in hypertensive patients. J Int Med Res. 2000; 28(4): 149-67. doi: 10.1177/147323000002800401. PMID: 11014323.

Received on 19.06.2023      Revised on 03.04.2024

Accepted on 22.10.2024   Published on 20.01.2025

Available online from January 27, 2025

Research J. Pharmacy and Technology. 2025;18(1):173-176.

DOI: 10.52711/0974-360X.2025.00026

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