Analyzing Antihypertensive Drugs Floating Times for Efficiency Evaluation: A Review

The main objective of oral controlled Drug Delivery Systems (DDS) is to optimize and enhanced bioavailability while ensuring predictability. These systems aim to achieve prolonged drug release and maintain desired drug concentrations at the target site, thereby improving patient compliance and reducing administration frequency. Various methods are employed to develop dose forms that can remain in the stomach for extended periods, including:

•  Systems with low density

•  Systems with high density

•  Systems that are swelling and growing

•  Very porous hydrogenls

• Systems that are hydrodynamically balanced

• Systems that are generating gas

• Systems that are forming raft.

• Floating systems

• resins that exchange ions

Gastro-Retentive Drug Delivery Systems (GRDDS) offer added advantages such as increased bioavailability, site-specific medication delivery for gastrointestinal illnesses, and reduced dosage frequency. Challenges in designing controlled release systems include ensuring localization of dose forms in the desired gastrointestinal region and addressing the complex factors influencing drug absorption. The small intestinal transit time plays a critical role in the absorption of medications with partial absorption characteristics. Factors affecting gastric emptying, motility patterns, and physiological and formulation elements influencing gastric emptying are discussed in the context of basic human physiology. Prolonged stomach retention benefits medications with low solubility in high pH environments, leading to increased bioavailability, reduced drug wastage, and enhanced solubility. This retention enables localized drug administration to the stomach and nearby small intestines, facilitating the availability of novel therapeutic options with significant patient benefits. While oral controlled drug delivery systems offer simplicity in administration and handling, their efficacy is limited with medications exhibiting poor absorption throughout the gastrointestinal tract (GIT). Modulating GI transit time poses a significant challenge in developing oral controlled drug delivery systems, necessitating the exploration of various methods to extend drug release and maintain plasma concentration over an extended duration. Techniques such as mucoadhesion, flotation, sedimentation, expansion, modified shapes, or concurrent administration of pharmacological agents delaying gastric emptying are utilized to retain solid dose forms in the stomach under controlled conditions, thereby enhancing drug efficacy and patient outcomes.^[1]

Floating drug delivery systems:

Low-density formulations that show buoyancy in stomach contents are what define floating drug delivery systems (FDDS) or hydrodynamically balanced systems (HBS). This prolongs gastric residence duration and ensures regulated release of the medication component. This mechanism enables targeted pharmacokinetic release rates at specific sites to achieve desired pharmacological actions.

Basic Physiology of the Gastrointestinal Tract:

Three regions make up the stomach's anatomy: the fundus, the body, and the antrum (pylorus).

Fundus: The area nearest to you.

Body: Acts as a storage space for materials that have partially broken down.

Pylorus: Acts as a location for mixing materials and inflates to act as a pump as the stomach empties.

Stomach Physiology:

The stomach is an expanded part of the digestive tract that is located between the esophagus and the small intestine. When the stomach is empty, its mucosa and submucosa constrict and create unique folds called rugae.

The surface of the stomach is covered by four main types of secretary epithelial cells, which also extend into gastric pits and glands:

Alkaline fluid is secreted by mucous cells.

Parietal cells: Release the acid hydrochloric acid.

Chief cells: Release the proteolytic enzyme pepsin.

Gastrin is secreted by G cells.

Stomach Physiology: The stomach is an expanded part of the digestive tract that is located between the esophagus and the small intestine.

When the stomach is empty, its mucosa and submucosa constrict and create unique folds called rugae.

Gastric Emptying:

The inter-digestive myo-electric cycle (MMC), which consists of four stages—Phase I (Basal), Phase II (Preburst), Phase III (Burst), and Phase IV—is responsible for gastric emptying in both fed and fasting phases. The MMC takes place in the intestines and stomach every two to three hours. The type of meal, whether fed or not, age, frequency of feeding, concurrent medicine administration, density, size and shape, calorie content, gender, and posture are some of the factors that affect how long a dose form remains in the stomach.

Classification of Floating Drug Delivery Systems (FDDS):

A. Effervescent FDDS:

1.Gas generating system

2.Volatile liquid containing system

B. Non-Effervescent FDDS:

1. Barrier made of colloidal gel 2. Tablets with two layers of floating

3. System of microporeous compartments

4. Alginate/Floating Beads

5. Hollow microspheres and micro balloons

C. Raft-forming mechanism

Effervescent Floating Drug Delivery System (FDDS):

Using a floating chamber filled with water, vacuum, air, or inert gas, this device introduces CO2 created by the effervescent interaction between organic acids (such citric acid) and carbonate/bicarbonate salts. The process makes use of matrices composed of swellable polymers, such as chitosan-based polysaccharides, effervescent chemicals like citric acid, sodium bicarbonate, and tartaric acid, or chambers filled with a liquid that is gasifying at body temperature.

Non-Effervescent Floating Drug Delivery System (FDDS):

The non-effervescent FDDS in the GI tract depends on polymer swelling or bioadhesion to the mucosal layer. Typical excipients for non-effervescent FDDS consist of:

1. Gums that are hydrophilic

Gel-forming or extremely swellable hydrocolloids of the cellulose type.

2. Acrylamides

Using a floating chamber filled with water, vacuum, air, or inert gas, this device introduces CO2 created by the effervescent interaction between organic acids (such citric acid) and carbonate/bicarbonate salts. The process makes use of matrices composed of swellable polymers, such as chitosan-based polysaccharides, effervescent chemicals like citric acid, sodium bicarbonate, and tartaric acid, or chambers filled with a liquid Materials such as polystyrene, polycarbonate, polymethacrylate, and polyacrylate that form matrices Chitosan and Carbopol are examples of bioadhesive polymers. Single-layer floating tablets and colloidal gel barrier systems:These systems contain large amounts of gel-forming hydrocolloids of the cellulose type, highly swellable polysaccharides, and matrix-forming polymers.that is gasifying at body temperature.

3. Floating tablets with two layers:

A bi-layer tablet consists of two layers: the immediate-release layer releases the initial dose, and the sustained-release layer absorbs stomach contents to build an impermeable colloidal gel barrier on its surface. These tablets' bulk densities are still below one.

System of raft forming:

Most antacids and other medications for gastrointestinal disorders and infections are administered via raft-forming devices. When gastric fluid comes into touch with the gel-forming solution, it expands, creating a thick, compact gel that contains trapped CO2 bubbles. This gel layer forms a raft on top of the gastric fluid and gradually releases the pharmaceutical material into the stomach.^[2] In this study, we are determining how long antihypertensive medications stay in the stomach and comparing their effectiveness to other medications in the same therapeutic class.

Methods For Evaluation Of Floating Tablets:

There are several methods for evaluating the floating tablets:

Bulk density: The ratio of powder mass to bulk volume is known as bulk density, and it depends on the morphology, interparticle cohesiveness, and particle size distribution. Using a wide-mouthed funnel, a carefully calibrated amount of powder is poured into a graduated measuring cylinder. The volume that results is the initial bulk volume, and it is usually expressed in grams per milliliter (g/ml). M/Vo is the bulk density. where M is the powder's mass Vo is the powder's bulk volume..^[3]

Tapped density: To find the tapped density of a powder, 10 grams of the powder are added to a 100 ml measuring cylinder that has been well cleaned and dried. Tapped density is defined as the mass of a powder divided by its tapped volume. After that, the cylinder is tapped 100 times from a fixed height, and the tapped volume is noted. This parameter is computed using the following formula and is represented in grams per milliliter (g/ml): Tapped density is equal to M/Vt, where M is the powder's mass and Vt is its final tapping volume ^[4]

Angle of repose (θ): The angle of repose (θ) is the maximum angle that can be created between the surface of a powder pile and the horizontal plane. This parameter was found using the fixed funnel method. A level horizontal platform with graph paper on it was covered with a funnel fixed to it, with the tip of the funnel positioned at a predefined height 'h' above the surface. The resulting conical pile's top was precisely where the funnel's tip was when the powder was gradually added to it. The angle of repose was then calculated using the following equation.

Repose angle Ø = tan1(h/r)^[5]

Hausner’s ratio: Hausner’s ratio, employed for predicting powder flowability, parallels the compressibility index method. It is expressed by the equation:

 Hausner’s ratio = Tapped density / Bulk density.^[6]

Weight Variation test (U.S.P.): The Weight Variation test, as outlined in the U.S. Pharmacopeia (U.S.P.), involves the individual weighing of 20 tablets. Following this, the average weight is determined and each tablet's weight is compared to this mean value. To meet the U.S.P. criteria, the test is considered successful if no more than 2 tablets exhibit deviations beyond the specified percentage limit, and if no tablet demonstrates a variance exceeding twice the percentage limit.^[7]

Hardness: Tablet hardness and strength are critical factors ensuring the tablet's ability to withstand the shocks and stresses encountered during manufacturing, packaging, transportation, and patient handling. Various testers such as the Monsanto tester, Strong-Cobb tester, Pfizer tester, Erweka tester, and Schleuniger tester are employed to assess tablet hardness.^[8]

Dimensionl Analysis: Dimensional analysis involved the utilization of a vernier caliper to determine the thickness and diameter of tablets. Twenty tablets were randomly selected from each batch, and the mean values for both dimensions were computed.^[9]

Size and Shape: Tablet dimensions are subject to dimensional description and control in manufacturing processes. Among these dimensions, tablet thickness is the primary variable. Measurement of tablet thickness can be performed using a micrometer or other appropriate devices. It is crucial to maintain tablet thickness within a ± 5% variation from the standard value to ensure stringent quality control standards are met.^[10]

Floating lag time and total floating time: Visual measurements were made of the floating lag time (FLT) and total floating time (TFT) of floating tablets using a dissolution apparatus type II and 100 mL of 0.1 N HCl solution. One of the devices was a paddle that revolved at 50 revolutions per minute at 37 ± 0.5 degrees Celsius, a temperature that was similar to pH 1.2.

Dissolution Study: In the dissolve investigation, a USP type II dissolving apparatus with a paddle was used to test drug release from the formulation in vitro. It rotated at a speed of 50 rpm and was kept at a temperature of 37 ± 0.5 °C under sink circumstances. The dissolution medium that was used was 0.1 N HCl in 900 mL volume. Over the course of six hours, samples were taken out at predetermined intervals and replaced with new media. After being suitably diluted, these removed samples were examined with a UV/Visible spectrophotometer.

Disintegration test:  According to the U.S.P., the Disintegration Test is performed using an equipment that consists of six glass tubes, each measuring three inches in length, with ten mesh screens at the bottom and an open top. One tablet is placed into each tube to measure the disintegration period, and the basket rack is submerged in water, simulated gastric fluid, or simulated intestinal fluid at a temperature adjusted to 37 ± 2 °C. The tablets are placed so that, when moving higher, they stay 2.5 cm below the liquid's surface and, when moving downhill, they get no closer than 2.5 cm to the beaker's bottom.  The basket that holds the pills is moved back and forth between 5 and 6 cm at a rate of 28 to 32 cycles per minute.Each tablet has a perforated plastic disc on top of it to stop it from floating. Tablets must fully dissolve in the test, with every particle going past the 10 mesh screen in the allotted amount of time. Any residue that is left over ought to be soft in bulk. For uncoated pills, the disintegration period is 5 to 30 minutes, and for coated tablets, it is 1-2 hours..^[11]

Swelling index:

Using distilled water as the medium and a USP Dissolution Apparatus II that revolved at 50 rpm while maintaining a volume of 900 mL, the swelling index of the tablets was ascertained. Throughout the experiment, a constant temperature of 37 ± 0.5 °C was maintained. The tablets were taken out, extra water was carefully drained, and they were allowed to equilibrate after a predetermined amount of time. The water uptake (WU) % was computed using the following formula to represent the swelling features of the tablets: [12]

Buoyancy/Floating test:

The floating or buoyancy test measures the flotation and floating lag times, or the amount of time that passes between adding a tablet to the medium and it reaching the top third of the dissolving vessel. 0.1 mol/liter HCl solution or simulated stomach fluid, kept at 37°C, are frequently used for these assessments. The dissolution medium comprises 900 ml of 0.1 mol/liter HCl within a USP dissolution apparatus.^[13]

Factors influencing gastric residence time (GRT) of floating drug delivery systems include:

Density: The density of the tablets in floating drug delivery systems (FDDS) significantly affects the gastric retention time (GRT). To enhance GRT, the density of the dose form should be lower than the density of the gastric contents, which typically ranges around 1.004 g/mL. ^[14] Size and form: In drug delivery systems, size and form factors have a major impact on gastric retention time (GRT). Dosage forms larger than 7.5 mm in diameter are preferred over 9.9 mm ones. Furthermore, gastrointestinal transit (GIT) efficacy is improved by tetrahedral-shaped dosage forms and annular devices, which have flexural moduli of 48 and 22.5 KSI, respectively, and achieve retention rates of 90% to 100%. Compared to other geometries, these qualities make them better choices for floating drug delivery systems (FDDS).^[15] Viscosity Viscosity of polymers is an important factor that affects buoyancy and drug release in floating drug delivery systems (FDDS). Compared to high-viscosity polymers like HPMC K4M, low-viscosity polymers like HPMC K100 LV have better buoyancy properties, making them better candidates for FDDS. Furthermore, a decrease in the rate of drug release from the formulation is correlated with an increase in polymer viscosity..^[16]

Meal type: When indigestible polymers or fatty acid salts are given, the stomach moves into a fed state, which has a substantial impact on gastric motility patterns. This shift slows down the rate at which the stomach empties, which extends the time that medication releases..^[17]

Gender: The mean stomach residence time (GRT) after a meal is lower for men (3.4±0.4 hours) than for women of equal age and race (4.6±1.2 hours), regardless of differences in height, weight, or body surface area..^[18]

Age: The persons who are having age more than 70 have longer GRT.^[19]

Comparative pharmacokinetic assessment of gastric retention times for various antihypertensive medications:

Here are the list of drugs that comes under the antihypertensive drugs.

• Bisoprolol fumarate
• Atenolol
• Captopril
• Diltiazem HCl
• Lercanidine HCl
• Lisinopril
• Losartan
• Metoprolol
• Olmesartan
• Prazosin
• Quinapril
• Verapamil
• Alfuzosin
• Enalapril Maleate
• Perindopril
• Telmisartan
• Saccubitril

Bisoprolol Fumarate:

In the contemporary context, hypertension has emerged as a prominent complication, potentially attributed to shifts in lifestyle habits. Timely intervention is crucial in mitigating morbidity and enhancing life expectancy. Beta blockers constitute a primary class of antihypertensive medications utilized in the management of hypertensive individuals. Bisoprolol, a cardioselective beta blocker, is employed for hypertension control. Bisoprolol, chemically identified as 1-[4-[[2-(1-Methylethoxy) ethoxy]-methyl]-3-[(1- methylethyl) amino]-2-propanol], typically administered at a daily dosage ranging from 5 to 10 mg. Given its short half-life of approximately 3-4 hours, frequent dosing is necessary to maintain consistent plasma levels for optimal therapeutic efficacy and patient adherence. The utilization of controlled-release formulations of bisoprolol addresses these challenges. Moreover, bisoprolol's susceptibility to degradation in the colon underscores the potential benefits of gastric-retentive formulations, facilitating improved therapeutic outcomes. Ankit A.et al. conducted an evaluation of floating tablets of Bisoprolol fumarate by formulating eight   variants (F1- F8) with varying concentrations of Bisoprolol Fumarate, HPMC 4,000cps,HPMC 10,000 cps, Sodium bicarbonate, Magnesium Stearate, Talc, Lactose as main ingredients. The Buoyancy Lag Times (FLT) of formulations F1-F8 were 100.66,128.16,135.9,168.21,96.96,125.10,139.72 and 175.48 recorded as  respectively. These findings indicate that the F5 formulation, characterized by a lower FLT, is optimal for meeting the requirements of floating capacities, resulting in the most effective gastric residence time and controlled release.^[20]

Atenolol:

The beta-blocker atenolol, a beta (1)-adrenergic antagonist, is used to treat angina pectoris and hypertension. 4-[2-hydroxy-3-[(1-methyl ethyl)amino]propoxy] benzene acetamide is its chemical name. Atenolol has a half-life of six to seven hours for elimination and experiences very little hepatic first-pass metabolism. Atenolol is currently administered by parenteral and oral methods. With a 50% oral bioavailability and inadequate absorption from the gastrointestinal tract, the remaining portion is eliminated unaltered in feces. As such, it is considered appropriate for use in the gastroretentive floating drug delivery system (GFDDS). In vitro dissolving tests have been conducted by Harshal Ashok Pawar et al. to assess the medication Atenolol. By creating eighteen versions (F1–F18) with different amounts of atenolol, HPMC K4M, sodium bicarbonate, Avicel, and magnesium stearate as the primary ingredients, they evaluated floating tablets of atenolol. Formulations F1 through F18 have reported buoyancy lag times (FLTs) of 3,2.4,2.1,2.1,2.06,1.60,1.53,1.40,1.20,1.15,1.18,1.10,1.17,1.06,1.09, and 1.02, in that order. According to these results, the F18 formulation—which has a lower FLT—is best suited to satisfy floating capacity requirements, producing the most efficient stomach residence duration and controlled release..^[21]

Captopril:

Angiotensin-converting enzyme (ACE) inhibitors like captopril work by preventing angiotensin I from becoming angiotensin II. As a result, blood pressure is eventually lowered. Angiotensin II is a strong vasoconstrictor and a negative feedback regulator of renin activity. Its action lowers its levels. widely used to treat congestive heart failure and hypertension. Sameer Nine tablets (F1–F9) were created by Singh et al. with the main ingredients being a combination of drug, HPMC K4M, HPMC K15M, HPMC K100M, NaCO3, citric acid, lactose, MCC, and magnesium stearate. Using the paddle method, they performed in vitro dissolution testing in accordance with Indian Pharmacopoeia (IP) recommendations. Table 1 and Figure 1 show the release characteristics of formulations F1, F2, and F3, which were made.  The floating lag time was measured to be 42, 48, and 45 seconds, with cumulative percentage drug releases recorded at 95.23%, 94.15%, and 90.35% for the respective batches. The floating lag times (FLT) of F1 to F9 are 42,48,45,30,40,55,30,65,40 (in sec) respectively. The results showed that the F4 and F7 has the lowest FLT and has a superior gastric residence time and has more effective floating property.^[22]

Diltiazem Hydrochloride:

Diltiazem hydrochloride is used to treat essential hypertension, some arrhythmias, and classical and vasospastic angina pectoris. It is a non-dihydropyridine (non-DHP) calcium channel blocker with vasodilator qualities. Even after oral administration, it is rapidly and almost entirely absorbed, but it experiences significant first-pass hepatic metabolism. As a result, floating tablets were created to deal with this problem.

Chaudhary et al. conducted dissolution studies on Diltiazem hydrochloride utilizing a USP XXIV type-II paddle apparatus under specified conditions. They formulated nine formulations (F1-F9) containing Diltiazem HCL, HPMC K4M, Sodium Alginate, PVP K30, Sodium bicarbonate, Citric acid, Magnesium stearate, Talc, and Lactose as primary constituents. The floating lag times (FLT) of F1-F9 were recorded as 60, 58, 62, 40, 61, 57, 55, 59, and 58 seconds respectively. This suggests that the F4 exhibited the lowest FLT, indicative of prolonged gastric residence time and favorable floating characteristics.^[23]

Lercanidipine HCl:

Lercanidipine, a calcium channel blocker, exerts its antihypertensive effects by vasodilating blood vessels, thereby reducing blood pressure and easing cardiac workload. This normalization of blood pressure aids in managing hypertension.

Shabbeer et al. conducted evaluation tests on lercanidipine HCl, formulating nine formulations containing Drug, Ethylcellulose, HPMC E 50, Chitosan, PVP, Eudragit RS 100, Ethanol, Dichloromethane, and Sodium lauryl sulfate (0.1%) as primary constituents. Buoyancy tests were performed on all formulations, yielding buoyancy percentages of 87.5, 96.0, 88.5, 83.5, 88.5, 88.2, 89.2, 91.21, and 97 for formulations F1 through F9, respectively. The results indicate that formulation F4 exhibited the lowest buoyancy lag time, suggesting superior floating characteristics compared to other formulations.^[24]

Lisinopril:

Lisinopril, an angiotensin-converting enzyme (ACE) inhibitor, regulates blood pressure by attenuating specific vasoconstrictive mediators, thereby facilitating smoother blood flow and enhancing cardiac function. Untreated hypertension poses a risk of end-organ damage, encompassing cerebral, cardiac, vascular, renal, and other systemic complications, potentially culminating in cardiovascular pathologies such as myocardial infarction, heart failure, cerebrovascular accidents, renal impairment, visual disturbances, and related morbidities. Lifestyle modifications are integral alongside pharmacotherapy for effective blood pressure control.  Sumayya Jabeen et al. conducted evaluation tests on Lisinopril floating tablets, formulating nine variants (F1-F9). The floating lag times (FLT) were determined as 26, 24, 20, 28, 25, 23, 26, 23, and 21 seconds, respectively. These findings indicate that formulation F3 exhibited the lowest  FLT and gastric residence time, thus demonstrating superior floating characteristics compared to other formulations .^[25]

Losartan:

Losartan acts as an angiotensin II receptor antagonist, attenuating vasoconstriction by blocking the angiotensin II receptors. This action induces vasodilation, leading to increased coronary perfusion and oxygen delivery to the myocardium, resulting in decreased blood pressure.  Patel et al conducted an evaluation study on losartan floating tablets, formulating nine variants (F1-F9) containing Losartan potassium, hydroxypropyl methylcellulose (HPMC), ethyl cellulose (EC), and sodium alginate as key components. The floating lag times (FLT) observed were 65, 62, 69, 42, 55, 69, 85, 96, and 95(in min) respectively. These findings indicate that formulation F4 exhibited the lowest FLT, suggesting prolonged gastric residence time compared to the other formulations.^[26]

Metoprolol Tartarate:

Metoprolol (Lopressor), a β1-selective adrenergic receptor antagonist, is indicated for hypertension, angina pectoris, tachycardia, post-myocardial infarction prophylaxis, and migraine prevention. It is available for oral or intravenous administration.

Brahmaiah et al. developed eight formulations (F1-F8) of Metoprolol tartarate with varying concentrations of Metoprolol Tartrate, HPMC K15M, HPMC K100M, NaHCO3, Magnesium Stearate, Talc, and Microcrystalline Cellulose as primary components. These formulations exhibited buoyancy lag times of 4, 10, 8, 6.1, 5.0, 3, 8.5, and 8.6 minutes, respectively. The formulation with the shortest buoyancy lag time demonstrated superior gastric residence time and improved floating time efficacy.^[27]

Olmesartan:

Olmesartan is an angiotensin II receptor blocker (ARB) that exerts its effects by antagonizing the action of angiotensin II, thereby inhibiting vasoconstriction. This vasodilatory effect leads to decreased peripheral resistance, resulting in lowered blood pressure, enhanced myocardial oxygen supply, and improved coronary blood flow.Olmesartan is an angiotensin II receptor blocker (ARB) that exerts its effects by antagonizing the action of angiotensin II, thereby inhibiting vasoconstriction. This vasodilatory effect leads to decreased peripheral resistance, resulting in lowered blood pressure, enhanced myocardial oxygen supply, and improved coronary blood flow.

Pratik P Kadam et al. developed ten formulations (F1-F10) of olmesartan medoxomil with varying concentrations of olmesartan medoxomil, HPMC K4M, HPMC K100M, HPMC K15M, Mannitol, and NaHCO3 as primary ingredients. These formulations exhibited buoyancy lag times of 65, 72, 83, 69, 82, 93, 75, 89, 96, and 64 minutes, respectively. The study demonstrates that the F10 formulation is the best formulation as it  possesses the shortest buoyancy lag time and the longest gastric residence time^{. [28]}

Prazosin:

Prazosin, marketed as Minipress, is an α1-adrenergic receptor antagonist indicated for the treatment of hypertension, symptoms associated with benign prostatic hyperplasia (BPH), and nightmares related to post-traumatic stress disorder (PTSD). It is considered a less preferred option for hypertension management. Additionally, prazosin may be used off-label for heart failure and Raynaud syndrome.

Virendra P. Omre conducted a study on 10 formulations (F1-F10) of prazosin, employing varying compositions of prazosin, HPMC K15M, HPMC K4M, CARBOPOL 934 P, MCC, Sodium Bicarbonate, Citric Acid, PVP, and Magnesium Stearate as primary constituents. The findings indicate that the F8 formulation of prazosin exhibited superior characteristics, demonstrating enhanced controlled drug release and prolonged gastric residence time^.[29]

Quinapril:

Quinapril, marketed as Accupril by Pfizer Corporation, is an antihypertensive medication utilized as a first-line pharmacotherapy for hypertension, heart failure, and diabetic nephropathy.Mali et al. formulated 9 variants (F1-F9) of quinapril with varying concentrations of Quinapril HCl, HPMC K4M, Citric acid, Sodium bicarbonate, Carbopol 934P, Lactose, Magnesium stearate, and Talc as primary components. The formulations displayed floating lag times of 119, 116, 114, 94, 98, 104, 99, 116, and 121 seconds, respectively. Results indicate that F4 exhibited the optimal characteristics with the shortest floating lag time and the longest gastric residence time^.[30]

Verapamil:

Verapamil is a calcium channel blocker that is used to treat angina (chest discomfort) and high blood pressure as well as some cardiac rhythm issues like supraventricular tachycardia and atrial fibrillation. It acts by causing blood arteries to relax and altering the heart's electrical activity. Verapamil is also employed off-label for cluster headaches, migraines, and prevention of recurrent episodes of atrial fibrillation.Asha Spandana KM et al evaluated the floating tablets of Verapamil.They formulated six formulations of verapamil(F1-F6) comprising of Verapamil HCL , HPMC K100 , Carbopol 940 , Sodium Bicarbonate , Citric acid , Lactose  as the main ingredients of varying concentrations. The floating lag times of F1 to F6 are 9.5,9.1,6.4,3.3,3 and 1 (in min) respectively. This suggests that the F6 formulation having (1min) lowest FLT is has more gastric residence time thus more effective in floating behavior.^[31]

Alfuzosin:

One drug that is categorized as an alpha-1 adrenergic blocker is alfuzosin. The main disease for which it is used is benign prostatic hyperplasia (BPH), an enlargement of the prostate gland that makes urinating difficult. Alfuzosin works by relaxing the muscles in the prostate and bladder neck, which helps to improve urine flow and reduce symptoms such as hesitancy, urgency, and frequency of urination. It is important to note that alfuzosin should be used with caution in patients with low blood pressure, liver impairment, or certain heart conditions, as it can cause dizziness and fainting. Kadam V. S. et al. conducted an evaluation of floating tablets of Alfuzosin hydrochloride through the formulation of two variants (F1-F2) with varying concentrations of Alfuzosin HCl, Polyoxwsr301, HPMCK4M, Xanthan Gum, MCC102, NaHCO3, Talc, and Magnesium stearate as the primary ingredients. The floating lag times (FLT) of formulations F1 and F2 were recorded as 80 and 89 seconds, respectively. These findings indicate that the F1 formulation, with a lower FLT, is the preferred formulation due to its superior gastric residence time, rendering it more effective as a floating tablet.^[32]

Enalapril Maleate:

The main conditions treated with enalapril maleate, an ACE inhibitor, are hypertension (high blood pressure) and heart failure. It functions by preventing ACE, an enzyme that narrows blood vessels, from doing its job. Enalapril maleate lowers blood pressure and improves blood flow by blocking ACE, which also helps to relax blood vessels. In certain situations, this drug is also utilized to increase heart attack survivability. Usually taken orally, enalapril maleate can be taken with or without food.L. V. Vamsi Krishna et al. assessed the formulation of six variants (F1–F6) with a total weight of 50 mg that included enalapril maleate, HPMC K15, Xanthan Gum, sodium alginate, poly vinyl pyrrolidine, sodium bicarbonate, citric acid, microcrystalline cellulose, magnesium stearate, and talc as the main ingredients. The floating lag times (FLT) of formulas F1 through F6 were 1.1, 3.2, 1.1, 3.1, 4, and 5.1 minutes, respectively. According to this study, formulations F1 and F3 showed higher stomach residence times and lower FLTs, indicating that they are more effective in terms of floating capacity.^[33]

Perindropril:

Perindopril, an ACE inhibitor, is primarily used to treat hypertension and heart failure by blocking ACE, which relaxes blood vessels, reduces blood pressure, and improves blood flow. It is also utilized to lower the risk of cardiovascular events in stable coronary artery disease. Administration is typically oral, with or without food, following prescribed dosages and instructions. Common side effects include dizziness, headache, cough, and fatigue. Patients should be cautious when changing positions quickly due to potential blood pressure drops. It is important for patients to disclose all medications to their doctor, as perindopril may interact with potassium supplements and NSAIDs. Srinivas Martha et al evaluated the Perindopril floating tablets by formulating into nine formulations comprising Perindopril, HPMC K4M , Xanthan gum , NaHCO3 , MCC , Magnesium stearate , talc as the main ingredients. The floating lag times (FLT) of F1 to F9 are 0.09,0.12,0.89,1.52,2.14,2.89,1.95,2.8, and 3.10 respectively. These studies shows that the F1 formulation has the shortest FLT and has more gastric residence time and thus more effective floating tablet.^[34]

Telmisartan:

One of the main reasons telmisartan, an angiotensin II receptor blocker (ARB), is administered to patients with established cardiovascular disease is to lower their risk of cardiovascular events and to treat hypertension, or high blood pressure. It functions by preventing the hormone angiotensin II from acting, which narrows blood vessels and raises blood pressure. Telmisartan lowers blood pressure, improves blood flow, and relaxes blood arteries by blocking angiotensin II. This medication is also used to treat diabetic nephropathy in patients with type 2 diabetes and hypertension. Manoj Kumar Goyal et al. conducted an evaluation of floating tablets of Telmisartan by formulating five variants (F1-F5) with varying concentrations of Telmisartan. The Buoyancy Lag Times (FLT) of formulations F1-F5 were recorded as 61.26, 63.19, 60.81, 68.21, and 74.02, respectively. These findings indicate that the F3 formulation, characterized by a lower FLT, is optimal for meeting the requirements of floating capacities, resulting in the most effective gastric residence time and controlled release^.[35]

Saccubitril:

Heart failure with reduced ejection fraction (HFrEF) is treated with sacubitril, a neprilysin inhibitor taken in combination with valsartan. It works by inhibiting neprilysin, an enzyme that breaks down beneficial peptides involved in regulating blood pressure and fluid balance. By inhibiting neprilysin, sacubitril allows these peptides to remain active, leading to vasodilation (widening of blood vessels) and improved sodium and fluid balance. Pathak Sudhakaret al. conducted an evaluation of floating tablets of Telmisartan by formulating seveteen  variants  (F1- F17) with varying concentrations of Saccubitril, Valsartan, HPMC K100M , Sod. Bicarbonate, Ca. carbonate , Citric Acid , DCP , Talc , Mg. stearate as the main ingredients. The Buoyancy Lag Times (FLT) of formulations F1-F17 were 840,35,30,45,19,105,35,43,40,50,20,22,25,20,19,17 and 20 recorded as  respectively. These findings indicate that the F16 formulation, characterized by a lower FLT, is optimal for meeting the requirements of floating capacities, resulting in the most effective gastric residence time and controlled release^.[36]

CONCLUSION:

In this review we concluded  that the gastric residence time of antihypertensive drugs increases with decrease in floating capacities. Total Floating Time and Floating Lag Time are the two important parameters that must be fulfilled by any drug to meet the sustained release and gastric residence time.Among all antihypertensive drugs  Perindropil  has the highest floating time(>10h) and lowest floating lag time(0.09 sec). This suggests that the  perindropil has superior gastric residence time and has highest sustained release capacity among all formulations.

Tabulation Showing Flt and TFT of Antihypertensive Drugs: