A Novel Drug Delivery System: Floating Microspheres in the Development of Gastroretentive Drug Delivery System

 

Vandana Gupta, Jaya Singh1*

Innovative College of Pharmacy, Greater Noida, Uttar Pradesh - 201308

*Corresponding Author E-mail: jayasingh.2902@gmail.com, Vandugpt69@gmail.com

 

ABSTRACT:

Gastric emptying is a complicated process in the human body because it is very inconstant, resulting in ambiguous in vivo drug delivery system efficacy. To combat this variability, scientists have been working on developing a regulated medication delivery system with a long gastric residence period. This review article on gastroretentive drug delivery systems (GRDDS) focuses on numerous gastroretentive approaches that have recently emerged as a leading methodology in the field of site-specific orally administered controlled release drug administration. Gastroretentive medicines come in a variety of forms on the market, including tablets, granules, capsules, floating microspheres, laminated films, and powders. Floating microspheres are currently garnering more attention than previous techniques because of their benefits, which include more consistent drug absorption and a lower risk of local discomfort. The primary goal of this method is to increase gastric retention time in the GIT, which is defined as more than 12 hours in the stomach with an absorption window in the upper small intestine. Longer stomach retention improves bioavailability, reduces drug waste, and boosts solubility for medications that are less soluble in a high pH environment. The medicines are released into the stomach for a long time and consistently thanks to the floating microsphere systems. The current study compiles the most recent research on the techniques of production, characterization, and numerous aspects that impact the performance of floating microspheres for oral administration.

 

KEYWORDS: Gastroretentive, Floating microspheres, Bioavailability, novel drug delivery, absorption window.

 

 


INTRODUCTION:

There are several medication administration methods, the most frequent and extensively utilized of which is the oral route of drug administration. Patients accept the oral route approach because it is convenient, flexible, safe, cost-effective, and most natural. As a result, it has received the majority of the focus. 

 

The primary disadvantage of traditional oral medication administration is that it must be taken many times per day to keep medicine concentrations within therapeutically active ranges (depending on the dosing regimen) and that not all drugs are absorbed evenly throughout the GIT. Oral controlled medication delivery systems have been developed to overcome these challenges. Gastroretentive Floating Microspheres are commonly used as an oral controlled medication delivery system because the bulk density of the dosage form is lower than that of the stomach juice in this system. It is also known as a low-density system. Because the device floats above the gastric fluid, it prolongs drug release in the stomach, increases gastric residence time, and improves bioavailability by maintaining a constant concentration of medicine in the GIT fluid. As a result, drug waste is reduced considerably, and low-solubility medicines are improved.

 

Bioadhesive systems, floating systems (also known as low-density systems), non-floating systems (also known as high-density systems), magnetic systems, swelling systems, unfoldable and expandable systems, raft forming systems and super porous systems, and biodegradable hydrogel systems are some of the modern approaches to improving the gastric residence time of drug delivery systems.

 

Fig: 1 GRDDS (a) Low- density systems and (b) High-density System

 

Table 1. Comparison of Gastro Retentive and Conventional Drug Delivery Systems1

S. No.

Conventional Drug Delivery System

Gastro Retentive Drug Delivery System

1

Additional unintended consequences

There is no concern of dosage dumping

2

Gastric retention time is reduced.

Increases the period that food remains in the stomach

3

Patient cooperation is low

Patient compliance is improved.

4

Not recommended for the administration of medicines having a narrow absorption window in the small intestine.

Appropriate for delivering medicines to the small intestine with a restricted absorption window.

5

Drugs that have a local effect in the stomach and disintegrate in the colon with fast absorption via the GIT are not helpful.

Drugs that are beneficial for patients have a local effect in the stomach and disintegrate in the colon, with fast absorption through the GIT

 

FLOATING SYSTEM:

Davis was the first to use floating medication delivery in 1968. The moniker "floating medication delivery" was suggested based on the microspheres' properties. The bulk thickness or density of this drug delivery method is lower than that of GI fluid (1.004g/cm3). This characteristic of the floating system allows it to maintain buoyancy in the belly for an extended length of time without affecting the pace of gastric emptying. During the GRT, the medication floats on the stomach content and then delays its release at the appropriate pace from the system. The drug plasma core improves as a result of this technique, and the stomach residence duration increases2

 

Advantages of floating microspheres2

·       Floating microspheres reduce dosing frequency

·       Floating microspheres have high patient acceptance.

·       Floating microspheres have a low drug-induced mucosal irritation

·       Floating microspheres drug lengthens the gastric residence time, which improves drug absorption.

 

Disadvantages of floating microspheres2

·       Drugs that have issues with gastric fluid stability and solubility are not suitable for floating microspheres.

·       Some factors, such as gastric motility, the presence of food, and pH, influence the drug retention of the floating system.

·       Drugs that irritate the gastric mucosa are not permitted in this type of drug delivery system.

 

Classification of Floating delivery of drugs:

Floating drug delivery has been classified into two types: -

1.     Effervescent system

2.     Non-effervescent system

 

Effervescent medication delivery systems are made up of a matrix and a swellable polymer like methylcellulose or chitosan, as well as effervescent chemicals like sodium bicarbonate that react with the natural acid (HCl) present in the GIT when it comes into contact, resulting in the formation of carbon dioxide and the bouncy of the drug.

 

The effervescent system is further classified as

A: Volatile liquid containing system

B: Gas generating system

 

Volatile liquid containing system:

Within this drug delivery system, there are two chambers. The first chamber holds the medication, while the second chamber contains a volatile liquid, such as ether or cyclopentane. This system is a deformable unit that expands from its collapsed state and then returns to its original position to extend the duration of medication administration. 

 

Gas generating system:

Because the matrix contains bicarbonate material, when it reacts to an acidic environment, it contributes to the production of carbon dioxide, lowering their bulk thickness or specific gravity and assisting them in swimming over the GI fluid (Chyme)

 

Non-effervescent system:

After the medication is taken, it interacts with gastric fluids in the GIT and expands, reducing its bulk density and preventing it from passing through the stomach.

 

These systems are sometimes referred to as "plug-type" systems because they have a tendency to stay in the GIT for a long period and not cross the pyloric sphincter, therefore extending the amount of time they spend in the stomach.3

System of Micro Porous Compartment

2. Micro-Balloon Floating

3. Barrier colloidal gel device

4. Beads Alginate

 

Mechanism of microsphere floating4

Because the outer layer of the floating microballoons includes polysaccharides and polymer hydrates to form a colloidal gel barrier that controls the movement of gastricfluid in and out after administration of the dosage type, low-density microspheres communicate with the gastric fluid (acid) in the stomach, resulting in increased gastric retention with reduced fluctuations in plasma drug concentration. The air molecule is trapped inside the inflated polymer. It helps to decrease its bulk density below that of the gastric fluid, allowing it to swim over the gastric fluid surface. For maximal cases, a lesser volume of stomach fluid is required for flotation of the floating dose type.

 

Unique and innovative equipment for determining resultant weight has been published in the literature to quantify the floating force kinetics.

 

F = F buoyancy - F gravity = (Df - Ds) gv

 

Where,

F= total vertical force;

Df = fluid density;

Ds = object density;

v = volume;

g = acceleration due to gravity

 

Fig: 2

 

Table 2 List of drugs explored for various floating dosage forms

Marketed products of FDDS4

S. No.

Drugs

Dosage form

1

Aspirin, Ibuprofen

Microspheres

2

Diclofenac sodium, Indomethacin

Granules

3

Diazepam, Furosemide, L-Dopa

Capsules

4

Amoxycillin Trihydrate, Ampicillin

Tablets/Pill

 

Table 3. Potential drug candidate for gastro-retentive Drug Delivery system5

S. No.

Drug candidates

Example

1

Medicine that act locally in the GIT

Antacids, Anti-ulcer drugs, drugs against H. Pylori, Misoprostol, Clarithromycin, Amoxicillin etc

2

Medicine with narrow absorption window in Gastrointestinal tract (GIT).

 

Cyclosporine, Methotrexate, Levodopa, Repaglindine, Riboflavin, Furosemide, Para-aminobenzoic Acid, Atenolol, Theophyllin etc

 

3

Medicine that are unstable in the intestinal environment

Captopril, Ranitidine HCl, Metronidazole, Metformin HCletc

 

4

Medicine caused imbalance of normal colonic microbes

Antibiotics against H. Pylori, Amoxicillin Trihydrate etc

 

5

Medicine that have poor solubility at high pH values

Diazepam, Chlordiazepoxide, Furosemide, Verapamil HCl etc

 

 

Table 4. Inappropriate drug candidate for gastro-retentive Drug Delivery system5

S.No.

Drug candidates

Example

1

Medicine that have  very poor solubility in GIT

Phenytoin

2

Medicine that exhibit gastric instability

Erythromycin

3

Medicine that are used for selective colon release

5 – amino salicyclic acid and corticosteroids

 

Table 5 List of polymer used in different dosage forms6

S. No.

Polymer

Dosage Form

1

Xanthan Gum, Karaya Gum, Guar Gum, Carrageenan,

Hydroxypropyl Methylcellulose (HPMC K4M, HPMC K100M) HPMC E15LV, HPMC E50LV, HPMC K100LV, Polyvinyl Pyrrolidone (PVP K30) HPMC K15M, Carbopol, Sodium Carboxymethyl Cellulose, PVP K30 Psyllium Husk, Crospovidone

Tablets

 

2

Ethylcellulose,Eudragit RL100, Cellulose Acetate

Microspheres

 

3

HPMC K4M, HPMC K15M, HPMC K100K, Ethyl Cellulose

Matrix Tablet

 

4

HPMC, Carbopol 934P,Ethyl

Cellulose, Chitosan, Sodium Carboxymethyl Cellulose

Superporous Hydrogel

 

5

HPMC K4M, Ethyl Cellulose

Microballoons

 

Different floating microsphere preparation processes are:

1    Technique for Single Emulsion

2    Technique of Double Emulsion

3    Coacervation technique of phase separation

4    The Ionic process of gelation

5    Evaporating Solvent

6    Spray Drying

7    Diffusion of Quassi emulsion solvent

8    In this process, Wax Coating and Hot Melt

 

Single Technique of Emulsion:

 

The technique of Double Emulsion:

 

Coacervation technique of phase separation:

 

Evaporating Solvent

 

Spray Drying:

 

Evaluation of floating microballoons in terms of physicochemical properties:

1) Particle Size and Shape:7

Optical microscopy was used to assess or determine particle size with the assistance of a calibrated eyepiece micrometer and a stage micrometer. The average particle size of microspheres is obtained by multiplying the size of 100 microspheres. 

 

D mean = ∑ n d / ∑ n

 

Where

n = number of microspheres checked;

d = Mean size

 

2) Determination of encapsulation efficiency8

By precisely weighing 50mg of microspheres and smashing them appropriately with the assistance of a glass mortar and pestle, drug entrapment efficiency was achieved. The microspheres were then suspended and dissolved in 50mL of hydrochloric acid buffer (pH 1.2) and set aside for 24 hours. content in the filtrate was measured spectrophotometrically at 232nm using a UV spectrophotometer after appropriate dilution.

 

[Drug Entrapment efficiency = Actual weight of microspheres/Theoretical weight of drug and polymer × 100]

 

3) Tapped density8

Accurately weighed 10g of microballoon powder sample, which was put in a 25ml measuring cylinder. The cylinder was dropped 100 times from a height of one inch onto a hard hardwood surface at 2-second intervals. The final volume is measured after 100 taps, and the tapped density is computed using the equation (values in gm/cm3). 

 

Tapped Density = Sample Weight /Volume Tapped

 

4) The angle of repose (θ)9

The funnel was placed in a burette stand with the stem of the funnel 2.5cm above the horizontal surface. The microspheres sample powder was allowed to flow out the funnel until the pile's height just touched the funnel's tip. The pile radius was then calculated by drawing a border around the pile's circle and averaging the radius of the circumference across three attempts. The connection between flowability and the angle of repose.

A formula is used to compute the angle of repose.

 

θ = tan-1 h/r

 

Where θ is the angle of repose, h is the height of the pile; r is the radius of the pile.

 

Table 6: Relationship between the angle of repose (θ) and flowability

The angle of repose(θ)

Flowability

<20

Excellent

25–30

Good

30–40

Passable

>40

Very poor

 

5) Percentage Yield:10

It's determined by multiplying the weight of microspheres obtained from each batch by the total weight of all non-volatile ingredients (drug and polymer) used to make that batch by 100.

The following formula is used to express it.

 

% Yield =

(Actual weight of floating microspheres/Weight of drug taken + Total polymer weight) ×100

 

6) Swelling Index:11

It's calculated by measuring how much microspheres swell in a specific solvent.

For the Swelling examination of the material, dissolution equipment, optical microscopy, and other advanced methods are employed. Swelling of 5mg of dried microspheres poured in 5ml of buffer solution overnight in a measuring cylinder determines the equilibrium swelling degree of microspheres.

It has been computed.

 

Swelling Ratio = Wet Formulation Weight/ Formulation Weight

 

7) Buoyancy determination11

The microspheres were weighed and distributed across the surface of a USP dissolving type II device filled with 900 ml of 0.1 N HCl containing 0.02 percent Tween 80. A paddle spinning at 100 rpm was used to stir the medium. Separately, the floating and settling parts of microspheres were collected.

 

The microspheres were weighed after drying. The ratio of the mass of the microspheres that stayed floating to the overall mass of the microspheres was used to determine buoyancy percentage.

 

Percentage buoyancy = Wf/ Wf+Ws x 100

 

Where,

Wf- Floating Weight,

Ws-Settled Microsphere, respectively

 

8) Surface Morphological Study using SEM11

The exterior and interior morphology of the microspheres, as well as the surface degradation of biodegradable microspheres, were determined using scanning electron microscopy (SEM).

 

9) In vitro drug release of microbaloons11

In vitro dissolution tests were carried out per the United States Pharmacopoeia (USP) I basket type dissolving apparatus at a specified speed. A sample of floating microspheres equal to the medication dosage is introduced to 900ml of 0.1N HCL dissolving media and agitated at 100rpm at 370.5°C. After a predetermined period, samples are removed and examined using any appropriate analytical method, such as UV spectroscopy.

 

10) Evaluation In-Vivo11

In vivo investigations are often conducted by giving floating microspheres to healthy albino rabbits weighing about 2-2.5kg. The animals fast for 24 hours before the trials, but food and water are supplied to the rats throughout the experiments, and a radiological technique is used for monitoring. Blood samples of 2ml are taken. In-vivo investigations employ X-ray photography to study the floating behavior and location of microspheres in GIT

 

11) Stability Studies11

Sealing was done with aluminum packing. Inside is a polyethylene coating that has been optimized. For three months, samples were stored at 40°C and 75 percent RH in the stability chamber. Samples were examined for physical appearance and drug content after the experiments.

 

Table 7 Drugs used in the formulation of GRDDS

1

Tablets

Verapamil HCI, Isosorbide di nitrate, Sotalol, Isosorbide mononitrate, Aceraminophen, Ampicillin’ Cephalexin, Ziduvudine, Losartan, Pentoxyfillin, Cholrpheniramine maleate, Theophylline, Furosemide, Ciprofloxacin, Metformin Hydrochloride

2

Capsules

Propranlol, Urodeoxycholic acid, Pepstatin, Celiprolol HCl, Nicardipine, L-Dopa and benserazide, chlordizepoxide HCI, Furosemide, Misoprostal, Diazepam

3

Microspheres

Theophylline, Nifedipine, Nicardipine, Dipyridamol, Rosiglitazone maleate, Flurbiprofen, Orlistat, Verapamil, Aspirin, Griseofulvin, and p-nitroanilline, Ketoprofen, Tranilast, Iboprufen, Terfenadine

4

Granules

Isosorbide mononitrate ,Isosorbide dinitrate, Ranitidine HCl, Indomethacin, Diclofenac sodium, Prednisolone, Cinnarizine, Diltiazem, Fluorouracil

5

Films

Prednisolone, Quinidine gluconate, Cinnarizine, Drug delivery device, Albendazole, P-aminobenzoic Acid

6

Powders

Several basic drugs-Riboflavin, Sotalol, Theophylline

7

Beads

Curcumin β-cyclodextrin complex, Diltiazem HCl, Ranitidine HCl, Loratadine

8

Bilayer tablet

Diltiazem HCI and Lovastatin, Atenolol, Misoprostal, Trimetazidine hydrochloride and Metoprolol succinate

 

CONCLUSION:

In this study, we found that when medication is administered orally, absorption via the gastrointestinal system varies greatly. Floating Gastroretentive medication delivery devices are used to overcome this problem. Floating microspheres are now widely utilized across the world due to their ease of use and therapeutic effect. Microspheres stay in the stomach for more than 12 hours due to their low density, which allows them to float over gastric contents. These microspheres are employed as a gastric retention dosage form because they have a high potential for gastric retention, which means they increase medication absorption in the upper GI tract (stomach, duodenum, and jejunum) and improve bioavailability. Most businesses are expanding their attention and research in the manufacture of floating gastroretentive microspheres as a consequence of their good results and increased demand among patients. Optimized multi-unit floating microspheres are intended to provide doctors with a new alternative for an affordable, healthful, and extra bioavailability treatment for a variety of illnesses.

 

ACKNOWLEDGMENT:

The authors would like to thank the Innovative Institute of Pharmacy, Greater Noida, India, our teachers, friends/classmates, and our loving parents for their blessings and assistance during my literature review.

 

DECLARATION OF INTEREST:          

The author declares no potential conflicts.                            

 

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Received on 09.09.2021            Accepted on 19.09.2021           

Accepted on 01.10.2021              ©A&V Publications all right reserved

Research J. Topical and Cosmetic Sci. 2021; 12(2):86-92.

DOI: 10.52711/2321-5844.2021.00012