INTRODUCTION:

Conventional oral dosage forms such as tablets and capsules provide a specific drug concentration in systemic circulation which does not release the drug at a constant rate for a prolonged period of time. Controlled release drug delivery system (CRDDS) provides drug release at a pre-controlled, predictable rate either systemically or locally for intended duration of time and optimizes the therapeutic effect of a drug by controlling its release into the body with lower and less frequent dosing.Controlled‐release drug delivery system is capable of achieving the benefits like maintenance of therapeutic amount of drug concentration in blood for an extended time period; enhancement of activity of duration for drugs having short half life; elimination of side effects; reducing the fluctuations of drug concentration and frequency of dosing; it optimized therapy and better patient compliances [1].

Gastro retentive drug delivery systems (GRDDS):

Dosage forms that can be retained in the stomach for longer duration are called as gastro retentive drug delivery systems (GRDDS). GRDDS are helpful in improving the absolute bioavailability, therapeutics efficiency, gastric residence time (GRT) of drugs. They are also useful in reduction of the dose, and drug waste and improves the solubility of drugs that are less soluble in a high pH environment.

Floating drug delivery system:

Floating drug delivery systems are low-density based systems with sufficient buoyancy to float over the gastric contents. While the system is floating on the gastric contents, the drug is released slowly at a constant rate from the system. After release of the drug, the residual system is evacuated from the stomach. This results in an increased GRT, reduces fluctuation of drug and thus enhances bioavailability. Many floating systems have been generated such as granules, powders, capsules, tablets, laminated films, beads and hollow microspheres. It can be classified into two systems:

Effervescent Systems:

These are matrix systems prepared with the help of swellable polymers such as methylcellulose and chitosan and various effervescent compounds, e.g., sodium bicarbonate, tartaric acid, and citric acid. The matrices are fabricated so that upon arrival in the stomach, carbon dioxide is liberated by the acidity of the gastric contents and is entrapped in the jellified hydrocolloid. This produces an upward motion of the dosage form and maintains its buoyancy. A decrease in specific gravity causes the dosage form to float on the chime. Effervescent system is further classified into:

· Volatile liquid containing systems (Intragastric floating GRDDS)

· Gas-generating Systems (Intra gastric single layer and bilayer floating tablets, Multiple unit type floating pills)

Non-Effervescent Systems:

Non-effervescent floating dosage forms use a gel forming or swellable cellulose type of hydrocolloids, polysaccharides, and matrix-forming polymers like polycarbonate, polyacrylate, polymethacrylate, and polystyrene. The formulation method includes a simple approach of thoroughly mixing the drug and the gel-forming hydrocolloid. After oral administration this dosage form swells in contact with gastric fluids and attains a bulk density of < 1. The air entrapped within the swollen matrix imparts buoyancy to the dosage form. The so formed swollen gel-like structure acts as a reservoir and allows sustained release of drug through the gelatinous mass [2].

Non- Effervescent system is classified into:

1. Hydro colloidal gel barrier systems.

2. Micro porous compartment system.

3. Alginate and pectin beads

4. Hollow microsphere (Microballoons)

Microballoons:

Microballoons are non-effervescent type of gastro retentive drug-delivery systems. They are hollow microspheres which are generally empty particles and spherical in shape without a core. These microspheres are characteristically free flowing powders consisting of proteins or synthetic polymers, ideally having a size less than 200 micrometers. Microballoons are considered as one of the most favourable buoyant systems with unique characters such as better floating properties, because of central hollow space inside the microsphere [3].

Advantages:

· Improves patient compliance by decreasing dosing frequency.

· Gastric retention time is increased.

· Plasma drug concentration is maintained.

· Controlled release of drug for prolonged period of time.

· Site-specific drug delivery to stomach can be achieved.

· No risk of dose dumping.

· Enhanced absorption of drug which solubilizes only in stomach.

The slow release of drug at a desired rate and better floating properties mainly depend on the type of polymer, plasticizer and the solvents employed for the preparation.

GENERAL METHOD OF PREPARATION:

Hollow microspheres/microballoons loaded with drug in their outer polymer shell are prepared by a novel method such as solvent evaporation or solvent diffusion/ evaporation to create a hollow inner core. The drug and an enteric acrylic polymer mixture are dissolved in ethanol/ dichloromethane solution and it is poured into an agitated solution of Poly Vinyl Alcohol (PVA) that is thermally controlled at 40ºC. After the formation of stable emulsion, the organic solvent is evaporated from the emulsion by increasing the temperature under pressure or by continuous stirring. The gas phase is generated in the droplet of dispersed polymer by the evaporation of dichloromethane and thus formed the hollow internal cavity in the microsphere of the polymer with drug. The microballoon continuously floats over the surface of an acidic dissolution media containing surfactant for more than 12 hours [4].

MECHANISM OF ACTION:

Microballoons are low-density systems that have sufficient buoyancy to float over gastric fluid and remain in stomach for prolonged period of time. As the system floats over gastric fluid, the drug is released slowly at desired rate resulting in increased gastric retention with reduced fluctuations in plasma drug concentration. When microballoons come in contact with gastric fluid, the gel forms and polymers hydrate to form a colloidal gel barrier that controls the rate of fluid penetration into the device and consequent drug release. As the outer surface of the dosage form dissolves, the gel layer is maintained by the hydration of the adjacent hydrocolloid layer. The air trapped by the swollen polymer makes the density lower than the gastric fluid and confers buoyancy to the microspheres. However, a minimal gastric content needed to allow proper achievement of buoyancy. Hollow microspheres of acrylic resins, eudragit, hypromellose, polyethylene oxide, cellulose acetate, polystyrene floatable shells, polycarbonate floating balloons and gelucire floating granules are the recent advancements [5].

Fig. 1: Mechanism of action of Hollow microspheres

FORMULATION OF MICROBALLOONS:

Drugs:

Drugs with narrow therapeutic window that are mainly absorbed from the stomach and upper part of GIT, locally act in the stomach, degrade in the colon, disturb normal colonic bacteria are suitable candidates to be formulated into microballoons. E.g. Aspirin, Salicylic acid, Ethoxy benzamide, Indomethacin and Riboflavin, Para amino benzoic acid, Furosemide, Calcium supplements, Chlordiazepoxide, Scinnarazine, Riboflavin, Levodopa, Antacids, Misoprostol, Ranitidine HCl, Metronidazole and Amoxicillin trihydrate.

Polymers:

Cellulose acetate, chitosan, eudragit, acrycoat, methocil, polyacrylates, polyvinyl acetate, carbopol, agar, polyethylene oxide, polycarbonates, acrylic resins and polyethylene are the polymers of choice for microballoons [6].

Solvents:

Solvents having good volatile properties are selected, so that it should easily come out from the emulsion leaving hollow microspheres e.g., ethanol, dichloromethane (DCM), acetonitrile, acetone, isopropyl alcohol (IPA), dimethylformamide (DMF).

Processing Medium:

It is used to harden the drug and polymer emulsified droplets when the drug and polymer solution is poured into it. It should not interact with the drug and polymer emulsified droplets. Liquid paraffin, polyvinyl alcohol or water is mainly used as a processing medium.

Surfactants:

These are stabilizers or emulsifiers that harden the microspheres E.g. Tween 80, Span 80 and SLS.

Cross linking agent:

Chemical cross-linking of microspheres can be achieved using cross linking agents such as formaldehyde, glutaraldehyde or by using di acid chlorides such as terephthaloyl chloride. The method is limited to drugs that do not have any chemical interaction with cross- linking agents.

Hardening agent:

This helps to harden the microspheres formed in the processing medium E.g. N-hexane, petroleum ether (in case the processing medium is liquid paraffin [7].

Method of preparation:

Microballons are prepared by means of novel techniques like simple solvent evaporation method, emulsion-solvent diffusion method, single emulsion technique, double emulsion technique, phase separation coacervation technique, polymerization technique, spray drying and spray congealing method and hot melt encapsulation method.

Solvent evaporation method:

Polymers such as Eudragit, HPMC K4 and ethyl cellulose etc are used in this method. Polymers are mixed with drug and further this mixture is dissolved in the solution of ethanol, acetone or dichloromethane either alone or in combination to get homogeneous polymer solution. The resulting solution is poured into 100 ml of liquid paraffin rotating at 1500 rpm. The so formed emulsion is heated at 35^oC for 3hrs. After the formation of a stable emulsion, the acetone or dichloromethane is completely evaporated and resulting solidified microspheres are filtered using whatman filter paper. These hollow microspheres posses floating and sustained release properties [8].

Fig 2: Solvent evaporation method

Emulsion solvent diffusion method:

The mixture of drug and polymer is dissolved in the solution of ethanol: dicloromethane (1:1) and this mixture is added dropwise to the polyvinyl alcohol solution. This solution is stirred at 1500rpm for 1 hr.

In this method the affinity between the drug and organic solvent is stronger than that of organic solvent and aqueous solvent. The drug is dissolved in the organic solvent and the solution is dispersed in the aqueous solvent producing emulsion droplets even though the organic solvent is miscible. The organic solvent diffuses gradually out of the emulsion droplets into the surrounding aqueous phase and the aqueous phase diffuses into the droplets by which the drug crystallizes [9].

Fig 3: Emulsion solvent diffusion method

Spray drying and spray congealing technique:

Spray drying:

This method involves solidification of coating by rapid evaporation of the solvent in which coating material is dissolved. Spray drying is the most widely used industrial process for particle form and drying. It is an ideal process where the required particle size distribution, bulk density and particle shape can be obtained in a single step.

Spray congealing:

Spray congealing involves solidification of coating can by thermally congealing a molten coating material. The removal of solvent is done by sorption, extraction or evaporation

Method:

Firstly the polymer is dissolved in a suitable volatile organic solvent such as dichloromethane, acetone etc. to form a slurry. The slurry is then sprayed into the drying chamber. Concentration gradient develops inside the small droplet with higher concentration at the droplet surface. This is because the time taken for the solute to diffuse is greater than that of the solvent in the droplets to evaporate during the drying process. Subsequently, a solid shell appears leading to the formation of microspheres. Separation of the solid products from the gases is usually accomplished by means of a cyclone separator while the traces of solvent are removed by vacuum drying and the products are saved for later use [10].

Fig 4: Spray drying and spray congealing technique

Single Emulsion technique and Double Emulsion technique [12]:

Fig 6: Single Emulsion and Double Emulsion Technique

EVALUATION OF MICROBALLONS:

Percentage Yield:

The percentage yield of hollow microspheres is determined for drug and is calculated using the following equation.

Yield= M x 100

______

Where

M = weight of beads

M_o = total expected weight of drug and polymer.

Micromeritic properties:

Microballoons are evaluated for their micromeritic properties such as particle shape and size, bulk density, tapped density, Hausner’s ratio and flow properties are determined by Carr’s index and angle of repose. Particle size is determined by optical microscopy, and average diameter of the particle is calculated with the help of a calibrated ocular micrometer (by measuring 200 to 300 particles). True density is determined by liquid displacement method; tapped density and compressibility index are calculated by measuring the change in volume using a bulk density apparatus; Angle of repose is determined by fixed funnel method. The hollow nature of microspheres is confirmed by scanning electron microscopy [13].

The compressibility/Carr’s index can be c calculated using following formula:

I = V_b –V_t x100

_______________

V_b

Where, V_b is the bulk volume and V_t is the tapped volume.

True density is determined using a Helium densitometer. Porosity (e) is calculated using the following equation:

e = 1- Tapped density×100

____________________________________

True density

Angle of repose of the microballoons is determined by the fixed funnel method.

In vitro Buoyancy:

Appropriate quantity of hollow/empty microspheres are placed in 900 ml of 0.1N HCl. The mixture is stirred at 100 rpm for 8-10 hours in dissolution apparatus. After 8 to 10 hours, the layers of buoyant microspheres are pipetted and separated by filtration. Particles which lie in the sink layer are separated by filtration. Particles of both types (buoyant microspheres and settled microspheres) are dried in a desiccator until constant weight is achieved. Both the fractions of empty or hollow microspheres are weighed, and in vitro buoyancy is determined by the weight ratio of floating microspheres to the sum of floating and sinking microspheres [14].

Buoyancy (%) = Wf × 100

______________________

Wf + Ws

Where,

W_f and W_s are the weights of the floating and settled microspheres

Scanning Electron Microscopy:

Dry hollow microspheres are placed on an electron microscope brass stub coated with gold in an ion sputter. Then pictures of the microspheres are taken by spectro random scanning of the stub. The microspheres are viewed at an accelerating voltage of 20KV40.

In-vitro drug release studies:

The release rate of hollow microspheres is determined using USP type II dissolution apparatus i.e. Basket type of dissolution apparatus.

A weighed amount of hollow microspheres (filled into a hard gelatin capsule) equivalent to the dose of drug is placed in a basket of dissolution apparatus containing dissolution medium. The dissolution fluid is maintained at 37 ± 1°C and the rotation speed is maintained at a specific rpm. Perfect sink conditions should be maintained during the drug release study. 5 ml of the sample is withdrawn at each time interval and is analyzed using Liquid chromatography or Mass spectroscopy method to determine the concentration of microballoons present in the dissolution medium. The initial volume of the dissolution fluid is maintained by adding 5 ml of fresh dissolution fluid after each withdrawal. All experiments are run in triplicate [15].

Swelling studies:

Swelling studies are performed to calculate molecular parameters of swollen polymers. They are determined by using dissolution apparatus, optical microscopy and other sophisticated techniques, which include H1NMR imaging, Confocal laser scanning microscopy (CLSM), Cryogenic scanning electron microscopy (Cryo-SEM), Light scattering imaging (LSI) etc. The swelling studies by using Dissolution apparatus is calculated as per the following formula [16].

Swelling ratio = Weight of wet formulation

_______________________________________________________

Weight of formulations

In-vivo studies:

The in-vivo studies are performed on suitable animal model such as rats, beagle dogs etc. The floating behavior can be investigated by radiographical studies using barium sulphate microballoons.

APPLICATIONS OF MICROBALLOONS:

· Microballoons can ameliorate the pharmacotherapy of the stomach through local drug release and it leads to high drug concentration in the gastric mucosa, thus eliminating Helicobacter pylori from the sub mucosal tissue of the stomach and making it possible to treat stomach and duodenal ulcers, gastritis and oesophagitis.

· These empty microspheres allow sustained drug release behavior and release the drug over a prolonged period of time. Hollow microspheres are fabricated as a floating controlled drug delivery system.

· Floating microballoons can greatly enhance the absorption of those drugs which have poor bioavailability and thus improves absolute bioavailability

· Floating microballoons are site specific drug delivery especially for those drugs which are specifically absorbed from stomach or from proximal part of small intestine.

· Microballoons can be used to transport the drugs with narrow absorption window, i.e. are taken up only from very specific sites of the GI mucosa. For example, antiviral, antifungal and antibiotic agents such as Sulphonamides, Quinolones, Penicillins, Cephalosporins, Aminoglycosides and Tetracyclines

· Empty microspheres of NSAIDS are very successful in producing controlled release as well as it reduces the side effects such as gastric irritation; for example floating microspheres of Indomethacin is quite beneficial for rheumatic patients [17].

MARKETED FORMULATIONS:

Table 1: List of marketed formulations of Microballoons

Drug	Brand name	Manufacturer name
Nizatidine	Tazac	Dr. Reddy Laboratories Ltd.
Propranolol Hydrochloride	Inderal	Pellets Pharma Limited
Domperidone	Motilium	Nishchem International Pvt. Ltd
Theophylline	Uniphyl	Kores India Limited

CONCLUSION:

Microballoons are low-density systems that have sufficient buoyancy to float over gastric contents and remain in stomach for prolonged period without any irritation to gastrointestinal tract. The drug is released in controlled manner at a desired rate when it floats over gastric fluid, resulting in reduced fluctuations in plasma drug concentration. Hollow spheres promises to be a potential approach for gastric retention. Optimized microballoons are novel drug delivery, particularly in diseased cell sorting, diagnostics, gene and genetic materials, safe, targeted and effective in vivo delivery.

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Received on 20.05.2020 Revised on 13.06.2020

Asian J. Pharm. Res. 2020; 10(4):312-318.

DOI: 10.5958/2231-5691.2020.00053.2