INTRODUCTION:

The oral drug delivery system suggests numerous merits basically, the design of flexible dosage forms and patient compliance. The optimization of the pharmacokinetic and pharmacodynamic and biopharmaceutical properties of the medication are the main aspects of controlled drug delivery. Consequently, the therapeutic maintenance of the medication target, reducing the frequency of drug administration, diminishing the side effects with desirable therapeutic concentration and improving patient compliance could be achieved,¹Beads considered as one of the multiparticulate delivery systems comprising an inner core and outer coating constituents, thus providing extended/ controlled release and improving bioavailability. As the term indicates, beads are characterized by small, spherical shaped particles. The Particle sizes varied from 12 to 300 microns in diameter, and the thickness of the wall may fluctuate from numerous microns to as low as 0.1 microns.

Much attention has been given to beads as oral multi-unit dosage form thus, providing a modified /controlled drug delivery system besides, these systems offer uniformity of drug distribution in the gastrointestinal tract, as a result, uniform drug absorption and the diminished patient to patient variability would be attained.² Hydrogel beads are one of the successful multiparticulate systems by which drug can be targeted for a specific site, in review to previous works of literature this successful technique utilizes natural and synthetic polymers, as carriers for bioactive agents, especially drugs, thus improving the release kinetics, adjusting pharmaceutical agents transport or circulation half-life possessions, furthermore allowing passive and active drug delivery systems.³Natural hydrophilic polymers such as polysaccharides (polyelectrolytes) have been extensively exploited as drug release modifiers in numerous controlled drug delivery systems for their beneficial goods over synthetic polymers such as biocompatibility, biodegradability, ability to amend the characteristics of the aqueous environment, moreover induce thickening, emulsification, stabilization, encapsulation, swelling, forming gels and films.^4,5 The present review shed the light on beads as a multiparticulate system covers the merits and limitation, address the most common polymers, methodologies for preparations, application in the pharmaceutical industry, in addition to investigate the characteristics of the beads.

Merits of beads as a multiparticulate drug delivery system⁶

1. Beads offer a persistent and prolonged therapeutic effect.

2. Improves patient compliance by reducing the dosing frequency.

3. The small size and spherical shape of beads could be exploited to be injected into the body

4. Better drug utilization will enhance bioavailability and reduce the occurrence or intensity of adverse effects.

5. The morphology of beads permits a controllable variability in degradation and drug release

Limitation of beads as a multiparticulate drug delivery system⁷

Several limitations were found to be as follows:

1. Variation of the rate of release from one dose to another and controlled release pattern that might be due to several factors like food and gastric emptying rate

2. Potential toxicity caused by any loss of integrity of intended release characteristics of beads especially if contain a high load of drug

3. This multi -particulate system is prohibited from crushing or chewing

Main materials used in the beads technology^8-11

Beads usually use polymers. They are classified into two types:

1. Natural polymers

2. Synthetic Polymers

1. Natural polymers obtained from different sources like carbohydrates, proteins and chemically modified carbohydrates

Carbohydrates: Agarose, Carrageenan, Chitosan, Starch

Proteins: Albumin, Collagen and Gelatin Chemically modified carbohydrates: Poly dextran, Poly starch

2. Synthetic polymers: are divided into two types.

Biodegradable polymers: Lactides, Glycolides & their co-polymers, Poly anhydrides, Poly alkyl cyanoacrylates

Non-biodegradable polymers: Polymethyl methacrylate (PMMA), Glycidyl methacrylate, Acrolein, Epoxy polymers

In addition to polymers, multivalent ions are essential for preparation of beads: cations: Calcium (Ca⁺²)Potassium (K⁺¹), Ferric (Fe⁺²), Barium (BA⁺²), Sodium (Na⁺¹), Magnesium (Mg⁺²), Aluminum (Al⁺³), Zinc (Zn) ⁺², anions: tripolyphosphate (TPP^-), sodium sulfate.

Common polymers utilized in beads technology:

In view of recent pharmaceutical literature, the following polysaccharide polymers were widely utilized in beads preparation, in most common chitosan and sodium alginate in combination or separately were extensively being used for beads preparation.¹²

Sodium alginate:

One of the efficacious and popular polymers that are utilized for the preparation of medicated beads as a drug delivery system is sodium alginate, which is a salt of alginic acid, characterized by bio-compatibility, non-toxicity, sodium alginate is a naturally originated polysaccharide entirely present in different kinds of brown algae. Alginate has an exceptional property of gel construction in the existence of multivalent cations such as calcium ions in aqueous media. Alginate beads possess a significant criterion that is essential for this promising drug delivery system, the incapability to re-swell in a low pH environment and effortlessly re-swell in a high pH environment, as a consequence, the acid-sensitive drugs will remain intact from the harsh low pH environment. The concentration of sodium alginate plays a key role in formulation features, the increment in sodium alginate concentration has a positive impact in improving the gelling capacity, while the lower concentration extended the drug release in a sustained manner providing a controlled drug release characteristic. Alginate can be cross-linked with divalent cations (as Ca2+, Cu2+, Ba2+) that act as cationic bridges mainly between sequences that are rich in guluronic acid residues (G-G sequences) along two aligned chains of alginate, forming an 'egg-box' structure.^13-15 Iswandana et al developed promising calcium alginate -tetrandrine beads using the ionic gelation method.¹⁶

Chitosan:

Chitosan is one of the utmost promising polymers for the preparation of medicated beads with specific targeting characteristics, it considered the most significant derivative of chitin, a polysaccharide that naturally originates in the exoskeleton of shellfish like shrimp and crab. Alkaline condition or enzymatic hydrolysis are favorable conditions for the deacylation of chitin and the practical production of chitosan. Chitosan is a non-toxic biodegradable linear polymer, chitosan has two functional groups: amino (–NH2) and hydroxyl (–OH) groups, the amine group of chitosan provides an interacting site for a crosslinker with an opposite charge through ionic bonding thus eventually produce the crosslinked network, tri-poly phosphate considered as the most common polyanionic crosslinker used for the formulation of chitosan. The most efficient multiparticulate beads for drug delivery can be designed through utilizing naturally originated polymers of alginate and chitosan.^17,18,19

Carboxy Methyl Cellulose:

Carboxy methyl cellulose (CMC) can be produced by manipulation of cellulose product by carboxymethylation process, the iontopic gels can be formed by interactions of the carboxylic groups of the CMC with multivalent metal ions, this type of hydrogel majorly stabilized through electrostatic interaction. Furthermore, the possible reason behind the water insolubility and stability of the hydrogel beads is related to the interactions between the –OH groups of the polymer and the metal ions. The crosslinking between CMC and ferric/aluminium salt attributed to the formation of biodegradable hydrogel beads. Controlled release pattern can also be improved by coating these hydrogels with chitosan/gelation and by cross-linking.^20,21,22

Gellan gum:

Gellan gum is a linear anionic polysaccharide obtained from the exocellular secretion of the microorganism, Pseudomonas elodea. It consists of tetra-saccharide repeating units: α-l-rhamnose, β-d-glucuronic acid and β-d-glucose in the molar ratio 1:1, the gellan gum possesses stability and improved gel strength, provide flexibility and thermo-reversibility, gellan gum has an extensive diversity of applications mostly in food and pharmaceutical industries.²³

Gellan gum possesses a free carboxylate group which is responsible for anionic nature thus, providing the undergoing ability for ionic gelation in the abundance of mono-and divalent cations, with much more affinity for divalent cations. The gelation is achieved by the formation of a double helical connection zone followed by aggregation of double-helical segments to yield a three-dimensional matrix, this is attributed to complexation with cations besides hydrogen bonding, the matrix system contains evenly dispersed material throughout the crosslinked gellan gum.²⁴In a review of literature on the gellan gum beads, osmalk et al designate gellan gum beads for modified release of meloxicam²⁵. Adrover et al prepared successfully modified-release guar gum beads of Theophylline and vitamin B12.²⁶

Pectin:

Pectin is a non-toxic, low methoxy polysaccharide extracted from the citrus peel or apple pomace and it has been used as a gelling agent. Pectin has colloidal poly galacturonic acid where many carboxylic groups are esterified with methyl groups. D-galacturonic acid compromises the major constituent of pectin, the degree of esterification is less than 50% also it can form gels in the presence of calcium ions or other multivalent cations. Pectin will minimize the interfacial tension between an oil phase and a water phase which used for the preparation of emulsions.²⁷ Atara et al prepared successfully pectin beads for azathioprine colon targeted beads.²⁸

Different techniques of beads technology¹

· Ionotropic gelation technique

· Emulsion internal Ionotropic gelation.

· Ionotropic gelation followed by coacervation.

· Multi polyelectrolyte beads.

1- Ionotropic gelation technique:

Among variable methods for beads preparation, ionotropic gelation is one of the more reasonable in cost and easier steps to achieve daily laboratory work. The ability of polyelectrolytes to cross-link in the presence of counterions is the cornerstone for the Ionotropic gelation technique to be successfully achieved, capturing drugs and biomolecules inside tiny structures can be achieved through this technique, besides having the release rate hindering effect characteristics. In addition, natural polymers possess some anions in their chemical structure. The process of gelation and formation of insoluble meshwork like structure is triggered by anions as they will combine with their counteracting cations. Addition of drug-loaded polymeric solution through dropping gently into polyvalent cationic solution yield hydrogel beads. The cations diffuse into drug load polymeric drops forming a three-dimensional lattice of the ionically cross-linked moiety. The counter ions used for the ionotropic gelation method are calcium chloride, barium chloride, zinc chloride, copper chloride, cobalt chloride, pyrophosphate. The beads isolation is achieved by filtration then washed with distilled water and dried.^29,30

2-Emulsion Internal Ionotropic Gelation Technique:

The emulsion method considered to be progressive in comparison to the previous method, as the oil phase is gently homogenized with an aqueous phase in which the polymer is included and then extruded into crosslinker solution³¹An emulsification/internal gelation method is proposed for producing small diameter beads in a large amount. The struggle of using dispersion/external gelation techniques with ionic polysaccharide is mainly the limited solubility of calcium source in the oil phase. As a substitute, internal gelation of the dispersed polymer droplets can be originated by releasing the divalent crosslinker from an insoluble complex (calcium vector) through pH reduction. The technique primarily include dissolving the polymer in an aqueous phase, the drug encapsulant is added to the polymeric aqueous solution, the preparation is mixed with an insoluble crosslinker vector (calcium salt), then the mixture is dispersed into an oily phase containing emulsifying agent with continued agitation until eventually an emulsion is formed, an acid is added to aggravate the liberation of the crosslinker (calcium ion) and the gelation will be initiated,³² the oil-bead suspension is added with gentle mixing to calcium chloride bath. The external gelation of beads begins to appear as a consequence of the coalescence between the aqueous droplets containing initially gelled beads and those containing the calcium chloride solution.^{33, 34}

3- Ionotropic gelation followed by coacervation:

This advanced method involves the utilization of the Ionotropic gelation process by cross-linker then coacervation process by using a polyelectrolyte complexation, the cross-linked polymer boosts the limited solubility of beads by ionotropic gelation and polycation-polyanion coacervation, consequently leading to polyionic links between the core bead and the external coating layer.²⁰The methodology involves preparing a core bead solution, this solution is extruded dropwise using a specific needle with a certain gauge into a crosslinker bath under gentle stirring, at room temperature. The formed beads were allowed to harden in curing medium for a certain time and then rinsed with distilled water. Subsequently, the beads are further exposed to a coating solution for a specific time interval with continuous agitation at room temperature.^35,36 This method imparts improvement in the stability and Physico-chemical properties of prepared beads.³⁷

4- Multi polyelectrolyte beads:

This technique involves the formation of a polyelectrolyte complex between two polymeric candidates typically polyions (polycation and polyanion), this approach provides an enhancement in the quality of the beads, by overcoming the poor encapsulation and leakage of the drug in the hardening medium. Through the last two decades, there was certain consideration toward the use of polyelectrolyte complex methodology, this is related to the advantage of omitting the need for certain toxic crosslinkers for sustained/modified delivery of drugs.³⁸ Polyelectrolyte complex can be attributed due to inter-chain interactions when two aqueous solutions of oppositely charged macromolecules are mixing, this interaction may be determined by coulombic attraction or other interactions such as hydrogen bonding, dipole-dipole interaction, charge-transfer interaction, and the hydrophobic effect.³⁹ The final cationic -anionic complex undergoes phase separation as coacervate liquids, the properties of these beads relied on different factors for instance concentrations, the mixing condition and the structure of counter partner polymers. The polyelectrolyte beads methodology considered as a modification for ionic gelation method as a polymer with anionic functional groups dissolved into the aqueous solution then extruded into cationic polymeric solution using a syringe with certain needle gage at room temperature under continuous agitation the beads will be formed immediately, after letting the beads to be cured for a while in the hardening medium, filtration and washing the beads with deionized water, the obtained beads were dried and kept in a desiccator for further use.⁴⁰The distinctions of hydrogel beads prepared by this method are the mechanical strength and permeability barrier that exposed improvement.³⁶

Applications of beads in the pharmaceutical industry⁴¹

· Masking the taste and odour

· Postponing volatilisation

· Isolation of incompatible substances

· Improving the flow properties of powders

· Enhancing the stability of the drug against the exterior circumstances

· Promoting the safe handling of toxic substances

· Improving the solubility of water-insoluble substances through incorporating dispersion of such substances in aqueous media

· Alteration of liquid dosage form into solids, thus provide ease of handling of oils

Evaluation characteristics of hydrogel beads:

Particle size analysis by optical microscopy:

Measuring particle size of bead formulation can be achieved by using an optical microscope. the microscope is fitted with an ocular and stage micrometer and particle distribution can be detected.⁴²

Fourier transform infrared spectroscopy (FTIR) studies:

The intermolecular interaction and the functional structure of beads can be detected by using an FTIR spectrophotometer.⁴²

Scanning electron microscopy (SEM):

The investigation of the interior structure and surface morphology of the hydrogel beads can be attained by using a scanning electron microscope (SEM). Coating the Vacuum dried beads to a certain thickness with gold-palladium before microscopy. The coated beads can be investigated underneath scanning electron microscopy instrument and at desired magnification.⁴³

Swelling studies:

The Swelling of hydrogel beads can be measured in numerous pH range. Swelling plays a key role in the release of captured drug from the hydrogel beads, due to the straight proportion between swelling and drug release. The behaviour of hydrogel beads characterizes by slight swelling in the stomach, swelling gradually increases as intestinal pH increases and reach the maximum in the colon. According to (M. K Younis et al) the dynamic swelling study of the beads was carried out by mass measurement as a function of pH, the swelling ratio can be studied by measuring the percentage water uptake by the beads. The beads are initially weighed in a dry state, then re-weighed after immersing in the swelling media at certain time intervals, the excess swelling media are removed from detached beads by using a filter paper. Swelling (%) is estimated according to the following formula.⁴⁴

Swelling index= (S-T) / T*100

Where: S = The weight of the hydrogel beads after swelling, T = The initial weight of the hydrogel beads.

Drug entrapping efficiency:

The entrapment of water-soluble drug is much fewer than the poorly water-soluble drug, the water-insoluble drugs having good entrapment efficiency, this can be attributed to drug loss in the medium since most of the mediums are aqueous. As the curing time is extended the entrapment efficiency will be lesser.⁴⁵An additional contributing factor for enhancing entrapment efficiency is the drug concentration, the higher concentration of the drug, the entrapment will be more efficient, also with the increment in coating polymer concentration the drug entrapping efficiency will be further enhanced.^46-47The % entrapment efficiency can be determined using the following formula:

Entrapment efficiency = Total amount of drug found in formulation/total amount of drug used in the formulation

Estimation of Drug content:

To guarantee the uniformity of drug within multiparticulate units, each particulate unit should possess the precise content of active substance with an acceptable deviation around the label claim, as the dosage units are known as a single dose or a part of a dose of a therapeutic ingredient in each dosage form. Drug content can be estimated generally by measuring equivalent weight drug-loaded polymeric beads, a suitable solvent will be chosen to dissolve the drug encapsulated in the beads. The mixture subject to continue stirring by using a magnetic stirrer. The final solution will subject to filtration and the filtrate will be appropriately diluted with a suitable solvent. Finally, the drug content can be estimated spectrophotometrically.^48-49

In vitro release studies of Hydrogel beads:

Performing the dissolution study on pharmaceutical products considers as one of the most vital quality-control tests and presently the study developed into an innovative tool for estimating the bioavailability and determining the bioequivalence as a replacement of clinical study in some cases, the release study strategy differs according to the target site for the dosage form, according to (Kumar M et al) the release study of colonic targeted mesalamine was carried out in simulated gastric fluid (pH 1.2) for 2hrs, simulated intestinal fluid (pH 6.5) for 3 to 5 hrs and simulated colonic fluid (pH 7.4) for 6 to 24 using USP XXIII apparatus at 100 rpm maintained at a temperature of 37+1°C,⁵⁰and according to (Conway R et al) the release study of gastroretentive alginate beads of metronidazole is performed using USP type 1 apparatus in 0.1N HCl (pH 1.2) agitated at 100 rpm, the in-vitro release was maintained at 37 ±1°C.⁵¹At periodic time intervals, the samples are withdrawn at a specific time interval and assayed spectrophotometrically at the wavelength of maximum absorbance and cumulative percent drug release was calculated. A certain volume of fresh dissolution media was added each time to maintain the sink conditions.⁵²

ACKNOWLEDGMENT

This article is supported by the College of Pharmacy, Mustansiriyah University, Baghdad, Iraq.

CONCLUSION:

The present review declares that the recent drug delivery innovations are enabling the incorporation of the pharmaceutically active ingredient into different dosage forms, the market of these innovations is in continuous evolution at a remarkable rate, consequently, abundant therapeutic and commercial returns will be provided. Multiparticulate drug delivery systems (Beads) provide the opportunity in controlling and delaying the drug release by encapsulating the active pharmaceutical ingredients into spheres using natural polymers commonly, hence beads possess several physical and technical merits, additionally, beads provide progression toward optimization of therapy through enhanced adaptability and flexibility by clinicians and researchers of product developments. Features of polymers, beads preparation technologies, evaluation characterization presented in this review, will bounce the researchers with improved comprehension for beads as a microparticulate drug delivery arena.

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Received on 08.04.2021 Modified on 28.09.2021

Research J. Pharm. and Tech 2022; 15(9):4283-4288.

DOI: 10.52711/0974-360X.2022.00719