INTRODUCTION:

One of the most challenging regions of research in pharmaceuticals is the improvement of novel delivery systems for the controlled release of drugs and delivery at the targeted site in the body to minimize side effects and enhance the therapeutic efficacy of drugs¹. So, a well-designed controlled drug delivery system can triumph over some of the issues of conventional therapy and enhance the therapeutic efficacy of a given drug.

There are numerous approaches to delivering a therapeutic substance to the target site in a sustained controlled release fashion.

The method of targeting and site-specific delivery with absolute accuracy can be done through Polymeric cross-linked carrier matrices, such as microparticles, hydrogels, and supramolecular polymer aggregates are standard examples of common drug transport systems. One such good approach is using microspheres as carriers for drug delivery which maximizes the drug concentration at the target site. A microsphere can be used for the controlled release of drugs, vaccines, antibiotics, and hormones².

Microspheres are described as “Monolithic sphere or therapeutic agent distributed throughout matrix either as a molecular dispersion of debris” (or) may be defined as structure made up of continuous phase of one or more miscible polymers in which drug debris is dispersed at the molecular or macroscopic level. Microspheres are small spherical debris, with diameters withinside the micrometre range (commonly 1μm to 1000μm). Microspheres are sometimes known as microparticles³.

In the current technology of drug discovery, the polymer is an extensively used and precious excipient indifferent pharmaceutical formulations. It additionally has an excessive overall performance in the parenteral area, controlled drug release, and drugs focused on particular organs. Now in current years, polymer aggregate or mixing is used to enhance the polymer properties to subside the poor organic properties or development inmechanical strength of the polymer⁴.

The idea of IPN 1914 and the primary interpenetrating polymer network (IPN) become invented through Aylsworth the term IPN become first of all given by Miller withinside 1960s in a scientific observation about polystyrene networks⁵.

An IPN is a mixture of at the least polymers, showing unique characteristics, it is prepared when at least one polymer network is synthesized or crosslinked independently withinside the presence of the other without any covalent bonds between them⁶. IPN can produce a synergistic effect by sharing the properties of both the polymers consequently avoiding the limitations of natural as well as synthetic polymers. IPN is regarded as one of the most valuable novels biomaterials⁷. Interpenetrating polymer network (IPN) is no longer formed from usually mixing or more polymers and does no longer produce from copolymers. So IPN based drug delivery system is designed to deliver drugs in zero-order kinetics with minimum fluctuation.

CLASSIFICATION OF IPN:

Based on chemical bonding:

Irretrievable chemical links are formed by the chemical bond which, in turn, helps in absorption of water and/or bioactive compounds without dissolution and drug release permit through the diffusion process⁸.

Covalent Semi IPN:

It contains two separate polymer systems are crosslinked to form a single polymer networksystem.

Non-Covalent Semi IPN:

Only one of the polymers is crosslinked in the systems.

Non-Covalent Full IPN:

In which the 2 separate polymers are individually crosslinked⁹.

Based on the arrangement pattern:

Novel IPN:

Polymer comprising two or more polymer networks that are at least partially inter‐locked on molecular scale however no longer covalently bonded to every different and cannot be separated until chemical bonds are broken.

Sequential IPN:

In this sequential IPN formation second polymeric component network is polymerized after the completion of polymerization of the first component network¹⁰.

Simultaneous IPN:

Simultaneous IPN is prepared via way of means of a technique in which each component network is polymerized concurrently, the IPN can be referred to as a simultaneous IPN¹¹.

Semi IPN:

In this systemif only one component ofassembly is Cross-linked left the further in a linear form, system called semi‐IPN. IPNs have a linear structure asalternative to a network structure. The IPNs properties can be modified by the linear component. These types of IPNs are prepared by an either sequential or simultaneous process¹².

Latex IPN:

In this type of IPN network of the single latex particle, the second monomer comes together and bindswith the first cross-linking monomer of the original seed of latex with crosslinking agent and initiator by polymerization technique¹³.

Gradient IPN:

This type of IPN composition/cross-link, density varies as function of position in a sample. Here, first cross-linked polymer is moderately swollen by the monomer of a second crosslinked polymer, followed by a rapid polymerization technique before reaching diffusional equilibrium¹⁴.

Thermoplastic IPN:

IPN involves two physically cross-linked polymers which arise from an ionic group, glassy domains, and crystallinity. This type of IPN, the materials flow at elevated temperature, acts like a conventional thermoset IPN where one element is a block copolymer, and the other one is the semi-crystalline or a glassy polymer¹⁵.

Homo-IPN:

In this type of IPN, both polymers have formed a network that has the same structure. In theoretical work, homo-IPN are used as model of materials¹⁶.

Merits of IPN¹⁷:

· An IPN can incorporate one natural polymer interpenetrated/cross-linked with the other artificial polymer and with the synergistic properties of both polymers resultant IPN can be better used for the controlled release of the drug likely to be immobilized.

· Mechanical properties of the final product IPN enhance.

· When the blends are subjected to pressure, they can keep the separate phases together.

· IPN is also helpful in creating the synergistic effect from the component polymer.

· Due to the infinite zero-viscosity of the gel, phase separation among the component polymers isn't possible.

Disadvantages of IPN¹⁸:

The most important disadvantage of IPN is that

· On occasion the polymers interpenetrate to such a quantity and the drug released from the matrix becomes difficult.

· The problem with the non-covalent system is that it also can be a problem with the covalent system because of the loss of a powerful interface.

Features of IPN¹⁹

· IPN can swell but does not dissolve in a solvent.

· When the blends are subjected to pressure, they keep the phases separated together.

· In ideal IPN creep and flow are suppressed.

· IPN is distinguishable from blends, block copolymers, and graft copolymers.

· IPN mainly forms an insoluble network.

· IPNs are heterogeneous systems that contain one rubbery phase and one glassy phase to produce a synergistic effect yielding.

· Materials formed from IPN share the properties that are characteristic of each network however, homopolymer alone cannot meet divergent demand in terms of bothproperties and performance. so, therefore, a composite or anideal IPN of two or three different polymers would be abetter choice.

· Polymer comprises two or more polymer networks which are at smallest in part interlaced on a molecular scale though not covalently bonded to each other and cannot be separated until chemical bonds are broken.

Hence, IPN based systems have gained lot of potential to develop the controlled release delivery of drugs.

METHODS OF PREPARATIONS:

Emulsification cross-linking:

This technique is based on phase separation. This method is used widely to form a cross-linked polymer network. Usually, the cross-linked is prepared by water-in-oil (w/o) emulsion. In w/o emulsification, an aqueous polymeric solution was prepared by adding the water-soluble polymer to form a homogeneous solution by stirring. After that, this aqueous phase was introduced to the oil phase. Recently, water-in-water (w/w) emulsion has been advanced to form IPN. The toxicity effect of w/w emulsion is fewer compared to w/o emulsion as there is no use of an organic solvent as the w/w emulsification technique is completely dependent on the aqueous environment²⁰.

Wet granulation method:

Wet granulation is a technique of mixing a dry powder with granulating fluid which can be removed by drying. The liquid solution which is used for granulation can be any aqueous-based or solvent-based. The required quantity of polymer is mixed up manually for 15 min. Then, the required amount of blending agent is added to prepare a cohesive mass, and the wet mass passes through the # 22/24 mesh screen. The resulting are dried at 40° – 60°C for 12 h. After completion of the drying stage, the dry granules were passed through the #22 mesh screen. Then, magnesium stearate is mixed with the granules and compressed into a tablet²¹.

Ionotropic gelation method:

In this method is based on the interaction of the anionic polymer with the opposite charge polymer. Sodium alginate and the polymer have been dispersed and blended very well in distilled water and stirred for complete solubility. Then, the solution was poured dropwise with the help of 23 gauze syringe needles into another aqueous media of another ionic polymer (Al+3, Ca+2, etc.) with continued stirring²².

Free radical polymerization:

It is primarily used for polymer synthesis. It is a technique of polymerization where a polymer is formed by the consecutive addition of free radicals. First, the free radical position is created on the backbone polymer, and then the chemical compound gets attached through the chain extension process. The effect of adventitious impurities is much less compared to other ionic chain-growth reactions. First, in a round-bottom flask, the polymer was dissolved in distilled water. Then, it is permitted to hydrate for 4 h by continuously passing the nitrogen gas by heating at 80°C. Another polymer was added to this mixture with an initiator. This technique is continued for 1 h with continuous application of nitrogen gas. After 1 h, the grafted copolymer becomes cooled at room temperature²³.

Casting Evaporation:

This method is used widely to form a cross-linked polymer network. In this method, each polymer constituent is heated until it is dissolved and then added to the cross-linker solution. In case of the sequential process, the solution of polymer I is added to the cross-linker solution followed by the addition of polymer II solution. In both cases, the solution is heated and mixed and then cast and dried. IPN gels can be prepared by this technique²⁴.

Table 1. List of the current research on IPN microspheres:

Sl. No.	Nameof Polymers	Cross-linker	Drug	Formulation	References
1.	Chitosn + HPC	Glutaralhyde	Ritonavir	IPN Microspheres	26
2.	PVA + NaAlg	Glutaraldehyde	Naproxen sodium	IPN Microspheres	27
3.	Gelatine + Sodium carboxymethyl cellulose	Glutaraldehyde	Ketorolac Tromethamine	Semi-IPN Microspheres	28
4.	Xanthan gum + Superabsorbent polymers+ Poly(vinyl alcohol)	N, N’-methylene bisacrylamide	Ciprofloxacin HCl	IPN hydrogel microspheres	29
5.	Lepidium sativum + poly(vinyl alcohol)	Glutaraldehyde	Simvastatin	IPN Microspheres	30
6.	Acryl amide grafted Carboxymethylcellulose+ Sodium alginate	Glutaraldehyde	Triprolidine hydrochloride Monohydrate	IPN Microspheres	31
7.	Locust bean gum + Poly vinyl alcohol	Glutaraldehyde	Metformin HCl	IPN Mucoadhesive Microspheres	32
8.	Sodium carboxymethyl cellulose + poly(vinyl alcohol)	Glutaraldehyde	Diclofenac Sodium	IPN Hydrogel Microspheres	33
9.	Hydroxypropyl -methylcellulose + Poly(vinyl alcohol)	Glutaraldehyde	Ciprofloxacin hydrochloride	IPN Microspheres	34
10.	Chitosan + Gelatine	Glutaraldehyde	Isoniazid	IPN Microspheres	35
11.	Sodium alginate + Poly (vinyl alcohol)	Glutaraldehyde	Naproxen	IPN Microspheres	36
12.	Chitosan + guar gum-g-acrylamide	Glutaraldehyde	5-Fluorouracil	Semi-IPN Microspheres	37
13.	Sodium alginate + Polyvinyl alcohol	Glutaraldehyde	Diclofenac Sodium	IPN Microspheres	38
14.	Gellan gum + Poly(Nisopropylacrylamide)	-	Atenolol	Semi-IPN Microspheres	39
15.	Chitosan + Hydroxyethyl cellulose	Glutaraldehyde	Isoniazid	IPNblends microspheres	40
16.	Chitosan + Methylcellulose	Glutaraldehyde	Theophylline	IPN Microspheres	41
17.	Acrylamide grafted dextran + Chitosan	-	Acyclovir	Semi-IPN Microspheres	42

Miniemulsion/Inverse Miniemulsion method:

This approach allows one to create small stable droplets in a continuous phase by the application of high shear stress²⁵.

The concept of miniemulsion polymerization is to initiate the polymer in every of the small stabilized droplets. To prevent the degradation of miniemulsion via coalescence, a surfactant and a stabilizer are introduced that are soluble in the dispersed phase but insoluble in the continuous phase. So, in this method of IPN formation can be divided into 3 steps. In the primary step, constituent polymers are obtained through sonication using a particular initiator. In the second step, one of the constituent polymers is polymerized and cross-linked the use of a cross-linking agent. So as a result, a semi-IPN is formed till the second stage. In the 1/3 step, a complete IPN is shaped through polymerizing and cross-linking the second component polymer through the addition of a second cross-linker.

MECHANISM OF DRUG RELEASE:

Four different categories of drugs release from biodegradable microspheres theoretically⁴³.

Diffusion-controlled reservoir systems:

In this active agent is encapsulated by a rare controlling membrane through which the agent diffuses and the membrane erodes only after its delivery is completed. So, in this case, drug release is unaffected by the degradation of the matrix. A polymer that remains as such till the complete, release of the drug and then degrades by a homogenous mechanism so that device is removed from the body is better for this type of delivery.

Diffusion controlled monolithic system:

Here active agent is released by diffusion prior to or concurrent with the degradation of the polymer matrix. Degeneration of the polymer matrix affects rate of release and has to be taken into account. The rate of release also depends on whether the polymer degrades by a homogeneous or heterogeneous mechanism.

Degradation controlled monolithic system:

In degradation controlled monolithic microsphere systems, the drug is dissolved withinside the matrix and is distributed uniformly throughout. The drug is powerful to the matrix and is launched only at the degradation of the matrix. The diffusion of the drug is slow as compared with the degradation of the matrix. When degradation is through the homogeneous bulk mechanism, drug release is slow initially and will increase rapidly while rapid bulk degradation starts. Drug release from such forms of devices is independent of the geometry of the device.

Release from sphere is ruled through equation, wherein Mt is the quantity of the agent released at time t, and M∞ is the amount at time t∞ is the time for total erosion. Progesterone release from poly (glycolic-co-lactic acid) polymer films containing 10 weights% steroids is an example of this type of launch.

Mt /M∞ = 1-[(1-t/ t∞)]3

Erodible poly-agent system:

The active agent is chemically attached to the matrix and the rate of biodegradation of the matrix is gradual as compared to the rate of hydrolysis of the drug-polymer bond. Assuming that rate of diffusion of the active agent from the matrix to the surrounding is rapid, the restricting step is the rate of cleavage of the bond attaching the drug to the polymer matrix⁴⁴.

EVALUATION STUDIES OF IPN:

Different types of evaluation techniques were cited in pieces of literature for theevaluation of IPN microsphere formulations. A few of them are:

Particle size analysis:

With the assistance of a digital microscope or optical microscope, the particle's length can be determined. In an optical microscope, the eyepiece micrometre has calibrated the usage of the stage micrometre. This technique is tedious and specially used during laboratory scale-up⁴⁵.

Fourier-transform infrared analysis:

It is an analytical technique, that is used to discover the functional group in structure and intermolecular interaction of organic, polymeric, and in a few cases inorganic materials. The samples have been crushed with potassium bromide. Then below the hydraulic pressure of six hundred kg, the samples have been transformed into pellets, and that they have been scanned with inside the range of 500 and 4000 cm−1⁴⁶.

Drug entrapment efficiency:

The quantity of drug absorbed into IPN microspheres is estimated by drug entrapment efficiency. The required amount of IPN particles was pasted in a mortar and pestle and dissolved in a 50 ml solution of phosphate buffer (pH 6.8). At 50°C, the solution is heated for producing desired drug extraction. The drug extracted is calculated by a suitable analytical spectroscopy method⁴⁷.

Percentage of yield:

It is calculated by the ratio of the total amount of the prepared microspheres and the initial weight of polymer and drug which is taken as the theoretical value⁴⁸.

The total amount of microspheres

Percentage of yield = ––––––––––––––––––––––––––––––––– × 100

Initialamount of polymer and drug

X-ray diffraction analysis:

Many forms of polymers are there such as crystalline, semi-crystalline, amorphous, or crystalline. XRD is performed to evaluate the sample of different polymers whichprovides a solid state of structural information such as the degree of crystallinity. Moreover, scanning is also performed up to 2θ range of 0–50°C using a CuKα radiation source⁴⁹.

Swelling index:

The pH-sensitive response of IPN microbeads is proven by the swelling index. Weighed the required amount of microbeads and was allowable to swell in 25ml buffer solution of pH 1.2, pH 7.4 at 37°C. The pH of the surrounding solution is customized between 1.2 and 7.4 ph. At a predetermined time, microbeads are isolated from the buffer solution, and adhered solution on the surface of the microbeads is removed lightly. The weight comparison is measured before and after swelling⁵⁰.

Weight of wet microspheres - Weight of dry microspheres

Swelling Index = –––––––––––––––––––––––––––––––––––––––––

Weight of dry microspheres

Scanning electron microscope (SEM) analysis:

The use of an electron microscope, which produces a picture of a sample by scanning the surface with targeted beams of electrons, is done using an SEM. The sample is coated with platinum using a sputter coater and focused under a microscope at room temperature and detect the photograph was at a voltage of 10–40 kV⁵¹.

Differential Scanning Calorimetry (DSC) analysis:

DSC is a very effective thermal evaluation method that is used to evaluate polymer material properties which include thermal stability, melting point, purity, crystallization, specific heat capacity, and oxidation behaviour. This study is done in the existence of a nitrogen atmosphere and a heating rate of 10°C/min from 25°C to 400°C⁵².

Atomic force microscope (AFM) analysis:

AFM is also known as a scanning force microscope. It is composed of scanning probe microscopy with a resolution on the order of a fraction of micro millimetre which gives high resolution compared to optical diffraction. The frequency resonance of the probe is 250 kHz⁵³.

Texture analysis:

Texture analysis or tensile analysis is performed to measure the responsive behaviour example bio adhesiveness within the developed IPNs as viscosity, hydrogen-bonding capacity, and concentration of polymer have a notable effect on the adhesion force required for an IPN to be responsive as a bioadhesive⁵⁴.

CONCLUSION:

IPN has numerous advantages as a biomaterial and is widely used as a carrier system for the delivery of drugs and protein in the form of microspheres. The look at IPN for drug delivery systems may result in a better understanding of critical diseases. The concepts of high swelling capacity, specificity, and sensitivity play an important role in focusing on the delivery of drugs. By understanding the character of drug delivery systems and their durability withinside the body, that can have interaction with the systems, can be identified. There has been a sharp growth in the speed of discovery and development of IPN over the last few years. Current articles aid the theory that IPN can offer the resources to deliver drugs at a prolonged controlled release to particular targets. Once optimized, those targeted hydrogel microspheres will offer better treatment options. So, it could be inferred that IPN-based microspheres for numerous drug delivery systems are expected to become useful matrix substances for various therapeutic applications in the future.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGMENTS:

The authors would like to thank Mallige College of Pharmacy for their kind support during the writing of article provide lot of information and giving facilities.

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Received on 24.05.2022 Modified on 30.08.2022

Asian J. Pharm. Tech. 2023; 13(2):123-129.

DOI: 10.52711/2231-5713.2023.00023