INTRODUCTION:

Over the past 30 years pharma industry face many complications and Over the past 30 years pharma industry face many complications and to overcome these obstacles many new drug entities or formulations have been developed and to overcome these obstacles many new drug entities or formulations have been developed. So, one of them oral controlled release drug delivery paid a greater attention in health sector and a noble innovation in pharmaceutical era. Oral controlled drug delivery is one of the ideal administration routes for most of the therapeutic molecules. This route is found to be simpler and offers patient compliance. This drug delivery can potentially reduce cost comparing with parentral administration.

Controlled release dosage form that releases one or more drugs continuously in predetermined pattern for a fixed period of time either systemically or locally to specified target organ. Controlled release dosage forms is having better control of plasma drug levels, less dosage frequency less side effect, increased efficacy and constant delivery. It is a unique type drug delivery system that maintains release of drug in an adequate amount of drug over an extended period of time in a control manner.. Oral drug delivery is the ideal administration route for most of the therapeutic molecules. This route is found to be simpler offers patient compliance. This drug delivery can potentially reduce cost comparing with parenteral administration. However, oral delivery is primarily focused on small-molecule drugs. There are so many other therapeutic molecules of interest which include peptides, proteins and chemotherapeutics¹. Oral delivery of those molecules has been limited by low bioavailability due to enzymatic degradation and poor penetration of the intestinal membrane into the bloodstream^2. The biological barrier against any orally administered drug is the harsh acidic conditions inside the stomach (pH 1–2.5), denaturing/depurinating most of the administered molecules which drastically lower their activity. In addition to stomach acid, enzymes such as pepsin and gelatinase also act on biopharmaceuticals to degrade them³. Successful delivery requires innovative drug delivery techniques to overcome those above-mentioned obstacles, researcher made an innovative decision and invented a new formulation. Hydrophilic polymer matrix is widely used in formulating controlled release dosage form. An ideal drug delivery should be providing adequate amount of drug at regular time interval at right site of action with improve therapeutic effect and maintain the blood plasma drug level in the body. The controlled release formulations have some swelling polymer or waxes or both which controls release rate. The best example of hydrophilic or lipid system include hydrogels and Oleogels. Hydrogels are basically three-dimensional polymeric networks, containing of cross-linked to each other. Hydrogels is a type of drug delivery which is designed in a controllable manner where swelling and deswelling occurs reversibly in aqueous medium and retains large amount of liquid in swollen condition. Though hydrogels are new advanced drug delivery system with a lot of advantages, they also have some limitation. To overcome all these limitation Oleogels are derived from the word oil and gels. Generally, Oleogels are produced by the gelation of edible oils or other organic solvent. Oleogels are made up of molecules like fatty acids as a result those are lipid soluble and their biocompatibility is more than hydrogel. They can provide protection in delicate protein or peptide treatments. But Oleogels are most widely used in nutraceuticals and food technology than the pharmaceuticals.⁴

Hydrogel:

Hydrogel is a water-insoluble polymeric network. It may be found as a colloidal gel with water as dispersion medium. Physical integrity in aqueous media is maintained by crosslinks e.g., entanglements, crystallites, tie-points, junctions⁵. Hydrogels absorb substantial amounts of aqueous solutions. Additionally, hydrogels do not affect the metabolic processes of living organisms and metabolites can pass through the hydrogels without much obstruction⁶. Hydrogels are sensitive to external stimuli, such as temperature, pH, ionic strength, electric fields, and magnetic fields⁷. They can respond to these stimuli through swelling or shrinking⁸. Hydrogels can be formulated in to slabs, Microparticles, nanoparticles, coatings, and films. Hydrogels are commonly used in clinical practice and experimental medicine like in tissue engineering, regenerative medicine, diagnostics, in cellular immobilization, separation of biomolecules or cells, and barrier materials to regulate biological adhesions. Due to a wide range of acceptability the application, and the production of hydrogels represent an important era⁹.

Table 1: Classification of Hydrogels on different aspects.

Classification of Hydrogel¹⁰
Based on Sources	Natural Origin
Based on Sources	Synthetic Origin
According to Polymeric Composition	Homopolymer (derived single pieces of polymer)
	Co-Polymer (Two or more different species of monomer)
	Multi-Polymer (made of two independent cross-linked synthetic or natural Polymer components)
Based on Structure	Amorphous (Non-crystalline)
	Semi- crystalline (A complex mixture of amorphous and crystalline phase)
	Crystalline
Based on type of crosslinking	Chemical (permanent junction)
Based on type of crosslinking	Physical (transient junction such as ionic interaction, hydrogen bond, hydrophobic reaction)
Based on mechanism of controlling of drug release	Diffusion controlled release
	Swelling controlled release
	Chemically controlled release
	Environmental controlled release
Based on physical appearance	Matrix
	Film
	Microsphere
Based on network electrical charge	Non-ionic
	Ionic
	Amphoteric
	Zwitterionic
Water content or degree of swelling	Low swelling
	High swelling
	Superabsorbent
According to Porosity	Nonporous
	Microporous
	Microporous
	Super porous
Biodegradability	Biodegradable
Biodegradability	Non- biodegradable

Table 2: Characteristics, advantages and disadvantages of Hydrogels ¹¹

Characteristics of Hydrogel

Advantages of Hydrogel

Disadvantages of Hydrogel

· Colorless, odorless and absolute non-toxic.

· Hydrogel has ability to absorbed highest amount of water or it has ability to absorption capacity.

· It has highest swelling property that it swells in a specific extent of limit.

· It is photo-stable in nature.

· Highest durability and stability in during the storage and swelling environment.

· Biodegradable in nature without formation of toxicity.

· The lowest soluble content and residual monomer.

· Great elasticity nature due to their swelling property.

· They possess high degree of flexibility

· They have capacity to imbibe high amount of water due to which they behave like natural tissue.

· They should bio-compatible

· They should bio-degradable

· They possess better flexibility

· Easy to modify

· Have good transport property

· Non-adherent in nature and it secured by secondary dressing

· Have low mechanical strength

· Difficult to handle and storage

· Expensive

Respones of Hydrogel Sensitivity to Environmental Stimuli:¹²

Hydrogels is a type of drug delivery which is designed in a controllable manner where swelling and deswelling reversibly in aqueous medium and retaining large amount of liquid swollen condition. Those shrink and expand responses changes with external environmental condition like variety of physical and chemical stimuli, where the physical stimuli include temperature, electric or magnetic field, light , pressure and sound , while the chemical stimuli include pH, solvent composition, ionic strength and molecular species . In certain environmental conditions, hydrogels can take up large amounts of water or biological fluids, while remaining insoluble.

OLEOGEL:

Oleogel is a gel that imparts transparency and thixotropic body to oil, resin-oil or alkyd paint. They are semi-solid systems, with organic or oil liquid phase, immobilized into a three-dimensional network¹⁴. That network can be achieved by using organogelators. If we consider drug delivery, Oleo gels have been used for tetracycline, metronidazole, metronidazole benzoate, and their combinations using cellulose derivatives. They can enhance the permeation of drugs due to their lipophilic nature. Apart from this, the thermo-reversible property of the oleogels is a positive side for potential use of it as drug-delivery system¹⁵. The thermodynamic stable nature of the organogels can lead to the spontaneous formation of fibrous structure to be in a low energy state ¹⁶. The occurrence of the gel-to-sol transition above room-temperature indicates that external energy has to be supplied to the organogels to disrupt the three-dimensional structure and transformation of the gelled state to the sol state¹⁷. Organogels are also sensitive to the presence of moisture. This characteristic can be adopted to develop controlled delivery systems. Various oleogel-based formulations have been designed to administer the bioactive agents by different routes of administration. They are versatile alternatives to widely studied systems like hydrogels and organogels for applications requiring an injectable drug depot that slowly releases a pharmaceutical to a treatment site¹⁸.

General method of the preparation of oleogel ⁴:

Advantages of Oleogel

Disadvantages of Oleogel¹⁹

Ease of preparation.

More stable than other types of gel.

Enhanced the drug penetration.

Oleogels are moisture insensitive.

Cost reduction due to a smaller number of Ingredients.

Thermodynamically stable.

Short half-life drug used

Controlled release of drug, longer shelf life and for prolonged action used.

Reduces frequency of drug dosing.

They are less greasy and can be easily removed from the skin.

· Drugs with reasonable partition coefficient otherwise drug may not permeable through skin .

· The route is not suitable for drugs that irritate or sensitize the skin.

· If impurity present then no gelling will occur.

· Require proper storage condition.

· When the gel is taken up of liquid with an increasing volume known as swelling

· When a gel stands for some time, it often shrinks naturally, and some of its liquid is pressed out, known as syneresis.

Applications of gel-based formulations- hydrogel and oleogel in oral drug delivery:

Hydrogels are well accepted candidates for oral drug delivery as they are most compatible for hydrophilic molecules and macromolecular drug as well. Hydrophobic molecules can also be participated in hydrogel based oral drug delivery by modification of hydrogel designing²⁰. It contributes a number of adaptable parameters to enable controlled delivery of diverse therapeutic molecules. They provide a field for achieving controlled therapeutic delivery to specific sites in the gastro intestinal area. Protein and peptide drugs have poor stability in the gastro intestinal tract due to enzymatic degradation, acidic denaturation, low solubility and absorption²¹, that can be overcome by hydrogel approach. Stimuli-responsive hydrogels are of great interest in oral delivery for their response to environmental changes to alter network structure, swelling behavior, permeability or mechanical strength. For change of those physico mechanical characteristics, drug release from hydrogel-based drug delivery system also gets modified. Many physical and chemical stimuli have been explored in hydrogel systems. Physical stimuli are temperature, electric field, light and solvent composition. Chemical and biochemical stimuli can be enlisted as pH, ionic strength and molecular recognition events²². The stomach specific in-situ gel , prepared by ionic gelation method found to be a successful preparation^23,24

In oleogel the best part is that, combination of drugs with multiple APIs, each requiring precise release rates, can be used in this drug delivery. The delivery of bioactive molecules is possible application for oleogels, which has gained attention in recent years in the pharmaceuticals industry²⁵. The lipid medium of oleogel is well suited to increase the bioavailability of lipid soluble molecules and their gel matrix could offer benefits of sustained release as well as protection of the releasing molecule¹⁶. Several applications of edible oleogels have been reported in the literature for drug or nutraceutical delivery highlighting the relationship between gel network and drug delivery²⁶. Gelation has been found to be successful in preventing precipitation of bioactive and slow down the lipolysis process and release of nutraceuticals from the oleogel networks²⁷.

Cao et al studied-on silica nanoparticle-infused polymers for this purpose and optimized nanoparticle systems that are biocompatible and biodegradable. He also recommended research focused on nanocarriers to incorporate into polymers with bottle brush geometries for better tuning of drug release kinetics for combination drugs²⁸.

In general, lot of promises in the application of oleogels for drug delivery and most of them are in the research level.

Edible oleogels, structured by non-triglyceride networks, can be used for t delivery of lipid-soluble molecules. Their composition, functional properties, and structure make them suitable for this purpose. Several types of edible oleogels have been characterized, but some of the systems have been used in oral delivery applications so far¹⁹.

Hydrogel is having wide acceptance as mucoadhesive drug delivery specially as buccal dosage form²⁹

Several hydrogel formulations have been well accepted as buccal drug delivery³⁰. A thermo-responsive oral mucoadhesive hydrogel has been developed for the administration of the anti-cancer drug paclitaxel in the oral mucosa that provides a high local concentration of the drug and it is intended to decrease the systemic side effect ^31.

Oleogel based buccal mucoadhesive dosage form already been developed. DINTE et al prepared buccal Mucoadhesive Oleogel of ibuprofen and Metronidazole to study their rheologic, in vitro adhesive and drug release characteristics. The results were quite satisfactory³².

The retention time of a dosage forms in the GIT is one of the determinants of the bioavailability of oral drug delivery systems. Therefore, for developing a GRDDS, the challenging part is the retention of the delivery system in the stomach or the upper part of the small intestine for a sufficient period of time so that all the drugs can be released at a predetermined rate³³. Some physiological barriers and factors are the type of food, calorie content, gender and age. The pylorus size also plays an important role in gastric retention of any GRDDS³⁴. Hence, to develop an optimum GRDDS, the main challenges are to overcome the problems associated with the gastric emptying rate of the stomach with an appropriate drug release rate for an extended period of time before it gets metabolized. Hydrogels possess a diversity in features that can be tailored for a specific therapeutic effect³⁵. Crosslinked hydrogel networks can protect drugs from harmful environments, such as enzymes and low pH in the stomach³⁶. Suitable Crosslinking agent can be used to optimize loading and controlled diffusion of water-soluble drugs in or out of the network³⁷. Incorporation of hydrophilic groups in the crosslinking agent can impart high degree of swelling in comparison with those containing hydrophobic groups. Mesh size of the swollen network affects the physical properties of the gel, such as mechanical strength, degradation and diffusion of captured molecules³⁸. Reported mesh size of hydrogels in the swelling condition ranging from 5 to 100nm and that may be optimized for sustained release of macromolecules according to their hydrodynamic radii^39–41.

Sharp et al developed an oral pH-responsive microencapsulation system and demonstrated its capability for protection against both gastric acidic and gastric enzymatic environments⁴².

Super porous hydrogels (SPHs) are one of the advancements in gastro retentive drug delivery system (GRDDS) which also includes intragastric floating system (low density system), mucoadhesive system, high density system and swellable system^43,44

Intestinal drug delivery systems are advantageous as pH-responsive anionic hydrogels in protecting drugs from gastric environment and release drugs in specific locations, like upper small intestine and colon, further in the GI tract⁴⁵.

Vervoort et al, developed inulin hydrogels for colonic delivery of drugs and swelling property of these hydrogels was investigated⁴⁶. A number of hydrogel products made of different polymers like Guar gum, Pectin, Chitosan, Inulin have been used as colonic drug delivery⁴⁷.

Table 4: Some Reported gel based oral controlled release drug delivery

Oral Controlled Release Drug Delivery	Hydrogel Based	Oleogel Based
Buccal Drug Delivery	Mucoadhesive buccal gel⁴⁸, Buccal films ⁴⁹, Thermosensitive in-situ buccal drug delivery⁵⁰, Mucoadhesive patches ⁵¹	Buccal gel ⁵²
Gastroretentive/ Gastroprotective Drug Delivery	Superporous hydrogel^10,35Gastroretentive ^{53, 54}, Floating microsphere⁵⁵, Microgels⁵⁶, Nanogels⁵⁷	Organogel as novel oral controlled ⁵⁸
Intestinal Drug Delivery	Bioadhesive, superporous hydrogel⁵⁹, Local intestinal drug delivery ⁶⁰	Organogel nanoparticles^61,62
Colon Specific Drug Delivery	Colon specific, localised drug delivery^63-68, Mucoadhesive chitosan hydrogels ^69-70

CONCLUSIONS AND FUTURE PROSPECTS:

Hydrogels are having tremendous approaches in drug delivery in comparison to Oleogel. In different segments of oral controlled release drug delivery, hydrogels have been explored to prepare buccal, gastro-retentive, gastro-protective, intestinal and additionally as colonic drug delivery. However, the Oleogels are having acceptance in nutraceuticals and in food application. The properties of Oleogels are malleable and they can be modified by controlling for various physical parameters during the process of formulation. Such flexibility enables adjustment of an extensive variety of attributes, which makes Oleogel probably appropriate for a number of applications, going from pharmaceuticals therapeutic treatments, through dietary supplement. Future research is needed in order to study Oleogels with regard to the specific molecules loaded into the system for proper oral controlled drug delivery.

CONFLICTS OF INTEREST:

The authors declare no conflict of interest.

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Received on 22.03.2021 Modified on 06.06.2021

Research J. Pharm. and Tech. 2022; 15(5):2357-2363.

DOI: 10.52711/0974-360X.2022.00392