INTRODUCTION:

Gel:

Gel is defined as a two-component or combination of two phases which mostly contain liquid, but they behave like solids because of three-dimensional cross-linked network within the liquid.^[1]Usually, the solvent is the major component of the gel system. Gels are those formulations that are used for several routes of administration. They are useful in different formulations of topical, vaginal, rectal as well as injectable administration.^{[2] [3]}

Novel Injectable Gel:

The development of novel inject able in situ forming (gel) drug delivery systems has been a quite interesting topic as it has received a considerable interest over the last decade. The drugs which are designed to be injected in the form of viscous liquid are called injectables. The injection of gel follows the appropriate route for administration called subcutaneous route. It is a method of infusion to put the viscous liquid into the body, usually with an appropriate syringe and through the skin to a sufficient depth so that the material can be administered easily and freely into the body.^[3] The viscous liquid turns to gel in the surrounding tissue of body and start releasing the drug in a sustain manner. Since considerable attention has been paid to the development of injectable gel system over the last few years, so this interest has been spreading due to the various advantages shown by these delivery systems such as ease of administration, reduced frequency of administration improved patient compliance and comfort.^[4]

There are three main routes of administration of injectables used in humans and animals. The routes are as follows.

1. Intradermal (ID) Injection:

It is a process in which the drugs are delivered into the dermis, or the skin layer underneath the epidermis layer. The advantage is that, its usability allows the tool to be used by untrained staff. They also have less pain for the patient during use, and the shortness of the injection needle makes injections safer.

2. Intramuscular (IM) Injection:

An intramuscular injection is a process which delivers medication deep into the muscles. The medication is delivered directly into a muscle where the drugs are administered intramuscularly and are absorbed into the muscle quickly compared to other conventional system which is more gradual. Some injections are given to the buttocks which reach the bloodstream quickly due to the large amount of muscular tissue and corresponding blood supply.

3. Subcutaneous (SC) Injection:

A subcutaneous injection is a process used to administer as a bolus into the sub cutis that is the layer of skin directly below the dermis and epidermis. This technique is highly effective in administering vaccines and medications as well as for the sustain release of drugs in the body. Long-acting forms of subcutaneous or intramuscular injections are available for various drugs and are called depot injections. It is also a technique of injection where drugs deposit in a localized mass, called a depot and is slowly absorbed by surrounding tissue.^[5]
[6]

Sustained Release Drug Delivery System:

The term sustained release or prolong release can be defined as the system that is designed in such a way that it releases the dosage form slowly and continuously to a long period of time after administration of single dose and produce therapeutic effect. The main fundamental of prolong release is to sustain the drug action at a predetermined rate by maintaining a relatively constant, effective therapeutic drug level in the body by decreasing the undesirable or adverse side effects.^{[3] [4]}

Advantages of Sustained Release Drug Delivery System:

1. Duration of action of the drug is extended.

2. The dosing frequency of conventional dosage form is reduced quite easily.

3. The total amount of drug administration can be reduced by maximizing availability with minimum dose.

4. Minimizes the drug accumulation with chronic dosing.

5. Improve efficacy in treatment by controlling and reducing fluctuations in drug level.

6. Improve bioavailability of some drugs.

7. The drug absorption can be attained much better and effective.

8. Administration of dosage form can be made more convenient. ^{[7] [8]}

Disadvantages of Sustained Release Drug Delivery System:

1. In comparison to immediate release conventional dosage forms the systemic availability of injectable sustained release system is decreased.

2. Toxicity, poisoning or hypersensitivity reactions are a major drawback for retrieval of drugs after administration.

3. Reduced potential for dose adjustment of drugs normally administered in varying strengths.

4. The flexibility in dosage regimen for adjustment is limited.

5. The in vitro – in vivo correlation is poor.

6. The half life of the active compound must be short.

7. A large amount of drug is must to maintain a sustained effective dose for the short half life drugs.

8. The absorption in not effective in lower small intestine.^{[7] [8]}

Sustained Release Injectable Gel:

Prolong or sustained release of drugs through injection after IM or SC administration may occur due to use of stimuli responsive or “smart” polymers. “Smart” polymers are actually macromolecules having certain critical physical as well as chemical properties to change in response to small changes in their environment such as temperature, pH, light, magnetic field, ionic factors, etc. The changes are always reversible, and therefore, the smart polymers are capable of returning to its initial state sooner after the trigger is immediately removed.^[9]

Smart Polymers for Sustained Release Drug Delivery:

Smart polymers also called as intelligent polymers are in the vanguard of drug administration technology because those polymers show active response by changing its physical and chemical structure to small signs and changes in the surrounding environment, which transforms into significant changes in the physiological and chemical properties. These polymers are biocompatible, non-thrombogenic, strong, resilient, flexible, easy shaping and coloring. They keep the drug stable and to manufacture easily. The good nutrient carriers to the cells using cell adhesion ligands is possible to inject in vitro as liquid and changes itself to gel within the body at physiological body temperature.

The smart polymers that change the structural can be classified in three main groups as:

1. Chemical stimuli (pH and ionic strength).

2. Biological stimuli (enzymes and biomolecules).

3. Physical stimuli (ultrasound, light, mechanical stress, temperature). ^{[13] [11] [15]}

Chemical Stimuli (pH responsive polymers):

A good example of chemical stimuli is pH sensitive polymer which consists of pendant basic or acidic group that have the ability to accept or release a proton with the changes in environmental pH. Polymers with a large number of ionisable groups are known as polyelectrolyte’s. They are classiﬁed into two types: weak polyacids and weak polybases. At low pH weak polyacids accept protons and at neutral and high pH it releases protons. With the change of environmental pH the pendant acidic group undergoes ionization at speciﬁc pH called as pKa. Thus the molecular structure of the polymeric chain gets altered with the rapid change of the attached group. This transition to expanded state is mediated by the osmotic pressure exerted by mobile counter ions neutralized by network charges. PH-responsive polymers containing a sulphonamide group are another good example of polyacid polymers. These polymers have pKa values in the range of 3–11 and the hydrogen atom of the amide nitrogen is readily ionized to form polyacids. Narrow pH range and good sensitivity is the major advantage of these polymers over carboxylic acid based polymers.^{[11] [13] [15]}

Biological Polymers:

Biologically responsive polymer systems are increasingly important in various biomedical applications. The major advantage of bioresponsive polymers is that they can respond to the stimuli that are inherently present in the natural system. Bioresponsive polymeric systems mainly arise from common functional groups that are known to interact with biologically relevant species, and in other instances the synthetic polymer is conjugated to a biological component. Bioresponsive polymers are classiﬁed into antigen responsive polymers, glucose-sensitive polymers and enzyme responsive polymers.^{[11] [15]}

Physical Stimuli Polymers (i.e. Thermo Responsive Polymer):

The physical stimuli i.e. temperature sensitive polymers are generally called as thermo responsive polymers. These smart polymers are sensitive to the temperature and change their micro structural features in response to change in temperature. These are most safe polymers in drug administration systems and biomaterials. Thermo-responsive polymers present in their structure a very sensitive balance between the hydrophobic and the hydrophilic groups and a small change in the temperature can create new adjustments.^[16]These are the polymeric structures sensitive to both temperature and pH, they are obtained by the simple combination of ionization and hydrophobic (inverse thermo sensitive) functional groups. This approach is mainly achieved by the copolymerization of monomers bearing these functional groups, combining temperature sensitive polymers with polyelectrolyte’s or by the development of new monomers that respond simultaneously to both stimuli.^{[12] [13] [14]}

Mechanism of Thermo Sensitive Polymers:

Critical solution temperature is one of the important parameter that is considered in this type of polymer. The polymeric solution is categorized into lower critical and upper critical solution temperature. The polymeric solution changes at certain temperature and it is called as critical temperature. If such solution doesn’t change and remain same below that temperature, the so-called lower critical solution temperature become insoluble after heating. Such behavior is typical for the polymers that form hydrogen bonds to water and has wide range of biological applications such as cell patterning, smart drug release, DNA sequencing and others. In this approach control of the polymer temperature response in water is done by varying chemical composition of the monomer. The polymeric solution where the phase changes above certain temperature is called upper critical solution temperature (UCST). ^{[14] [16]}The reversible solubility of temperature sensitive smart polymers is caused by changes in hydrophobic/hydrophilic balance of uncharged polymer induced by increasing temperature or ionic strength. The uncharged polymers are soluble in water due to the hydrogen bonding with water molecules. The efficiency of hydrogen bonding reduces with increase in temperature. The phase separation of polymer takes place when the efficiency of hydrogen bonding becomes insufficient for solubility of macromolecule. The polymers with a lower critical solution temperature (LCST) are the most used on drug delivery systems. The therapeutic agents as drugs, cells or proteins can be mixed with the polymer when this is on its liquid state (temperature below the transition temperature) being able to be injected in the human body on the subcutaneous layer or in the damaged area and forming a gel deposit on the area where it was injected after increasing the temperature. This kind of pharmaceutical system delivers the drug on a controlled way without being too invasive. Smart polymers that are sensitive to the temperature can be used to increase chemotherapeutic agents in solid tumors. The accumulation of temperature sensitive polymeric systems in solid tumors is due to the increased impermeability effect to the tumor vascular net retention and to the use of an external impulse (heat source) on the tumor area. This temperature increase promotes the changing of the microstructure of the polymeric system, turning it into gel and releasing the drug, thus increasing the drug in the intra-tumoral area and the therapeutic efficiency, and reducing the side effects.^{[13] [16] [17]}

Examples of Thermo Sensitive Polymers:

Some temperature sensitive polymers are poly (N-isopropylacrylamide) (PNIPAAM); poly (oxyethylene-oxypropylene-oxyethylene) triblock copolymers (PEO-PPO-PEO); poly (ethylene glycol) - poly (lactic acid) - poly (ethylene glycol); poly (N-alkyl substituted acrylamides) and poly (N-isopropyl acrylamide) and poly (N-vinylalkylamides) like poly (N-vinyliso-butyramide).^[13]

Poly (N-isopropyl acrylamide):

PNIPAM is the mostly used and prominent candidate of thermo responsive polymer. It is a biocompatible polymer and changes structure itself under different physical temperature. The lower critical solution temperature (LCST) of PNIPAM is thus a candidate for controlled and sustained release application and is independent of the molecular weight and the concentration. PNIPA possesses an inverse solubility and phase separation takes place upon heating. It changes the hydrophilicity and hydrophobicity at temperature below the lower critical solution point. ^[13]

PNIPA have been used in gel actuators and by converting the stimuli to mechanical motion. Upon heating the solution above LCST, phase transformation takes place from hydrophilic to hydrophobic sate. It has been used in the tissue engineering as temperature sensitive scaffolds for the manipulation of cell sheets. Poly (NIPAAm-co-acrylic acid) & poly (NIPAAm-co-AA) gels have been applied as extracellular matrix for pancreatic islets in biohydrid pancreas. ^[13]
[19]

Triblock copolymer (PEO-PPO-PEO) or Poloxamers and its derivatives:

Triblock copolymer has been extensively used in the delivery of active drugs. The hydrophilic polymer part i.e. PEO separates from the hydrophobic part (PPO) after the increment of lower critical solution temperature. At certain ratios, the two different polymers behave individually in situ and thus gelation occurs with the corresponding physiological temperature. It is used for tissue engineering as well as smart delivery of drugs.^{[19] [20]}

The use of water soluble vehicles with high viscosity (known as hydrophilic gels) are one of the best ways to obtain a controlled delivery system. It represents an area which is important in scientific research. The copolymer blocks based on PEO-PPO sequences constitutes one family of triple blocks of commercialized copolymers with the following names.^[21]

Pluronics, Poloxamers, Tetronics are non ionic polymers having different composition ratios of poly (oxyethylene-oxypropylene-oxyethylene) (PEOn-PPOn-PEOn), with many pharmaceutical uses. These polymers are composed by white granules soluble in water with no odor or taste. They present a sol-gel transition phase below or near the physiologic body temperature and a gel-sol transition around 50º C in relatively highly concentrations. The triple block copolymers PEO-PPO-PEO get into gel at body temperature in concentrations above 15% (m/m); however this kind of formulas, when injected by intraperitoneal via, presents high toxicity and increases the plasma concentration of cholesterol and triglycerides.^[22]
[24]

The Poloxamers normally used are: 188 (F-68), 237 (F-87), 338 (F-108) and 407 (F-127). “F” refers to the polymer in the form of flakes. Pluronics® and Tetronics® are polymers approved by FDA to be used as food additives, pharmaceutical ingredients, and drug carriers in parenteral systems, tissue engineering and agricultural products. PluronicF-127 (Polaxamer 407, PF-127) can also be used as carrier in several routes of administration, including oral, cutaneous, intranasal, vaginal, rectal, ocular and parenteral. In the last years, PF-127 has had a special role on dermal and transdermal drug delivery systems. Pluronic® F127 (PF-127) or poloxamer 407 (P407) (copolymer polyoxyethylene₁₀₆- polyoxypropylene₇₀-polyoxyethylene₁₀₆) contains about 70% of ethylene oxide which contributes to its hydrophilicity. PF-127 is a copolymer with 12,000 Daltons, a PEO/PPO with ratio of 2:1 which is non toxic and low viscosity below 4ºC and forming a semi solid gel at body temperature. PF-127 is more soluble in cold water than in hot water due to the hydrogen linkages at low temperatures.^[23]

Applications of thermo sensitive polymers:

Smart drug delivery:

The “smart” polymeric carrier is used to deliver drugs. These carriers allow delivery of the drug at the right time and concentration by only releasing the drug in response to an external stimulus. For example the polymer chains of a carrier may expand as a result of the temperature increasing, thus enabling the drug to diffuse out and be released from the carrier.^[25] Stimuli occurring externally of internally include temperature, electric current, pH etc. When an enzyme is immobilized in smart hydrogel, the product of enzymatic reaction could themselves trigger the gel’s phase transition. The swelling or shrinking of smart polymer beads in response to small change in pH or temperature is used to control the drug release, because diffusion of the drug out of beads depends upon the gel state. These smart polymers become viscous and cling to the surface. And as a result it provides an effective way to administer drugs, either topically or mucosal or injectable, over long timescales by dissolving them in solution, which contain hydrophobic regions.^{[25] [26]}

Tissue Engineering:

Thermo responsive polymers in this field are commonly used in two situations such as substrates that enable the cell growth and proliferation and as injectable gels, for in situ of the scaffold. The first situation states that, the thermo responsive ability of the polymers is used to regulate the cells' attachment and detachment from a surface. In fact, in one study, the polymer surface was even reusable for repeated cell culture. The second application involves the encapsulation of cells in 3D structures in the body. The in situ formation of cell or scaffold contrast compared to the in vitro formation of the construct allows the delivery of encapsulated cells, nutrients and growth factors to defects of any shape using minimally invasive techniques. Specifically, the thermo responsive polymer is mixed at room temperature with the cells and then injected into the body. Upon injection due to the temperature increase (to 37 C) that is above the polymer's LCST, the polymer forms a physical gel. The cells are encapsulated within the 3D structure of the gel.^[25]

For example: Poly-N-Isopropylacrylamide based hydrogels are non-adherent below the LCST and adhere above the LCST; at high temperature bioactive molecule can be entrapped and subsequently released upon lowering the temperature. Temperature-sensitive hydrogels have gained considerable attention in the pharmaceutical field due to ability of the hydrogels to swell or shrink as a result of changing the temperature of the surrounding fluid. Numerous researchers studied various applications of these hydrogels such as on-off drug release regulations, biosensors and intelligent cell culture dishes.^{[11] [25]}

Stimuli-responsive surfaces:

The change in the surface properties of the thermo responsive polymers from hydrophobic above the critical temperature to hydrophilic below it has been used in tissue culture applications. Mammalian cells are cultivated on a hydrophobic solid culture dishes and are usually detached from it by protease treatment, which also causes damage to cells. This is rather an inefficient way in that only some detached cells are able to adhere onto new dishes because the rest are damaged. At temperature of 37°C, a substrate surface coated with grafted poly (N- Isopropylacrylamide) is hydrophobic because this temperature is above the critical temperature of the polymer and cells grow well. However when the temperature is decreased by 20°C, the surface becomes hydrophilic, and the cells can be easily detached without any damage. The cells can be used for further culturing. The cells are detached maintaining the cell-cell junction. This enables the collection of the cultured cells as a single sheet which is highly effective when transplant to patients due to tight communication between cells and cells.^{[11] [15]}

Gene therapy:

It aims at the treatment of many genetic diseases as it is a technique for correcting defective genes slowing down tumor growth and stopping neurodegenerative diseases. Specifically, the delivery of the appropriate, therapeutic gene (DNA) into the cells and finding of the gene that will replace, repair or regulate the defective gene that causes the disease. Nonviral gene carrier of two types which are to be cationic in nature in order to form complexes with anionic DNA and the complex has to have net positive charge to interact with the anionic cell membrane and undergo endocytosis. During attachment of coil forming endosome, binding of carrier and DNA is to be high and he complex should be easy to dissociate to move the DNA into nucleus to initiate transcription. In particular, in studies where PEI with grafted PNIPAM, chitosan grafted with PNIPAM. Further by the use of temperature sensitive polymer more selective gene expression is possible in terms of site, timings and duration.^{[11] [12]
[25]}

Applications of polymers based on their structure

Hydrogels:

Hydrogels mainly constitute 99% w/w water to polymer which is actually a polymer networks dispersed in water to form semi solid states called gels. These gels can be either covalently linked polymer networks or physical gels. With reference to thermo responsive polymers, covalently linked networks exhibit a change in their degree of swelling in response to temperature. When cross linked into hydrogels, the coil-to-globule transition causes a rapid decrease in the volume of the gel resulting in a fast release of entrapped drug and solvent followed by a more linear, diffusion controlled release. The swelling kinetics of co-networks of NIPAM with BuMA, P (NIPAAm-co-BuMA), commenting on the need for zero order drug release profiles and found that after a burst release of drug from the outer part of the hydrogel a sustained release can be obtained. Other thermo responsive monomers have been utilized for the preparation of hydrogels including PDMAAm. PDMAAm-co-Poly (methoxyethyl acrylate) and showed that at body temperature this hydrogel releases drug following a Fickian diffusion process with a linear relationship in respect to the square root of time. Co-networks of PNIPAM, poly (HEMA) and a lactic acid monomer were synthesized by Ma et al. and found to exhibit LCSTs of 10–20°C with PNIPAM contents of 80% or more. The gels had high tensile strength and degraded over several months with no cytotoxic byproducts when used in tissue engineering.^[15]^{[21] [25]}

Micelles:

Block copolymers are a combination of hydrophilic and hydrophobic monomers and allows the formation of ordered structures in solution called micelles. Micelles are useful for encapsulating hydrophobic drugs and delivering them into an aqueous environment.^{[12] [21]}Several studies have focused on using PNIPAM as the thermo responsive block in the formation of thermo responsive micelles.Micelles of P(NIPAM-co-DMAAm)-b-PLA, where PLA was poly(lactic acid), and showed that these micelles were able to internalize into cells above their LCST, specifically due to the increased interaction between the hydrated NIPAM outer sphere and the cells. Degradable copolymers of (HEMAmlactate) to form micelles above a critical micelle temperature dependant on the polymer LCST. Thermo responsive star block copolymer based on L-Lactide and NIPAM. These star polymers were found to self assemble into large micelle structure in water which showed a fast on/off drug switching with temperature. ^{[22] [25] [27]}

Films:

Copolymer films of PNIPAM and poly (N-butylacrylamide) to give a sustained release of drugs from the film over a considerable time period. They showed the released amounts of drug loaded at room temperature to be inversely proportional to the hydrophobic monomer content once heated to 37 C. The possibility of using a copolymer of PNIPAM with PAAm as a stimuli responsive membrane for the control of permeation of molecules for numerous applications like drug delivery. Cell growth and selected cell detachment was shown to be achievable with this approach. The production of plasma polymerized PNIPAM films onto micro heater arrays produced using photolithography. This method allows for localized heating and specific area detachment of cells with many possible applications. An interesting 3D cell culture method was envisaged.^{[12] [25]}

Particles:

Nanoparticles of thermo responsive polymers possessed sensitivity to a reducing environment, such as the intracellular cytoplasm, by reduction of the disulfide bonds in the polymer chain resulting in breakdown of the nanoparticles. Coated insoluble nanoparticles with PNIPAM rendering them stable in aqueous solutions with temperature dependant solution properties and suggested uses in drug delivery and biological sensing. PVC and PVC-graft-PEG microgels were formed by heating the polymer above its LCST and using salicylic acid as a crosslinker. The salicylic acid formed hydrogen bonds between the polymer chains forming a physical hydrogel. By adding a solution of polymer and drug to a solution containing the crosslinker at temperatures greater the LCST, hydrogel particles were formed which showed sustained release. Interestingly, the PEG graft copolymers showed a slower drug release due to an increase in hydrogen bonding and hence increase packing from the PEG chains.^{[12] [25]}

Interpenetrating networks:

Interpenetrating networks specifically, an interpenetrating network of PAA and PAAm forms hydrogels that swell above their upper critical solution temperature, UCST, due to hydrogen bonding between the two different networks being disrupted at higher temperatures allowing the networks to swell. Recent work on the same IPN with grafted β-cyclodextrin showed a faster thermo response and lower UCST (35 C) and a lowered effect of salt on the swelling. Incorporation of a model drug, ibuprofen, showed a positive drug release with a controlled rate above and below the UCST.^{[12] [25]}

Evaluation and Characterization of in situ gel system

Viscosity and Rheology:

Viscosity and rheological properties of in situ forming drug delivery systems may be assesses using Brookfield rheometer or other viscometers such as Ostwald’s viscometer. The viscosity of these formulations should be such that no difficulties are envisaged during their administration by the patient, especially during parenteral and ocular administration. For in situ gel forming systems incorporating thermo reversible polymers, the sol-gel transition temperature may be defined as that temperature at which the phase transition of sol meniscus is first noted when kept in a sample tube at a specific temperature and then heated at a specified rate. Gel formation is indicated by a lack of movement of meniscus on tilting the tube. Gelling time is the time for first detection of gelation from sol.^[28]
[29]

Gel Strength:

This parameter can be evaluated using a rheometer. Depending on the mechanism of the gelling of gelling agent used, a specified amount of gel is prepared in a beaker, from the sol form. This gel containing beaker is raised at a certain rate, so pushing a probe slowly through the gel. The changes in the load on the probe can be measured as a function of depth of immersion of the probe below the gel surface. ^[28]
[30]

In vitro drug release studies:

For the in situ gel formulations to be administered by oral, ocular or rectal routes, the drug release studies are carried out by using the plastic dialysis cell. The cell is made up of two half cells, donor compartment and a receptor compartment. Both half cells are separated with the help of cellulose membrane. The sol form of the formulation is placed in the donor compartment. The assembled cell is then shaken horizontally in an incubator. The total volume of the receptor solution can be removed at intervals and replaced with the fresh media. This receptor solution is analyzed for the drug release using analytical technique. For injectable in situ gels, the formulation is placed into vials containing receptor media and placed on a shaker water bath at required temperature and oscillations rate. Samples are withdrawn periodically and analyzed.^{[29] [31]}

Drug Content Uniformity:

Percentage of drug content is evaluated with uniformity. The uniformity of drug distribution displays the ability to release drug in-vitro and in-vivo. It is generally investigated by UV spectrophotometer after certain dilution. The results found are co-related to in vitro as well as in-vivo drug release and shows the performance of drug content of the formulation.^[28]

Fourier transforms infra-red spectroscopy and thermal analysis:

During the process of gelation, the nature of interacting forces can be evaluated using this technique by employing potassium bromide pellet method. Thermo-gravimetric analysis can be conducted for in situ forming polymeric systems to quantitative the percentage of water in hydrogels. Differential scanning calorimetry is used to observe if there are any changes in thermogram as compared with the pure ingredients used thus indicating the interactions.^{[30] [31]}

Texture analysis:

The consistency, cohesiveness or the firmness of hydrogels are analyzed using texture analyzer. The analyzer generally indicates the syringe ability of sol and determines whether the formulation can be administered in vivo to humans or animals. Higher values of adhesiveness of gels are needed to maintain an intimate contact with surfaces like tissues.^{[33] [32]}

Gelation temperature and Gelation time:

The gelation temperature is one of the important parameter to be noted for injectable gel. It is defined as the exact temperature when the viscous liquid changes its phase to sol form after its contact with the environmental temperature. Generally in-situ formation of gel takes place with the physiological body temperature. The time required for gelation of viscous liquid or in-vitro and in-vivo phase transformation with the change in temperature is called gelation time. The experiment can be performed by visual measurement. ^[28]

CONCLUSIONS:

The “smart-polymers” or stimuli-responsive polymers have a very wide range of applications such as modified release of drugs, tissue engineering, bio-separation devices, active membrane etc. However intelligent polymers like thermo sensitive polymers offer great advantages and benefits in different way and in biomedical uses which includes from tissue engineering to the delivery of active drug molecules. Thermo sensitive polymer which aims to deliver the drugs in a controlled or sustained manner at the physiological body temperature has a great impact in the pharmaceutical field. The uses of such polymers are suitable candidate for formulation of pharmaceutical dosage form including modified release (i.e. sustained or prolong release) and distribution of the active drug to a specific target and thus reducing the side effects or adverse systemic reactions. This type of pharmaceutical formulation provides other advantages like reduction in therapeutic doses, and a consequent patient compliance. In addition such systems became quite easy for production in pharmaceutical industry. The versatility of thermo responsive polymers makes the pharmaceutical excipients a class of potential materials in the field of pharmacy and chemistry.

LIST OF ABBREVIATIONS:

ID : Intradermal

IM : Intramuscular

SC : Subcutaneous

UCST : Upper critical solution temperature

LCST : Lower critical solution temperature

PNIPAAM: Poly (N-isopropylacrylamide)

PEO-PPO-PEO: polyethylene oxide- polypropylene oxide - polyethylene oxide

NIPAAm-co-AA: Poly (NIPAAm-co-acrylic acid)

PEI : Polyethyleneimine

PDEAM : Poly (N, N-diethylacrylamide)

BuMA : Butyl methacrylate

HEMA : H+droxyethyl methacrylate

PEG : Poly (ethylene glycol)

PVC : Poly vinyl glycol

PLA : Poly lactic acid

PDEAM : Poly (N,N-diethylacrylamide)

PDMAAm: Poly (dimethyl acrylamide)

PVC : Poly vinyl chloride

DNA : Deoxyribonucleic acid

REFERENCES:

1. Kaur LP, Guleri TK. Topical Gel: A Recent Approach for Novel Drug delivery. Asian Journal of Biomedical and Pharmaceutical Sciences. 2013; 3(17), 1-5.

2. Chakraborty T, Saini V, Sharma S, Kaur B. Antifungal Gel: For Different Routes of Administration and Different Drug Delivery System. International Journal of Biopharmaceutics. 2014; 5(3), 230-240.

3. Karode NP, Prajapati VD, Solanki HK, Jani GK. Sustained release injectable formulations: Its rationale, recent progress and advancement. World Journal of Pharmaceutical Science. 2015; 4(4), 720-722.

4. Kumbhar AB, Rakde AK, Chaudhari PD. In-Situ Gel Forming Injectable Drug Delivery System. International Journal of Pharmaceutical Sciences and Research, 2013; 4(2), 597-609.

5. Hoffman AS, Stayton PS, Bulmus V. Really smart bioconjugates of smart polymers and receptor Proteins. Journal of Biomedical Materials Research. 2000; 52(4), 577–586.

6. Tahami A, Singh J. Smart polymer based delivery systems for peptides and proteins. Recent Patent on Drug Delivery & Formulation. 2007; 7(1), 65–71.

7. Kumar KPS, Bhowmik D, Srivastava S, Paswan S, Dutta AS. Sustained Release Drug Delivery System Potential. The Pharma Innovation. 2012; 1(2), 48-60.

8. Dixit N, Maurya SD, Sagar BPS. Sustained release drug delivery system. Indian Journal of Research in Pharmacy and Biotechnology. 2013; 1(3), 305-310.

9. Bari H. A prolonged release parenteral drug delivery system- An overview. International Journal of Pharmaceutical Science and Research. 2010; 3(1), 001

10. Mahajan A, Aggarwal G. Smart Polymers: Innovations in Novel Drug Delivery. International Journal of Drug Development & Research. 20113; 3(3), 16-30.

11. Ghizal R, Fatima GR, Srivastava S. Smart Polymers and Their Applications. International Journal of Engineering Technology, Management and Applied Sciences. 2014; 2(4), 104-115.

12. Gandhi A, Paul A, Sen KK. Studies on thermo responsive polymers: Phase behavior, drug delivery and biomedical applications. Asian Journal of Pharmaceutical Sciences. 2015; 10(2), 99-107.

13. Almeida H, Amaral MH, Lobao P. Temperature and pH responsive polymers and their applications in control and self regulatory drug delivery. Journal of Applied Pharmaceutical Science. 2012; 2(6), 1-10.

14. Strandman S, Zhu XX. Thermo-responsive blocks copolymers with multiple phase transition temperatures in aqueous solutions. Progress in Polymer Science. 2015; 42, 154-176.

15. Aguilar MR, Elvira C, Gallardo A, Vazquez B, Roman JS. Smart Polymers and their Applications as Biomaterials. Topics in Tissue Engineering. 2007; 3, 1-25.

16. Bonacucina G, Cespi M, Mencarelli G, Giorgioni G, Palmieri GF. Thermo sensitive self-assembling block copolymers as drug delivery systems. Polymers. 2011; 3(2), 779-811.

17. Gil ES, Hudson SM. Stimuli responsive polymers and their bioconjugates. Progressive Polymer Science. 2004; 58(2), 409-426.

18. Lee YM, Ha DI, Lee SB, Chong MS. Preparation of Thermo-Responsive and Injectable Hydrogels Based on Hyaluronic Acid and Poly(N-isopropylacrylamide) and their Drug Release Behaviors. Macromolecular Research. 2006; 14(1), 87-93.

19. Hari Kumar SL, Singh K, Kaur H. Design and development of sustained release injectable in-situ gel of cytarabine. Pharmacophore. 2013; 4(6), 252-267.

20. Sindhu SK, Gowda DV, Datta V, Siddaramaiah P. Formulation and Evaluation of Injectable In-Situ Gelling Matrix System for Controlled Drug Release. Indian Journal Advances in Chemical Science. 2014; 2(1), 89-92.

21. Danhong Long TG, Zhang Z, Ding R. Preparation and evaluation of phospholipid-based injectable gel for the long term delivery of Leuprolide Acetate. Acta Pharmaceutica Sinica B. 2016; 6(4), 329-335.

22. Sharma MK, Aswal PA. Self-Assembly of PEO-PPO-PEO Triblock Copolymers in Aqueous Electrolyte Solution. Bhaba Atomic Reasearch Centre. 2007; 1, 285.

23. Patel HR, Patel RP, Patel MM. Poloxamers: A pharmaceutical excipients with therapeutic behaviors. International Journal of PharmTech Research. 2009; 1(2), 299-303.

24. Paschalis, Haton A. Review on PEO-PPO-PEO block copolymer surfactants in aqueous solutions and at interfaces. Physicochemical and Engineering Aspects. 1995; 3(1), 1-9.

25. Ward MA, Georgiou TK. Thermo responsive polymers for biomedical applications. Polymers. 2011; 3, 1215-1242.

26. Saeednia L, Usta A. Injectable Thermo sensitive Hydrogels as Drug Delivery Systems. Graduate Research and Scholarly Projects. 2013; 9, 69-70.

27. Wang Q, Wang Z, Liu H. Preparation and characterization of a positive thermo responsive hydrogel for drug loading and release. Journal of Applied Polymer Science. 2009; 111(3), 1417-1425.

28. Jabarian EL, Rouini MR, Atyabi F, Foroumadi A, Nassiri SM, Dinarvand R. In vitro and in vivo evaluation of an in situ gel forming system for the delivery of poly ethylene glycolated octreotide. European Journal of Pharmaceutical Sciences. 2013; 48, 87–96.

29. Xin C, Lihong W, Hongzhuo QL. Injectable long-term control-released in situ gels of hydrochloric thiothixene for the treatment of schizophrenia: Preparation, in vitro and in vivo evaluation. International Journal of Pharmaceutics. 2014; 469(1), 23-30.

30. Geng Z, Luo X, Li H, Tian J, Zugong Y. Study of an injectable in situ forming gel for sustained-release of Ivermectin in vitro and in vivo. International Journal of Biological Macromolecules. 2016; 5, 271-276

31. Shaker DS, Mohamed K, Ghorab, Klingner A, Mohamed S. In-Situ injectable thermo sensitive gel based on poloxamer as a new carrier for tamoxifen citrate. International Journal of Pharmacy and Pharmaceutical Sciences. 2013; 5(4), 429-437.

32. Das S, Samanta A, Bose A. Design, Development and Evaluation of Fluconazole Topical Gel. Asian Journal of Pharmaceutical and Clinical Research. 2015; 8(2), 132-135.

33. Madan M, Bajaj A, Udupa N, Baig JA. In Situ Forming Polymeric Drug Delivery Systems. Indian Journal of Pharmaceutical Sciences. 2009; 3, 242-251.

Received on 27.03.2017 Modified on 12.05.2017

Research J. Pharm. and Tech. 2017; 10(6): 1840-1847.

DOI: 10.5958/0974-360X.2017.00323.7