Injectable In-Situ Gelling Controlled Release Drug Delivery System

Kulwant Singh, S. L. HariKumar*
Rayat & Bahra Institute of Pharmacy, Sahauran, Kharar, District Mohali, Punjab, India-140104.
Corresponding Author: Dr. S. L. Hari Kumar Director, Rayat & Bahra Institute of Pharmacy, Sahauran, District Mohali, Punjab -140104, India E.mail: [email protected]
Received:09 April 2012 Accepted: 18 April 2012
Citation: Kulwant Singh, S. L. HariKumar* “Injectable In-Situ Gelling Controlled Release Drug Delivery System”, Int. J. Drug Dev. & Res., April-June 2012, 4(2):56-69 doi: doi number
Copyright: © 2010 IJDDR, S. L. HariKumar et al. This is an open access paper distributed under the copyright agreement with Serials Publication, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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The administration of poorly bioavailable drug through parenteral route is regarded the most efficient for drug delivery. Parenteral delivery provides rapid onset even for the drug with narrow therapeutic window, but to maintain the systemic drug level repeated installation are required which cause the patient discomfort. This can be overcome by designing the drug into a system, which control the drug release even through parenteral delivery, which improve patient compliance as well as pharmacoeconomic. One of the such system is injectable in-situ gelling system This biodegradable injectable in-situ gelling drug delivery system offer attractive opportunities for protein, anti cancer or NSAIDs drug delivery and could possibly extend patent life of these drugs. This article explores the injectable in-situ gelling system for prolonged release parenteral drug delivery system and their strategies of preparation, their potential benefits/drawbacks mechanism of work and in-vitro testing methods.


injectable in-situ gel, strategies of parenteral systems, biodegradable injectable polymers


For the past many years, there has been enhanced demand for more patient compliance dosage forms. As a result, the demand for their technologies has been increasing three fold annually since the developmental cost of a new chemical entity is very high; the pharmaceutical companies are focusing on the development of new drug delivery systems for existing drug with an improved efficacy and bioavailability together with reduced dosing frequency to minimize side effects.
The development of in-situ gel systems has received considerable attention over the past few years. In- situ gel forming drug delivery systems are in principle, capable of releasing drug in a sustained manner maintaining relatively constant plasma profiles. These hydro gels are liquid at room temperature but undergo gelation when in contact with body fluids or change in pH. These have a characteristic property of temperature dependent, pH dependent and cation induced gelation. Compared to conventional controlled release formulations, in-situ forming drug delivery systems possess potential advantages like simple manufacturing process, ease of administration, and reduced frequency of administration, improved patient compliance and comfort. [1-3] In-situ gel forming drug delivery is a type of mucoadhesive drug delivery system.
In contrast to very strong gels, they can be easily applied in liquid form to the site of drug absorption. At the site of drug absorption they swell to form a strong gel that is capable of prolonging the residence time of the active substance. Both natural and synthetic polymers can be used for the production of in-situ gels. In-situ gel formation occurs due to one or combination of different stimuli like pH change, temperature modulation and ionic cross-linking [4-6] So, in-situ gels are administered by oral [7], ocular [8], rectal [9], vaginal [10], and injectable [11] and intra peritoneal routes. [12]

Types of Parenteral Controlled Drug Delivery Systems

In principle, there are three ways to achieve prolonged release of parenteral dosage form viz. pharmacological, chemical, and physical methods. Pharmacological methods include intramuscular or subcutaneous administration instead of intravenous; the simultaneous administration of vasoconstrictors (adrenaline in local anesthetics; ephedrine in heparin solutions); and blocking the elimination of drugs through the kidneys by simultaneous administration of a blocking agent, such as probenecid with penicillin or p-amino salicylic acid. Chemical methods include the use of salts, esters, and complexes of the active ingredient with low solubility. Physical methods include the selection of the proper vehicle, thereby giving prolonged release (use of oleaginous solutions instead of aqueous solutions); the addition of macromolecules that increase viscosity (CMC, NaCMC, PVP, tragacanth, etc.); the use of swelling materials to increase viscosity in oleaginous solutions (aluminium monostearate); the additions of adsorbents; the use of solutions from which, upon administration, the drug is precipitated when it contacts body fluids; the use of aqueous and oleaginous suspensions; and the use of implants.
* Surgical implants
* Microspheres
* Injectable gels
Surgical implants can be made from biodegradable polymers using well-controlled manufacturing processes, such as extrusion, injection moulding, and compression moulding. These devices normally have very reproducible release profiles. However, because of their size, they require surgical implantation, which often limits the product's market potential due to patient and physician acceptance issues. Microspheres designed for parenteral delivery, on the other hand, can be injected into the body using conventional needles and syringes. Thus, they have been the most widely accepted biodegradable polymer system for parenteral use. However, the manufacturing processes for microspheres are often complex and difficult to control. As a result, there are often questions involving costs and batch-to-batch product uniformity.[13-14] Liposome’s on the other hand are versatile carriers for both hydrophilic and lipophilic drug molecules but suffer from several disadvantages like, high production cost, leakage of drug, short half life and low solubility.[15] Biodegradable injectable in-situ gel forming drug delivery systems represent an attractive alternative to microspheres and implants as parenteral depot systems. It consists of biodegradable polymers dissolved in a biocompatible carrier. When the liquid polymer system is placed in the body using standard needles and syringes, it solidifies upon contact with aqueous body fluids to form solid implant. If a drug is incorporated into the polymer solution, it becomes entrapped within polymer matrix as it solidifies. Drug release occurs over time as polymer biodegrades. Biodegradable polymers used in these systems are Polyhydroxyacids, polyanhydrides, polyorthoesters, polyesteramides and others. Their importance will grow as numerous proteins will lose their patent protection in the near future.[16]

Injectable In-Situ Gels

Polymeric delivery systems[17] pose the attractive capability to control the release of drug substances to obtain defined blood levels over a specified time. In several cases this capability would provide a significant advantage. For instance, permanent medication thereby often benefit from long-term delivery systems to improve patient compliance. For permanent medication and several other applications in humans and in animals, the need for appropriate depot systems exists. Injectable in-situ forming depots comprise a specific class of polymeric delivery systems that possess the advantages of a straight forward manufacturing even for sensitive molecules and ease of application as a liquid, which solidifies after application by phase separation. When based on a polymer such as poly (d,l-lactide-co-glycolide) (PLGA), the depot is biodegradable in vivo. Currently, there are two injectable in-situ forming depots on the market: Atridox® and Eligard®. Both products were developed based on the Atrigel technology of Dunn et al. This technology employs PLGA dissolved in N-methyl-2-pyrrolidinone (NMP), which is a water miscible solvent, and a drug powder suspended in this solution prior to application.[18,19] Injectable in-situ setting semi-solid drug depot are being developed as alternative delivery system. These implants are made of biodegradable products, which can de injected via a syringe into the body and once injected, solidify to form a semi-solid depot.[20] The major prerequisite characteristics of the solvent of an injectable in-situ depot system include good solubility properties for the polymer, chemical compatibility, biocompatibility and overall stability. Additionally, a suitable solvent for subcutaneous (s.c.) or intramuscular (i.m.) injection should be minimally irritating to the injection site, and its metabolic products should not have deleterious sideeffects on the organism. The ICH classification of solvents in pharmaceutical products narrows the use by the permitted daily exposure (PDE) of excepients.[20]

Advantages of Injectable In-situ Gels

This system serves many advantages over conventional methods of drug administration including tablets, capsules etc. this include-
Compatibility with a broad range of pharmaceutical compounds: Water soluble and insoluble compounds and high and low molecular weight compounds like peptides and proteins, vaccines and natural products can be easily administered by injectable in-situ systems.
Less invasive technique: The application is less invasive and painful compared to implants, which require local anaesthesia and a small surgical intervention.
Direct delivery to a target area: This helps in achieving higher drug concentrations at the desired site of action to minimize systemic side effects.
Protection of drug: In-situ drug delivery system of a protein drug helps in protection of peptide drugs.
Sustained drug release: Helps in reduction of dose, achieve release for extended periods, so there is increase in patient compliance, important for those protein drugs having narrow therapeutic indices.
Sustained drug release: Helps in reduction of dose, achieve release for extended periods, so there is increase in patient compliance, important for those protein drugs having narrow therapeutic indices.
Biodegradable and biocompatible: Injectable in-situ system is made of biodegradable polymers and biocompatible solvents so do not require removal
Economic factors: Microspheres have to be washed and isolated after preparation; operating expenses for the production of in-situ forming applications are marginal, thus lowering investment and manufacturing costs.[18-20]

Method of Manufacturing

In-situ forming drug delivery systems (ISFD)

Injectable in-situ forming implants are classified in to four categories based on the mechanism of achieving solidification in vivo.[20]
1. Thermoplastic Paste
2. In-situ cross linking system
3. In-situ polymer precipitation
4. Thermally-induced gelling system
5. In-situ solidifying organogels

1) Thermoplastic pastes (TP)

Thermoplastic pastes are semisolid polymers, which injected as a melt and form a depot upon cooling to body temperature. They are characterized as having a low melting point or Tg (glass transition temperature) in the range of 25-65°C and an intrinsic viscosity in the range of 0.05-0.8 dl/g.[21-22] Below the viscosity of 0.05 dl/g, no delayed release could be observed, where as above 0.8 dl/g the ISFD was no longer injectable using a needle. At injection temperature above 37°C but below 65°C these polymers behave like viscous fluids which solidify to highly viscous depots. Drugs are incorporated into the molten polymer by mixing without the application of solvents. Bioerodible thermoplastic pastes could be prepared from monomers such as D,L-lactide, glycolide, E-caprolactone, dioxanone and orthoesters.[21-23] Polymers and copolymers of these monomer have been extensively used in surgical sutures[24], ocular implants[25-26], soft tissue repair[26]etc.
Zhang et al developed a thermoplastic ABA triblock polymer system composed of poly (D,L lactide)- poly(ethylene glycol)-poly(D,L-lactide) and blend of ABA triblock copolymer and polycaprolactone (PCL) delivery of Taxol within tumor resection sites.[27]Both give release of Taxol[28] for more than 60days but the rate of release was very slow. Another disadvantage associated with this polymeric system was the high melting temperature of thermoplastic pastes requiring injection temperature at least 60°C. This led to very painful injections and necrosis at the injection site resulting in the encapsulation of the depot by scar tissue, which again inhibited paclitaxel diffusion.[29] Poly(orthoesters), POE have well suited properties for TP due to their good biocompatibility, relatively low softening temperatures in the range of 35-45°C and degradation by surface erosion.[22-23]
2) In-situ cross-linked polymer systems
The formation of a cross-linked polymer network is advantageous, to control the diffusion of the hydrophilic macromolecules. Cross-linked polymer network can be found in-situ by free radical reactions initiated by heat (thermosets) or absorption of photon or ionic interactions between small cation and polymer anions.
Dunn et al, used biodegradable copolymers of D, Llactide or L-lactide with E-caprolactone to prepare a thermosetting system for prosthetic implants and slow release drug delivery systems.[30] It requires free radical producing agents such as benzoyl peroxide into the body which may induce tumor promotion.[31] Hibbell et al. described a photopolymerizable biodegradable hydrogel as a tissue contacting material and controlled release carrier.This system consisted of a macromer, PEG(polyethylene glycol)- oligo-glycol-acrylate, using a photo initiator, such as eosin and visible light.[32-34]The controlled release of protein was observed over a period of several days. These hydrogel are restricted to surgical sites accessible to a light source as they form with difficulty after injection into the body. Ion-mediated gelation has been reported for a number of polymers, e.g. alginates/calcium ions or chitosan /phosphate ions.[35-36] The concentrations of the counter ion available under physiological conditions are usually insufficient for cross-linking of the above mentioned polymers. Only the calcium concentration in the eye led to in-situ formation of alginate formulations.[36] Despite these applications, there are two important factors which limit the use of calcium-alginate. The first factor is their potential immunogenicity and the second is longer time in vivo degradability.[37]

3) In-situ polymer precipitation

Dunn and coworkers first developed the concept ISFD based on polymer precipitation in 1990.[38] A water-insoluble and biodegradable polymer is dissolved in a biocompatible organic solvent to which a drug is added forming a solution or suspension after mixing. When this formulation is injected into the body, the water miscible organic solvent dissipates and water penetrates into the organic phase. This leads to phase separation and precipitation of the polymer forming the depot at the site of injection. This method has been designed as AtrigelTM technology, which used as a drug carrier for EligardTM contains the leuteinizing hormone releasing hormone (LHRH) agonist leuprolide acetate (7.5, 22.5 or 30mg) and poly(lactide-coglycolic acid)(PLGA) 75/25 dissolved in N-methyl-2- pyrrolidone (NMP) in a 45:55 (m/m) polymer: MP ratio.[39-40] This system led to suppression of testosterone levels in dogs for approximately 91d. One of the problems with these systems is the possibility of a burst in drug release especially during the first few hours after injection into the body. In order to control the burst effect, four factors have been examined, the concentration of polymer in the solvent [41], the molecular weight of the polymer, the solvent used and the addition of surfactant.[42-44] Also the drug burst is directly related to the dynamics of the phase inversion. Brodbeck et al demonstrated that protein release kinetic from ISFD was influenced by solution thermodynamics, e.g. solvent strength and water miscibility.[45-46] They studied NMP, triacetin and ethyl benzoate ternary phase systems with PLGA and water. NMP shows rapid phase inversion associated with a high drug burst where as triacetin and ethylbenzoate yielded low phase inversion rates, resulting in a slow gelation which reduced the drug burst of protein significantly. Himmelstein and joshi studied that polymer complex of PEG, polymethacrylic acid(PMA), and polyacrylic acid(PAA) is stable below pHK5.7, the complex is insoluble in water but dissolves in a hydroalcoholic solvent to yield a clear viscous solution. After injection the diffusion of ethanol from the liquid transforms the system into a gel upon contact with physiological condition. The gel disappears from the site with time due to complex dissociation into water soluble and low molecular weight component, which can be eliminated by glomerular filtration.[47] Carbopol is a pH dependent polymer, which forms a low viscosity gel in alkaline environment (e.g. pH- 7.4) and stays in solution in acidic pH. The addition of HPMC, a viscosity inducing agent, to carbopol reduces the carbopol concentration and hence the solution acidity while preserving the viscosity of the in-situ gelling system. This system gels upon an increase in pH when injected.[48]

4) Thermally induced gelling system

Many polymers undergo abrupt changes in solubility as a function of environmental temperature. The thermo sensitive polymer, poly(N-isopropyl acrylamide) [poly(NIPAAM)] exhibit sharp lower critical solution temperature, LCST at about 32°C.[49] which can be shifted to body temperature by formulating poly NIPAAM based gels with salt and surfactant. Unfortunately, poly NIPAAM is not suitable for biomedical applications due to its wellknown cytotoxicity (activation of platelets)[50] and non-biodegradability.[51] Triblock poly(ethylene oxide)-poly(propylene oxide)- poly(ethylene oxide) copolymer, PEO-PPO-PEO (pluronics or poloxamers), have shown gelation at body temperature when highly concentrated polymer solution >15% w/w were injected.[52-53] These polymer concentration shown disadvantage of changing the osmolarity of the formulation, kinetics of the gelation, and causes discomfort in ophthalmic applications due to vision blurring and crusting.[54] Macro med produced thermo sensitive biodegradable polymers based on ABA and BAB triblock copolymers. Where A is hydrophobic polyester block and B denotes the hydrophilic PEG block. The aqueous polymer solution of PEG-PLA-PEG is loaded with drug at 45°C after injected into animal form a gel at body temperature, which continuously releasing hydrophilic model substances fluorescein isothiocyanate dextran (FITC-dextran), over 10- 20days.[55-56]
Veyries et al.[57] demonstrated the possibility of controlled release of vancomycin from Pluronnic F127. They investigated Poloxamer 407 (Pluronic F127) 25% formulations aimed at prolonging the residence time of vancomycin, a time dependent antibiotic, in a body site with a high infectious risk. It appeared that neither the rheological properties of the Poloxamer matrices nor the antibacterial activity of vancomycin was altered by their combination. Two formulations were prepared, one saturated and one unsaturated (solubilized) with vancomycin. In vitro, the dispersed form (saturated) exhibited prolonged release, with a lower diffusion coefficient of vancomycin compared to the solubilized form (4.7 X 10-8 vs. 2.1X10-7 cm2 s-1 ). In rats, a single dose was well tolerated and resulted in a high local concentration for 24 h (>131 mg/ l), followed by lower but effective antibacterial levels for at least 8 days. Based on the release profiles, good preservation of vancomycin activity, good tolerability in rats, and ease of administration, it was concluded that Poloxamer 407 might be useful as a vancomycin delivery vehicle for local prophylaxis of infections, especially in prosthetic surgery.

5) In-situ solidifying organogel

Organogels are composed of water insoluble amphiphilic lipids, which swell in water and form various types of lyotropic liquid crystals. The amphiphilic lipids examined for drug delivery are glycerol monooleate, glycerol monopalmitostearate, glycerol monolinoleate, sorbitan monostearate (SMS) and different gelation modifiers (polysorbates 20 and 80) in various organic solvents and oils. These compound forms a cubic liquid crystal phase upon injection into an aqueous medium which is gel like and highly viscous.[58] SMS organogels containing either w/o or vesicular in water in oil (v/w/o) emulsion were investigated in vivo as delivery vesicles for vaccines using albumin (BSA) and haemagglutin (HA) as model antigens.[59-60] Intramuscular administration of the v/w/o gel yielded the long lasting depot effect (48hr). Gao et al achieved controlled releases of contraceptive steroids levonorgestrel and ethinyl estradiol. In these work biodegradable organogels formulations prepared from glycerol palmitostearate (precirol) in derivatized vegetable oil, show in vitro release of levonorgestrel up to 14 days. [61] While subcutaneous injection into rabbits demonstrated an estrus blockage for up to 40days[62] Subcutaneously injected in-situ forming organogels prepared from L-alanine derivatives in safflower oil were used in the long term delivery of leuprolide, a LHRH agonist used in prostate cancer.[63] The gels were shown to slowly degrade and release the therapeutic peptide for a period of 14 to 25days.


Materials that exhibit sol to gel transition in aqueous solution at temperatures between ambient and body temperature is of interest in the development of sustained release vehicles with injectable in-situ gelation properties.[64]
Some of the polymers used as injectable in-situ gelling agents are:
· Gellan gum
· Alginic acid
· Pluronic F127
· Chitosan
· Carbomer

Gellan gum

Gellan gum (GelriteR) is a linear, anionic heteropolysaccharide secreted by the microbe Sphingomonas elodea (formerly known as Pseudomonas elodea). The polysaccharide can be produced by aerobic fermentation and then isolated from the fermentation broth by alcohol precipitation. The polymer backbone consists of glucose, glucuronic acid, and rhamnose in the molar ratio 2:1:1.[65] These are linked together to give a tetrasaccharide repeat unit . The native polysaccharide is partially esterified with L-glycerate and acetate.[66], but the commercial product Gelrite has been completely de-esterified by alkali treatment.[67] GelriteR (deacetylated gellan gum) is one of the most interesting injectable in-situ gelling polymers that has been tested since it seems to perform very well in humans. GelriteR has been granted regulatory approval as pharmaceutical excipient and is marketed by Merck in a controlledrelease glaucoma formulation called BlocardenR Depot (TimopticR). Formulations with the Gelrite can be administered to ocular mucosa as a low viscosity solution. On contact with cations in tear fluid the formulation will form a clear gel.[68] This is caused by cross linking of the negatively charged polysaccharide helices by monovalent and divalent cations (Na+, K+, Ca2+). Gellan gum produces temperature dependent or cations induced in-situ gelling.[69]

Alginic acid

Alginic acid is a linear block copolymer polysaccharide consisting of T-D-mannuronic acid (M) and U-L-guluronic acid (G) residues joined by 1,4-glycosidic linkage.[70] Alginate is a well known polysaccharide widely used due to its gelling properties in aqueous solutions related to the interactions between the carboxylic acid moieties and bivalent counter ions, such as calcium, lead, and copper; it is also possible to obtain an alginic acid gel by lowering the environmental pH value. Dilute aqueous solutions of alginates form firm gels on addition of di and trivalent metal ions by a cooperative process involving consecutive guluronic residues in the U-L-guluronic acid blocks of the alginate chain.[71] Alginate with a high guluronic acid content will improve the gelling properties and reduce the total polymer to be introduced into the eyes. Alginate has also been proposed in the field of pharmaceutics for its injectable in-situ gelation properties,particularly for the application of alginate gels for ocular drug delivery, since this dosage form is so effective as compared to solutions. The systems are based on the in-situ gelling properties of high guluronic content alginates, with experiments being carried out both in vitro, with simulated lachrymal fluid, and in vivo on rabbit eyes. A prolonged delivery of two different drugs (pilocarpine and carteolol) was obtained in comparison to the same drugs instilled as solutions. Alginic acid is mucoadhesive.[72], biodegradable and non toxic polymer. Because of these applications it is widely used as a vehicle for ophthalmic in-situ gelling system.

Pluronic F127

The Poloxamers or pluronic consists of more than 30 different non-ionic surface active agents. These polymers are ABA-type triblock copolymers composed of polyethylene oxide (PEO) (A) and polypropylene oxide (PPO) units (B). The Poloxamer series covers a range of liquids, pastes, and solids, with molecular weights and ethylene oxide– propylene oxide weight ratios varying from 1100 to 14,000 and 1:9 to 8:2, respectively.[73] Poloxamers, commercially available as Pluronic, are the most commonly used thermal setting polymers in ophthalmology. They are formed by central hydrophobic part (polyoxypropylene) surrounded by hydrophilic part (ethylene oxide). Depending on the ratio and the distribution along the chain of the hydrophobic and hydrophilic subunits, several molecular weights are available, leading to different gelation properties. Pluronic F-127, which gives colorless and transparent gels, is the most commonly used polymer in pharmaceutical technology.[74] Poloxamer formulation generally increased drug residence time at application sites, resulting in improved bioavailability and efficacy.[75] (PluronicR F127) was found to gel at a concentration of 20 % wt. at 25 °C, which is less than that of the other members of the Poloxamer series. At room temperature (25°C), the solution behaves as a mobile viscous liquid, which is transformed into a semisolid transparent gel at body temperature (37°C). Pluronics or Poloxamers also undergo in-situ gelation by temperature change. Pluronic F-127 was used as injectable in-situ gel forming polymer together with mucoadhesive polymers such as Carbopol 934 and hydroxyl propyl methylcellulose to ensure long residence time at the application site.


Chitosan is obtained from chitin by deacetylation reaction usually carried out in alkaline medium, a natural component of shrimp and crab shell. Chitosan exhibits several favorable properties such as biodegradability and biocompatibility.[76] It also has mucoadhesive properties due to its positive charge at neutral pH that enable an ionic interaction with the negative charges of sialic acid residues of mucus.[77-78] It is a biocompatible, pH-dependent cationic polymer, which is soluble in water up to pH 6.2. Basification of chitosan aqueous solutions above this pH leads to the formation of an hydrated gel-like precipitate. Chenite et al.[79-80] developed a novel approach to produce thermally sensitive neutral solutions based on Chitosan / polyol salt combinations. Thus the terms chitin and chitosan describe a continuum of copolymers of N- acetyl-Dglucosamine and D-glucosamine residues, the two being distinguished by insolubility or solubility in dilute aqueous acid solutions. Chitosan-based gels may be broadly divided into thermally non-reversible gels and the far smaller group of thermally reversible gels. Within the first group a further subdivision into those formed by N-acylation and those produced by Schiff’s base (aldimide) formation is useful


Cross-linked poly (acrylic acid) of high molecular weight, commercially available as Carbopol, is widely used in ophthalmology to enhance precorneal retention to the eye.[81] carbopolR 934 is a synthetic polymer composed of 62% of carboxyl groups with a high molecular weight (approximately 3×106) formed by repeating units of acrylic acid, cross-linked with either allylsucrose or allylethers of pentaerythritol.[82] Carbopol offers the advantage of exhibiting excellent mucoadhesive properties when compared with other polymers (e.g. cellulose derivatives, and polyvinyl alcohol). As the concentration of carbopol increases in the vehicle, its acidic nature may cause stimulation to the eye tissues. In order to reduce the total polymer content and improve the gelling properties, an ocular drug delivery system based on a combination of carbopol and methylcellulose has been developed.[83] Carbopol is a polyacrylic acid (PAA) polymer, which shows a sol to gel transition in aqueous solution as the pH is raised above its pKa of about 5.5.[84] A pH induced injectable in-situ precipitating polymeric system (an aqueous solution of carbopol-HPMC system) was designed and developed by Ismail et al. for plasmid DNA delivery.[85]

6) Synthetic polymers

Synthetic polymers are of increasing interest in drug delivery as therapeutic agent. Synthetic polymers are popular choice mainly for parenteral preparations. Aliphatic polyesters such as poly (lactic acid), poly
(glycolic acid), poly (lactide- coglycolide), poly (d calactone), poly Z caprolactone have been the subject of the most extensive recent investigations.[20] Various other polymers like triblock polymer systems composed of poly (D,L-lactide)-block poly (ethylene glycol)-block-poly (DL-lactide), blends of low molecular weight poly (D,L-lactide) and poly (Z- caprolactone) are also in use. These polymers are mainly used for the injectable in-situ formulations. The feasibility of lactide/glycolide polymers as excipients for the controlled release of bioactive agents is well proven.


A number of marketed products based on this technology are enlisted in Table 1. These products have been approved by FDA.



The clarity of formulated solution determined by visual inspection under black and white background

Texture analysis

The firmness, consistency and cohesiveness of formulation are assessed using texture analyzer, which mainly indicates the syringe ability of sol so the formulation can be easily administered in-vivo. Higher values of adhesiveness of gels are needed to maintain an intimate contact with surface like tissues.

Sol-Gel transition temperature and gel time

For in-situ gel forming system incorporating thermo reversible polymer, 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 specific rate. Gel formation is indicated by a lack of movement of meniscus on tilting the tube.

Gel strength

This parameter can be evaluated using a rheometer. It depends on the mechanism of the gelling of gelling agent used; a specific 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 change in the load on the probe can be measured as a function of depth on immersion of the probe below gel surface

Viscosity and rheology

This is an important parameter for in-situ gels to be evaluated. The viscosity and rheological properties of the polymeric formulation, either in solution or in gel made with artificial tissue fluid were determined with Brookfield rheometer or some other type of viscometer such as Ostwald’s viscometer.

Fourier Transforms Infrared Spectroscopy and Thermal analysis

During gelation process, the nature of interacting forces can be evaluated using this technique by employing potassium bromide (KBr) pellet method. Thermo-gravimetric analysis (TGA) can be conducted for in-situ forming polymeric system to quantitate the percentage of water in hydro gel. Differential Scanning Calorimetry (DSC) is used to observe any change in thermograms as compared with pure ingredients used thus indicates the interaction.[18-20]

Mechanism of Drug Release From Atrigel System

The formulation of these systems includes the dissolution of the water insoluble biodegradable polymer into a biocompatible solvent. The drug is next added to the solution where it dissolves or forms a suspension. This drug/ Polymer mixture is then easily and conveniently injected into the body where it forms a solid implant inside the tissue. Most commonly used polymers are poly (dl-lactide), lactide/glycolide copolymers, and lactide/caprolactone copolymers because of their degradation characteristics and their approval by the Food and Drug Administration (FDA). The solvents employed in the Atrigel system to dissolve the polymers range from the more hydrophilic solvents such as dimethyl sulfoxide, N-methyl-2-pyrrolidone (NMP), tetraglycol, and glycol furol to the more hydrophobic solvents such as propylene carbonate, triacetin, ethyl acetate, and benzyl benzoate. The most frequently used solvent is NMP because of its solvating ability and its safety/toxicology profile. A Drug Master File on this solvent has been filed with the FDA.[92]
When this formulation is injected into the body the water miscible organic solvent dissipates and water penetrates into the organic phase. This leads to phase separation and precipitation of the polymer forming a depot at the site of injection.


The injectable in-situ gelling system for prolonged release through parentral delivery ensures that a promising system which can control as well as target the region where it is required. This compilation completely discusses the method of manufacture, physical characterization and other issues in detail.

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