INTRODUCTION:

Polymer science has played a important role in both the design of novel drug carriers for treatment of diseases and the enhancement of the efficacy and bioavailability of existing drugs. The major advantage of these polymer-based carriers is the easy modification of their structural and functional features, an advantage that may overcome the limits of natural carriers, like safety and production costs, by providing the appropriate properties for therapeutics to mass producible polymers and their assemblies. For this reason, interest has recently centered on the improved functionalities and the chemical structures of polymer assemblies.^1-2 In this paper we are describing the various aspects of pluronic as its mechanism of thermoreversible, advantage, drawback and applications.

Temperature sensitive formulations:

These formulations are able to swell or de-swell as a result of changing in the temperature of the surrounding fluid. Temperature sensitive formulations are classified into negatively thermo sensitive, positively thermo sensitive and thermally reversible gels.^3,5

(1) Negatively Thermo Sensitive:

Negative temperature sensitive formulations have a lower critical solution temperature (LCST), such formulations contract upon heating above the LCST. Formulations with negative thermosensitive polymer show an on-off drug release⁴ with on at a low temperature and off at high temperature allowing pulsatile drug release. LCST systems are mainly relevant for controlled release of drugs and of proteins in particular⁶. Copolymers of Nisopropyl acrylamide are usually used for negative temperature release.

(2) Positively Thermo Sensitive:

Positive temperature sensitive formulations have an upper critical solution temperature (UCST), such formulations contracts upon cooling below the UCST. Polymer networks of poly (acrylic acid) and polyacrylamide or poly (acrylamide-co-butyl methacrylate) have positive temperature dependence of swelling ⁵.

(3) Thermoreversible:

Thermoreversible is the interesting characteristic in which the formulation are liquid at refrigerated temperatures (4-5°C), but gel upon warming to room temperature. The gelation is again reversible upon cooling. Polymer solution is a free-flowing liquid at normal temperature which make easy administration of formulation into desired body cavity but at body temperature formulation convert into gel which minimize the drainage of formulation. The most commonly used thermoreversible formulations are prepared from poly(ethylene oxide)-b-poly(propylene oxide)-b-poly (ethylene oxide) (Pluronics, Tetronics, Poloxamer) ^5,6. Some natural polymers like xyloglucan may also form thermoreversible gels ⁷. Among the maximum thermoreversible polymers, Pluronics have a great attention of researcher due to it wide acceptability and low toxicity.

Pluronics:

Pluronic was introduced in the 1950. Pluronics are block co-polymers of poly(ethylene oxide) and poly(propylene oxide). The polymers are usually synthesized by anionic polymerization in the form of XYX triblock using a difunctional initiator⁸ pluronics are white, waxy, free-flowing granules that are practically odorless and tasteless⁹. Due to the self assembly of hydrophobic PPO chains, pluronic molecules confirm micelles and gel.

General structure of Pluronics:-

Poly (ethylene oxide) (referred to as PEO) is the simplest hydrophilic polymer and its neighbor in the homologous series poly (propylene oxide) (referred to as PPO) is lipophilic polymer at ambient temperature. It has been established that the PEO block is dominantly hydrophilic within the temperature range from 0 to 100 °C, whereas the water solubility of the PPO block undergoes dramatic decrease as temperature is increased above 15 °C [10]. Many type of pluronic can exist because length of the polymer blocks can be customized with different properties as shown in table-1.

There is a specific meaning of digits in pluronics,

(First two digit * 100) = Approximate molecular weight of polyoxypropylene core and (last digit * 10) = Percentage polyoxyethylene content.

E.g. - Pluronic F127 = Pluronic with a polyoxypropylene molecular mass of 12000 g/mol and a 70% polyoxyethylene content.

Pluronic F127, which contains 70% ethylene oxide and 30% propylene oxide by weight with an average molecular weight of 12,600, is the most commonly used gel- forming polymer matrix to deliver drugs. PF-127 gives colorless and transparent gels. PF-127 is more soluble in cold water than in hot water as a result of increased solvation and hydrogen bonding at lower temperatures. This polymer exhibits a reversible thermal gelation in aqueous solution at a concentration of 20% or more. Thus the polymer solution is a liquid at room temperature (< 25°C), but gels rapidly at body temperature (37°C). Although the polymer is not degraded by the body, the gels dissolve slowly and the polymer is eventually cleared.

Table no. 1: Some Characteristics of different grades of Pluronic Block Copolymers ¹¹

Copolymer	MW	Average number of EO units (x)	Average number of PO units (y)	HLB
L35	1,900	21.59	16.38	19
L43	1,850	12.61	22.33	12
L44	2,200	20.00	22.76	16
L61	2,000	4.55	31.03	3
L62	2,500	11.36	34.48	7
L64	2,900	26.36	30.00	15
F68	8,400	152.73	28.97	29
L81	2,750	6.25	42.67	2
P84	4,200	38.18	43.45	14
P85	4,600	52.27	39.66	16
F87	7,700	122.50	39.83	24
F88	11,400	207.27	39.31	28
L92	3,650	16.59	50.34	6
F98	13,000	236.36	44.83	28
L101	3,800	8.64	58.97	1
P103	4,950	33.75	59.74	9
P104	5,900	53.64	61.03	13
P105	6,500	73.86	56.03	15
F108	14,600	265.45	50.34	27
L121	4,400	10.00	68.28	1
P123	5,750	39.20	69.40	8
F127	12,600	200.45	65.17	22

Gelation mechanism:-

Concern to gelation mechanism of pluronic F127 at low temperatures in aqueous solutions, a hydration layer surrounds the molecules of pluronic F127. However, when the temperature is raised, the hydrophilic chains of the copolymer become desolvated as a result of the breakage of the hydrogen bonds that had been established between the solvent and these chains. This phenomenon favors hydrophobic interactions among the polyoxypropylene domains, and leads to gel formation. Because of the dehydration process, the hydroxyl groups become more accessible.

Some concentrated Pluronic aqueous solutions exhibit two thermoreversible phase transitions. As the temperature increases: the sol-to-gel transition take place at the lower critical gelation temperature (LCGT), and the gel-to-sol transition take place at the upper phase-transition temperature.

The gelation mechanism of the Pluronic aqueous solutions has been intensively investigated. Ultrasonic velocity and DLS measurements on the Pluronic F127 solutions indicated that the gelation was attributed to the thermo-induced changes in micellar properties, i.e., the aggregation number and micellar symmetry ¹².

In contrast to the previous studies that only focused on the changes in the micellar properties, Chu et al. pointed out that there are three temperature regions of the Pluronic aqueous solutions, namely Unimer, Transition and Micelle ¹³. Further studies by light-scattering, small-angle X-ray scattering (SAXS), rheology and dielectric behavior measurement of the Pluronic solutions clearly indicated the

Unimers-to-Micelles transition, and the gelation occurred when the micellar volume fraction increased to a critical value (~0.53) for hard-sphere crystal formation ^{10, 14–19}.

As the temperature further increased, the aggregation conformation of some Pluronic hydrogels changed from the spherical micelles closely-packed in a cubic lattice into the rod-like micelles packed in a hexagonal system, resulting in the decrease of the intermicellar interactions.^10,15,19 The upper phase-transition of gel-to-sol at higher temperature was believed to be due to the reduction of inter-micellar interactions caused by partial dehydration of the PEO blocks.

Properties of Pluronics F127: ²⁰

The Pluronic formulations exhibit following properties.

· Pluronics provide considerable viscosity, partial rigidity in a certain persistence time, due to the ordered micellar packing structure and inter-micellar entanglements. So this is convenient for the incorporation of both hydrophilic and hydrophobic drugs.

· Some concentrated Pluronic aqueous solutions exist as a sol state at room temperature but form a gel at the physiological temperature means exhibit reverse thermal gelation and are being tried as solubilizing, emulsifying, and stabilizing agents. Thus, a depot drug delivery system can be created using Pluronics whereby the product is a viscous injection that gels upon IM injection.

· Pluronics can prevent protein aggregation or adsorption/absorption and can help in the reconstitution of lyophilized products.

· Pluronic F127 gel delivery system increases the contact time of any drug with the absorbing tissue in the body cavity, thereby improving drug bioavailability.

· As compared with solutions, the Pluronic hydrogels can prolong the release period of drugs.

· Pluronics are used in many pharmaceutical formulations because these are Biocompatible and increase solubility of many drugs.

Drawbacks of Pluronics F127: ²¹

However, there are still many drawbacks in the Pluronic formulations as follow.

· Weak mechanical strength is major drawback of pluronic F127.

· Rapid erosion makes immediate dissolution of pluronic F127.

· Pluronic F127 show short residence time as compared to other thermoreversible polymer.

· Pluronic F127 also shows high permeability.

· Limitation of molecular weight.

· Non-biodegradability of PEO-PPO-PEO which prevents the use of high molecular weight polymers that cannot be eliminated by renal excretion.

The above mentioned drawbacks of Pluronics lead to the limitation of their applications in advanced drug-delivery systems. Therefore, to overcome these drawbacks, Pluronics were recently improved. Several oligomers of Pluronic F127 were prepared by coupling the F127 monomers using hexamethylene diisocyanate (HMDI) or phosgene as the coupling reagent²². The oligomers exhibited viscosities at least 15 times higher than F127 at 37 °C.

Applications of Pluronic F-127:

The unique thermoreversible and promising drug release characteristics of Pluronic F127 render it an attractive candidate as a pharmaceutical vehicle for drugs through different routes of administration. This is emphasized as follow, which summarizes the research into Pluronic F127 uses in pharmaceutical formulations.

Research of Pluronic F127 gel in pharmaceutical formulations:

Majithiya et al. developed Thermoreversible-Mucoadhesive gel for nasal delivery of Sumatriptan using thermoreversible polymer pluronic F127 and mucoadhesive polymer Carbopol 934P and found that the polymer combination enhance nasal residence time and permeation and absorption of sumatriptan succinate. ²³ and Shinde et al. formulate insitu mucoadhesive nasal gel of metoclopramide hydrochloride with thermogelling pluronic F127, sodium alginate and PEG and found that the PEG-6000 increased the gelation temperature, while the mucoadhesive polymer decrease the gelation temperature of Pluronic F-127 and increase the mucoadhesive strength with increasing concentration. From the results of formulation study it was concluded that the PEG-6000 increased drug diffusion and permeability while mucoadhesive strength gets decreased. ²⁴

Moghimi, et al. carried out Modulation of lymphatic distribution of subcutaneously injected Pluronic F127 coated nanospheres: the effect of the ethylene oxide chain configuration and found Lymphatic distribution of interstitially injected Pluronic F127 coated nanospheres is controlled by surface configuration of the ethylene oxide (mushroom-like configuration).²⁵ and Barichello, et al. carried out Use of Pluronic F127 gels, poly-lacticcoglycolic acid nano-particles and their combi-nation for parenteral delivery of peptides and proteins having short half-lives using insulin as a model drug and found Pluronic F127 gel formulations containing either drug or drug-nanoparticles could be useful for the preparation of a controlled delivery system for peptides and proteins having short half-lives²⁶ other researches related to this are shown in table-2.

Table no. 2: Research of Pluronic F127 gel in pharmaceutical formulations.

Author	Research	Outcome	References
Nalbadian, et al	Pluronic F127 in third- degree thermal burns	The Accelerated rate of healing.	27
Eurokova, et al.	Pluronic F127 on permeation of weak acids and bases through bilayer lipid membranes	Pluronic F127 facilitates the permeation of large molecules across lipid bilayers	28
Zhang, et al.	Development and evaluation in vitro of sustained release Pluronic F127 gel formulation of Ceftiofur	The overall rate of release of Ceftiofur is controlled by dissolution of the Pluronic F127	29
Miyazaki, et al	Indomethacin, anticancer agents, (adriamycin, 5-flur-ouracil), and Mitomycin C in Pluronic F127	Pluronic F127 is a good vehicle for topical and rectal administration of Indomethacin and excellent for sustained–release of Mitomycin C	30, 31, 32
Lenaerts, et al.	Rheological study of Pluronic F127	Exponential relationship between viscosity and temperature	33
Hokket, et al	Enhanced rate of human gingival fibroblast sprea-ding and attachment	Pluronic F127 is beneficial in early post-surgical wound healing	34
Shin, et al.	Effects of non-ionic surfactants as permeation enhancers on piroxicam from the poloxamer gel through rat skin	Skin pretreated with the Pluronic F127 gels containing various surfactants showed a loosely layered stratum corneum and wide intercellular space	35
Westerink, et al.	Effect of mucosal administration of tetanus toxoid (TT) in the presence of a non-ionic block copolymer, Pluronic F127, with chitosan on the systemic and mucosal immune response	Pluronic F127/chitosan represents a novel mucosal vaccine delivery system that appears to exert an additive or synergistic effect on the immune response	36
Di Biase, et al.	Epidermal growth factor (EGF) in Pluronic F127	Feasible to develop a topical product with EGF	37, 38
Bentley,et al	the Influence of lecithin in rheology and permeation properties	The presence of lecithin in Pluronic F127 gel generates skin retention of lipophilic drugs.	39
Wang, et al.	In vitro and in vivo skin absorption of capsaicin and nonivamide from hydro-gels	Moderate correlation between in vitro skin permeation and in vivo erythema responses of topically applied capsaicin and nonivamide.	40
Shin, et al.	Bioadhesive gels containing triamcinolone acetonide using different enhancers	Permeation of triamcinolone through buccal mucosa was best using deoxycholate as an enhancer.	41
Paavola, et al.	Long acting, single dose gel injection to improve epidural pain treatment The possibility of using liposomal systems to control the release and dural permeation of ibuprofen was investigated in vitro	The liposomal gel controlled ibuprofen release and dural permeation in vitro showed a permeation pattern favorable for maintaining constant drug levels	42
Chi, et al.	Anti-inflammatory and analgesic transdermal gel	Prolonged anti-inflammatory and analgesic activities	43
Paustin, et al	Use of Pluronic F127 intra-venously in rats to heal burnt wounds	Skin appeared markedly less damaged	44
Kattan, et al	Effect of four terpene enhancers on the percutaneous permeation of ketoprofen	The highest increase in the ketoprofen permeation was observed using limonene followed by nerolidol, fenchone, and thymol.	45
Charreaue, et al	Pluronic F127 as a thermogelling and adhesive polymer for rectal administration of short-chain fatty acids	The 18% Pluronic F127 concentration provided a solution that was liquid at room temperature, and gelled at 37 ºC, possessed adhesive properties, and controlled short-chain fatty acid release	46
Veyries, et al.	Control of staphylococcal adhesion to polymethyl methacrylate and enhancement of susceptibility to antibiotics by Pluronic F127	The combination of Pluronic F127 with antibiotics could be a promising approach to the prevention of infection of foreign material	47
Liaw,et al.	Pluronic F127 as a release vehicle for percutaneous administration of fentanyl	Pluronic F127 is useful for percutaneous delivery of fentanyl	48

CONCLUSION:

From the above discussion it is conclude that Pluronic F127 can be considered as a suitable thermoreversible polymer for the delivery of drug into various body cavities. Its micellar properties and gelation behavior provide excellent residence capability which makes it suitable for the development of controlled drug delivery system. Administration of Pluronics formulations in the liquid state provides convenience of application and allows an intimate contact between the formulation and the biological tissue. The formulation with pluronic can be administered into body cavity where the formulation are converted into gel, mechanism reduce the chance of drug removal from the site of application. The thermal gelation behavior of Pluronic is also able to form a depot, increasing the contact time which produces a prolonged pharmacology action. So Pluronic F127 water-based polymeric gels offer several advantages

over traditional oleaginous bases in terms of ease of application, cosmetic acceptability and desirable drug release characteristics in controlled manner.

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