poly(ethylene oxide)-poly(propylene oxide)

In: Handbook of Hydrogels: Properties, Preparation… ISBN: 978-1-60741-702-6 Editor: David B. Stein © 2009 Nova Science Publishers, Inc. Inserted , between references on page 10 Corrupt equation on page 6

Chapter 14

POLY(ETHYLENE OXIDE)-POLY(PROPYLENE OXIDE) BLOCK COPOLYMER MICELLES AND GELS IN DRUG DELIVERY: STATE-OF-THE-ART AND FUTURE PERSPECTIVES Carmen Alvarez-Lorenzo1, Angel Concheiro1 and Alejandro Sosnik2,3* 1

Departmento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782-Santiago de Compostela, Spain. 2 Department of Pharmaceutical Technology, Faculty of Pharmacy and Biochemistry, University of Buenos Aires and 3National Science Research Council (CONICET), 11113-Buenos Aires, Argentina

ABSTRACT Amphiphilic poly(ethylene oxide)-poly(propylene oxide) block copolymers (PEO– PPO) are thermo-sensitive biomaterials that display a unique concentration-depending behaviour in aqueous medium. They are commercially available in a broad variety of compositions and molecular weights. At relatively low concentrations, above the critical micellar concentration (CMC), they form stable aggregates known as polymeric micelles. Due to the presence of a hydrophobic core, these micelles are useful in the solubilization and stabilization of poorly water-soluble drugs. When higher concentrations are attained some of the PEO-PPO materials show a transition from a liquid solution to a viscoelastic gel upon heating. This temperature-governed gelation motivated the interest in these copolymers for the development of injectable drug delivery implants. The present chapter presents a thorough overview of the most important developments comprising the application of PEO-PPO block copolymers in the solubilization, stabilization and sustained delivery of both hydrophobic and hydrophilic drugs. In addition to pristine copolymers, the advances on structural modification through chain extension using *

Corresponding author: Dr. Alejandro Sosnik, Department of Pharmaceutical Technology, Faculty of Pharmacy and Biochemistry, University of Buenos Aires, 956 Junín St, 6th Floor, Buenos Aires CP1113, Argentina, Phone/Fax: +54-11-4964-8273. E-mail: [email protected]

2

Carmen Alvarez-Lorenzo, Angel Concheiro and Alejandro Sosnik blocks of the same or different nature and on cross-linking approaches are described. Hybrid formulations in which the PEO-PPO copolymers are combined with other functional polymers are also presented. Specific examples of the application of each type of PEO-PPO-based system are shown and their potential for administering drugs through different routes and improving drug bioavailability and therapeutic effect is discussed.

1. INTRODUCTION Advances in medicine and related sciences along the 20th century led to an important extension in lifespan. One of the pillars has been the access to novel therapeutic agents. The ability to massively produce pharmaceuticals together with constant and pronounced advances in Pharmaceutical Technology (PT) made medicines available for broad portions of the population. The goal of PT is to transform active pharmaceutical ingredients (API) into therapeutically efficient, safe and stable medicines. Drug dosage forms facilitate the administration of active compounds and the design of novel drug delivery systems (DDS) enable to control the site and rate of the drug release. Altogether the progresses in the different avenues led to the simplification of treatment schedules and made it possible to face up therapeutic aims unthinkable a few years ago. Nevertheless, there are still challenging issues that make drug formulation difficult and that can even prevent a promising drug candidate to become a medicine. Among such issues, drug solubility is the most remarkable one. In fact, more than 50% of the FDA-approved compounds and nearly the 90% of the new drug candidates are poorly water soluble [1]. The relevance of the solubility problem is taken into account in the Biopharmaceutic Classification System (BCS) for drugs that are intended to be orally administered, which has been adopted by FDA and EMEA [2,3]. BCS makes a global analysis of the solubility and permeability through biological membranes to classify drugs into four groups: Class I (high solubility and permeability), Class II (low solubility and high permeability), Class III (high solubility and low permeability) and Class IV (low solubility and permeability) [4]. In the case of Class II and Class IV drugs, oral absorption is poor because an insufficient solubility of the administered dose and the dissolution rate becomes the limiting step in the absorption process. A higher bioavailability of Class II drugs can be attained improving their solubility [5]. In contrast, Class IV drugs display low permeability and further modifications are demanded in order to attain appropriate absorption through body membranes (e.g., preparation of prodrugs). Nevertheless, an increase in the apparent solubility of Class IV drugs can increase the number of molecules available for permeating the membrane, also improving the bioavailability to some extent [6]. Furthermore, when the low bioavailability is the result of efflux pumps activity, co-administration of inhibitors of these transporters may notably enhance the absorption rate [7]. Since only the solubilized drug molecules can permeate the biological membranes, limited solubility is a problem common to all administration routes. Inclusion of hydrophobic molecules within micellar systems is among the most broadly investigated approaches in order to water-solubilize and stabilize poorly water-soluble drugs. Similarly to low molecular weight surfactant micelles, polymeric micelles are nanoscopic aggregates (usually with size > 100 nm) generated by the self-assembly of amphiphiles above a minimal concentration known as the critical micellar concentration (CMC) [8]. Polymeric

Poly(Ethylene Oxide)-Poly(Propylene Oxide) Block Copolymer Micelles …

3

micelles display an inner and outer zone called, respectively, core (constituted by the hydrophobic blocks of the amphiphilic copolymers) and corona (a region in which the hydrophilic blocks become the interface between the core and the surrounding aqueous medium). Due to its hydrophobic nature, the core enables the incorporation and solubilization of hydrophobic drug molecules [9]. Polymeric micelles are more kinetically stable than regular micelles. Hence, upon dilution, micelles made of amphiphilic copolymers disassemble very slowly even when the final concentration is below the CMC, enabling longer residence times in the biological environment. In addition, micelles where the hydrophilic blocks are composed of poly(ethylene oxide) are sterically stabilized in the aqueous medium and opsonization and further uptake by macrophages is less feasible [10,11]. Amphiphilic poly(ethylene oxide)-poly(propylene oxide) (PEO-PPO) block copolymers are particularly appealing excipients for drug delivery and comprehensive reviews can be found elsewhere [12,13]. The capability of PEO-PPO block copolymers to self-assemble and form polymeric micelles and also to undergo sol-gel transitions upon heating confer them the quality of “smart” or “intelligent” materials [14]. According to the structure of the main chain, PEO-PPO block copolymers can be classified into two main families: i) linear and bifunctional PEO-PPO-PEO triblocks or poloxamers (Pluronic®, Scheme A) and ii) X-shaped derivatives known as poloxamines (Tetronic®, Scheme 1B). A HOCH2-CH2-(CH2-CH2-O)a-1-(CH2-CH-O)b-(CH2-CH2-O)a-1-CH2CH2OH CH3 B CH2OH

CH2OH

Scheme 1. Molecular structure of A) poloxamers and B) poloxamines.

They are commercially available in a broad spectrum of molecular weights and EO/PO ratios (Table 1). They show good cell compatibility [15,16] and do not cause significant irritation following topical or parenteral administration (e.g., intraperitoneal) [17]. Although PEO-PPO materials do not degrade under physiological conditions, copolymers with molecular weights between 10 and 15 kDa are cleared by renal filtration [18,19]. These advantageous features have paved the track to obtain FDA and EMEA approval for some of the linear PEO-PPOPEO triblocks in food, pharmaceutical and agricultural industries [20,21,22]. Additionally, Tetronic® 1304 and 1107 meet the requirements of FDA for being used as moisturizers and protein build-up prevention agents in wetting solutions of hydrogel and silicone contact lenses [23,24].

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Carmen Alvarez-Lorenzo, Angel Concheiro and Alejandro Sosnik Table 1. Commercially available PEO-PPO block copolymers. Copolymer Pluronic® L10 L35 F38 L42 L43 L44* L61 L62 L64 L65 F68* F77 L81 P84 P85 F87* F88 L92 F98 L101 P103 P104 P105 F108* L121 L122 P123 F127* Tetronic® 304 701 704** 803** 901 904 908 1107*** 1301 1304*** 1307

MW (Da) 3200 1900 4600 1630 1850 2200 2000 2500 2900 3400 8400 6600 2750 4200 4600 7700 11,400 3650 13,000 3800 4950 5900 6500 14,600 4400 5000 5750 12,600

Total Average PEO units 7.3 21.6 83.6 7.4 12.6 20.0 4.55 11.4 26.4 38.6 152.7 105.0 6.3 38.2 52.3 122.5 207.3 16.6 236.4 8.6 33.8 53.6 73.9 265.5 10.0 22.2 39.2 200.5

Total Average PPO units 49.7 16.4 15.9 22.5 22.4 22.8 31.0 34.5 30.0 29.3 29.0 34.1 42.7 43.5 39.7 39.8 39.3 50.3 44.8 59.0 59.7 61.0 56.0 50.3 68.3 69.0 69.4 65.2

Total Weight PEO units (Da) 320 950 3680 325 555 880 200 500 1160 1700 6720 4620 275 1680 2300 5390 9120 730 10,400 380 1485 2360 3250 11,680 440 1000 1725 8820

Total Weight PPO units (Da) 2880 950 920 1305 1295 1320 1800 2000 1740 1700 1680 1980 2475 2520 2300 2310 2280 2920 2600 3420 3465 3540 3250 2920 3960 4000 4025 3780

1650 3600 5500 5500 4700 6700 25,000 15,000 6800 10,500 18,000

15.0 8.2 50.0 37.5 10.7 60.9 454.5 238.6 15.5 85.5 286.4

17.1 55.9 56.9 66.4 72.9 69.3 86.2 77.6 105.5 108.6 93.1

660 360 2200 1650 470 2680 20,000 10,500 680 4200 12,600

990 3240 3300 3850 4230 4020 5000 4500 6120 6300 5400

*FDA-approved. Available in National Formulary quality, **Discontinued by BASF,***Used as preservative in contact lense solutions and approved as Class II device by FDA.

PEO-PPO amphiphiles show a unique concentration-dependent aggregation behavior in water and two critical concentrations can be described for them. The first governs the transition from unimolecular (unimer) to multimolecular (micelle) aggregates and determines the CMC. Regardless the lipophilic/hydrophilic balance (HLB) and the molecular weight, all the derivatives display micellization in aqueous medium. The thermo-responsiveness of the amphiphiles makes the CMC values to decrease as temperature increases. Structural properties influence the aggregation profile; the higher molecular weight and the smaller


5

EO/PO ratio, the lower CMC values are [25,26,27]. The second critical concentration, Ci, is the minimal concentration required for gel formation upon heating, under any temperature condition. In general, micellization is observed at much lower concentrations (15 wt%) [28]. Several mechanisms have been ascribed to explain the gelation [29,30]. All of them comprise the formation of a 3D packed micellebased physical network. Their ability to form gels is intimately associated with the structural properties of the molecule (EO/PO ratio and molecular weight). For a given concentration, the temperature at which the sol-gel transition takes places is called Ti. Thus, gel formation can be fine-tuned by changing the concentration or the temperature of the solution. Materials showing Ti around 37oC are especially attractive, not only as solubilizers of hydrophobic drugs, but also as components of in situ gelling systems for the sustained release of drugs. Injectable parenteral depots and implants for drug delivery in diverse tissues constitute a remarkable growing area that has attracted much attention during the last fifteen years. PEOPPO copolymers that display a sol-gel transition around 37oC can be injected into the body as liquid solutions at room temperature and, once at the physiological temperature, they become semi-solid to solid gels [31,32]. A proof of the interest in injectable implants is the steady increase in the number of scientific publications devoted to the design of suitable materials for developing systems implantable by minimally invasive procedures (Figure 1). Easy and fast application, minor discomfort, use of local anesthesia and lower costs, represent some of the advantages of this approach [33]. Higher conformability and accessibility to tissues and body sites otherwise unreachable are additional features.

Citations in Scopus "Injectable implants"

400

300

200

100

0 1975-1979 1980-1984 1985-1989 1990-1994 1995-1999 2000-2004 2005-2008

Years

Figure 1. umber of scientific articles in Scopus reporting on the development of “injectable implants”.

The most comprehensive research work was conducted on the poloxamers. For polymers displaying similar molecular weight and EO/PO ratio, the linear copolymers are longer and the sol-gel transition is attained at lower concentration compared to poloxamines. For example, whereas Pluronic® F127 (70 wt% PEO, MW 12.6 kDa) shows a Ci around 14.8%, Tetronic® 1107 (70 wt% PEO, MW 15 kDa) needs a minimal concentration around 30% to undergo sol-to-gel transition. Although such a high concentration may be a drawback for some purposes, poloxamines present two molecular features that worth mention:

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Carmen Alvarez-Lorenzo, Angel Concheiro and Alejandro Sosnik

i). The presence of a central ethylenediamine moiety confers the molecules pHresponsiveness and makes the copolymers dually stimuli-sensitive [34]. These functional groups also increase the thermal stability of the micelles. Moreover, they make further chemical modification of the molecule (e.g., methylation) possible [35]. ii). The X-shaped structure and the higher functionality provide a more versatile platform for the generation of highly chemically cross-linked networks [36]. Thus, in the case of poloxamines, parameters ruling the degree of protonation of the tertiary amine moieties such as pH and ionic strength strongly determine the self-assembly and the gelation phenomena. These remarkable and unique differences, compared to the linear poloxamers, have motivated an increasing interest for the study of the branched derivatives. Overall, PEO-PPO-made biomaterials appear as very versatile means for drug administration and delivery. In this context, the present chapter introduces a concise and comprehensive state-of-the-art of the application of PEO-PPO block copolymers as a technological platform for drug vehiculization and delivery.

2. PRISTINE PEO-PPO BLOCK COPOLYMERS The first feature capitalized in PEO-PPO polymers was the incorporation of highly hydrophobic drugs into the core of polymeric micelles. A limited solubility improvement can be achieved by the interaction between the drug and the hydrophobic segments of unimers [37]. Once the CMC is attained, a sharp increase in the apparent solubility of the solute is usually found [38].The solubilization process at concentrations below and above the CMC can be described using the following model [37]. Case 1: Cs < CMC

S apparent S

= 1 + K unimer ·Cs

Case 2: Cs > CMC

Sapparent S

1 K unimer·CMC

K micelle ·( Cs CMC )

where Sapparent represents the apparent aqueous solubility in the polymer solution, S the intrinsic solubility in polymer-free water, CS the concentration of surfactant in the aqueous phase, and Kunimer and Kmicelle are equilibrium constants describing the solute-unimers (CMC) interactions, respectively. In general, incorporation of drug molecules into the micellar core results in its enlargement, which is shown as an increase of the hydrodynamic radius. Another phenomenon that could take place is a secondary aggregation or micellar fusion, originated in strong interactions between densely packed aggregates. The solubilization capacity depends on the molecular weight and the EO/PO ratio. In general, the more hydrophobic the molecule is, the higher the solubilization extent found [39]. In addition, for similar lipophilic/hydrophilic balances, higher molecular weights render


7

Griseofulvin solubility (mg/100ml)

better solubilization. Finally, since PEO-PPO materials are reverse thermo-responsive, the apparent aqueous solubility of a solute raises substantially with temperature due to the formation of more micelles [40]. Combining poloxamers of different molecular weight and EO/PO ratio provides mixed micelles that demonstrated more efficient solubilization of certain drugs and higher stability upon dilution [41]. Furthermore, drug bioavailability can be also notably improved using poloxamers as carries owing to the capability of the unimers to inhibit the activity of an efflux pump, the P-glycoprotein [42]. For example, an enhancement of the analgesic effect of an opioid peptide and morphine using Pluronic P85 below and above the CMC was observed [43]. Due to the inhibition of the cellular efflux machinery a clear increase in the peak effect and a longer analgesia were apparent. In recent years, the dual responsiveness of poloxamine and the possibility of adjusting the aggregation by means of the pH of the medium have motivated an extensive investigative work. In general, the higher the pH is, the stronger the micellization tendency and the higher the solubilization ability of poloxamines [39]. This has been proved for drugs with pHindependent solubility, such as griseofulvin in Tetronic T904 (Figure 2, [44]) and the antiretroviral drug efavirenz in different linear and branched derivatives [45]. Chiappetta et al. reported for the first time the vehiculization of a pH-dependent drug, the topical antibacterial agent triclosan, in T1107 [46]. In this case, an increase of the pH led to the ionization of the aromatic –OH group of the triclosan, curtailing the formation of hydrogen bonds with the polyether chain. Hence, a decrease in the solubility was apparent at higher pH-values. Gonzalez-Lopez et al. lately published a thorough and comprehensive investigation of the aggregation properties of a broad spectrum of regular and reverse sequential poloxamines (Table 2, [47]). 32 28 24 20 16 12 8 4 0 0

1

2

3

4

5

6

7

8

9

pH

Figure 2. Griseofulvin solubility in media of different pH and ionic strength without (open symbols) or with (full symbols) 10% T904. Legend: HCl 0.1M (squares), pH 5.8 phosphate buffer (up triangles), pH 7.4 phosphate buffer (down triangles), water (circles) and 0.9% NaCl solution (diamond). Reproduced from (44) with permission from Elsevier.

Poloxamines with lower EO/PO ratio and large molecular weight generated larger and more hydrophobic cores. Hosting of labile drugs (e.g., the lactone form of simvastatin) within the core effectively increases the apparent solubility and protects the drug from chemical degradation (Table 3).

8


Table 2. Micellar parameters of poloxamines in 10 mM HCl medium at 37ºC. N: aggregation number; rh: hydrodynamic radius; δt: expansion factor; rt: thermodynamic radius; A2: virial coefficient; rc: radius of micellar core; ve: volume of the hydrated EO unit; nw: water molecules associated to each EO unit. Reproduced from (47) with permission from the American Chemical Society. Poloxamine

T901 T904 T908 T1107 T1107-met T1301 T1307 T150R1

Micellar molecular weight 92,000 167,000 63,000 47,000 346,000 88,000 -

N

rh (nm)

δt

rt (nm)

A2·104 (cm3·mol2·g-2)

rc (nm)

ve (nm3)

nw

14 7 4 3 51 5 -

40 5.9 5.6 7.6 4.9 12.1 8.3 50

1 2.2 1.1 3.2 2.2 1.9 3.6 1

4.1 4 4.1 3.7 6.3 4.9 -

0.9 0.3 2.1 1.4 0.2 2 -

3.5 3 2.4 2.2 5.7 2.7 -

0.52

15 5 33 27 35 34 -

0.98 0.75 0.83 -

Aiming to target the drug release to specific tissues, a unique strategy combining micellar inclusion with locally applied ultrasound was explored by Rapoport and colleagues, who designed doxorubicin-loaded nanocarriers for delivery to tumors [48-,49,50,51,52,53,54]. A notable reduction of adverse effects on healthy tissues was found. Table 3. Simvastatin solubilization parameters in 4% poloxamine solutions in HCl 10 mM, and ratio of lactone to hydroxy acid forms of simvastatin in drug-saturated 10% poloxamine solutions in HCl 10 mM. Reproduced from (47) with permission from the American Chemical Society. Poloxamine (4%)

304 901 904 908 1107 Met-1107 1301 1307 150R1

Lactone/hydroxy acid ratio**

Solubilization parameter χ

P

12.8·10-3 4.01·10-3 2.13·10-3 7.81·10-3 12.6·10-3 20.9·10-3 379·10-3 22.0·10-3 171·10-3

9.32 1.69 0.69 0.38 1.51 3.49 100.4 2.20 47.5

Gs0 (cal/mol)

-3927.5 -3245.7 -2871.5 -3641.5 -3923.3 -4418.1 -5940.0 -4255.1 -5469.8

fmicelle*

simvastatin/ PO (mg/g)

molecules per micelle

0.90 0.63 0.41 0.28 0.60 0.77 0.99 0.69 0.98

2.73 0.33 0.21 0.34 0.87 1.99 20.1 1.32 9.90

0.032 0.054 0.050 0.116 19.3 0.110 -

0:1 0.2:1 0:1 0.2:1 0:1 1.5:1 20:1 8:1 7.5:1

*Fraction of drug solubilized by incorporation to the micelle; **A solution of simvastatin in the mobile phase resulted in a lactone/hydroxyl acid ratio of 1:0.

Despite all PEO-PPO derivatives aggregate under appropriate conditions, the number of materials able to undergo the thermal sol-gel transition when a further increase in the concentration of the polymer takes place is limited. It is important to mention that also hydrophilic drugs have been vehiculized in these gel-forming materials. Water-soluble species accommodate within the micellar corona or even in the interstitial aqueous medium [55]. This approach was early evaluated by Dumortier et al for the treatment of pain using morphine acetate [56]. The delivery of insulin from Pluronic F127 gels by rectal, subcutaneous and buccal administration has been also evaluated and in all cases a relatively


9

prolonged hypoglycemic effect was apparent [57,58,59]. Other works capitalized on the properties of the gels to incorporate drug-loaded micro and nanoparticles. The matrix retained the particles at the implantation site and prevented migration. Moreover, it performed as a drug delivery controlling phase and minimized the burst effect observed when the same particles were suspended in water [60]. For example, plasmid DNA-containing poly(lactic-coglycolic acid) nanoparticles suspended in F127 for nasal administration provided sustained release with minimal burst effect [61,62,63]. Poloxamer gels loaded with other nanocarriers such as liposomes and ethanol-made vesicles (ethosomes) have been also evaluated [64]. As occurred with the polymeric micelles, the potential of poloxamines has not been fully explored in the framework of the gels for drug delivery [27,65]. Figure 3 shows the evolution of the loss and the storage moduli of 30% T904 systems as the temperature raises. Except for those prepared in HCl 0.1 M, systems displaying higher pH-values exhibited a sol-gel transition around 30 ºC. Also here, as the temperature rises, the PPO and PEO blocks become less soluble in water and hence, more hydrophobic. Consequently, more micelles are formed at a given concentration as the temperature increases, resulting in the gelation due to the close packing of the micelles into body centered cubic phase gels [65]. The increase of the micellar volume fraction is shown as a maximum in the values of both moduli at a certain temperature. At even greater temperatures, the dehydration of PPO chains (and also of PEO blocks), causes the polymer to phase separate, and G’ and G’’ values to decrease. The absence of storage modulus for T904 solutions prepared in HCl 0.1 M clearly indicates that the self-assembly is hindered when the polymer chains are protonated. Therefore, in a highly acidic physiological environment T904 systems are not expected to gel.

Storage and loss moduli (Pa)

104 103 102 101 100 10-1 10-2 10-3 10-4 20

30 40 50 Temperature (ºC)

60

Figure 3. Evolution of the loss (open symbols) and the storage (full symbols) moduli of 30% T904 systems as the temperature increases. The solutions were prepared in water (circles), HCl 0.1M (squares), pH 7.4 phosphate buffer (up triangles), and NaOH 0.02M (down triangles). Reproduced from (44) with permission from Elsevier.

Griseofulvin diffusion from the 30% T904 solutions was evaluated using Franz-Chien diffusion cells. The release profiles fitted quite well to the square-root kinetics. The values of the diffusion coefficients obtained for 30% T904 systems prepared in HCl 0.1 M (1.46·10-4; s.d. 8.5·10-6 cm2/min) were almost twice those recorded for the same systems prepared in pH 7.4 phosphate buffer (0.89·10-4; s.d. 8.7·10-6 cm2/min). The higher affinity of the drug for the

10


micelles and the greater viscosity of the systems prepared at pH 7.4 explain the pHdependence of the process. Table 4 collects the most important investigations employing unmodified PEO-PPO based systems. [66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89, 90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113, 114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134, 135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155, 156,157,158,159] Table 4. Scientific studies on solubilization, stabilization and drug delivery of drugs from unmodified PEO-PPO block copolymer based systems. Polymer family Pluronic®

Drug

Copolymer

Aims and observations

Ref.

Sulprostone

F127

66

Lidocaine hydrochloride and base Tropicamide

F127

Local application as a method for preoperative cervical priming. Diffusion in the water channels between the polymer segments was apparent.

L-64, P65, F68, P75, F77, P84, P85, F87, F88, F127 P85

Testosterone ProstaglandinE2 Haloperidol Morphine

Estriol

F68 F68 P85 P85 F127 L64 L64

Nifedipine Dichloroplatin um (II) complexes Angiotensin II

F127 F68

Cyclosporin Heparin

F68 F127

Nitrofurazone

F68

Epirubicin

L61, P85, F108

Naproxen

F127

Doxorubicin (DOX)

P105

F127

P105

Solubility increased linearly with surfactants concentration. Higher solubility for higher EO content. Solubility increased 1.9 times, faster peak and longer activity. Release followed Higuchi diffusion model. Swelling controlled release model. 5-fold increase in solubility. Increased analgesia due to both an increase in peak effect and prolongation of effects. Water-soluble drug. Prolonged delivery. Solubility increased with Pluronic concentration and temperature. Higher solubility with higher polymer and salt concentration. Improved solubility. Stable colloidal suspension. Effective against hormone sensitive MXT-M-3.2 breast cancer. Topical application inhibits neointimal proliferation after vascular injury. Thermal analysis of solubilization process. Good penetration through excised human skin. Drug-loaded gel reduces proliferation of Staphylococcus aureus in wounds better than silver sulfadiazine. Lifespan of animals and inhibition of tumour growth considerably increased with drug/copolymer compositions. Increased solubility. Longer half-life after i.v. injection. Local ultrasonic irradiation of the tumor increased drug accumulation in the tumor cells. Substantial decrease of the tumor growth rates. Lower in vitro proliferation of rat prostate carcinoma cells (MatLu) with micellar system.

67

68

69 70 70 71 43 56 72 73 74 75

76 77 78 79

80

81,8 2 4854

83

Poly(Ethylene Oxide)-Poly(Propylene Oxide) Block Copolymer Micelles … P85

Pilocarpine

F127 F127

Clonazepam Propranolol Propranolol.H Cl

F68 F127 F68, F127

Insulin

F127

F127

F127

Vancomycin

F127 F127

Diclofenac

F127

F127 F127 Ketoprofen

F127 F127

Piroxicam

F68, F127

Indomethacin

F68, F127

Lidocaine/ Prilocaine

F68, F127

Triamcinolone

F127

Digoxin

P85

Griseofulvin

Synperonic P941

Deslorelin and GnRH

F127

Biphalin

P85

A formulation containing Pluronic P85 and doxorubicin prevents the development of multidrug resistance in human breast carcinoma cell line, MCF7. Enhanced activity after ophthalmic administration. Polymer combined with additives displayed higher solubilization capability. 3.5-fold solubility increase. Improved release profile. Water soluble drug located outside micelles. Improved bioavailability when combined with mucoadhesives. Formulations containing unsaturated fatty acids. Rectal insulin absorption enhanced. Marked hypoglycemic effect. Slower and more prolonged hypoglycemic effect was attained at higher polymer concentrations. Formulations containing unsaturated fatty acids. Buccal insulin absorption enhanced. Marked hypoglycemic effect. Controlled release and good preservation of the drug. Drug delivered to infected inner ear and effective inhibition of profileration of methicillin-resistant Staphylococcus aureus. High permeation ratio and steady-state flux were observed with low Pluronic F-127 concentrations in transdermal delivery. Solubility study on diethylamine derivative and sodium salt. Effect of salts on the solubility and absorption of sodium diclofenac. Enhancers increase drug permeation through the skin. Ibuprofen and ketoprofen bioavailabilities were higher when released from xyloglucan gels compared to Pluronic F127 gels in percutaneous administration. Occlusive dressing techniques enhanced the bioavailability of ibuprofen released from Pluronic gels. Better percutaneous absorption from Pluronic gels. Increased solubility and chemical stability. Prolonged in vitro drug diffusion and high physiological tolerance on rabbit eyes. Eutectic mixture. Amount of the active ingredients in the micelle phase depends on the pH: greater at higher pH (non-ionic drug). Enhanced permeation through the buccal mucose. Delivery of digoxin to the brain through the inhibition of the P-glycoprotein-mediated efflux mechanism. Lower solubilization ability than copolymers with poly(oxybutylene) or poly(oxyphenylethylene) hydrophobic blocks. Broader and lower peak of luteinizing hormone (LH) and delayed activity with the gel. Study to improve BBB transfer. Higher peak effect and longer activity.

11 84

85 86,8 7 88 89 90

57

58

59

91 92

93

94 95 96 97

98 99

100

101 102

103

104

43

12

Carmen Alvarez-Lorenzo, Angel Concheiro and Alejandro Sosnik Timolol maleate Timolol

F127 F127

Benzoporphyri n

P123, L122

Estradiol

F127

Propofol

F68, F127 F68, F127 and mixed micelles P105

Fluorescent molecule model Camptothecin (CPT)

F127, L92 versus materials modified with poly(acrylic acid) blocks

Nystatin

F127, F68, P85 F127/ L61 mixed micelles versus materials modified with poly(acrylic acid) blocks F68, F98, P105, F127

Ibuprofen

F68

Paclitaxel (PTX)

P123

Octaethylporph ine Mesotetraphenyl porphine Rofecoxib Glibenclamide Interleukin-2

F127

c-myc Antisense oligonucleotide s Epidermal growth factor Cefazolin Tyrphostin 47

F127

Megestrol

c-myb Antisense oligonucleotide s Granulocyte colony

Soluble drug. About 2.4-fold improved ocular bioavailability Transdermal delivery controlled by stratum corneum at low polymer concentrations and by the gel at high concentrations The longer the hydrophobic block, the better the stabilization of tetrapyrrolic drugs in monomeric form in aqueous suspensions. Increased solubility above CMC. Modulation of drug release from carbopol gels. Enhanced solubility. Enhanced solubility in mixed systems Local ultrasonic irradiation of the tumor increased drug accumulation in cancerous ovarian tissue. 3- to 4-fold higher solubility. Amount of CPT solubilized per PPO greater in the PluronicPAA than parent, suggesting solubilization by the hydrophobic cores and hydrophilic shells. Enhanced stability. Improved oral absorption estimated in vitro. Bioadhesive tablets for grastrointestinal retention and enhanced bioavailability

Solubility increased from 20 to > 350 M. The higher the polarity of the copolymer the lower the solubility. Ibuprofen in eutectic mixture with menthol.

105 106

107, 108 109 110 111 112

113

114 115

116

117 118

F127, F68, P85

Enhanced solubility, prolonged blood circulation and modified the ability of the drug to biodistribution. t1/2 was 2.3-fold higher. Increased accumulation of PTX in ovary, uterus, lung and kidney, but decreased accumulation in liver and brain. Improved oral absorption estimated in vitro.

F127

Improved oral absorption estimated in vitro.

119

F68, F127 F127

Enhanced solubility. Efficient nasal absorption and hypoglycemic activity comparable to oral administration. Higher effectiveness of rIL-2/F127 in vivo than free IL-2. Potential application in vasculoproliferative disease.

120 121

F127

Gel evaluated as a potential topical vehicle.

124

F127 F127

Stability studies 11% delivered over 21 days. Sustained local delivery does not result in a reduction of neointimal proliferation in the rat carotid injury model. Local administration in aorta inhibited neointimal hyperplasia.

125 126

F127

F127

Prolonged action and greater bioavailability of the injected G-CSF.

119

122 123

127

128

Poly(Ethylene Oxide)-Poly(Propylene Oxide) Block Copolymer Micelles … stimulating factor 5Aminolevulini c acid Nitric oxide

13

F127

Topical system in esophagus for photodynamic therapy.

129

F127

NO donor S-nitroso-N-acetylpenicillamine loaded gel. NO donors S-nitrosoglutathione and Snitroso-N-acetylcysteine loaded in the gel. Topical application of a NO donor (Snitrosoglutathione) improves cutaneous wound repair in rats. Nasal gels to improve absorption and patient compliance. Topical administration of cilostazol may suppress neointimal hyperplasia by inhibiting cell proliferation. Poor delivery performance in topical buccal application. IgG antibody responses were significantly enhanced by F127.

130

Perivascular release of neomycin inhibits neointimal hyperplasia. Enhanced vector transduction to the conducting airways (e.g., cystic fibrosis). Continuous and controlled release of the plasmid with minimal burst effect. Effective in nasal delivery. Treatment of experimental vein grafts is associated with increased apoptosis in the vascular wall and reduction of neointimal hyperplasia. Delivery of viral vectors to CNS and release localized in areas of brain or spinal cord injury. Evaluation of angioplasty-induced hyperplasia by injection in carotid artery.

137

F127 F127

Vitamin B12

F127

Cilostazol

F127

Piroxicam

F127

Tetanus and diphtheria toxoids, anthrax recombinant protective antigen Neomycin

F127

Genes

F127

Plasmid DNA

Poly(lactic-co-glycolic acid) nanoparticles in F127

Rapamycin

F127

Lentiviral vector

F127

Virus expressing dominantnegative p67phox (Adp67dn), Antisense oligodeoxynucl eotides Sertaconazole

F127

F127

F127

F127 and hydroxypropylbeta-cyclodextrin

Insulin

F127

Methotrexate

F127

Recombinant hirudin

F127

Salbutamol

Ethosomes and liposomes embedded in F127 gel

Rapid penetration throughout the spinal cord and significant knockdown of target protein connexin 43. 100-fold increase in solubility and temperature-dependent drug diffusion coefficients to control the release for 1 week at 37 °C. Gel sustains insulin release from microparticles through a subcutaneous injection Potential direct administration into solid tumors In vitro and in vivo studies suggested usefulness for subcutaneous delivery of peptides and proteins with short half-lives to increase bioavailability Ethosomal systems more efficient for transdermal delivery.

131 132

133 134

135 136

138 61,6 2,63 139, 140

141

142

143

144

145

146 147

148

14

Carmen Alvarez-Lorenzo, Angel Concheiro and Alejandro Sosnik Dexamethason e Spantide II, a neurokinin-1 receptor fms-like tyrosine kinase-3 ligand

F127

Gel provided sustained release for 24 h.

149

F127

Effective delivery in epidermis and dermis for the treatment of allergic contact dermatitis.

150

F127

Single injection of mixture stimulated more rapid hematopoietic progenitor cell mobilization to the spleen and peripheral blood than the daily injection of Flt3L in saline solution. Delivery for immunotherapy in pancreas adenocarcinome. Enhanced the survival of tumor-bearing mice. Release controlled by the erosion of the gel matrix. Zero-order kinetics. Gel prevents burst effect in intrathecal infusion.

151

F127

F127/F68 mixtures Baclofen

Tolfenamic acid Honokiol

Tetronic®

Efavirenz Aspirin Indomethacin Plasmid DNA

1

Drug-loaded poly(lactideco-glycolide) microparticles suspended in F127 gel F127 Poly( -caprolactone)poly(ethylene glycol)poly( -caprolactone) (PCEC) nanoparticles dispersed in F127 F127, F108, F68 T1508* T908 Poly(lactic-co-glycolic acid) nanoparticles in

Griseofulvin

T904

Simvastatin

Triclosan

T304, 901, 904, 908, 1107, 1301, 1307, T150R1 and methylated-T1107 T1107

Efavirenz

T1107, T1307

Enhanced solubility and sustained release. Sustained release for more than 1 week in vitro. Potential for the local delivery of hydrophobic drugs.

Up to 5300-fold solubility increase. Despite viscosity increase, aspirin hydrolysis was not reduced. Rectal formulations. Sustained release with minimal burst effect.

pH-sensitive copolymer aggregation and drug solubilization and release. More hydrophobic T1301 and T150R1 were more effective in solubilizing and protecting the lactone form of the drug from hydrolysis 15,000-fold solubility increase. Improved activity against S epidermidis biofilm. Up to 5300-fold solubility increase.

152

153 154

155, 156 157

45 158 159 61,6 2,63 65 47

46 45

Synperonic® is another PEO-PPO-PEO triblock trademark (ICI C&P). Synperonic P94 (PEO21-PPO47PEO21) has a molecular weight of 4600 and 60 wt% PEO. *Also know as T908.

Among the gel-forming materials, the highly hydrophilic FDA-approved Pluronic F127 and F68 have emerged as the most popular poloxamers. Low molecular weight and hydrophobic counterparts are mainly exploited for solubilization. Regardless the viscosity increase after heating, the relatively weak mechanical properties and most critically, the high permeability to water in the biological environment have hampered the clinical application of the gels [160,161,162,163]. Accordingly, aiming to enhance the performance of these materials, a number of modifications were pursued.

3. STRUCTURAL MODIFICATION OF PEO-PPO BLOCK COPOLYMERS The present section describes various approaches investigated in order to extend the clinical applicability of the PEO-PPO block copolymer gels.


15

3.1. Chemical Modification of PEO-PPO Block Copolymers One strategy to modify the performance of the systems in vivo is the grafting of chemically different polymeric segments in the edges of PEO-PPO-PEO triblocks. Bromberg and coworkers synthesized and profusely characterized poloxamers with terminal poly(acrylic acid) (PAA) blocks [164,165,166]. The materials became dually temperature- and pHresponsive and were assayed as drug carriers [167] and pharmaceutical excipients in solid dosage forms for sustained delivery [168,169]. For example, inclusion of camptothecin, in its lactone and active antineoplasic form, into PAA-modified poloxamers stabilized the drug molecule. In this way, hydrolysis was withstood and the formation of the inactive open derivative prevented [170]. Also, the drug concentration in the modified micelles was higher than in the pristine poloxamer ones, suggesting that the drug is also hosted within the hydrophilic PEO-PAA shell. Other scientists overtook this technology to design delivery systems for ophthalmic administration of antibiotics with similarly successful results [171,172]. In a similar approach, also poly(vinyl alcohol) chains were introduced [173]. The potential of using Pluronic-PAA micelles for oral chemotherapy has been recently comprehensively reviewed by Bromberg [174].

3.2. Chain extension of PEO-PPO-PEO Precursors The group of Cohn addressed the low viscosity and high permeability issue of pure PEOPPO gels by chain extending PEO-PPO-PEO precursors with a bifunctional coupling agent, hexamethylenediisocyanate. Polymerized Pluronic® F127 (PF127) and other high molecular weight poloxamer derivatives were obtained [175,176]. The degree of polymerization (namely the number of poloxamer triblocks linked in one molecule of polymerized material) was fine tuned by changing the molar ratio between the poloxamer precursor and the coupling agent. Physical reverse thermo-responsive gels were produced using copolymer concentrations as low as 5% and they displayed a sharper viscosity increase and higher stability in aqueous environment. Moreover, this methodology conferred gelation properties to pristine poloxamers that lacked a sol-gel transition under any concentration and temperature condition [176]. Incorporation of degradable segments (e.g., polycaprolactone and poly(lactic acid)) made the polymers biodegradable [177]. These novel derivatives enabled a more controllable release of active agents with a broad spectrum of molecular weights. For example, a 30% Pluronic® F127 gel was rapidly eroded by the aqueous medium and concomitantly released the antibiotic metronidazol within 2 days and following a zeroorder profile. Contrary to this, a polymerized material (degree of polymerization 4) attained 88.4% cumulative release at day 10 (Figure 4) [178]. In addition, the gel initially swelled slightly and no erosion was found during the assay, suggesting a diffusion mechanism. Release profile between days 0 and 6 fitted a Higuchi pseudo-first order model (R2 = 0.986). A similar trend was found with methylene blue [178]. When a polymeric experimental antirestenotic drug (RG-13577) was tested, a more prolonged delivery (about 40 days) was observed [175]; the polymeric nature of the drug strengthened the structure of the gels and even a 30% F127 control became less penetrable by the water and maintained the delivery for about 10 days [175] The polymerized counterpart released the drug over a 40 days period.

16


A different alternative was to couple stimuli-insensitive PEG and PPG blocks using bifunctional molecules such as phosgene (COCl2) and diacyl chlorides (e.g., succinyl chloride) to produce (PEO-X-PPO)n multiblock materials; X being the coupling agent [175,179,180]. The materials were fully degradable in aqueous medium [181].

Cumulative release (%)

120 100 80 60 40 20

F127 30% PF127 30% Crosslinked F127-silane 30%

0 0

2

4

6

8

10

12

Time (days)

Figure 4. Release of the antibiotic metronidazol from 30% pristine F127, hexamethylenediisocyanatepolymerized (PF127) and silane-cross-linked Pluronic® F127.

A

B

Figure 5. Environmental Scanning Electron Microscopy (ESEM) microphotographs of freeze-dried cross-linked F127-DMA. A) 5 wt% and B) 15 wt%. Scale bar = 100 m.

3.3. Cross-Linking of PEO-PPO Materials In order to sophisticate the existing systems and to adjust the features to more specific applications, Sosnik et al. described the modification of PEO-PPO-PEO triblocks with reactive moieties that enabled the further chemical cross-linking under physiological settings [182-,183,184]. Accordingly, aqueous solutions combined a primary thermally induced gelation and the formation of a physical gel and a latter chemical cross-linking (under physiological conditions) that generated mechanically stable networks. Two chemical approaches were followed. In a first attempt, a Pluronic® F127-dimethacrylate was synthesized by reacting the –OH terminal groups with methacryloyl chloride [182,184]. The macromonomers were further polymerized within 1-5 minutes by means of thermal- or photoinitiated free radical polymerization reactions using different initiators. Interestingly, the temperature-dependent viscosity profile of the original system remained almost unchanged


17

and confirmed that the incorporation of the methacrylate end-groups did not hinder the gelation [182]. The uniaxial compression analysis of the cross-linked hydrogels indicated that as expected, cross-linking substantially increased the compression modulus in the linear region [182]. Analysis of the viscoelastic behaviour showed that the storage modulus (G’) was much higher than the loss modulus (G”); these findings indicating that the cross-linked systems behave as gels. Freeze-dried specimens showed a highly porous sponge-like structure, as exemplified for 5 and 15% cross-linked F127 materials (Figure 5) [178]. The main limitation of these systems relied on the fact that only drugs withstanding the crosslinking process could be incorporated into the networks prior to the polymerization. Otherwise, the only way to load the drug to be delivered would be its incorporation by a swelling procedure, after the cross-linking. Due to their higher functionality, poloxamines enabled the production of highly crosslinked hydrogels using relatively low polymer concentrations [35,185]. In this framework, introduction of degradable polyester segments prior to the methacrylation reaction rendered degradable materials [186]. Cross-linked poloxamer networks were also employed in the preparation of biomedical composites introducing reinforcements of different nature to generate materials with improved mechanical properties [187]. Hubbell et al. employed a different chemistry to cross-link poloxamines: Michael-type additions of thiol to acrylate moieties [188]. The systems were compatible for cell encapsulation. In order to fine-tune the cross-linking rate and to avoid the incorporation of initiators that could affect the integrity of the drug to be loaded and delivered, F127 was also modified with ethoxysilane groups [183,184]. The hydrolysis-condensation sol-gel process, where inorganic siloxane networks are finally generated, was monitored under physiological conditions. As previously described for the F127-dimethacrylate, the silane-modified poloxamers retained the fast temperature-dependent gelation behaviour. Under physiological conditions, the reversible gels gradually cross-linked and became mechanically robust. The release from these inorganic-organic hybrids is illustrated in Figure 4 for metronidazol. Cross-linked matrices extended the release of this low molecular weight antibiotic (MW = 171.15) from 2 to more than 4 days and showed a Higuchi diffusion profile (R2 = 0.991) [178]. It is important to remark that an increase in the molecular weight of the drug extended the release time to up to 15 days, as observed for methylene blue [183]. Very recently, Park et al. designed physically cross-linkable poloxamers by introducing complementary D- and L-poly(lactic acid) oligomers able to form stereocomplexes upon mixture [189,190]. These materials showed zero-order release profiles of human growth hormone. A summary of the modified materials is introduced in Table 5. [191,192,193,194,195]

4. HYBRID PEO-PPO-CONTAINING NETWORKS Aiming to confer thermo-sensitivity to non-responsive systems, a number of investigations are focused on the development of poloxamer-containing hybrids. In this context, Pluronic® lecithin organogels (PLOs) were developed by combining Pluronic® F127 with lecithin as the main components. These matrices are intended for topical and transdermal delivery [196,197]. Applications in both human and veterinary medicine have shown a very ambiguous performance, generally depending on the properties of the drug. For example, a

18


diclofenac-containing PLO delivered the drug and led to reduced pain in patients [198]. In contrast, morphine was mainly retained by the matrix and failed to provide pain relief [199]. Table 6 summarizes the research on the delivery of drugs from PLOs. [200,201,202,203, 204,205,206,207,208,209, 210,211,212,213,214,215] Table 5. Studies on solubilization, stabilization and delivery of drugs employing chemically modified PEO-PPO block copolymers. Drug Megestrol

Copolymer L92-poly(acrylic acid) microgels

Ferricyanide, acetylferrocene Camptothecin (CPT)

F127-poly(acrylic acid) F127-poly(acrylic acid) F127 and L92 modified with poly(acrylic acid)

Methylene blue

Poly(F127) (PF127)

RG-13577

Cross-linked-F127-silane PF127

Metronidazol Gatifloxacin Human growth hormone

FITC-dextran Theophylin Hydrochlorothiaz ide Nitrofurantoin Doxorubicin (DOX)

Cross-linked-F127-silane, PF127 F127-poly(acrylic acid) copolymers End-capped D- or L-lactic acid oligomers with various chain lengths Chain extended end-capped Dor L-lactic acid oligomers with various chain lengths displaying stereocomplexation Bisacrylate ester-modified F127 F127-poly(acrylic acid) as excipient in DDS tablets F127-poly(acrylic acid) as excipient in DDS tablets F127-poly(acrylic acid) as excipient in DDS tablets L61, L92 and F127/poly(acrylic acid) microgels P85-poly(acrylic acid) F87-poly(acrylic acid)

Ku86 antisense oligonucleotide

P85-polyethyleneimine

Aims and observations Improved gastrointestinal retention of microgelbased tablets and minor burst effect. Release significantly affected by ionic strength.

Ref. 115

Controlled release tablets. CPT solubility 3- to 4-fold higher. CPT solubilized per PPO greater in the Pluronic-PAA than parent, suggesting dug incorporation to hydrophobic cores and hydrophilic shells. Enhanced stability. Extended release for 7-10 days compared to original F127 (1-2 days). Extended release from 2 to 15 days. Release extended from 10 to 40 days with polymerized poloxamer. Release extended from 2 to 4-10 days.

169 170

Ophthalmic release dependent on gel dissolution. Prolonged residence time and higher bioavailability. Sustained release via an erosion-dependent mechanism.

167

178 183 175 183, 178 171, 172 189

Physically cross-linked gels with lower critical gelation concentration and temperature compared to the uncomplexed counterparts. Zero-order release for 13 days. Pluronic F127 hydrogels cured by redox initiation are potentially useful in delivery of macromolecules. Zero-order release kinetics.

190

168

Zero-order release kinetics.

168

Zero-order release kinetics.

168

Microgels enhanced the overall cell absorption when efflux transporters were inhibited. pH-triggered release in acidic environment.

179

Improved inclusion due to interactions between PAA and the drug. Efficient delivery in management of resistant malignancies.

181

191

180

182

Combination of poloxamers with light-sensitive copolymers enables drug delivery controlled by both the temperature and the light wavelength [228]. Photoresponsive poly(N,N-dimethylacrylamide-co-methacryloyloxyazobenzene) (DMA-MOAB) undergoes a trans to cis isomerization when irradiated by 366 nm light. Under dark conditions the azobenzene groups of DMA-MOAB in the trans conformation self-associate and the interactions with Pluronic® F127 are minimal. Upon irradiation, the azobenzene groups adopt a cis conformation, which is more hydrophilic and causes the DMA-MOAB micelles to


19

dissociate, allowing the unimers to form mixed micelles with the poloxamer. This phenomenon leads the sol-gel transition temperature of the DMA-MOAB/F127 blend to be 10 °C lower upon irradiation at 366 nm compared to that under the dark conditions. It has been found that Pluronic® F127 (10-12 wt %)/DMA-MOAB (5-6 wt %) aqueous solutions display low viscosity when equilibrated in the dark and undergo a sol-gel transition when irradiated, at 37oC. Such a transition strongly alters the diffusion of solutes [229]. Others combined poloxamers with different natural polymers. Westernick et al. showed that administration of tetanus toxoid dispersed in a F127/chitosan blend (ProJuvant®) improves the immune response when administered intranasally [230]. Combining several approaches, the group of Park modified both poloxamer and hyaluronic acid with unsaturated bonds and photo-crosslinked the mixtures [231,232]. Materials showed a more controlled release of human growth hormone and plasmid DNA with an erosion-governed pattern. In a similar strategy, the same group designed poloxamer/heparin hydrogels for the delivery of angiogenic growth factor [233]. Due to the presence of natural polymers, and as opposed to cross-linked chemically poloxamer networks, these matrices were bioresorbable under physiological conditions. Table 7 summarizes the drug delivery systems based on this approach.[234,235,236,237,238,239] Table 6. Pluronic® lecithin organogels developed for topical or transdermal delivery of drugs Drug Morphine Selegiline Diltiazem Methadone, Buprenorphine Fentanyl Ketoprofen Piroxicam Diclofenac Dexamethasone Promethazine Ondansetron Metoclopramide Ketamine Fluoxetine Methimazole Clonidine Carbamazepine Baclofen Insulin Haloperidol Amitriptyline Buspirone

Aims and observations Transdermal drug delivery is unlikely to provide relief of cancerrelated pain. Similar results in veterinary studies. Methadone was effective in pain relief in cats. Buprenorphine was not. Median plasma concentrations did not overcome the limit of detection in dogs. Drug is retained in the matrix. Significant pain reduction. Absorption following topical application was not detectable. Reduced pain, mechanical hyperalgesia and inflammatory flare produced by subcutaneous capsaicin. For oral use in pain relief. Bioavailability of topical formulation was 10% of oral route. None to some improvement observed in cats after topical administration. For oral use in pain relief. For oral use in pain relief. For oral use in pain relief. Effective control of glucose plasma levels in one clinical case. Improved control of vomiting in one clinical case. Systemic absorption by the transdermal route was poor compared with the oral route. Systemic absorption by the transdermal route was poor compared with the oral route.

Ref. 196,199-201 196 196 200 201 202 203 200,204 205 206 207 208 208 209 210,211 211 211 212 213 214 215 215

20

Carmen Alvarez-Lorenzo, Angel Concheiro and Alejandro Sosnik Table 7. Pluronic® F127-based hybrids designed for sustained drug delivery. Drug Tetanus toxoid

Copolymer F127/chitosan

Human growth hormone

F127/Hyaluronic acid chemically cross-linked matrices Cross-linked F127/hyaluronic acid hydrogels F127/heparin hydrogels

Plasmid DNA

Angiogenic growth factor Pilocarpine Acetaminophen Sumatriptan Cromolyn Timolol Methylene blue

Venlafaxine

F127/alginate F68/polyvinyl alcohol blend F127/carbopol F127/carbopol and F127/alginate mixtures F127/chitosan mixture F127/poly(N,Ndimethylacrylamide-comethacryloyloxyazobenz ene) (DMA−MOAB) Heparin-immobilized F68/polyvinylalcohol composite microparticles

Aims and observations F127/chitosan systems exert additive or synergistic effect on the immune response after intranasal administration and boost immunization. Sustained release profile which followed a mass erosion pattern.

Ref. 218

DNA fractions released maintained transfection efficiency in vivo.

220

Heparin enabled the controlled release over one month in a near zero order profile. Prolonged activity and higher bioavailability of the base drug and the hydrochloride form.. Pulsatile temperature-dependent delivery.

221

Increased permeation rate and prolonged nasal residence time. In situ gelling vehicles for ophthalmic drug delivery. Increased ocular retention and higher drug transport across cornea. Sol−gel transition under UV-irradiation. The transition strongly alters the diffusion of solutes. Complexation of cis-azo groups with cyclodextrins prevent formation of mixed micelles. Heparin enabled stabilization of microparticles and rendered efficient drug loading and delivery.

219

222 223 224 225 227 217

226

5. PERSPECTIVES PEO-PPO block copolymers have gone a long way as drug vehicles and injectable matrices for sustained drug delivery. Regardless a number of drawbacks (e.g., incomplete aggregation of the more hydrophilic derivatives and limited performance of the gels in vivo), they have attracted the attention of scientists and researchers worldwide. Remarkable critical features have supported their increasing popularity: i) commercial availability (very important in pharmaceutical sciences), ii) very broad range of varieties differing in molecular weight and EO/PO ratio, iii) proven cell- and bio-compatibility for most of the derivatives, iv) versatility of applications in drug solubilization, stabilization and delivery, and v) FDAapproval for several poloxamer and poloxamine-based pharmaceutical formulations. Diverse strategies have been pursued in order to overcome existing limitations or to provide new features. Among these, cross-linking, grafting or physical combination with other polymers have been designed to enhance the mechanical resistance, the sensitiveness to various stimuli, in vivo biodegradation or to provide zero-order drug release kinetics. So far, preliminary data supports the biocompatibility of some of the modified materials and their potential for the development advanced drug delivery systems. Nevertheless, further pre-clinical and clinical investigations are demanded in order to prove their safety to be employed in veterinary and human medicine.


21

ACKNOWLEDGEMENTS This work was financed by Ministerio de Educación y Ciencia and FEDER (PCI2006A7-0049, SAF2008-01679), and Xunta de Galicia (PGIDT07CSA002203PR), Spain.

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