*7.5.1 Transportation mechanisms*

Liposomes can interact with cells through different mechanisms [129]:

*Endocytosis*. Carried out by phagocytic cells of the reticuloendothelial system such as macrophages and neutrophils.

*Adsorption* to the cell surface either through nonspecific weak hydrophobic or electrostatic forces or specific interactions with cell surface components.

*Fusion* with the plasmatic cell membrane through the insertion of the lipid bilayer of the liposome into the plasma membrane with the simultaneous release of the liposomal content into the cytoplasm.

*Transfer* of liposomal lipids to cellular or subcellular membranes, or vice versa, without any association of liposomal contents.

## *7.5.2 Evaluation*

Liposomal formulation and processing for a specific purpose are characterized for ensuring their predictable in vitro and in vivo performance [132]. Characterization parameters for the purpose of evaluation may be classified into three broad categories that include:

Physical characterization. It evaluates the size, shape, surface features, lamellarity, phase behavior, and drug release profile.

Chemical characterization. It includes studies in order to establish the purity and potency of various lipophilic constituents.

Biological characterization. Biological characterization is helpful in establishing the safety and suitability of the formulation for therapeutic applications.

Some parameters are the vesicle's shape and lamellarity, vesicle size and size distribution, encapsulation efficiency (expressed as percentage (%)), phase response, and transitional behavior and drug release. Zeta potential (ZP) refers to the potential difference between the electric double layer (EDL) (an adsorbed double layer developed on the surface of dispersed charged particles) of movable particles and the layer of dispersant around them at the slipping plane. A stabilized nanosuspension is a suspension that may be affected by several factors such as pH, ionic strength, and the concentration of particles. The phospholipid composition of liposomes is the main content that influences the overall surface charge of liposomes.

### *7.5.3 Applications of liposomes in medicine*

Liposomes are versatile carriers for the delivery of numerous challenging molecules, and they have remarkable advantages compared to other colloidal systems. They have been investigated for a wide range of applications in pharmaceutical technology through topical, transdermal, nasal, and oral routes for efficient and effective drug delivery. Liposome formulations have potential advantages that other drug delivery systems do not have:


**41**

*Breaking down the Barrier: Topical Liposomes as Nanocarriers for Drug Delivery…*

x.Nontoxic, flexible, biocompatible, and completely biodegradable.

xi.Size may vary in order to incorporate smaller or larger drug molecules.

xiii.The therapeutic activity of chemotherapeutic agents may be improved

or lower than those required for maximum therapeutic activity.

xiv.They help reduce exposure of sensitive tissues to toxic drugs.

through liposomal encapsulation. This reduces deleterious effects similar to

ii.Leakage and fusion of encapsulated drug molecules with certain preparation

vi.Improved transfer of hydrophilic, charged molecules.

xii.They can be administered through various routes.

vi.Phospholipids undergo oxidation and hydrolysis.

viii.Allergic reactions to liposomal constituents may occur.

Liposomal formulations have several applications in cancer chemotherapy. Due to the nature and behavior of cancer tissues and the large difference between them and regular tissues, cancer tissues are considered an appropriate target for liposome drug delivery systems. For example, the tumor vasculature is characterized by a leaky vasculature and limited lymphatic drainage; consequently, drug molecules can easily be accumulated in intercellular spaces of a large variety of tumors. Numerous different liposome formulations of several anticancer agents were shown to be less toxic than free drugs [131, 133–135]. Examples of these drugs are doxorubicin and daunorubicin citrate for Kaposi sarcoma; doxorubicin for ovarian cancer and solid tumors; nystatin, vinorelbine, cisplatin and its analog docetaxel, tretinoin, siRNA, topotecan, irinotecan, paclitaxel, and camptothecin for solid tumors; cisplatin and its analog for colorectal neoplasms, Grb-2 in leukemia; Bcl-2 for lymphoma; BikDD for pancreatic cancer; and DOTAP (Chol-Fus I) for the

Some of the disadvantages of liposomes are:

i.Production cost is high.

methods.

iii.Short half-life.

iv.Less stability.

v.Low solubility.

vii.Leakage and fusion.

*DOI: http://dx.doi.org/10.5772/intechopen.86601*

viii.Site avoidance mechanism.

vii.Improved penetration into the tissues.

ix.They offer site-specific targeting.

*Breaking down the Barrier: Topical Liposomes as Nanocarriers for Drug Delivery… DOI: http://dx.doi.org/10.5772/intechopen.86601*


*Role of Novel Drug Delivery Vehicles in Nanobiomedicine*

such as macrophages and neutrophils.

the liposomal content into the cytoplasm.

three broad categories that include:

ity, phase behavior, and drug release profile.

potency of various lipophilic constituents.

*7.5.3 Applications of liposomes in medicine*

drug delivery systems do not have:

iii.Reduced toxicity and increased stability.

iv.Increased efficacy and therapeutic index of the drug.

drugs.

liposomes.

*7.5.2 Evaluation*

without any association of liposomal contents.

*Endocytosis*. Carried out by phagocytic cells of the reticuloendothelial system

*Adsorption* to the cell surface either through nonspecific weak hydrophobic or

*Transfer* of liposomal lipids to cellular or subcellular membranes, or vice versa,

*Fusion* with the plasmatic cell membrane through the insertion of the lipid bilayer of the liposome into the plasma membrane with the simultaneous release of

Liposomal formulation and processing for a specific purpose are character-

Physical characterization. It evaluates the size, shape, surface features, lamellar-

Chemical characterization. It includes studies in order to establish the purity and

Biological characterization. Biological characterization is helpful in establishing

Some parameters are the vesicle's shape and lamellarity, vesicle size and size distribution, encapsulation efficiency (expressed as percentage (%)), phase response, and transitional behavior and drug release. Zeta potential (ZP) refers to the potential difference between the electric double layer (EDL) (an adsorbed double layer developed on the surface of dispersed charged particles) of movable particles and the layer of dispersant around them at the slipping plane. A stabilized nanosuspension is a suspension that may be affected by several factors such as pH, ionic strength, and the concentration of particles. The phospholipid composition of liposomes is the main content that influences the overall surface charge of liposomes.

Liposomes are versatile carriers for the delivery of numerous challenging molecules, and they have remarkable advantages compared to other colloidal systems. They have been investigated for a wide range of applications in pharmaceutical technology through topical, transdermal, nasal, and oral routes for efficient and effective drug delivery. Liposome formulations have potential advantages that other

i.Suitable for the delivery of hydrophobic, amphipathic, and hydrophilic

ii.They protect the encapsulated drug from the external environment.

v.The sustained-release system of systematically or locally administered

ized for ensuring their predictable in vitro and in vivo performance [132]. Characterization parameters for the purpose of evaluation may be classified into

the safety and suitability of the formulation for therapeutic applications.

electrostatic forces or specific interactions with cell surface components.

**40**


Some of the disadvantages of liposomes are:


Liposomal formulations have several applications in cancer chemotherapy. Due to the nature and behavior of cancer tissues and the large difference between them and regular tissues, cancer tissues are considered an appropriate target for liposome drug delivery systems. For example, the tumor vasculature is characterized by a leaky vasculature and limited lymphatic drainage; consequently, drug molecules can easily be accumulated in intercellular spaces of a large variety of tumors. Numerous different liposome formulations of several anticancer agents were shown to be less toxic than free drugs [131, 133–135]. Examples of these drugs are doxorubicin and daunorubicin citrate for Kaposi sarcoma; doxorubicin for ovarian cancer and solid tumors; nystatin, vinorelbine, cisplatin and its analog docetaxel, tretinoin, siRNA, topotecan, irinotecan, paclitaxel, and camptothecin for solid tumors; cisplatin and its analog for colorectal neoplasms, Grb-2 in leukemia; Bcl-2 for lymphoma; BikDD for pancreatic cancer; and DOTAP (Chol-Fus I) for the

treatment of lung cancer [130]. Many other drugs are being researched in order to make them affordable for liposomal drug delivery systems.

In dermatology, liposomes have successfully been used in atopic dermatitis (taxifolin glycoside) as antibacterial, antifungal (metronidazole nitrate, amphotericin B), and anti-leishmaniasis treatments (amphotericin B, meglumine antimoniate). Antioxidants such as natural flavonoids (catechin and naringenin) have been used to prevent the oxidation of cutaneous disorders and as photoprotective (quercetin), antipsoriatic, anti-inflammatory agents and anti-acne drugs [136].

In the same context, prostaglandin has been used in peripheral vascular disease, meglumine antimoniate for cutaneous leishmaniasis, fentanyl for pain relief, amikacin in cystic fibrosis, and prilocaine in dental anesthesia, all of them are more examples of liposomal drug products for medical use [136]. Furthermore, antihypertensive drugs have been used for the management of cardiovascular disorders (propanol hydrochloride, valsartan, and nifedipine have been developed in liposomal formulations) [136]. There are publications regarding local anesthetic drugs [137–139], drug delivery to the brain in anti-migraine and anti-Parkinson drugs [140–143], and the nasal delivery of liposomal formulations (salbutamol).

The application of liposomes in vaccine formulations and toxoids is one of the main achievements of modern medicine. Vaccination activates particular parts of the immune system in order for it to express specific immune responses followed by the induction of long-lasting immunological memories to defend against subsequent infectious attacks [144]. Most available immunizations are intramuscularly delivered, which is painful and requires an aseptic technique, as well as skilled and trained personnel for their administration. Thus, biological products (vaccines and toxoids) are suitable as a noninvasive approach compared to conventional methods, and they have numerous obvious advantages such as increased patient compliance, reduced systemic side effects, and constant plasma concentrations. Ding et al. reported on antigens such as vaccines and toxoids. Depending on the type of antigens, the dose to be delivered, immunization schedule, the presence of co-stimulatory factors, and liposomal composition, the immunization of antigens loaded in ELs elicits an effective immune response with serum IgG levels comparable to those obtained after subcutaneous injections [145–148]. Transcutaneous immunization (TCI) is a novel technique, and it requires the simple introduction of antigens into the host tissue through topical application on the skin [148]. This offers ease of administration and the potential to elicit a robust immune response as compared to conventional painful (needle injections) methods prescribed in equivalent doses [145].

Image-guided delivery is another opportunity area for liposomal formulations. Imaging plays an integral part in modern precision and individualized medicine. Wide applications of imaging such as monitoring drug delivery, accurate diagnosis of diseases, determining the response to therapy, and guiding minimally invasive procedures are some of the applications of imaging in the clinic. However, traditional imaging modalities, such as computed tomography (CT), positron-emission tomography (PET), magnetic resonance imaging (MRI), and single-photon emission computed tomography (SPECT), all suffer from target specificity, which limits their clinical utility. Nanoparticles, with their versatility in surface functionalization, provide opportunities to enhance target specificity and label NPs with various isotopes, which enables them to act as contrast agents. Recent developments in multimodality imaging to better diagnose diseases and monitor treatments have embarked on using liposomes as a diagnostic tool. Conjugating liposomes with different labeling probes enable the precise localization of these liposomal formulations by using various modalities such as PET, SPECT, and MRI [149].

**43**

*Breaking down the Barrier: Topical Liposomes as Nanocarriers for Drug Delivery…*

tial to reach the vitreous cavity with a significant concentration of the drug.

Liposomal vesicles have potential advantages when compared to conventional drug delivery methods. Liposomes in different forms are still one of the most investigated drug delivery carrier systems for the ocular delivery of drugs in both preclinical studies and clinical trials. They seem to be an almost ideal drug-carrier system since their morphology is similar to that of cellular membranes and because of their ability to incorporate various substances. They are valued for their biological and technological advantages as optimal delivery systems for biologically active substances, both in vitro and in vivo, and are considered to be the most successful

Several liposome formulations have been used in ophthalmology to target the anterior segment of the eye. The use of liposomal formulations to enhance the bioavailability of topical applied acyclovir and ganciclovir has been evaluated with promising results [152]. Antibacterial drugs, such as tetracycline, gentamycin, ciprofloxacin, norfloxacin, and chloramphenicol, have been prepared as liposomal solutions with higher activity compared to that of standard solutions [153]. Antifungal agents such as amphotericin B and fluconazole have been under research [152], and liposomal formulations were highly effective in treating *Candida* keratitis. Anti-inflammatory drugs and immunomodulatory agents are widely used in the treatment of ocular inflammatory and immunological diseases. In order to enhance ocular bioavailability and reduce the toxic effects following topical or intravitreal administration, liposomal forms of many of these drugs have been evaluated (diclofenac, cyclosporine, tacrolimus) with promising results and better concentrations than standard formulations [152, 153]. Similarly, liposomal antiglaucoma agents' formulations (pilocarpine, latanoprost, acetazolamide) were more effective in reducing intraocular pressure (IOP). In the same context, lubricants and antioxi-

dants have also other potential uses for liposomal formulations.

NCT0198732357; ClinicalTrials.gov identifier, NCT02466399).

Liposomal drugs that have transitioned from preclinical research to clinical phase trials include latanoprost-loaded conventional liposomes developed for subconjunctival administration [154]. Phase I and II trials on the safety and efficacy of latanoprost-loaded liposomes in the treatment of ocular hypertension and primary open-angle glaucoma have been completed (ClinicalTrials.gov identifier,

*7.5.5 Topical liposomes for drug delivery into the posterior segment of the eyeball*

Different efforts have been performed to deliver drugs into the posterior segment of the eye through the instillation of loaded liposomes (**Table 2**) [155–163].

Glucocorticoids (GC) are one of the most popular and versatile classes of drugs available to treat chronic inflammation and cancer, but side effects and resistance constrain their use. In order to overcome these hurdles, which are often related to the uniform tissue distribution of free GC and their short half-life in biological fluids, new delivery vehicles have been developed, including PEGylated liposomes, polymeric micelles, polymer-drug conjugates, inorganic scaffolds, and hybrid NPs. While each of these nanoformulations has individual drawbacks, they are often superior to free GC in many aspects, including therapeutic efficacy when tested in cell cultures or animal models. The characterization and pharmacokinetics of triamcinolone acetonide-loaded liposomal topical formulations for vitreoretinal drug delivery [150] have been published by Altamirano-Vallejo et al. They showed that a formulation with triamcinolone acetonide-loaded liposomes is feasible and that it has the poten-

*DOI: http://dx.doi.org/10.5772/intechopen.86601*

drug-carrier system known to date [151].

*7.5.4 Liposomes in ophthalmology*

*Breaking down the Barrier: Topical Liposomes as Nanocarriers for Drug Delivery… DOI: http://dx.doi.org/10.5772/intechopen.86601*

Glucocorticoids (GC) are one of the most popular and versatile classes of drugs available to treat chronic inflammation and cancer, but side effects and resistance constrain their use. In order to overcome these hurdles, which are often related to the uniform tissue distribution of free GC and their short half-life in biological fluids, new delivery vehicles have been developed, including PEGylated liposomes, polymeric micelles, polymer-drug conjugates, inorganic scaffolds, and hybrid NPs. While each of these nanoformulations has individual drawbacks, they are often superior to free GC in many aspects, including therapeutic efficacy when tested in cell cultures or animal models. The characterization and pharmacokinetics of triamcinolone acetonide-loaded liposomal topical formulations for vitreoretinal drug delivery [150] have been published by Altamirano-Vallejo et al. They showed that a formulation with triamcinolone acetonide-loaded liposomes is feasible and that it has the potential to reach the vitreous cavity with a significant concentration of the drug.

Liposomal vesicles have potential advantages when compared to conventional drug delivery methods. Liposomes in different forms are still one of the most investigated drug delivery carrier systems for the ocular delivery of drugs in both preclinical studies and clinical trials. They seem to be an almost ideal drug-carrier system since their morphology is similar to that of cellular membranes and because of their ability to incorporate various substances. They are valued for their biological and technological advantages as optimal delivery systems for biologically active substances, both in vitro and in vivo, and are considered to be the most successful drug-carrier system known to date [151].

#### *7.5.4 Liposomes in ophthalmology*

*Role of Novel Drug Delivery Vehicles in Nanobiomedicine*

make them affordable for liposomal drug delivery systems.

antipsoriatic, anti-inflammatory agents and anti-acne drugs [136].

treatment of lung cancer [130]. Many other drugs are being researched in order to

In dermatology, liposomes have successfully been used in atopic dermatitis (taxifolin glycoside) as antibacterial, antifungal (metronidazole nitrate, amphotericin B), and anti-leishmaniasis treatments (amphotericin B, meglumine antimoniate). Antioxidants such as natural flavonoids (catechin and naringenin) have been used to prevent the oxidation of cutaneous disorders and as photoprotective (quercetin),

In the same context, prostaglandin has been used in peripheral vascular disease,

The application of liposomes in vaccine formulations and toxoids is one of the main achievements of modern medicine. Vaccination activates particular parts of the immune system in order for it to express specific immune responses followed by the induction of long-lasting immunological memories to defend against subsequent infectious attacks [144]. Most available immunizations are intramuscularly delivered, which is painful and requires an aseptic technique, as well as skilled and trained personnel for their administration. Thus, biological products (vaccines and toxoids) are suitable as a noninvasive approach compared to conventional methods, and they have numerous obvious advantages such as increased patient compliance, reduced systemic side effects, and constant plasma concentrations. Ding et al. reported on antigens such as vaccines and toxoids. Depending on the type of antigens, the dose to be delivered, immunization schedule, the presence of co-stimulatory factors, and liposomal composition, the immunization of antigens loaded in ELs elicits an effective immune response with serum IgG levels comparable to those obtained after subcutaneous injections [145–148]. Transcutaneous immunization (TCI) is a novel technique, and it requires the simple introduction of antigens into the host tissue through topical application on the skin [148]. This offers ease of administration and the potential to elicit a robust immune response as compared to conventional painful (needle injections) methods prescribed in

Image-guided delivery is another opportunity area for liposomal formulations.

Imaging plays an integral part in modern precision and individualized medicine. Wide applications of imaging such as monitoring drug delivery, accurate diagnosis of diseases, determining the response to therapy, and guiding minimally invasive procedures are some of the applications of imaging in the clinic. However, traditional imaging modalities, such as computed tomography (CT), positron-emission tomography (PET), magnetic resonance imaging (MRI), and single-photon emission computed tomography (SPECT), all suffer from target specificity, which limits their clinical utility. Nanoparticles, with their versatility in surface functionalization, provide opportunities to enhance target specificity and label NPs with various isotopes, which enables them to act as contrast agents. Recent developments in multimodality imaging to better diagnose diseases and monitor treatments have embarked on using liposomes as a diagnostic tool. Conjugating liposomes with different labeling probes enable the precise localization of these liposomal formulations by using various modalities such as PET,

meglumine antimoniate for cutaneous leishmaniasis, fentanyl for pain relief, amikacin in cystic fibrosis, and prilocaine in dental anesthesia, all of them are more examples of liposomal drug products for medical use [136]. Furthermore, antihypertensive drugs have been used for the management of cardiovascular disorders (propanol hydrochloride, valsartan, and nifedipine have been developed in liposomal formulations) [136]. There are publications regarding local anesthetic drugs [137–139], drug delivery to the brain in anti-migraine and anti-Parkinson drugs [140–143], and the nasal delivery of liposomal formulations (salbutamol).

**42**

equivalent doses [145].

SPECT, and MRI [149].

Several liposome formulations have been used in ophthalmology to target the anterior segment of the eye. The use of liposomal formulations to enhance the bioavailability of topical applied acyclovir and ganciclovir has been evaluated with promising results [152]. Antibacterial drugs, such as tetracycline, gentamycin, ciprofloxacin, norfloxacin, and chloramphenicol, have been prepared as liposomal solutions with higher activity compared to that of standard solutions [153]. Antifungal agents such as amphotericin B and fluconazole have been under research [152], and liposomal formulations were highly effective in treating *Candida* keratitis. Anti-inflammatory drugs and immunomodulatory agents are widely used in the treatment of ocular inflammatory and immunological diseases. In order to enhance ocular bioavailability and reduce the toxic effects following topical or intravitreal administration, liposomal forms of many of these drugs have been evaluated (diclofenac, cyclosporine, tacrolimus) with promising results and better concentrations than standard formulations [152, 153]. Similarly, liposomal antiglaucoma agents' formulations (pilocarpine, latanoprost, acetazolamide) were more effective in reducing intraocular pressure (IOP). In the same context, lubricants and antioxidants have also other potential uses for liposomal formulations.

Liposomal drugs that have transitioned from preclinical research to clinical phase trials include latanoprost-loaded conventional liposomes developed for subconjunctival administration [154]. Phase I and II trials on the safety and efficacy of latanoprost-loaded liposomes in the treatment of ocular hypertension and primary open-angle glaucoma have been completed (ClinicalTrials.gov identifier, NCT0198732357; ClinicalTrials.gov identifier, NCT02466399).

#### *7.5.5 Topical liposomes for drug delivery into the posterior segment of the eyeball*

Different efforts have been performed to deliver drugs into the posterior segment of the eye through the instillation of loaded liposomes (**Table 2**) [155–163].


**45**

**Drug** Triamcinolone acetonide

Chitosan, phosphatidylcholine, and CH

Calcium acetate gradient method that implies hydration and is freeze-thawed

TA-CHL penetrates into the posterior segment of the eye. Chitosan-coated liposomes were a more efficient ocular delivery system of triamcinolone acetonide to the posterior segment of the eye as eye drops than non-

coated liposomes

Triamcinolone acetonide chitosan-coated liposomes (TA-CHL)

Annexin A5-surface-

Phosphatidylserine, phosphatidylethanolamine, and anionic phospholipid-

Calcium acetate gradient method that implies hydration and is freeze-thawed

binding protein annexin A5

The modification of ligand (transferrin), which binds

No

[160]

to a specific receptor in RPE cells to the liposomes,

improves gene delivery efficacy to the posterior

segment of the eye

Annexin A5-surface-modified liposomes deliver physiologically significant concentrations of bevacizumab to the posterior segment of rat eyes (127 ng/g) and rabbit retinas (18 ng/g). Annexin A5-mediated endocytosis enhances the delivery of bevacizumab

modified liposomes

> pDNA

pDNA/PEI complex-loaded liposomes

EPC and CH

Detergent removal

method

modified with

transferrin

TMAG liposome

TMAG liposomes, TMAG

Hydration method

Gene expression was found in retinal ganglion cell

No

[163]

until 1 month after the topical application of liposomes

and DOPE; DC-CH

liposome, DC-cholesterol

and DOPE

*at the terminal of the molecule; SA, stearyl amine; TMAG, N-(alpha-trimethyl ammoniacetyl)-didodecyl-D-glutamate.*

**Table 2.** *Reported liposomes for drug delivery to the posterior segment of the eyeball.*

*CH, cholesterol; DC, dicetyl phosphate; DC-cholesterol, 3beta [N-(N′-N′-dimethylaminoethane)-carbamyl] cholesterol; DLPC, dilauroylphosphatidylcholine; DOPE, dioleoylphosphatidylethanolamine;* 

*DSPC, L-α-distearoyl phosphatidylcholine; EPC, egg phosphatidylcholine; PEI, polyethylenimine; PVA 205, polyvinyl alcohol; PVA-R, polyvinyl alcohol derivatives bearing a hydrophobic anchor (C16H33 S)* 

and DC-CH

liposome

Plasmid DNA with

β-galactosidase gene

Bevacizumab

**Liposome description**

**Liposomal composition**

**Synthesis method**

**Main findings**

**Clinical trials**

No

[164]

**Reference**

*Breaking down the Barrier: Topical Liposomes as Nanocarriers for Drug Delivery…*

*DOI: http://dx.doi.org/10.5772/intechopen.86601*

No

[156]


**Table 2.** *Reported liposomes for drug delivery to the posterior segment of the eyeball.*

*Breaking down the Barrier: Topical Liposomes as Nanocarriers for Drug Delivery… DOI: http://dx.doi.org/10.5772/intechopen.86601*

*Role of Novel Drug Delivery Vehicles in Nanobiomedicine*

**44**

**Drug** Coumarin-6

**Liposome** 

**Liposomal composition**

**Synthesis method**

**Main findings**

**Clinical** 

**Reference**

**trials**

**description**

Poly-L-lysine

Poly-L-lysine, EPC, DCP,

Hydration method

Noncytotoxic in corneal and conjunctival cells

No

[155]

surface-modified

and CH

liposomes

Submicron-sized

DSPC, EPC, DCP or SA,

Hydration method

Delivery efficiency of coumarin-6 to the retina was

No No

[162]

[157]

altered depending on particle size

The magnitude of fluorescence in the retina was

closely related to both liposome rigidity and particle

size. Images of the entire eye showed that ssLip

was delivered via the non-corneal pathway after

Luminescence intensity in the retina was higher

No

[161]

when a ssLip formulation composed of DSPC was

administration

liposomes (ssLips)

Submicron-sized

EPC or DSCP, DCP, and CH

Hydration method

liposomes (ssLips)

and CH

Coumarin-6 Coumarin-6 5(6)-Carboxyfluorescein

Diclofenac

PVA 205 or PV-R

PVA 205 or PV-R, DSPC,

surface-modified

and CH

liposomes

Edaravone Triamcinolone acetonide

Triamcinolone

Polyethylene glycol (PEG-12) glyceryl dimyristate

QuSomes®; self-forming,

thermodynamically

stable

acetonide-loaded

liposomes

formulations

(TA-LF)

Submicron-sized

EPC and CH

Calcium acetate

gradient method that

implies hydration and

is freeze-thawed

cytotoxicity

liposomes (ssLips)

Submicron-sized

DSPC and EPC

Calcium acetate

gradient method that

implies hydration and

applied

is freeze-thawed

Calcium acetate

The increase in particle size of the liposomal

No

[158]

formulation was inhibited in the presence of PVA

205 or PV-R. In vivo animal study revealed that the

concentration of diclofenac in the retina-choroid

was enhanced 1.8-fold through surface-modified

liposome entrapment compared to that of the

unaltered diclofenac solution

Edaravone-loaded ssLips showed a stronger inhibition

No

[159]

of in vitro light-induced ROS production and cell

death than free edaravone. ssLips showed modest

TA-LF, topically administered, can deliver TA to the

Yes

[150]

vitreous cavity and efficiently reach the retina with

no adverse effects in rabbits. TA-LF was well tolerated

and improved the best corrected visual acuity and the

central foveal thickness in patients with refractory

pseudophakic cystoid macular edema

gradient method that

implies hydration and

is freeze-thawed

liposomes (ssLips)

For example, fluorescent probes used as drug models, such as coumarin-6 and 5(6)-carboxyfluorescein, have efficiently been released into the posterior segment of the eyeball by liposomes [155, 157, 161, 162]. On the other hand, drugs like edaravone and diclofenac were successfully released into the vitreous and the retina by liposomes [158, 159].

Special mention is reserved for the study performed by Davis BM et al. This group demonstrated that the topical instillation of eye drops containing annexin A5 associated with liposomes loaded with bevacizumab is able to deliver physiologically significant concentrations of this large therapeutic protein (monoclonal antibody against vascular endothelial growth factor A) into the posterior segment of the eye in animal models (rats and rabbits) [156]. Moreover, liposomes can release genetic material into the vitreous and the retina [160, 163].

Lastly, a topical triamcinolone acetonide-loaded liposomes formulation (TA-LF) was used to successfully deliver TA into the vitreous and the retina of rabbits. Besides the authors report that TA-LF was well tolerated by the study animals and that no toxicity was observed in cell culture assays and no adverse events like corneal and conjunctival erosions were observed [150]. Recently, Jin Li et al. [164] validated in animal models (mice) that eye drops containing chitosan-coated liposomes carrying TA are an efficient method to deliver this drug into the posterior segment of rabbit eyeballs, supporting the previous findings published by Altamirano-Vallejo et al. Even though Li et al. reached superior TA entrapment efficiency in their TA-loaded liposomes prepared through the calcium acetate gradient method, it seems that this characteristic does not compromise the therapeutic activity of TA-LF. TA-LF has been tested in clinical assays where its efficiency and safety profile have satisfactorily been demonstrated. In a recent report, TA-LF was efficient in the management of refractory pseudophakic cystoid macular edema [20], where the use of this formulation was associated with the improvement of best corrected visual acuity and central foveal thickness with no reports of adverse events. At this time, phase II trials are underway to demonstrate the efficacy of TA-LF for macular edema.
