Drug Delivery

ISSN: 1071-7544 (Print) 1521-0464 (Online) Journal homepage: http://www.tandfonline.com/loi/idrd20

Photosensitive drugs: a review on their

photoprotection by liposomes and cyclodextrins

Giuseppina Ioele, Michele De Luca, Antonio Garofalo & Gaetano Ragno

To cite this article: Giuseppina Ioele, Michele De Luca, Antonio Garofalo & Gaetano Ragno (2017)
Photosensitive drugs: a review on their photoprotection by liposomes and cyclodextrins, Drug
Delivery, 24:sup1, 33-44, DOI: 10.1080/10717544.2017.1386733

To link to this article: http://dx.doi.org/10.1080/10717544.2017.1386733

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 DRUG DELIVERY, 2017
VOL. 24, NO. S1, 33–44
https://doi.org/10.1080/10717544.2017.1386733

REVIEW ARTICLE

Photosensitive drugs: a review on their photoprotection by liposomes and

cyclodextrins
Giuseppina Ioele, Michele De Luca, Antonio Garofalo and Gaetano Ragno
Department of Pharmacy and Health and Nutrition Sciences, University of Calabria, Rende (CS), Italy

ABSTRACT ARTICLE HISTORY

Nowadays, an exciting challenge in the drug chemistry and technology research is represented by the Received 10 July 2017
development of methods aimed to protect molecular integrity and therapeutic activity of drugs from Revised 26 September 2017
effects of light. The photostability characterization is ruled by ICH (The International Council for Accepted 27 September 2017
Harmonization of Technical Requirements for Pharmaceuticals for Human Use), which releases details
KEYWORDS
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throughout basic protocols of stability tests to be performed on new medicinal products for human Photolabile drugs; stability
use. The definition of suitable photoprotective systems is fundamental for pharmaceutical manufactur- tests; phototoxicity;
ing and for human healthy as well, since light exposure may affect either drugs or drug formulations photoprotection; supra-
giving rise even to allergenic or mutagenic by-products. Here, we summarize and discuss the recent molecular matrices
studies on the formulation of photosensitive drugs into supramolecular systems, capable of entrapping
the molecules in a hollow of their structure by weak noncovalent interactions and protecting them
from light. The best known supramolecular matrices belong to the ‘auto-assembled’ structures,
of which liposomes are the most representative, and the ‘host-guest’ systems, of which cyclodextrins
represent the most common ‘host’ counterpart. A relevant number of papers concerning the use
of both liposomes and cyclodextrins as photoprotection systems for drugs has been published over
the last 20 years, demonstrating that this topic captures interest in an increasing number of
researchers.

Introduction for Human Use (ICH), adopted in 1996 in Europe and in 1997 in
the USA and Japan, prescribes a basic protocol to be applied for
Photostability of drugs has become a very important topic in
the photostability evaluation of new drugs (ICH, 1996). FDA
the field of pharmaceutical research over the last decades. A
requires such a protocol as a part of tests to be necessarily per-
very limited number of articles on this argument has been
formed before the marketing of new drugs, for the assessment
published before the 1970 s. A few years later, the United of drug photostability aimed to exclude unacceptable structure
States Pharmacopeia XIX introduced early recommendations modifications. Impurities coming from both synthesis and deg-
toward light-protection of drugs, suggesting the use of sim- radation must be always identified and quantified. The toxico-
ple light-shielding containers as a preventive expedient (The logical aspects of such impurities should be carefully
United States Pharmacopeia 19th Rev, 1975). A decisive investigated through specific studies, when necessary. ICH
impulse in this field was generated later by the appearance photo-stability rules include tests on the pure active principle as
of several papers dealing with toxic effects to humans caused well as pharmaceutical formulation and commercial packet.
by some by-products from drug photodegradation. In the Sunlight irradiation should not be not used during the tests
last few years, chemical mechanisms and photodegradation because of its significant variation due to geographical and cli-
kinetics have been described for a more and more increasing matic factors (Moore, 2010).
number of drugs. Usually, the most common effect of photo- Two alternative light sources are recommended accord-
degradation on a drug results in the loss or reduction of its ingly: (1) a xenon or metal-halide lamp releasing visible and
pharmacological activity, in some cases accompanied with UV radiations, equivalent to D65 standard for the outdoor day-
the formation of toxic by-products. Reviews or collections of light and ID65 standard for the indoor indirect light; (2) a
monographs that deal very deeply with photolabile drugs fluorescent lamp coupled with an UV 320–400 nm bulb. A
and their formulation problems date back to the first decade careful temperature monitoring is required in order to minim-
of the twentieth century (Albini & Fasani, 1998; Piechocki & ize the interference due to the heat produced by the lamps.
Thoma, 2006; Tønnesen, 2001, 2004). These rules have been subject to criticism and review pro-
At present, a guide issued by The International Council for posals over the years. In 2010, an important paper by
Harmonization of Technical Requirements for Pharmaceuticals Baertschi and his research team discussed the application of

CONTACT Gaetano Ragno gaetano.ragno@unical.it Department of Pharmacy, Health and Nutrition Sciences, University of Calabria, via Bucci 87036, Rende
(CS), Italy
ß 2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.
 34 G. IOELE ET AL.

ICH Guideline to drug stability tests (Baertschi, 2010). Later, intense dermatitis. The phototoxic drugs can be contained in
from 2013 to 2016, the same Authors published a series of a topical administration or it may reach the skin via systemic
three papers for conducting photostability tests on various circulation following oral or parenteral administration.
pharmaceutical forms (Baertschi et al., 2013, 2015). Phototoxic reactions occur after the harmful effects of
In addition to the accurate assessment of the drug’s pho- light-activated compounds on cell membranes and, in some
tostability profile, the development of pharmaceutical formu- cases, DNA. Photoallergic reactions are cell-mediated immune
lations that can minimize photodegradation is of paramount responses to a slightly activated compound. The drugs, or its
importance (Allain et al., 2016). Most therapeutic agents are metabolites, react to light as chromophores and absorb
marketed in solid or liquid formulations. Usually, the solid energy, becoming an ‘excited’ state. High-energy content is
pharmaceutical forms are more stable to light than solutions. transferred to the tissues when the molecules return to the
Strategies aimed at preventing or minimizing drug photo- fundamental state, causing damage to DNA or cell mem-
degradation represent an outstanding research topic and branes. In addition to the toxic degradation products, free
new approaches toward the management of this problem radicals can also be formed.
are proposed constantly throughout the literature. The most It is very important to identify the species responsible for
customary method is still represented by the use of contain- allergy or phototoxic effects. An interesting work of 2007
ers made with dark or opaque glass, able to halt light of spe- addresses this issue for dihydropyridines (Pizarro et al., 2007).
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cific wavelengths responsible for photodegradation. This Some drugs of this class were exposed to stressing artificial
strategy is particularly effective against high-energy radiations, light and a significant production of single oxygen, super-
which shows to be the most effective in promoting the trans- oxide or both was demonstrated. The formation of these spe-
formation of drug compounds. On the other hand, a major cies demonstrates the potential of these drugs to cause
drawback is the preclusion of a visual inward inspection. phototoxic dermatitis. In particular, felodipine and nimodi-
The formulation employing excipients able to increase pine are both capable of generating single oxygen, but
photochemical stability of a drug represents an alternative exhibiting a different reactivity: the former proves to be very
approach widely investigated. Such additives present absorp- reactive in its ground state while the second in the excited
tion spectra overlapping those of the drug molecules. Even state.
some antioxidant agents have produced good results in Isotretinoin, deriving from the photolysis of tretinoin, has
terms of increased photoprotection, due to their ability of been proved capable of producing teratogenic effects, so
preventing free radicals and singlet-oxygen intermediates for- precluding its use during pregnancy (Ioele et al., 2005). The
mation. Ascorbic acid and a-tocopherol are the most studied photo-degradation of naproxen leads to toxic products
antioxidants (Ray et al., 2002). In recent years, the use of (Isidori et al., 2005). Several sunscreens degrade under sun-
supramolecular matrices in drug formulations has aroused light, so reducing their protecting potential against UV rays
lively interest since, in addition to the already known proper- and giving rise to allergenic derivatives (Perioli et al., 2006).
ties of increasing the solubility of many substances, they Endogenous alterations caused by the light can also occur
have also been shown to provide valid photoprotection.
after drug administration for interaction of the drug with
Supramolecular chemistry is based on two distinct concepts:
endogenous molecules. A well-known example is the irrevers-
the self-assembly process, of which liposomes represent the
ible binding of photo-excited psoralens to lymphocytes
most well-known matrix, and the host-guest inclusion chem-
because of UVA absorption (Song & Tapley, 1979). Two
istry including cyclodextrins as the most representative
reviews in 1991 and 1997 discuss in depth the phototoxic
example. The host component generally consists of organic
and phototherapeutic problems of the drugs (Beijersbergen
molecules forming a central cavity in which the drug, namely
Van Henegouwen, 1991, 1997). Other documents with lots of
the guest, is incorporated. The chemical bonds established
information on this subject have been published in 2004 and
throughout the host–guest complexes are necessarily weak,
2008 (Henry et al., 2009; Tønnesen, 2008).
noncovalent bonds.
In this review, the studies dealing the use of liposomes
and cyclodextrins (CD) for the drug photoprotection, will be Supramolecular matrices
presented. Since these supramolecular systems have also been
applied in nonstrict pharmaceutical field but also in related Supramolecular chemistry involves only reversible interac-
areas such as cosmetics and supplements, their application to tions, such as hydrophobic and hydrogen bonds, van der
some vitamins and sunscreens is also cited in this review, given Waals and ion–ion interactions. The number of scientific
the high light sensitivity of many of these compounds. papers in the supramolecular chemistry field is today impres-
Despite the fact that the study on the supramolecular sys- sive and growing day by day up (Atwood & Steed, 2004;
tems and their application in the pharmaceutical field started Lehn, 2005; Ariga & Kunitake, 2006; Schalley, 2007; Jones,
many years ago, the review focuses on the latest findings 2008). Over time, supramolecular chemistry has become an
and collects works published over the last twenty years. important topic in contemporary chemistry, showing remark-
able advancements in the areas of chemistry, biochemistry,
biology, environmental and materials science.
Photoxicity of drugs
Molecular self-assembly is a process capable of generating
Phototoxicity is a skin irritation induced by chemical products a structural arrangement of particular molecules without
(e.g. drugs) which react to light, usually causing more or less any external forces participation. Micellar structures and
 DRUG DELIVERY 35

liposomes represent the most studied self-assembly aggre-

gates. The most interesting property for such matrices is their
capacity of dispersing a compound in a certain solvent, in which
it is normally insoluble, by incorporation into their nucleus.
Nowadays, pharmaceutical formulations based on micelles
or liposomes are largely used as drug delivery systems
(Figure 1). Owing to their small dimension, liposomes can be
targeted to highly vascularized zones, such as inflamed or
cancerous tissues (Ramamurthy, 2000; Pillai & Panchagnula,
2001; Vincenti & Irico, 2002; Zarif, 2002; Al-Jamal et al., 2005).
CD, but also calixarenes, porfirins and crown ethers, result
also of great interest in the host-guest chemistry and are
potentially useful for a rationale design of controlled release
Figure 1. Liposome for drug delivery.
of drugs (Figure 2), also because the absence of any relevant
toxic or antigenic effect (Zhang & Cao, 2001; Yang & De different nature due to their structural affinity with biological
Villiers, 2004). Recent approaches to the controlled release of membranes.
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drugs involve incorporation of the drugs into the matrix of The high penetration in the tissues and the controlled
microscopic polymer particles or solid systems as micro- release of drugs is another advantageous property for lipo-
spheres or microcapsules. somes as a vehicle system (Ahmed & Goldberg, 2004;
Optimum temperature conditions for the storage of lipo- Immordino et al., 2004; Basu, 2005; Smith, 2005;
somes and CD are below 10
C. Liposomes stored in buffer at Uhumwangho & Okor, 2005; Go
mez-Hens & Fern
andez-
pH 7.4 and 4
C do not show structural changes for 2- Romero, 2006; Kassem et al., 2006). Several medical and cos-
3 weeks. After this time, the system destabilizes with the metic formulations in liposomal matrices are today on the
release of free fatty acids generated by lipid hydrolysis. CD market (Cheng et al., 2004; Rao et al., 2004; Verma et al.,
solutions can be stored for several weeks at room tempera- 2004). Liposomes have been proposed for topic preparations
ture. However, over 25
C, the hydrolysis of the structure due to a significantly increase in drug absorption rate (Fang
shows a degradative ring opening. et al., 2006; Ning et al., 2006). Several vaginal formulations are
based on the incorporation of drugs into liposomes due to the
Properties and use of liposomes in pharmaceutical long lasting release and an improved bioavailability of the drug
field as well (Ning et al., 2005, 2006, Paveli
c et al., 2001, 2005).
Liposomes result of great interest in the anticancer
Liposomes are spherical vesicles formed by phospholipids or chemotherapy since they can increase selectively the drug
amphipathic lipids bilayer. The most used lipids are phos- release to the cancerous tissue with respect to normal tis-
phatidylcholine and phosphatidyl-ethanolamine, made of a sues, thus limiting ordinary side effects of the chemotherapy
long hydrocarbon chain headed with a cation or anionic moi- agents (Allen & Martin, 2004; Pan & Lee, 2004; Straubinger
ety. Intermolecular forces driving the spontaneous formation et al., 2004; Andresen et al., 2005). Doxorubicin release from
of the vesicles in aqueous media are represented by hydro- light sensitive liposomes proved to be capable of promoting
philic interactions between the ionic ends and hydrophobic cell death (Yavlovich et al., 2011). Furthermore, a complex lip-
interactions. Hydrogen bonds with water molecules partici- osomal system including doxorubicin and one of its photo-
pate to the assembly process (Uhumwangho & Okor, 2005). sensitizer has been assembled in order to treat cancer with
Liposomes are constituted by lipid bilayers, even the multila- magnetic hyperthermia, photodynamic therapy and chemo-
mellar ones, the overall dimensions varying from 20 nm to therapy, at the same time (Shah et al., 2016).
several micrometers. The use of liposomal matrices in the In the modern pharmaceutical industry, niosomes are
pharmaceutical field is well known today. Liposomes are often used as an alternative to liposomes. Niosomes are non-
already used for the formulation of drugs (e.g. insulin, antitu- ionic liposomes with dimensions lower than 200 nm formed
mor agents) and vaccines or enzymatic preparations. of amphiphilic nonionic synthetic lipids organized in a bilayer
Hydrophilic drug molecules can be trapped after inter- membrane. A preparation of pro-niosomes charged with tre-
action with the charged ends, while lipophilic drugs are tinoin was developed for improving drug efficacy and
incorporated into the phospholipidic layer or dissolved in the patient’s compliance, by the reduction of side effects. This
aqueous core (Torchilin & Weissig, 2003; Uhumwangho & new formulation effectively showed an improved efficacy
Okor, 2005). The success of liposomes for pharmaceutical, together with a low skin irritation potential when compared
but also cosmetic, applications is firstly due to a good bio- to commercially available medicinal products on a number of
compatibility of their components, devoid of any toxic effect, volunteers (Rahman et al., 2014).
and to their ability in including both lipophilic and hydro-
philic substances. Later, liposomes also gained interest for
Liposomes as drug stabilizers
the ability to protect the incorporated substances from
chemical and physical agents. Liposomes are today consid- The characteristic function of liposomes to include substan-
ered as a model for the vehiculation of substances of ces of different nature has led many researchers to study
 36 G. IOELE ET AL.

Figure 2. Cyclodextrin: chemical and toroid structures.

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their application as degradation-preventing systems. liquid formulations of 1,4-dihydropyiridines, currently formu-

(Crosasso et al., 2000; Pietzyk & Henschke, 2000; Fatouros & lated only in tablets.
Antimisiaris, 2002). Some reviews summarize the contribu- Tretinoin (all-trans retinoic acid) is widely used for the
tions of many authors on the use of liposomes for the light treatment of acne vulgaris and others keratin related diseases
protection of drugs and cosmetics during the last decades of as well. The drug is used mostly in the acne local therapy
the twentieth century (Bisby et al., 2000; Brisaert et al., 2001; with an unavoidable light exposure. Topic applications are,
Ragno et al., 1993, 1995, 2006a, 2006b). Subsequently, many however, limited by the high liability of the molecule to pho-
other interesting studies and reviews in this field have been todegradation, suggesting the development of photo-pro-
published, which we are looking at in this review to report tected formulations. Tretinoin undergoes photodegradation
the main ones. to the 13-cis isomer which in turn is transformed to the 9-cis
Incorporation into liposomal systems has been deeply isomer, even though the most important step is the first iso-
investigated for drugs belonging to the class of 1,4-dihydro- merization of retinoic acid (Brisaert, 2000). The inclusion of
pyridines, known to be photosensitive and leading in most tretinoin into liposomes showed a significant increase in light
cases to the corresponding pyridine derivatives, devoid of stability, reducing almost completely the isomerization pro-
any therapeutic activity (Ioele et al., 2009). In particular, inclu- cess. Tretinoin showed a residual concentration of 60% after
sion of amlodipine showed a high protection degree with a a light irradiance of 3470 kJ/min m2, versus a value of 8% of
the ethanol solution (Ioele et al., 2005). Photostabilization of
rate of degradation comparable to that of solid pharmaceut-
tretinoin was also investigated in niosome matrices using a
ical formulations. The experiments were monitored by UV
30 W UV lamp set at 366 nm, showing a protection profile
spectrophotometry. Liposome and CD complexes showed a
even better than one resulting from liposome inclusion
degradation of 10%, respectively, at 220 and 480 min, com-
(Manconi et al., 2003, 2006).
pared with a value of only 10 min for the ethanol solution.
Some good results have been also obtained from the
Amlodipine pure powder and commercial tablets showed a
development of delivery systems for protein and peptide
10% degradation after 325 and 110 min. (Ragno et al.,
drugs (Goto et al., 2006). Sericin is a protein largely employed
2003a).
as a nutrient biomaterial for biomedical and cosmeceutic
The previous study was extended to a number of analogs
applications, despite its low stability to heat and light. The
with the aim of developing photostable liquid preparations protein was charged into copolymer-liposomes and stored at
as an alternative to solid formulations (Ragno et al., 2006b). different temperatures: 4, 30 and 45
C. The complex showed
Analogously to amlodipine, the liposome incorporation of high efficiency in the stabilization of structure and concomi-
felodipine, nitrendipine, nimodipine and nicardipine showed tantly caused improved dispersibility and biofeasibility
a satisfactory stability degree. The liposome inclusion allowed (Suktham et al., 2016). Additionally, this formulation proved
a mean drug recovery of 77%, after a light exposure of to be noncytotoxic to human normal cells even at high con-
30 min of irradiation (21 kJ/min m2). Stability proved to pro- centration (10 mg/mL).
portionally depend on the quantity of incorporated drug. A Some antibiotic agents have also demonstrated photol-
main drawback encountered in this work was the limited ten- ability and attempts to minimize degradation have been pro-
dency of these drugs to be included into the liposomal cav- posed by incorporation into liposomal systems. Among the
ities. In fact, the presence of bulky functional groups on both antibacterial agents, fluoroquinolones give rise to phototoxic
rings of the dihydropyridine derivatives made difficult their side effects from the formation of reactive oxygen species
incorporation, with respect to compounds with low molecu- after UV rays exposure. Photodegradation of ciprofloxacin,
lar weight and high hydrophilicity. A real benefit from studies ofloxacin and lomefloxacin has been investigated under sev-
on supramolecular complexes could be the preparation of eral UV radiations amounts (Budai et al., 2008). FS-20 lamp
 DRUG DELIVERY 37

(k ¼ 280–320 nm) was used for irradiation experiments. The based liposphere encapsulation (the degradation rates were
UVB-intensity was kept at 1.1 ± 0.1 mW/cm2 and the irradi- 19.6% and 5.6% for free and incorporated melatonin, respect-
ance was in the range 0–22 kJ/min m2. Lomefloxacin, indi- ively) (Tursilli et al., 2006).
cated by the Authors as the most phototoxic compound, was Since the proneness to the degradation of many vitamins
encapsulated into small mono- and multilamellar liposomes. has emerged, even under light exposure, the attention of
It was stated that the reduction of the photodegradation many researchers has been directed to the use of supra-
process greatly depends on the lipid nature. In particular, molecular systems to define protective systems. It is well
unsaturated fatty acid chains in the liposomal bilayer alter known that vitamin E (a-tocopherol) is photolabile and sev-
the lomefloxacin photodegradation pathway, increasing the eral attempts have been made in order to define photo-pro-
probability of CO2 loss, frequency of dehydrogenation and tective formulations by liposome vesicles incorporation. The
then de-fluorination. The main photoproducts were identified best results was obtained by dispersion of the vitamin in the
by mass spectrometry. Several anticancer drugs are photo- inner phase in the presence of the antioxidant ascorbic acid
sensitive. Due to the high toxicity, these drugs and their in the outer phase. No detectable alteration of the molecule
delivery systems are today widely studied in the pharmaceut- was recorded up after a nine hours irradiation time under
ical technology field and many of these studies are devoted UVB lamp in a range of 290–320 nm (Gallarate et al., 2004).
to the development of photo-protected formulations. The The use of liposomes to incorporate sunscreens has also
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high sensitivity of doxorubicin to natural or artificial light is yielded effective results. The encapsulation of the sunscreen
well known and this represents a relevant drawback since avobenzone into liposomes using isolecithines resulted
the drug presents a long half-life and accumulates into the highly efficient. A degradation of 22.07% against 32.96% of
derma, where the light exposure is more likely. Doxorubicin nonencapsulated avobenzene was recorded when subjected
encapsulated in polyethyleneglycol-coated liposomes was to irradiation in a solar simulation chamber at a power of
more stable in comparison to the photodegradation of the 1000 W/m2 for one hour (Madrid & Cabrera, 2011).
free drug and not influenced by concentration. During and In using the niosomes as an alternative to the liposomes,
after UV exposure, there was no release of the drug from lip- an interesting approach is the use of niosome vesicles made
osomes to the medium. After induced release of the drug, of nonionic surfactant, developed by Abdelkader et al. (2012)
the degradation kinetics of doxorubicin was identical to that to attempt autoxidation prevention of naltrexone hydrochlor-
of free drug (Bandak et al., 1999). ide. This drug is a promising agent for the treatment of cor-
The main metabolite isolated from Pothomorphe umbel- nea diseases associated with diabetes mellitus (diabetic
lata, namely 4-neroylcatechol, was complexed with liposomes keratopathy). Unfortunately, naltrexone suffers from stability
in order to evaluate the drug stability and the cytotoxicity problems due to autoxidation reactions. An aqueous solution
profile. The complex was subjected to forced degradation of the drug was maintained under exposure to artificial day-
and monitored by HPLC. The liposome complex resulted able light (10.000 lux) causing a remarkable drug degradation. The
to reduce the degradation rate in all the attempted condi- niosome formulations were shown to be able to significantly
tions, showing a half time 15% higher with respect to the (p < .05) protect the incorporated drug from photo-promoted
pure compound. Interestingly, contrariwise to the behavior of oxidation. A 1–3-fold decrease was estimated for the drug
the free drug, the liposome complex showed to be able to encapsulated in niosomes compared with the drug solution.
protect the erythrocytes from lysis (Gaeti et al., 2014). In the last few years, the attention of many researchers
Photostability of supramolecular structures charged with has been attracted by the inclusion of the binary complex
(E)-resveratrol, together with the skin penetration profile of CD/drug into liposomes. The effect coming from the two
nanostructured formulations, was investigated. Several supra- matrices combination seems able to offer effective drug pro-
molecular structures such as liposomes, lipid-core polymeric tection against several degradation agents. Photostability of
nanocapsules, nanospheres and solid lipid nanoparticles, barnidipine in combined CD/liposomes was investigated with
were designed as carriers for this nutraceutical compound. the aim to prepare liquid formulations of this drug, as an
Liposomes resulted as the most effective matrix for long pre- alternative to the solid commercial specialties (Ioele et al.,
serving resveratrol concentration. On the other hand, the 2014). The residual percentage of barnidipine in liquid prepa-
small size complexes showed a reduced physical stability rations of liposomes and CD was 42.90 and 72.03%, respect-
under UVA radiations (Detoni et al., 2012). New and more ively, compared with a value of 29.81% for the drug in
thorough studies are today needed to optimize the vehicula- ethanol, after a radiation exposure of 225 kJ/minm2. When
tion in liposomes of resveratrol, but also of other nutraceuti- the drug–CD complex was in turn entrapped in liposomes, a
cals, also because of the increasing importance that these residual percentage of 90.78% was reached, very close to the
substances are taking for the human health. value of 96.03% carried out in degradation of tablet
The effect of lipid microparticles carrier systems on the formulations.
light-induced degradation of melatonin was also investigated. Incorporation of the hydroxypropyl/CD complex with the
Photodegradation experiments were carried out by using a sunscreen butyl methoxydibezoylmethane into lipospheres
Xenon lamp, wavelengths under 290 nm were filtered and was studied in order to assess the effectiveness of this sys-
temperature was maintained under 30
C. The solar simulator tem on drug photostability. The incorporation ternary system
emission was maintained at 500 W/m2. Photolysis experi- proved to be more effective than the binary complex or the
ments demonstrated that melatonin photo-decomposition simple drug/liposphere complex in improving photostability
markedly decreased after tristearin and phosphatidylcholine- of the drug. The samples were irradiated by a solar simulator
 38 G. IOELE ET AL.

Table 1. Papers concerning the photostabilization of drugs by liposome in the oligomer structure, wherein they are safely stored and
incorporation.
protected from air and external oxidation agents. For all
Drug Photostabilization in liposomes these reasons, CD have now become the most important
1,4-Dihydropyridines Ioele et al., 2009; Ragno et al., 2003a, 2006b
inclusion system in pharmaceutical field as well as in food
4-Nerolidylcatechol Gaeti et al., 2014
alpha-Tocoferol Gallarate et al., 2004 and cosmetic manufacturing. CD and several derivatives are
Amlodipine Ragno et al., 2003a studied as pharmaceutical excipients to improve water solu-
Anethole Gharib et al., 2017
Avobenzone Madrid & Cabrera, 2011
bility, stability and bioavailability.
Barnidipine Ioele et al., 2014 From a structural point of view, CD are cyclic oligosacchar-
Butyl methoxydibenzoylmethane Scalia et al.,2006 ides formed of glucopyranose monomers linked by a-(1,4)-
Doxorubicin Bandak et al., 1999
Fluoroquinolones Budai et al., 2008 glyosidic bonds. Based on the number of monomers (6, 7 or
Melatonin Tursilli et al., 2006 8), they are called a, b or c CD. The spatial arrangement of
Naltrexone Abdelkader et al. 2012 CD defines a sort of frustum of cone rigid shape with an
Penicillins and cephalosporins Uhumwangho & Okor, 2005
Resveratrol Detoni et al., 2012 inner hollow capable to accommodate a variety of functional
Sericin Suktham et al., 2016 substances. The structure presents a hydrophilic outer surface
Tretinoin Brisaert, 2000; Brisaert et al., 2001; while the inner surface of cavity is almost hydrophobic.
Ioele et al., 2005 Manconi et al., 2003;
Manconi et al., 2006 Similarly to liposomes, the complexes of CD/compounds are
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based on reversible interactions such as hydrogen bonds and

London dispersion forces.
equipped with a Xenon lamp, an optical filter to cutoff wave- Some recent reviews are particularly rich in information
lengths shorter than 290 nm and an IR-block filter to avoid about CD and their application in the pharmaceutical field
thermal effects. The solar simulator emission was maintained (Cagno, 2017; Iacovino et al., 2017).
at 500 W/m2 (Scalia et al., 2006). The most common application of CD in the pharmaceut-
A drug-in-CD-in-liposomes was applied as a carrier system ical field is toward the increase of drug solubility in aqueous
for anethole, an essential oil component. The free compound media. However, a remarkable role for CD refers to their cap-
in aqueous solution was found to be unstable upon exposure acity to protect drugs from different degradation processes.
to UV irradiation. Under irradiation, anethole disappeared In particular, CD are studied for their potential of stabilizing
completely after 2 h. Hydroxypropyl-b-CD/anethole inclusion several reactive cytotoxic drugs (Chakraborty & Naik, 2003). A
complexes were encapsulated into liposomes and exposed to number of ocular formulations including such inclusion sys-
UV light. Compared to the aqueous solution, a protection tems are already on the market (Sigurdsson et al., 2005).
factor of 66.7 times was obtained (Gharib et al., 2017). Moreover, administration of drugs by inhalation could take
Due to their lipid-based structure, liposomes themselves advantage by CD vehiculation, leading to an improved
showed to be in turn sensitive to light (Bisby et al., 2000). absorption of various steroids, peptides and proteins (Gu
Therefore, a careful monitoring of the photostability of lipo- et al., 2005; Arima et al., 2017; Wei, 2017).
somal matrices is always required. Since degradation is pro-
moted by both temperature and light exposure, low
Cyclodextrins as drugs stabilizers
temperature and light shielding are required during lipo-
somes manipulation and storage. The addition of anti-oxidant The potential of CD in improving the stability of drugs has
agents could be desirable to optimize the stability of been widely investigated in pharmaceutical technology. A
preparations. number of molecules entrapped in CD matrices have shown
Table 1 summarizes the literature meaning on the photo- an improved stability under various stressing conditions of
stabilization approaches by incorporation in liposomes. light, heating, oxidation agents, moisture. Many citations
regarding the ability of these matrices to protect the drugs
from light are also provided. Some reviews published some
Characteristics and use of cyclodextrins for
years ago provide very detailed information on the use of CD
pharmaceutical applications
in drug delivery and especially for topical formulations. Many
CD are known since 1953, but their wide application in references regarding the ability of these matrices to protect
pharmaceutical formulations was precluded by the high pro- the drugs from light are also provided. (Cal & Centkowska,
duction costs. During the 1970 s, the production was greatly 2008; Challa et al., 2005). Usually, the drug/CD ratio is 1:1
implemented due to the progress of biotechnology, which and the complex stability is generally higher at low tempera-
led to a significant cost cutting. Studies on the utilization of ture (Loftsson et al., 2001; Valle, 2004).
CD in the formulation of supramolecular matrices rose in Similarly to the liposomal systems, photodegradation of
turn up. Today, CD are produced at a reasonable cost directly 1,4-dihydropyridine antihypertensive agents, very sensitive to
from starch under the action of CD glycosyltransferase light, can be greatly lowered by CD incorporation, as
(CGTase), an enzyme easily accessible from various cultures reported by several recent studies herein reported.
of bacteria. A storage temperature of 2–8
C is required. Nifedipine, the lead compound of this series, proved to note-
CD are characterized by a high inclusion potential toward worthy gain stability after complexation with hydroxypropyl-
many compounds and the absence of evident toxic effects as CD and dimethyl-CD, even in solid state (Bayomi et al., 2002).
well. The functional molecules are complexed within a hollow Photochemical degradation of a series of 1,4-dihydropyrine
 DRUG DELIVERY 39

derivatives was investigated by comparing the free com- more stable than the pure drug after 4 days irradiation (Park
pounds with their corresponding CD complexes. The samples et al., 2013). Improvement of photostability of clinidipine was
were exposed to UV radiation by a Fluotest lamp, model NN also attempted. The drug was mixed with hydroxyl-b-propyl
15/30, k ¼ 254 nm from a 30 cm distance. Photodegradation CD and the results obtained after light exposure (4500 lx at
was found to be dependent on the position of the NO2 40
C) proved an increased stability for the complexed drug
group in the phenyl ring. Degradation rate of the ortho-iso- while the dispersibility increased by 10,000-fold (Hu et al.,
mer in the CD complex was 200 times slower than that for 2012).
this compound in the solid phase. In contrast, the presence Tretinoin is a very photosensitive compound, as above
of halogen groups caused a 4-fold increase in the photode- described (Brisaert, 2000). CD showed a good protective
gradation rate (Mielcarek, 1997). Photochemical transform- action for this drug, with only a minimal degradation after
ation of manidipine leads to both nitro-phenylpyridine and 48 h in phosphate buffer, pH 7.4 (Semenova et al., 2002). In a
nitrous-phenylpyridine derivatives. In this case, CD complex- subsequent study, tretinoin samples, in incubator at 37
C,
ation reduced the photodegradation rate, although to a 30 cm from three 6 W fluorescent tubes, showed a decrease
lesser extent with respect to analogs belonging to the same to the 20% of its initial drug concentration in 30 min, leading
series (Mielcarek & Szamburska, 2005). Photostability of amlo- to a number of by-isomers, some of them being toxic.
dipine was also checked in CD as well in liposomes and Complexation with a-CD and hydroxypropyl-b-CD resulted in
a stability increase, while incorporation into b-CD did not
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microspheres (Ragno et al., 2003a). The best results were

obtained by CD inclusion complex, which showed a 90% produce any significant photoprotective effect (Yap et al.,
residual degradation after nine hours of light exposure. 2005). In this study, molecular modeling was adopted to illus-
A comparative study on the effects of photoprotection by trate the complexation structures, proposing the computa-
supramolecular systems on eleven 1,4-dihydropyridine deriva- tional molecular modeling as a valid approach to predict
tives was also performed (Ragno et al., 2003b). Lacidipine, binding and protecting ability of various CD.
manidipine, nifedipine and nimodipine resulted the more In another paper, stability of free tretinoin in methanol
sensitive molecules, as they degraded less than 50% after and the complexed drug with b-CD was compared (Caddeo
5 minutes, in aqueous solution. The best results in photosta- et al., 2007). The drug/CD complex showed a clear increase
bilization were obtained for amlodipine, felodipine, nisoldi- in drug stability, under exposure to both UV and fluores-
pine and nitrendipine complexed with CD. A mean drug cence light. The amount of intact drug was 20–25% in com-
recovery of 90%, after 30 min of light exposure with an inten- plex form after 30 days under light, compared to the
sity of 21 kJ/min m2was carried out from CD inclusion com- complete degradation of the free form after the same time.
plexes. It was also established that steric factors greatly CD proved to be ideal vehicle agents also for anti-inflam-
influence the drug incorporation rate into CD and therefore matory preparations. Photolability of naproxen in aqueous
the photostabilization grade. In fact, lercanidipine and mani- solution, exposed under six 40 W fluorescence lamps, was
dipine, both bearing bulky substituents, showed a low drug significantly reduced by addition of polyvinylpyrrolidone to
inclusion value with a consequent less marked increase of the complex of the drug with hydroxypropyl-b-CD (Valero &
photostabilization. Esteban, 2004). Complexation of diflunisal, which is known to
Photostability studies of nicardipine were performed by induce phototoxicity, with CD showed a high rate of photo-
inclusion complexes with various CD and exposed to stabilization of the drug (Sortino et al., 2003). Complexes of
UVA–UVB radiations (Xe-arc lamp) for increasing irradiation sulfanilamide with b-CD and hydroxypropyl-b-CD were pre-
times. The photodegradation process was monitored by pared and subdued to stressing light. The latter complex
capillary electrophoresis, able of achieving enantio-resolution proved to be more photo-stable than the pure drug and the
of the racemic form (Pomponio et al., 2004). b-CD, hydroxy- b-CD complex as well (Taci
c et al., 2014). Sodium diclofenac
propyl-a-CD and (2-hydroxyethyl)-a-CD showed a photopro- was complexed with hydroxypropyl-b-CD and the subsequent
tective effect, while c-CD, methyl-b-CD, hydroxypropyl-b-CD, physic-chemical characterization was performed in order to
hydroxypropyl-CD and c-CD did not promote any increase in evaluate drug photo-stability. The results demonstrated that
photostability. Stereoselective photodegradation of rac-nicar- the photochemical degradation rate of the complexed drug
dipine was observed for the b-CD complex and two distinct was significantly reduced when an optimal 4:1 host:guest
photodegradation profiles, with different kinetic constants, ratio was used (Manikandan et al., 2016). Rhein, a major
were observed for the two enantiomers. These results are metabolite of the prodrug diacerein is used in the treatment
very interesting because suggest, in any case, the possibility of osteoarthritis and diabetic nephropathy. Its incorporation
of different photodegradation profiles for the enantiomers of in CD in a 1:1 host-guest system seems to efficiously improve
a chiral photoreactive drug. both dispersibility and stability when exposed to the visible
Sublingual tablets of isradipine and b-CD were developed light of a lamp (800 lx) (Petralito et al., 2009).
in order to optimize administration of this drug. Photodegradation is also considered important for the
Photostability studies were conducted by differential scan- antihistaminic drugs, which are often administered topically
ning calorimetry and X-ray diffraction. The complexed drug and therefore more exposed to effects of light. The effect of
was more stable if compared to the pure drug and the dis- b-CD complexation on the photostability of antazoline, xylo-
persibility was also improved (Himabindu et al., 2013). In metazoline and nafazoline was studied. Molecular mechanics
another paper, tablets prepared by direct compression of the allowed to set a 1:1 ratio structure for the inclusion com-
CD complex with hydroxypropylmethylcellulose resulted plexes, which in turn gave an idea about the energetically
 40 G. IOELE ET AL.

preferential structure of the complexes and consequent Table 2. Papers concerning the photostabilization of drugs by cyclodextrin
incorporation.
increase in stability (Bani-Yaseen et al., 2009). A significant
reduction of photodecomposition was also obtained after Drug Photostabilization in cyclodextrins
complexation of triprolidin (Ndlebe et al., 2004). 1,4-Dihydropyridines Mielcarek, 1997; Ragno et al., 2006b
13-cis-Retinoic acid Yap et al., 2005
Several sunscreens complexed with b-CD have been 3-Hydroxyflavone Tommasini et al., 2004
tested to verify possible photostability increases. The com- 4-Methylbenzylidene camphor Scalia et al., 2007
plex interaction of the sunscreen 4-methylbenzylidene cam- 5-Hydroxyflavones, flavonols Smith et al., 2000
Amlodipine Ragno et al., 2003a
phor with a-hydrophylic-CD, b-CD and c-CD in aqueous Antazoline, Xylometazoline, Bani-Yaseen et al., 2009
solution was studied by exposition in a solar simulator Nafazoline
equipped with a Xenon lamp, an optical filter to cut off Ascorbic acid Garnero & Longhi, 2010
Carvedilol Savic-Gajic et al., 2016
wavelengths shorter than 290 nm and an IR-block filter to Cilnidipine Hu et al., 2012
avoid thermal effects. Irradiation was fixed at 750 W/m2. The Diclofenac Manikandan et al., 2016
light-promoted degradation markedly decreased for the b-CD Diflunisal Sortino et al., 2003
Doxycycline Kogawa et al., 2014; Savic-Gajic et al., 2016
complex with a rate of 7.1% for the complex versus 21.1% Isradipine Himabindu et al., 2013; Park et al., 2013
for the free drug, as calculated by HPLC (Scalia et al., 2007). Lansoprazole Lu et al., 2012
Flavonoids are a well-known class of natural pigments play- Manidipine Mielcarek & Szamburska, 2005
Methotrexate Bourkaib et al., 2013
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ing a protective role in plants toward low wavelengths. This Naproxen Valero & Esteban, 2004
property is considered potentially useful for the protection of Nicardipine Pomponio et al., 2004
biological targets such as lipids, proteins and coenzymatic Nifedipine Bayomi et al., 2002
Ofloxacin Pandya et al., 2010
factors. The most representative members of this class, show- Oxolinic acid Orfanou et al., 2009
ing a 3-OH-flavonoid structure, present significant photoreac- Phenylpropanoids Kfoury et al., 2016
tivity (Smith et al., 2000). Pure flavonoid molecules and CD- Quercetin Anandam & Selvamuthukumar, 2014
Ranitidine Jamr
ogiewicz et al., 2014
encapsulated version were exposed to UV-A radiation in a Retinol Semenova et al., 2002
chamber emitting in the range 310–390 nm. Once again, the Rhein Petralito et al., 2009
inclusion process showed a ca. threefold reduction of the Sulfanilamide Taci
c et al., 2014
Tretinoin Caddeo et al., 2007
photodegradation quantum yield (Tommasini et al., 2004). Triprolidine Ndlebe et al., 2004
The photoprotective ability of CD has been also tested on
chemotherapeutic drugs. The effect on oxolinic acid, a bac-
tericidal chemotherapeutic belonging to the quinolone fam- The inclusion in a CD complex largely prevents transform-
ily, effective in the treatment of acute and chronic infections ation, probably due to the inclusion of the sensitive furan
of the urinary tract, was checked by complexation with moiety of the molecule into the CD cavity (Jamro
giewicz
hydroxypropyl-b-CD. The careful examination of photodegra- et al., 2014).
dation profile confirmed a first-order kinetics reaching photo- Other photosensitive drugs, belonging to different thera-
stabilization peak up to 94% (Orfanou et al., 2009). Ofloxacin, peutic classes, have been incorporated into CD to minimize
an effective fluoroquinolone derivative, which suffers from a degradation. The inclusion complex of b-CD with methotrex-
marked photochemical sensitivity, was complexed with b-CD. ate has been prepared with the aim to improve drug water
An increase in solubility of the drug was the unique result solubility and, at the same time, decrease drug photosensitiv-
obtained, since any reduction of unstability of the drug was ity. Light decomposition markedly decreases after complex-
not detected in this case (Pandya et al., 2010). Effects of ation (Bourkaib et al., 2013).
encapsulation in CD on solubility, photostability and antifun- Photostability of ascorbic acid was studied by comparison
gal activities of some phenylpropanoids were investigated. of a ternary triethanolamine and b-CD complex and a quater-
Photodegradation experiments were carried out by using 10 nary complex obtained by further addition of hydroxypropyl-
UVC lamps (254 nm, 15 W) and a Multirays apparatus. Results b-CD under artificial and diffused light. Sample solutions
showed that encapsulation in CD significantly increased dis- were irradiated with a Philips mercury arc lamp (range
persibility and photostability of the studied drugs (from 2- to 312–577 nm) transmitting light corresponding to exposure
17-fold and 2- to 44-fold, respectively). Encapsulation of phe- behind a glass window. Another set was positioned under
nylpropanoids, despite a reduced antifungal activity, could daylight fluorescent tubes (Philips, TLT 40 W/54, range
be helpful to solve drawbacks such as solubility and stability 400–600 nm). The obtained data showed that these com-
(Kfoury et al., 2016). plexes strongly reduce the drug photodegradation in a range
Some antireflux drugs also show degradation under light. of 11- to 35-fold, depending on the ligand concentration and
Lansoprazole, a proton pump inhibitor, was studied after the irradiation source (Garnero & Longhi, 2010).
complexation with b-CD and 2-hydroxypropyl-b-CD. The drug Quercetin is a flavonoid endowed with a strong antioxi-
solubilization rate and stability significantly improved in both dant activity and it is present in a variety of vegetables and
complex preparations. The first complex resulted more stable fruits. Its application in nutraceutical products is, however,
under lightening than the corresponding b-CD one, due to limited by low water solubility and scanty stability. In a
the inclusion of the sulfonyl moiety into the CD cavity (Lu recent study, both dispersibility and stability of quercetin
et al., 2012). The photo-oxidation process of ranitidine in were improved by complexation into nano-sponges CD
solid state, irradiated for 48 h in a stressing light cabinet, based. Five different types of nano-sponges were assembled
leads to variation of its color and unpleasant odor as well. by reacting varying amounts of diphenylcarbonate with
 DRUG DELIVERY 41

b-CD. Dissolution of quercetin-containing nano-sponges was can affect the performance of drug/CD complex. It is neces-
significantly greater than the free drug itself and a remark- sary to take into account the dimensions of the CD cavity
able increase of photostability was also achieved (Anandam and the drug to be incorporate, the charge of the drug,
& Selvamuthukumar, 2014). The antibiotic doxicyclin is a which can be influenced by the pH of the environment and
drug highly sensitive to light, so limiting the stability of its varying the strength of the complex.
pharmaceutical formulations. Once more, the inclusion of the The supramolecular systems that are generating great
drug into CD gave rise to a complex characterized by a interest in the pharmaceutical field are based on drug–cyclo-
higher drug stability in aqueous solution (Kogawa et al., dextrin complex incorporated in turn in the aqueous core of
2014; Savic-Gajic et al., 2016). liposomes, by defining the so-called drug-in-CD-in-liposomes
The most important studies regarding the incorporation of systems (Hatzi et al., 2006; Piel et al., 2006; Salem &
drugs in CD matrices for stabilization aims are summarized in Du€zgu€nes, 2003). The use of these matrices could be par-
Table 2. ticularly advantageous for photosensitive drugs that achieve
greater protection from light.
Supramolecular system-based drug delivery systems are
Conclusions and perspectives
proving to overcome the limitation of conventional drug
Studies on drug degradation are receiving great attention delivery systems, mainly characterized as controlled release
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from the scientific community. One of the main impulses in systems and targeted drug delivery systems. The main
this research field lies in the toxicity acquired by some drugs objective is to obtain systems with good loading and con-
after exposure to light. Drug-induced photosensitivity is obvi- trolled release of drugs, at the same time characterized by
ously more commonly found for topical applications, often low toxicity.
causing skin irritations, but also oral or parenterally adminis- In any case, the studies on photostability and the applica-
tered drugs can induce phototoxicity. Generally, the amount tion of photostability tests conducted under international
of drug needed to cause photoallergic reactions is consider- guidelines remain an important part of the formulation stud-
ably lower than that required for phototoxic reactions. ies, enabling the development of stable, safe and effective
In order to avoid such risks, proposals are being multiplied products.
to provide maximum photoprotection to drugs and thus min-
imize the effects of light on the integrity of products and
their therapeutic activity. The definition of photoprotective Disclosure statement
systems seems to be of paramount importance in the mod- The authors report no conflicts of interest in this work.
ern pharmaceutical industry. Recent studies are focusing on
new formulations that incorporate the drug into macromole-
cules that can exert physical light protection. Among them, Funding
supramolecular systems are characterized by trapping the Ministero Istruzione Universita Ricerca (MIUR), Italy, grant 2016.
drug into a cavity of their structure, involving only weak
binding interactions.
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