Medicina (Kaunas) 2011;47(Suppl 2):49-55
49
Selection of the Optimal Pharmaceutical Form
of 5-Aminolevulinic Acid and Its Application
in the Treatment of Oncologic Diseases
Vilma Armoškaitė, Kristina Ramanauskienė, Vitalis Briedis
Department of Pharmaceutical Technology and Social Pharmacy, Medical Academy,
Lithuanian University of Health Sciences, Lithuania
Key words: aminolevulinic acid; photodynamic therapy; pharmaceutical form; permeation
through skin; oncologic diseases.
Summary. The aim of this article is to review 5-aminolevulinic acid and its application in the
photodynamic treatment. 5-Aminolevulinic acid is a prodrug widely used in the treatment of different cancer forms, especially skin cancers. The main subjects of this article are different preparations
of 5-aminolevulinic acid, comparison of the methods, excipients, and other factors that have an
impact on the permeation of 5-aminolevulinic acid through skin. Therefore, these factors are extremely important in the evaluation of the quality of the 5-aminolevulinic acid therapy. The optimal
penetration methods and transdermal drug bases for skin permeation are singled out and evaluated.
Medicinal preparations containing 5-aminolevulinic acid and introduced into pharmacy market are
analyzed in the article as well. Therefore, the latest experiments have mostly been performed with
new pharmaceutical forms (gels, microemulsions, patches, etc.) and methods (microdermabrasion,
iontophoresis, laser, etc.) and have shown the greatest efficacy in treating oncologic diseases.
Introduction
5-Aminolevulinic acid (5-ALA) is one of the
most popular prodrugs used in the photodynamic
therapy (treatment of oncologic diseases). Photodynamic therapy (PDT) became more popular in the
last decade; therefore, it is relevant to analyze the
photosensitizing agents and the methods of applying photosensitizing agents to the skin. As it is mentioned in the guidelines for topical photodynamic
therapy (1), PDT is used in the treatment of various
diseases, of which the most important ones are skin
carcinoma, psoriasis, actinic keratoses, genital warts,
etc. It has also been emphasized that the main prodrugs in PDT are 5-ALA and its esters. In recent
years, many investigations considering PDT have
been performed, which confirmed the effectiveness of PDT (2–4). Briefly, it may be assumed that
various different pharmaceutical forms and methods
for increasing the permeation of 5-ALA have been
applied (5). This means that the detailed analysis
of literature data concerning these parameters is required.
Characteristics of 5-Aminolevulinic Acid
5-ALA (C5H9NO3) as a chemical substance is
characterized as a white crystalline powder, which
is flammable, soluble in water, hygroscopic, and
stable under ordinary conditions; its melting point
is 156°C–158°C. 5-ALA comes in forms of a base
Correspondence to V. Armoškaitė, Department of Pharmaceutical Technology and Social Pharmacy, Medical Academy, Lithuanian University of Health Sciences, A. Mickevičiaus 9, 44307
Kaunas, Lithuania. E-mail: [email protected]
and hydrochloride (6). Solutions in water and other
pharmaceutical forms are applied (7, 8). 5-ALA in
solutions where pH is higher than 5 (9) is unstable;
therefore, pyrazine-2,5-dipropionic acid (PY) is
produced by dimerization of the molecule (10, 11).
PY is not applicable in PDT because it does not
respond to a photodynamic effect of light sources.
In some cases, forms of methyl- and butyl-esters of
5-ALA are applied in photodynamic therapy due to
their more lipophilic properties and the difference
of permeation rate and depth to skin and other tissues (2, 8).
5-ALA is also known as the main substrate for
porphyrin synthesis. As porphyrins are one of principal compounds in rapidly dividing cells, this characteristic is used in the treatment of skin cancer and
some other diseases. Two molecules of 5-ALA are
condensed to form porphobilinogen. It is the firststep compound in porphyrin synthesis. Chemically,
porphyrin is classified as a compound of cyclic tetrapyrrolic ring structure joined by 4 methene bridges (=C–) through alpha-carbon atoms of 4 pyrroles.
In addition, porphyrins widely occur in animal and
human tissues and take part in important biological functions. They act as metal-binding cofactors
in hemoglobins and specific enzymes in cell respiration (12, 13).
5-ALA is a precursor of the endogenous photosensitizer protoporphyrin IX (PpIX). PpIX is a
Adresas susirašinėti: V. Armoškaitė, LSMU MA Vaistų technologijos ir socialinės farmacijos katedra, A. Mickevičiaus 9,
44307 Kaunas. El. paštas: [email protected]
Medicina (Kaunas) 2011;47(Suppl 2)
50
Vilma Armoškaitė, Kristina Ramanauskienė, Vitalis Briedis
Fig. 1. The metabolic pathways of aminolevulinic acid in a human (20)
penultimate product in heme biosynthesis (Fig. 1).
If an excess amount of 5-ALA is applied, it results
in accumulation of PpIX through bypass of feedback
inhibition by heme on 5-ALA synthase. Activation
of the sensitizing substance using visible light generates singlet oxygen and other reactive molecules
resulting in selective damage of cells containing the
photosensitizer. The pharmacological mechanism is
based on the fact that photosensitizing agents, in this
case 5-ALA, are normally pharmacologically inactive. After excitation by light of a specific wavelength,
they concentrate selectively in metabolically active
diseased tissue (14, 15). This tissue in many cases
is identified as a tissue under the influence of skin
disease or a cell pool of cancer origin. The photodynamic agents are then converted to active metabolites
to produce an effective reaction affecting the tissue by
the production of cytotoxic free radicals.
5-ALA is administered topically or systemically
and is used therapeutically to treat psoriasis, acne,
various types of neoplasms, superficial basal cell
carcinoma, squamous carcinoma, Bowen’s disease,
actinic keratosis, verrucous hyperplasia, oral leukoplakia, and other clinical entities (2, 16–19).
Comparison of Pharmaceutical Forms and
Guidelines of Their Development. Medicines
Containing 5-Aminolevulinic Acid
Due to the efficacy of agents that incorporate
into the porphyrin biopathway, different medicinal
formulations have been introduced to the pharmacy
market in the United States and the European Union.
Table 1 shows different registered medicinal
products containing 5-ALA and their clinical application. Scientific data suggest that 5-ALA may be
applied on the skin or per os in the form of a solution, cream, powder, ointment, etc. Only some of
the registered medicinal products containing 5-ALA
as an active substance are presented in Table 1. The
common practice in PDT is to manufacture the
ointments or gels ex tempore. These are manufactured in a pharmacy on prescription. In this case, it
is not essential to use an industrially manufactured
and registered product because there is a possibility
to incorporate the active substance (5-ALA) into a
base ex tempore. In some cases, the best decision
is to use formulations ex tempore as 5-ALA is not
stable in preparations stored for a long time after
their manufacturing. In addition, numerous studies on the enhancement of penetration using different excipients have been carried out. To increase
the permeation of topically applied 5-ALA through
the skin, glycerol monooleate or propylene glycol
was used. For example, an addition of 1% of glycerol monooleate to a 5% 5-ALA solution increases
the penetration flux 20 times (24). To mediate the
permeation of orally applied preparations, peptide
transporters (PEPT1) expressed from Pichia pastoris
Medicina (Kaunas) 2011;47(Suppl 2)
5-Aminolevulinic Acid and Its Application in the Treatment of Oncologic Diseases
51
Table 1. Registered Medicinal Products Containing 5-Aminolevulinic Acid and Their Clinical Application
Name of the Medicinal Product, Active
Indications
Substance, Strength, Pharmaceutical Form
Metvixia (methyl aminolevulinate) cream, Metvixia cream in combination with Aktilite CL128 lamp. Red light illumination
16.8%
is indicated for the treatment of thin and moderately thick, nonhyperkeratotic,
nonpigmented actinic keratoses of the face and scalp in immunocompetent patients (20)
Levulan Kerastick (aminolevulinic acid HCl) Levulan photodynamic therapy (Levulan PDT) is an advanced treatment for actinic
keratoses (AKs), or rough-textured, dry, scaly patches on the skin that can lead to
for topical solution, 20%
skin cancer (21)
Gliolan (5-aminolevulinic acid), 30 mg/mL, Gliolan is indicated in adult patients for visualization of malignant tissue during
powder for oral solution
surgery for malignant glioma (WHO grade III and IV) (5, 22, 23)
were used (25). All these abovementioned substances enhance the transport of 5-ALA and increase the
levels of 5-ALA in plasma.
The Application of 5-Aminolevulinic Acid by
Using Different Methods and the Modification
of Skin To Enhance the Penetration of
5-Aminolevulinic Acid
The application of 5-ALA ointment is problematic in terms of its stability, the rate of 5-ALA
to be released into the skin, and the discomfort of
the patients who use the medication. The ointment
containing 20% of 5-ALA is applied as a standard
(4). After the studies on the parameters of 5-ALA
ointments, the issue of stability has been brought
out. Stability of a 5-ALA preparation depends on
pH, concentration, and time of application. Low
5-ALA concentration at physiological pH or lower
is required to assure its stability (26). Unfortunately,
experiments carried out in the Clinic of Skin and Venereal Diseases, Hospital of Lithuanian University of
Health Sciences (former Kaunas University of Medicine), have shown that the ointment was stable only
for 24 hours. Therefore, the patients had to get a prescription for the ointment and make a reservation for
the medication in the evening so that the ointment
was manufactured ex tempore the next morning. The
patient then had to apply the ointment to the skin
and wait approximately for 6 hours for the aminolevulinic acid to permeate the skin and achieve a sufficient concentration for photodynamic therapy. Usually, the medication is applied in the late afternoon,
and the light treatment is performed the next morning. The patient has to assure that he/she will be able
to return for the treatment in 14 to 18 hours as the
treatment in many cases is applied in two stages – in
the morning and in the evening (27, 28).
To solve these problems, different enhancements
in methodology of transdermal application and
pharmaceutical forms are being discussed. In many
cases, the methodology is coherent with the pharmaceutical forms used in PDT (e.g., it is more common
to apply 5-ALA in iontophoresis as a gel preparation
due to the simplicity of ionizing the delivered mol-
ecule in comparison with the lipophilic vehicle, such
as an ointment, in vitro). Different modifications of
skin, such as peeling, laser therapy, microdermabrasior, etc., are applied in order to enhance the permeability of aminolevulinic acid. The efficacy of these
modifications is summarized in Table 2.
The study has shown YAG laser to be the most
effective tool for 5-ALA permeation via skin, followed by iontophoresis, microdermabrasion, and
electroporation (2, 17). It is recommended to apply
these modifications in order to reduce the period of
time required for 5-ALA to fully permeate the skin
and to improve patient comfort.
The permeation is dependent on the pharmaceutical form as well. The pharmaceutical form itself
is determined by its hydrophilic/lipophilic properties, application frequency, and other properties.
The dependence of 5-ALA permeation to the stratum corneum on different pharmaceutical forms is
demonstrated in Table 3. The data in Table 3 show
that hydrophilic gels and patches are more effective
pharmaceutical forms for 5-ALA as compared with
aqueous solutions and ointments – the penetration
increases 2 times.
The optimal penetration is obtained with YAG
laser and microdermabrasion (up to 305 times) in
comparison with passive penetration (Fig. 2). Microdermabrasion itself and iontophoresis are effective as
well, as they increase the penetration rate up to 5–15
times (25 to 75×10–6 cm2/s) (24, 30). Other pharmaceutical forms and methods, such as iontophoresis
with gel preparations, microemulsions, and patches,
also induce enhanced penetration (34, 37, 43).
Different vehicles are used for 5-ALA to penetrate
through skin (34, 48). Some of these vehicles are hydrophilic, amphophilic, or lipophilic. In particular,
oil-based ointment base might be an example of a
lipophilic agent; an amphophilic example of a base is
a sponge phase formed from monoglycerin, propylene glycol, and water. Carbopol might be used as a
vehicle with hydrophilic properties for iontophoresis
(49, 50). The delivery of 5-ALA from these bases
depends on the target tissue (for example, if the target tissue is of lipophilic nature, ointment is the best
Medicina (Kaunas) 2011;47(Suppl 2)
Vilma Armoškaitė, Kristina Ramanauskienė, Vitalis Briedis
52
Table 2. Comparison of Methods and Skin Modifications in the Application of 5-Aminolevulinic Acid
Application Method
Transdermal ointment (20% of
5-ALA in lipophilic vehicle),
passive permeation
YAG (neodymium-doped yttrium aluminium garnet) laser
(no
microdermabrasion)
YAG laser/microdermabrasion
Permeability
The exposure concentration in skin is reached
after 6 hours of exposure (5, 29)
Remarks
The permeation is too long and inefficient. It is essential to optimize it
Iontophoresis (hydrophilic gel as
a vehicle) – no electroporation
Iontophoresis (hydrophilic gel as
a vehicle)/ electroporation
Enhancement ratio increases approximately 15fold in comparison with ointment delivery (31)
The combination of iontophoresis or electropora- Electroporation itself adds up to 2-fold to
tion with the peeling techniques could further
delivery rate
promote ALA delivery to a great extent. The
additive output is greater than in laser/microdermabrasion method (26, 30)
Enhancement ratio is 4–246-fold in comparison
with ointment delivery (24, 30)
Permeation rate increases 4–305 times in comparison with the delivery from the ointment.
Microdermabrasion increases permeation up
to 5–15 times (30)
–
The microdermabrasion procedure was
applied in order to ablate and homogenize
a portion of the stratum corneum layers.
Microdermabrasion, which lasted from
3 to 10 s, had a positive effect on enhancing the transportation of 5-ALA through
skin and the quality of treatment
–
Table 3. The Influence of Pharmaceutical Forms on the Permeation of 5-ALA Through Skin
Pharmaceutical Form
Ointment/cream (passive permeation)
Gel (iontophoresis)
Permeability/Stability
The steady state and active concentration in
skin is reached after 5–6 h (32, 33)
The permeation rate increases up to 20 times
Patch/thin films
Thin films, in comparison with ointment,
increase the rate of 5-ALA permeation about
2 times (the permeation time decreases to 3.5
hours) (36, 37)
There was some enhancement in permeation
indicators with PC, stability and cytotoxicity
data, although GDL produced more PpIX in
the cells (40–42)
Liposome-loaded microsphere
(glycerol dilaurate, GDL;
phosphatidylcholine, PC)
Emulsions/microemulsions
Aqueous solution (20%)
Oil/water emulsions depending on constitutions and penetration enhancers increase the
penetration rate 2–15 times (43)
The permeability is similar to that of passive
permeation from an ointment (44, 45)
Other Remarks
The permeation is too long. The pharmaceutical form needs to be modified
Gel without iontophoresis also increased the
permeation up to 2 times (hydroxyethyl cellulose and cubic gels were used) (33–35)
Passive permeation from patches/film coats is
even higher than of gels (38, 39)
Since it has been reported that the chemical
stability of 5-ALA was preserved in acidic
solution, but degraded quickly under neutral
and basic conditions, 5-ALA was formulated
in a cationic liposome that had acidic pH
–
The instability is significant. Some amounts
of 5-ALA are lost in the process of dimerization
Aqueous solution with iron
Iron chelation does not influence permeability, The method is based on the fact that synthechelating agents
though it influences phototoxicity of permesis of heme requires iron. Due to this fact,
ated 5-ALA, but only when 5-ALA permeates the iron chelating agent (desferrioxamine) is
through skin at low concentrations (46)
added
Microneedle-mediated delivery The permeation is enhanced in deep lesions, It enhances the depth of permeation
such as nodular basal cell carcinomas, or lesions
with overlying keratinous debris (47)
solution for the delivery system or, on the contrary,
if the target tissue is of hydrophilic nature and ionic
content, hydrophilic or amphophilic gels might be
the optimal bases for pharmaceutical forms (1, 49).
Due to the relatively low bioavailability of the
5-ALA molecule, ester derivatives have been designed
with aliphatic side chains of different length. As soon
as 5-ALA esters are taken up by the cell, they are hydrolyzed to the active form by enzymes and metabolized in the same way as 5-ALA. 5-ALA or methyl/
butyl aminolevulinate may be used in the treatment of
a variety of diseases, not only in photodynamic treatment; it is also very effective in diagnosing malignant
diseases by means of fluorescence. Several advantages
of esters over 5-ALA have been reported, such as facilitated permeation through the stratum corneum
and cell membranes, higher selectivity (e.g., in solar
keratoses), increased PpIX formation, which leads to
higher fluorescence intensity and photodynamic activity, less pain, fewer systemic effects after local treat-
Medicina (Kaunas) 2011;47(Suppl 2)
5-Aminolevulinic Acid and Its Application in the Treatment of Oncologic Diseases
10
9
8
7
6
5
4
3
2
1
0
0.005
0.01 0.015
0.02
0.025
Penetration Flux, mmol/cm2/s
0.03
Fig. 2. Comparison of the penetration rates of different
5-aminolevulinic acid pharmaceutical forms in combination
with additional measures
1, aqueous solution; 2, ointment, cream; 3, gel; 4, patch;
5, aqueous solution + electroporation; 6, aqueous solution +
microdermabrasion; 7, microemulsion; 8, gel + iontophoresis;
9, aqueous solution + YAG laser; 10, aqueous solution + YAG
laser/microdermabrasion.
ment, and faster clearance from the cells (16, 51).
Concluding Remarks
In order to solve the problems associated with
the application of 5-ALA in PDT and optimize the
release of the active substance from the transder-
53
mal form, different application methods and forms
have been employed. In recent years, the development of iontophoresis and adjustment of various
pharmaceutical forms, such as patches, microemulsions, and gels, have taken place in scientific society.
However, the data are not totally consistent in terms
of enhanced permeation using iontophoresis as a
method of delivery of 5-ALA.
Topical transport of 5-ALA is a complicated process, which depends on the penetration enhancers,
such as excipients, penetration method, pH, and the
chemical structure of 5-ALA itself (5-ALA may exist in these forms: salt, base, methyl- or butyl-ester).
By categorizing these and other parameters, the optimal formulation might take place.
In conclusion, over several last years, the variety of different medicinal preparations containing
5-ALA as an active substance has increased. The
adjustment of new methods, optimization of older
methods, different modifications of these permeation techniques have also been established. Thus,
the physician who is performing PDT should consider the optimal application form in terms of the
purpose of application and target organ.
Statement of Conflict of Interest
The authors state no conflict of interest.
5-aminolevulino rūgšties optimalios vaistų formos parinkimas
sergančiųjų onkologinėmis ligomis gydymui
Vilma Armoškaitė, Kristina Ramanauskienė, Vitalis Briedis
Lietuvos sveikatos mokslų universiteto Medicinos akademijos Vaistų technologijos ir socialinės farmacijos katedra
Raktažodžiai: aminolevulino rūgštis (5-ALA), fotodinaminė terapija (PDT), farmacinė forma, skvarba
per odą, onkologinės ligos.
Santrauka. Straipsnyje apžvelgiamas 5-aminolevulino rūgštis ir jos pritaikymas fotodinaminei terapijai. 5-aminolevulino rūgštis – tai provaistas, plačiai vartojamas įvairioms onkologinėms ligoms (ypač
odos) gydyti. Šiame straipsnyje apžvelgiamos skirtingos aminolevulino rūgšties vaisto formos, lyginami
jų vartojimo būdai, vartotos pagalbinės medžiagos bei kiti veiksniai, veikiantys 5-aminolevulino rūgšties
prasiskverbimą per odą. Šie veiksniai yra vieni svarbiausių nustatant fotodinaminės terapijos aminolevulino
rūgštimi kokybę. Išskiriami ir įvertinami optimalūs prasiskverbimo metodai ir transderminių vaisto formų
pagrindai. Rinkoje esantys preparatai su 5-aminolevulino rūgštimi taip pat analizuojami šiame straipsnyje.
Taigi, atliekami naujausi eksperimentiniai tyrimai pritaikant naujas farmacines vaisto formas (pvz., gelius,
mikroemulsijas, pleistrus) ir metodus (mikrodermabraziją, jontoforezę, lazerius). Šios vaistų formos ir metodai buvo efektyviausi gydant sergančiuosius onkologinėmis ligomis.
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Received 20 October 2010, accepted 5 August 2011
Straipsnis gautas 2010 10 20, priimtas 2011 08 05
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