Formulation of
Topical Itraconazole Nanostructured Lipid Carriers (Nlc) Gel for Onychomycosis
Taranjeet Kukreja1,
Swarnlata Saraf *
1University
Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur - 492010, Chhattisgarh,
India
Abstract:
Itraconazole
is a triazole antifungal agent that is synthesised. Itraconazole has been
manufactured into a variety of pharmacological formulations and administered by
a variety of ways. Itraconazole pills are used to treat pulmonary fungal
infections that can spread throughout the body. Because Itraconazole is not yet
officially listed in any pharmacopoeia, only a few procedures for quality
control and stability testing in pharmaceutical formulations have been published.
The development of itraconazole-loaded nanostructured lipid carriers (ITZ-NLC).
Itraconazole NLC have been successfully developed. Itraconazole topical NLC
developed for the treatment of onychomycosis does not exist, according to my
survey.The development and evaluation of stable itraconazole topical gel
formulations proved successful. Itraconazole NLC was produced utilising the
microemulsion method, indicating the viability of adopting this method as a
continuous manufacturing tool for NLC formulation. Further, the ITZ- NLC was
incorporated in the gelling agent and we evaluated it under specific
parameters.
Keywords: Nanostructured
lipid carriers, Itraconazole, Nail delivery, Onychomycosis.
Introduction
Common
fungal nail infections include onychomycosis (OM) (Olbrich et al.,2022).
Dermatophytes typically cause onychomycosis, a nail fungal infection. However,
infections that cause nail disease include yeasts and non-dermatophyte moulds
(NDM). (Haghani et al., 2022). Tinea unguium is the term used to describe
onychomycosis brought on by dermatophytes. The word "onychomycosis"
includes diseases caused by yeasts, saprophytic moulds, and dermatophytes in
addition to dermatophytes. One kind of dystrophic nail is an aberrant nail that
is not brought on by a fungal infection. Both fingernails and toenails can have
onychomycosis, but the toenail infection is significantly more common. We'll
talk about the prevalence of the condition, clinical subtypes, staging,
diagnosis, and treatment options for toenail onychomycosis (Bodman., 2022).
About half of all nail illnesses are onychomycosis, which is brought on by
non-dermatophyte moulds (NDMs), a dermatophyte species. New epidemiologic
studies could aid in the treatment and prevention of onychomycosis as the
disease becomes more prevalent. (Razavyoon et al., 2022; Navarro-Bielsa.,
2022).
The
most typical fungus infection of the nail, onychomycosis, affects the area
beneath the fingertips and toes. Onychomycosis can currently be treated with
oral and topical medications, either separately or in combination. Poor drug
bioavailability and potential gastrointestinal and systemic side effects have
been linked to oral antifungal medication. (Dehari et al., 2022).
Reviewing
the literature on topical OM therapies used in clinical trials, evaluating
their effectiveness, and talking about potential barriers to their success were
the study's main goals. First, a thorough search of papers published in the MEDLINE
database (PubMed) between January 2004 and July 2022 was carried out, with a
particular focus on medications being tested in clinical settings for the
topical treatment of OM. It was evident that none of the papers chosen had
taken into account the fungi used NLCs treatment therapy. As a result, we thought
about various key OM factors, including nail structure and fungal invasion
mechanisms. (Costa et al., 2022).
Physicians
can determine the causes of nail disorders with the use of a detailed grasp of
nail anatomy. A diagnosis can be made by noting changes to the nail. Physical
examination, dermoscopy, and, occasionally, nail biopsy should all be part of
the patient evaluation process. The most prevalent nail ailment in the world,
onychomycosis, needs to be recognised from other nail illnesses with comparable
symptoms. Onychomycosis empiric treatment without confirmatory tests has been
suggested, but studies have shown that testing to avoid ineffective therapy is
cost-effective. (Mervak., 2022).
There
are few available choices for treatment; oral administration of antifungal
drugs typically requires lengthy regimens, which are linked to serious side
effects, medication interactions, and high recurrence rates (NogueirasNieto et
al., 2011; van Hoogdalem et al., 1997).
Although
topical therapies are more practical, their efficiency is limited by the nail
plate's rigidity and cohesiveness, which don't offer a different channel for
medication penetration as skin appendage structures (Nair et al., 2009).
As a
result, only a very little amount of nail medication can reach deeper layers
(middle and ventral nail plate) (Naumann et al., 2014).
Numerous
alternatives, including chemical (Brown et al., 2009; Nogueiras-Nieto et al.,
2011; Vejnovic et al., 2010) and physical approaches, have been suggested to
improve topical nail drug delivery. (Dutet and Delgado-Charro, 2009, 2010; Hao
et al., 2009).
Additionally,
colloidal carriers may be used alone or in conjunction with other approaches to
improve drug penetration to the nail plate. For instance, (Tanriverdi and
Ozer., 2013) used liposomes and ethosomes; (Naumann et al.,2014) used
nano/microemulsions; (Nogueiras-Nieto., 2013) used cyclodextrins (Chiu., 2015)
used polymeric nanoparticles associated with microneedles; and (Naumann et
al.,2014) used nanovesicles associated with permeation enhancers (nPEV) (Bseiso
et al., 2016). Despite signs they may be very promising methods to boost drug
nail penetration, to our knowledge.
Since
their lipid matrix can interact with the stratum corneum's lipid membrane and
facilitate skin drug administration, lipid nanoparticles including solid lipid
nanoparticles (SLN) and nanostructured lipid carriers (NLC) have been widely
employed for topical application (Pardeike et al., 2009; Yoon
et al.,
2013). Additionally, the occlusive layer that forms on the skin surface greatly
improves medication skin penetration and tissue hydration (Fan et al., 2013;
Jenning et al., 2000; Obeidat et al., 2010). Denoting these systems may also be
able to increase the amount of moisture in the nail plate, which would
facilitate medication penetration.
In
reality, one of the most significant elements that affects the physical
characteristics of nails is nail hydration (Wessel et al., 1999). Nail has a
network of holes that allows molecules to permeate when it is moistened, acting
like a hydrogel (Hao et al., 2008; Nogueiras-Nieto et al., 2011). In fact,
according to (Benzeval et al., 2013), the nail plate can absorb between
0.3 and 0.5 g of water for every gramme of dry nail, giving it a softer and
more flexible structure. Additionally, hydration has been shown to enhance the
size and number of nail pores (Nogueiras-Nieto et al., 2011).
Objective
Conventional
oral antifungal medications for onychomycosis (OM) frequently fail to
completely cure the disease and may be linked to side effects, medical
interactions, and compliance concerns that limit their usage in a large
population of patients. Although topical therapy can avoid systemic side
effects, it is nevertheless constrained by the nail plate's physical barrier
(Ortner., 2022). The purpose of treatment is to get rid of the disease-causing
organism and make the nail look normal again (Uemura., 2022). Onychomycosis
treatment is difficult, and the best treatment approaches have been
well-documented in the literature. On the other hand, little is known about how
onychomycosis is really managed in primary care. Information on practise is
crucial since it can show a lot, including how closely national recommendations
are implemented and which demographic groups seek or refuse treatment. (Sajeed
et al., 2021).
Materials
and Method
Itraconazole
was bought from Nosch laboratories Pvt. Ltd., Tween 80 was bought from Loba
chemie Pvt. Ltd., Stearic acid was bought from Loba chemie Pvt. Ltd., Methanol
Himedia laboratories Pvt. Ltd., Carbapol 940P Himedia laboratories Pvt. Ltd.,
Coconut oil was purchased of Dabur Parashute, Oleic Acid was purchased from
Loba chemie Pvt. Ltd., water used was distilled water prepared in the
laboratory. All other chemicals and reagents were of analytical grade or
superior.
Solid
and liquid lipid selection
The
choice of solid lipid was made based on itraconazole's solubility, which
produces a visibly clear solution in lipid that melts when observed with the
unaided eye in normal light. A lipid is Stearic acid, cetyl palmitate, and
cholesterol were the materials used in this study. Itraconazole (10mg) When
different amounts of chosen lipids were heated past their melting point in a 15
ml glass vial temperature-controlled water bath. After Under ordinary light,
the solubility of itraconazole was seen after melting the lipid in vials. (Shah
et al., 2007; Sharma et al., 2009).
Itraconazole's
behaviour during partitioning in different lipids
A
10 mg dose of Itraconazole was dissolved in a hot distilled water and 1 g of
melting lipid mixture (1ml). In a hot water bath set at 65°C for 24 hours, the
mixture was shaken. After cooling, the drug content was spectrophotometrically
examined after the aqueous phase was separated by ultracentrifugation (Bhalekar
et al., 2009).
Microemulsions
technique
Table 1 lists the SLN, NLC, and
surfactant compositions. We modified the microemulsion process to create the
formulations. Oleic acid and stearic acid were combined using a magnetic
stirrer, then melted at 75 0C to create a homogeneous and
transparent oil phase. The temperature of the aqueous phase, which consisted of
mixing the surfactant Tween-80 with double-distilled water, was kept at 75 0C.
A microemulsion was created by adding the oil phase drop-by-drop to the aqueous
phase and agitating the mixture for 20 minutes at 75 0C at 600 rpm.
(NLC) To create NLC, this warm NLC was diluted in cold water (2–3 0C)
while being mechanically stirred. then filtered for 15 minutes using Whatman
filter paper. The experiment was among the manufacturing parameters that were
tested in a systematic investigation.
Table 1: Formula table for preparation of
blank NLCs.
Formulation Code
|
Solid
Lipid
(Stearic acid)
|
Liquid
Lipid
(Oleic acid/coconut
oil)
|
Surfactant
(Tween-80)
|
NLC-I
|
2.5g
|
OLEIC ACID 5g
|
0.4 g
|
NLC-II
|
2.5g
|
OLEIC ACID 5g
|
0.3g
|
NLC-III
|
2.5g
|
OLEIC ACID 5g
|
0.2g
|
NLC-IV
|
2.5g
|
OLEIC ACID 5g
|
0.1g
|
NLC-V
|
2.5g
|
COCONUT
OIL 5g
|
0.4g
|
NLC-VI
|
2.5g
|
COCONUT
OIL 5g
|
0.2g
|
The
formulation of Itraconazole loaded NLC Gel
In
distilled water, disperse. Wait 15 minutes while gently agitating the polymer
to soak it out thoroughly. Pour 35 ml of glycerin in. The itraconazole solution
received 10 ml of itraconazole-loaded NLC. To create uniform hydro gel, the
dispersed mixture was agitated at 1000 rpm for 30 minutes. To neutralise the
itraconazole, slowly add 0.5 ml of triethanolamine. 15-20 minutes for the
mixture to fully gel. Carbopol was used as the gelling agent due to its
compatibility with the NLC dispersion and spreadability. Table 2 lists the
components of several gel formulations.
Table
2: Composition of NLC-based gel formulations
Ingredients
|
Formulation
|
Itraconazole
NLC solution
|
10ml
|
Glycerin
|
35ml
|
Triethanolamine
|
0.5ml
|
Characterization
of NLCs systems
Dispersion
stability studies
Dispersion
stability tests were done to solve the formulation's metastability issue. A few
formulations underwent a 30-minute centrifugation at 3000 rpm. The heating and
cooling cycle was used with the formulations that didn't exhibit any phase
separations (freeze thaw cycle). In a hot air oven, six cycles between 4°C and
45°C were completed, with storage at each temperature lasting at least 48
hours. For future research, the formulations that withstood the stability tests
at these temperatures were chosen.
Drug content and
entrapment efficiency (%EE)
The ethanol:dichoromethane (1:3) solvent mixture was used to
dissolve 1 mL of the produced NLCs, and the solutions were then immediately
injected into the cuvate of the UV system following the proper dilutions with
mobile phase. The solutions were then tested for the presence of drugs. NLC was
centrifuged at 20 0C for 30 min. (Eppendorf Centrifuge 54 30R) at
25,000 rpm to calculate the percent entrapment efficiency (percent EE). A
mixture of ethanol and dichloromethane (1:3) was used to dissolve the pellets,
and the amount of itraconazole that was trapped inside was then measured using
the UV Spectroscopy method before the pellets were appropriately diluted with
mobile phase. Table 3 shows the percent entrapment efficiency.
The E.E. was
calculated using the following equation:
EE(%)= total
amount of Itraconazole-free amount of itraconazole x 100
Total amount
of itraconazole
Table 3:
Entraptment Efficacy
S.No.
|
NLC
|
EE%
|
1
|
NLC –
I
|
91
|
2
|
NLC –
II
|
89
|
3
|
NLC –
III
|
90
|
4
|
NLC –
IV
|
86
|
5
|
NLC –
V
|
88
|
6
|
NLC –
VI
|
81
|
Result and Discussion
Appearance
The hydrogel was observed to be free from greatness and translucent that
conforms the equal distribution catalase loaded NLC inside the gel matrix.
pH study
Because gel is used directly to the nails and can prevent
irritation issues with the skin and nails, a pH analysis of the gel is crucial.
The pH of the skin is about between 6 and 7, while the pH of the nail surface
ranges from 5.1 to 5.6. This pH is suitable for topical use. A digital pH metre
was used to measure the pH of the generated plain gel, plain NLC loaded gel,
and itraconazole loaded NLC gel formulations at room temperature. The generated
unloaded NLC, itraconazole-loaded NLC, and plain gel all had pH values of 5.2,
5.4, and 5.5, respectively.
Drug Content Study
In a 25 mL volumetric flask containing 15 mL of methanol,
NLC loaded gel equivalent to 25 mg of ITZ was added, and the mixture was
agitated for 30 minutes. Methanol was used to bring the volume up to 25 mL. To
obtain 20 g/mL, 0.2 mL of the solution was further diluted using 4.8 mL of
methanol and 5 mL of 0.1 N HCl. Through a 0.45 membrane filter, the final
solution was purified. Using a spectrophotometric instrument (Shimadzu
UV-1800), the solution's absorbance was calculated at 258 nm.
Spreadability Study
Spreadability of the gel formulation may affect a topical
formulation's effectiveness and serve as a key indicator of patient compliance.
The spreadability of the unloaded gel with no NLC. NLC gel with itraconazole
was observed as. For topical formulation, this is okay. 4.1 cm, 4.3 cm, and 5.1
cm, which are suitable for topical application, respectively.
Viscosity study
Fig 1:
Brookfield Viscometer
At 25°C, the viscosity of the formulation was measured using
a Brookfield viscometer (Model DV-I). A 250 mL beaker containing 175 g of gels
was used to determine the viscosity. Spindle T 95 was used to measure the
viscosity of each gel.
Fig 2:
Viscosity of gel in RPM
In vitro
Release study
Utilizing egg
membrane, in vitro release tests were conducted on nanostructured lipid
carriers (NLCs) loaded with itraconazole. The investigations showed that 80.0%
of the medication release was visible after 24 hours.
Fig 3: In
Vitro Release Profile for ITZ Solution And ITZ-NLC Formulation.
Conclusion
The results of the
current study suggest that microemulsion technologies could be used to
successfully manufacture itraconazole's NLCs. The results of this investigation
also suggest that the entrapment efficiency is strongly influenced by the type
and quantity of liquid lipid. The selection of materials for the development of
the NLC formulation should take into account whether or not each component is
pharmaceutically acceptable, non-irritating, and does not cause skin
sensitization. The greatest amount of ITZ solubility was discovered among the
chosen oils that were screened.
NLCs can be used
in a variety of ways to administer medications to patients, but their topical
use has drawn more attention recently.
It is well
recognised that if drug molecules have any issues with solubility or
bioavailability along the GI tract, they are candidates for other routes of
administration, and if the drug acts topically instead of or in addition to the
GI tract, the results are better.
The final
Itraconazole-loaded gel formulation was tested for appearance, pH,
spreadability, drug content, viscosity, and invitro release, all of
which yielded satisfactory results.
Acknowledgment
I am thankful to
the University Institute of Pharmacy (UIOP), Pt. Ravishankar Shukla University,
Raipur, Chhattisgarh, India for my practical support. I also want to thank
Prof. Swarnlata Saraf, University Institute of Pharmacy (UIOP), Pt. Ravishankar
Shukla University, Raipur, Chhattisgarh, India for her valuable suggestions and
guidance. Thanks are due to Nosch laboratories Pvt. Ltd., India for providing
Itraconazole drug sample.
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