A Comprehensive Review on Formulation and Evaluation of Vitamin
D3 Emulgel for Enhanced Transdermal Delivery
Venkatesh, Chaithra N *, Parthasarathi K Kulkarni,
Siddartha H N, Hanumanthachar Joshi K
Sarada Vilas college of pharmacy, Mysuru, Karnataka, India.
INTRODUCTION
Transdermal drug delivery systems have acquired considerable
attention in recent years as a non-invasive and patient-friendly approach to
administering therapeutic agents. Topical delivery
of the drugs implies priority for their unique feature of by-passing first pass
metabolism for local and systemic action. Among
the essential nutrients, Vitamin D3 holds a pivotal role in various
physiological processes, including bone health, immune function and cellular
regulation. However, traditional oral supplementation of Vitamin D3 may present
challenges related to patient adherence and bioavailability. In response to
these challenges, innovative formulations, such as emulgels have emerged as
promising vehicles for enhancing the transdermal delivery of Vitamin D3.[1]
Emulgels
exhibit thixotropic properties and are characterized by being grease-free,
effortlessly spreadable, easily removable, emollient, non-staining,
environmentally friendly, transparent, and cosmetically approved. They
also have good cutaneous penetration and long shelf-life. These qualities
collectively render emulgels a favorable system for delivering topical
medications.
Emulgel represent a hybrid dosage form that combines the
advantages of both emulsions and gels. This unique formulation seamlessly
transitions from an emulsion state, providing stability and solubilization of
lipophilic compounds like Vitamin D3, to a gel upon skin contact, offering
enhanced adherence and localized drug delivery. The formulation of Vitamin D3
emulgels involves a careful selection of emulsifiers, gelling agents and
permeation enhancers to achieve an optimal balance of stability, viscosity and
skin permeability.[2]
This study aims to explore the formulation intricacies and
evaluate the performance of Vitamin D3 emulgels in facilitating transdermal
absorption. The choice of emulsifiers and gelling agents, along with their
concentrations, will be systematically optimized to ensure the stability and
efficacy of the emulgel formulation. Physicochemical parameters, including pH,
viscosity and drug content will be thoroughly characterized to assess the
quality of the emulgels.
Skin permeation tests employing Franz diffusion cells with
excised skin samples will give insights into the transdermal delivery
capability, in addition to the in vitro release studies undertaken to
understand the sustained release profile of Vitamin D3 from the emulgels. The in
vivo experiments will further evaluate the effectiveness of the created
emulgels in contrast to standard formulations by assessing blood Vitamin D3
concentrations in animal models.[3]
By combining advancements in pharmaceutical formulation and
transdermal drug delivery, this research seeks to contribute to the growing
body of knowledge on Vitamin D3 supplementation. The outcomes of this study may
have significant implications for the development of efficient and
patient-friendly approaches to enhance Vitamin D3 bioavailability through
topical application, addressing current challenges associated with traditional
oral supplementation.
Vitamin D is available in two primary forms: D2 and D3, as
well as other active analogs. Ergocalciferol (D2) is sourced from fortified milk, herring, mackerel,
tuna, salmon, sardines, eggs, as well as fortified cereals and baked goods.
Vitamin D3, otherwise known as cholecalciferol, is photochemically produced
upon UV exposure from the precursor sterol 7- dehydrocholesterol, which is
present in the epidermis of the skin. Vitamin D3 is an essential nutrient and
pro-hormone; itis present in animal products and fortified foods and can be
consumed from fish oil, eggs or fish. This
article outlines a pilot study investigating the feasibility of delivering
vitamin D3 topically. Vitamin D is lipophilic (fat soluble) in nature and
can be absorbed through the skin, it is stored in the body's fat cells. [4]
Vitamin D3, (cholecalciferol) as it is a fat-soluble vitamin
that plays a crucial role in calcium and phosphate metabolism. Its
physicochemical properties are important factors to consider when formulating
pharmaceuticals, supplements, or topical products. Here are some important
physicochemical features of Vitamin D3.
[5, 6]
Chemical structure
Figure 1:
Cholecalciferol
|
Vitamin D3 is a secosteroid, which means it has a steroid
structure with a broken ring. Vitamin D3 has a steroid nucleus with a side
chain in its chemical structure.
Molecular weight
Vitamin D3 has a molecular weight of around 384.65 grams per
mole.
Solubility
Vitamin D3 is lipophilic (fat-soluble) and exhibits very low
solubility in water. It dissolves readily in fat and oils. This characteristic
influences its bioavailability and absorption in the body.
Melting point
The
melting point of vitamin D3 is between 83 and 86 degrees Celsius (181 and 187
degrees Fahrenheit).
Stability
Vitamin
D3 is sensitive to light, heat, and air. Exposure to these factors can lead to
the degradation of the vitamin. It is often recommended to store vitamin
D3-containing products in dark and cool conditions to maintain stability.
Bioavailability
The bioavailability of vitamin D3 is influenced by its
solubility and absorption characteristics. It is absorbed in the small
intestine and undergoes hydroxylation in the liver and kidneys to become the
active form of vitamin D.
Photostability
Vitamin
D3 is susceptible to photodegradation when exposed to ultraviolet (UV) light.
This property should be considered when formulating products containing vitamin
D3, and appropriate packaging may be necessary to protect it from light.
Metabolism
The
body converts vitamin D3 into calcitriol (1,25-dihydroxyvitamin D3), the active
form of vitamin D that is essential for maintaining calcium and phosphorus
homeostasis, through a sequence of hydroxylation events that occur in the liver
and kidneys.
The
active form of vitamin D3 is calcitriol. Vitamin D3, also known as
cholecalciferol, is converted into calcitriol through a series of metabolic
processes in the body.
The
simplified overview of the conversion process:
Production
of Vitamin D3
Vitamin
D3 is synthesized in the skin when 7-dehydrocholesterol, a compound present in
the skin, is exposed to ultraviolet B (UVB) radiation from the sun.
Conversion
in the Liver
Vitamin
D3 is then transported to the liver, where it undergoes hydroxylation (addition
of a hydroxyl group) by the enzyme 25-hydroxylase. This forms 25-hydroxyvitamin
D3, also known as calcidiol.
Conversion
in the Kidneys
The
next step takes place in the kidneys, where 25-hydroxyvitamin D3 undergoes
another hydroxylation, this time by the enzyme 1-alpha-hydroxylase. This final
conversion results in the formation of the active form of vitamin D3, which is
calcitriol (1,25-dihydroxyvitamin D3).
Calcitriol
plays a crucial role in calcium and phosphorus metabolism. It acts as a hormone
that regulates the absorption of calcium and phosphate from the
gastrointestinal tract and helps maintain proper levels of these minerals in
the blood.
It's
important to note that while vitamin D3 is obtained from sunlight exposure,
dietary sources, or supplements, the conversion into its active form primarily
occurs in the liver and kidneys. The active form, calcitriol, then exerts its
effects on various tissues and organs throughout the body.
Reasons for Vitamin D3 deficiency[7,
8]
Lack
of exposure to sun rays.
Individuals
who live in areas with extreme pollution levels or in which towering buildings
obstruct the exposure to sun rays as well as who will be applying an excessive
amount of sunscreen will be impacted by a lack of vitamin D3.
Impaired
vitamin D absorption (due to a medical condition)
The
body may also be deficient in some nutrients if a person has gastrointestinal
diseases, problems with fat absorption, or lactose intolerance or allergy to
milk.
Medications
that interrupt the regular functioning of vitamin D in the body
Individuals
who have undergone weight loss surgery or those who are using anticonvulsant
medications.
Low
dietary intake of vitamin D
If
milk is not consumed on a regular basis, body might not be able to sustain the
necessary amounts.Vitamin D is the only vitamin that the body actually makes.
It is made in the skin and converted to a hormone. Autoimmune skin diseases
such rosacea, psoriasis, and eczema develop when vitamin D hormone levels are
out of equilibrium.
Irregularities
in Melanin
Melanin
functions as a natural sunblock, reducing the synthesis of vitamin D3 in the
skin. Individuals with a darker complexion or more pigmented skin require a
longer duration compared to those with fair skin to generate an equivalent
amount of vitamin D3.
Role of Vitamin D3 in maintaining healthy skin[7]
Promotes
longer telomeres.
It
prevents the premature aging of your skin. Telomeres, the caps of genetic
material on the free ends of DNA strands, shortens with increased age. The
shortening of telomeres results in DNA instability, a condition that continues
to deteriorate until the cell undergoes death.
Acts
as endogenous antibiotics.
It
is associated with antimicrobial peptides (AMP) production in the keratinocytes
(skin cells). It aids skin in overcoming conditions including vitiligo,
rosacea, acne, psoriasis, and atopic dermatitis, etc.
Modulates
the production of keratinocytes.
Regulates
skin cell growth, repair and maintains its metabolism. Both the formation of
new blood vessels and the process of wound healing are aided by Vitamin D3.
Additionally, it keeps the epidermal barrier intact.
Plays
a part in the immune responses of the skin.
It
oversees the regulatory mechanisms of skin immunity.
Serves
as an antioxidant.
Highly
reactive oxygen species, known as free radicals, disrupt lipid structures in
cell membranes as they seek electrons. They affect the DNA of the cells in a
manner utter damaging. If the same process is repeated every time, the damage
bulks up and can lead to different skin cancer forms.
Vitamin
D serves as a membrane antioxidant, preventing the degradation of epidermal
lipids. It neutralizes the free radicals, rendering them harmless. However, the
scavenging capability of vitamin D has not been conclusively demonstrated to a
satisfactory extent. Dermatologists advocate for well-conducted, high-quality
studies to affirm the antioxidant role of vitamin D.
Skin
barrier function
Vitamin
D plays a crucial role in controlling the production of keratinocytes, the
cells found in the epidermis, the outermost layer of the skin. These cells are
essential for preserving the functionality of the skin barrier. In addition to
keeping dangerous chemicals and bacteria out of the skin, the skin barrier also
aids in retaining moisture, preventing the skin from becoming dehydrated.
Boosting
skin immunity
One
of the main elements of the body's first line of protection is the skin, which
is the greatest defensive organ. Vitamin D is essential for activating immune
cells like macrophages and monocytes. These cells, part of the innate immune
system, are vital for detecting and combating foreign substances entering the
skin. Additionally, Vitamin D is necessary for the regulation of B cells and T
cells, the main components of the adaptive immune system. Excessive activation
of these cells can contribute to the development of autoimmune disorders.
Antimicrobial
effects
Vitamin
D has a direct antibacterial impact on skin cells in addition to supporting
barrier function and controlling immune system components. Vitamin D triggers
specific receptors that destroy bacteria when they enter the skin.
Photoprotective
effects
The
application of vitamin D3 topically has demonstrated protective effects against
UV light-induced skin damage. Vitamin D helps decrease cell mortality, enhance
cell survival, and alleviate redness resulting from photodamage caused by UV
radiation, to some degree.
Healing
wounds
Vitamin
D has been demonstrated to elevate the expression of cathelicidin, a protein
with antimicrobial properties. This protein plays a crucial role in repairing
damaged tissue and restoring proper mechanisms, making it essential for the
skin's wound healing process.
Role of vitamin D3 on alleviating symptoms of skin infections.[8]
Psoriasis
Psoriasis
refers to a condition where skin cells accumulate, leading to the formation of
scales and dry, itchy patches. The objective of vitamin D and its analogs is to
control the rate of skin cell proliferation, reducing the overactivity of these
cells and restoring them to a normal state.
Calcipotriene,
a synthetic analogue of vitamin D, stands as one of the frequently prescribed
medications for addressing psoriasis. Notably, it was the pioneering vitamin D3
analogue employed in the treatment of psoriasis. Specifically, calcitriol
ointment, an approved formulation, is recommended for managing mild-to-moderate
plaque psoriasis in patients aged 18 years or older.
Ichthyosis
The
manifestation of the rare disorder is closely linked to severely dry and
thickened skin, a condition often correlated with low levels of vitamin D in
the body. Ichthyosis, encompassing a group of genetic skin disorders, is
distinguished by the presence of dry, scaly skin. While vitamin D3
supplementation is not a primary treatment for ichthyosis, it may have certain
benefits for individuals with this condition. It provides anti inflammatory
effects, moisturizing and barrier functions.
Eczema
(Atopic dermatitis)
There
are two primary causes of the itchiness and inflammation associated with this
condition: improper function of the skin's epidermal barrier, Dysregulated
immune response of the skin, which interacts with the environmental factors.
The
topical use of vitamin D3 and its analogs increases the vitamin D receptors
(VDR) in the skin cells, which improves the epidermal barrier breakage. This,
in turn, lessens the transepidermal water loss there by retains moisture for longer
time.
Acne
The
studies conducted so far have not established a concrete link between acne and
vitamin D. If the acne is primarily due to bacterial overgrowth, vitamin D's
anti-microbial properties (when topically used) can calm down the symptoms.
The
anti-inflammatory nature of vitamin D may help to address the inflammation and
redness during recurrent acne.
Vitiligo
The
emergence of this uncommon disorder is intricately connected to the pronounced
dryness and thickening of the skin, a condition frequently associated with
diminished levels of vitamin D in the body. Ichthyosis, representing a
collection of genetic skin disorders, is characterized by the notable presence
of dry and scaly skin. "Vitamin D protects the epidermal melanin unit and
restores its integrity."
Current application of topical vitaminD3
Vitamin
D is present in a variety of over-the-counter (OTC) skincare products, serving
as either the primary active ingredient or an augmenting supplement. These
products include moisturizers, neck creams, oils, face washes, mist drops,
sunscreens, and more. Given that vitamin D dissolves in fats and oils, many
topical formulations are oil-based. The primary role of vitamin D in these
products is to function as a moisturizer and emollient, creating a thin
protective layer on the skin that effectively retains moisture. Also, it helps
to soften the skin and revive the dry textures.
Conventional
dosage forms of vitamin D3 typically refer to the traditional pharmaceutical
formulations or presentations in which vitamin D3 is administered for
therapeutic purposes. Some common conventional dosage forms of vitamin D3
include:
Oral
Tablets/Capsules: Vitamin D3 is often
formulated into oral tablets or capsules, allowing for convenient and
standardized dosing. These dosage forms are taken orally and are designed for
systemic absorption through the digestive tract.
Liquid
Formulations: Vitamin D3 can also be formulated as
a liquid, often in the form of drops or solutions. This is especially useful
for individuals who may have difficulty swallowing solid dosage forms, such as
infants or elderly individuals.
Injectable
Formulations: Vitamin D3 injections via
intramuscular or intravenous routes are used to treat specific medical
conditions, including malabsorption problem, osteoporosis, and chronic kidney
disease. Injectable forms are typically used under medical supervision and are
reserved for specific conditions where rapid and precise dosing is required.
Topical
Preparations: While less common, there are also
topical formulations of vitamin D3 available, such as creams or ointments.
These are applied directly to the skin and are designed for localized effects.
At
present, vitamin D supplements are available as oral and injection forms;
however, compliance of oral vitamin D
supplementation alone is only reported to be 20-60%. Consequently, the goal of
topical vitamin D therapy is to improve patient compliance.
Formulation
considerations[9, 10]
Due to
its lipophilic nature, vitamin D3 is often incorporated into formulations
containing fats, oils, or other lipids. It may be used in supplements,
pharmaceuticals and topical products.
It
is essential to comprehend these physicochemical characteristics in order to
formulate vitamin D3-containing topical products effectively. Formulators
need to consider stability, bioavailability, and compatibility with other
ingredients to ensure the efficacy and quality of the final product.
Active
Ingredient
Vitamin
D3 (cholecalciferol) is the active ingredient. The concentration of vitamin D3
in the emulgel should be determined based on the intended use and therapeutic
requirements. The concentration of vitamin D3 in topical formulations can vary
depending on the intended use, formulation type, and specific product design.
Generally, concentrations of vitamin D3 in topical formulations range from
1,000 to 5,000 international units (IU) per gram. It's important to comply with
regulatory guidelines for the allowed concentration of vitamin D3 in cosmetic
or pharmaceutical formulations.
Base
Ingredients
Water
- Forms the aqueous phase of the emulgel. Ex: Rose water, sterile water
Oil
Phase - Typically includes oils such as mineral oil, sunflower oil, Coconut oil
or other suitable oils.
Emulsifiers - Necessary for stabilizing the emulsion
and preventing phase separation. Common emulsifiers include
Tween-(20,40,60,80), PEG-(300,400,600), Span-(20,40, 60,80), cetyl alcohol, or
glyceryl stearate.
Gelling
Agents[11, 12]
Gelling
agents play a crucial role in the formulation of emulgels, providing the
desired texture, stability and rheological properties to the product and to
improve gel like consistency of the formulation. When formulating a vitamin D3
emulgel, the choice of gelling agent is important for achieving the desired
consistency and user experience. Some of the common gelling agents that could
be used in the formulation of vitamin D3 emulgels.
Carbomers
- Carbomers, such as Carbopol, are synthetic polymers that can form clear gels
when neutralized in an aqueous environment. They provide a smooth and pleasant
texture to emulgels. Carbomers are effective in stabilizing emulsions and can
be used in a wide range of pH conditions.
Xanthan
Gum - Xanthan gum is a natural polysaccharide produced by the fermentation of
sugars by the bacterium Xanthomonas campestris. It is recognized for its
ability to thicken and stabilize.
Hydroxyethylcellulose
(HEC) – HEC is a water-soluble polymer derived from cellulose. It is often used
as a thickening agent in emulgels. HEC provides a smooth and non-greasy
texture, improving the spreadability of the emulgel on the skin.
Gellan
Gum - Gellan gum is a microbial polysaccharide that forms
gels with unique properties. It can be used in combination with other gelling
agents to achieve the desired consistency in emulgels. Gellan gum provides a
stable gel structure and has good rheological properties.
Bentonite
Clay - Bentonite is a natural clay that can be used as a gelling agent in
emulgels. It also has the benefit of absorbing excess oil, making it suitable
for emulgels with a less greasy feel.
Polyvinyl
Alcohol (PVA) - PVA is a water-soluble
synthetic polymer that can be used as a gelling agent in emulgels. It is known
for its film-forming properties and can contribute to the stability of the
formulation.
The
choice of gelling agent depends on various factors, including the desired
product characteristics, compatibility with other formulation components, and
the intended use of the emulgel. Experimentation and optimization may be
necessary to achieve the right balance of texture, stability, and performance
in a vitamin D3 emulgel.
Penetration
enhancers
A
penetration enhancer, also known as absorption enhancer, is a substance that is
added to emulgel to improve the penetration of drugs or active ingredients
through the skin. It includes Propylene glycol, clove oil, isopropyl myristate,
olive oil, urea, DMSO.
Co-Solvents
Co-solvents
may be added to enhance solubility and stability. Common co-solvents include
propylene glycol or glycerin.
Preservatives
Preservatives
are essential to prevent microbial contamination and extend the shelf life of
the emulgel. Examples include parabens, phenoxyethanol, or benzalkonium
chloride.
Antioxidants
Antioxidants
like tocopherol (vitamin E) may be included to protect the formulation from
oxidation and improve stability.
pH
Adjusters
pH
adjusters are used to maintain the emulgel within a suitable pH range for
stability and skin compatibility. Citric acid, sodium hydroxide,
triethanolamine may be used for pH adjustment.
Fragrance
and Colorants
Fragrance
and colorants may be added for sensory appeal. It's essential to choose
ingredients that are compatible with the formulation and do not cause
irritation.
Emollients
and Humectants
Emollients,
such as fatty alcohols or esters, can contribute to the skin-feel of the
emulgel. Humectants like glycerin help maintain skin hydration.
Thickeners
Thickeners
may be included to enhance the viscosity of the emulgel. Examples include
hydroxyethyl cellulose or carbomer.
Stabilizers
Stabilizers
may be added to improve the stability of the emulgel over time. This can
include stabilizers for the emulsion system and the active ingredient.
Many
Obstacles may encounter while formulating vitamin D3 emulgel
Formulating a vitamin D3 emulgel poses several challenges due
to the unique characteristics of both the active ingredient (vitamin D3) and
the emulgel formulation. Emulgel is a combination of an emulsion (oil-in-water
or water-in-oil) and a gel, providing a stable and easily spreadable form. Here
are some challenges in the formulation of vitamin D3 emulgel:
Solubility
of Vitamin D3
Vitamin D3 is a fat-soluble vitamin, which means it has low
water solubility. Incorporating it into a water-based emulgel can be
challenging. Techniques such as using solubilizing agents or selecting
appropriate oils with good solubilizing properties may be necessary.
Chemical
stability
Vitamin D3 is sensitive to light, heat, and air. Formulating
an emulgel that protects vitamin D3 from degradation is crucial. The choice of
antioxidants and opaque packaging can help mitigate these stability issues.
Compatibility
with emulsion components
A
stable emulgel can only be achieved by ensuring compatibility between the
emulsion components, such as the water and oil phases. Phase separation brought
on by incompatibility may shorten the product's shelf life and efficacy.
Emulsion
stability
Emulsions
may phase separate over time due to their inherent thermodynamic instability.
Creating a steady emulsion that doesn't cream or separate is difficult. The
right choice of stabilizing methods, including adding thickening agents, and
emulsifying agents is essential.
Skin
penetration of vitamin D3
Vitamin D3 needs to penetrate the skin to exert its
beneficial effects. Achieving optimal skin penetration can be challenging due
to the lipophilic nature of vitamin D3. Enhancers or penetration enhancers may
be required to improve skin permeability.
Textures
and Aesthetics
Emulgels should have a pleasant texture, be easily
spreadable, and provide a non-greasy feel. Achieving the right balance between
oil and water phases, as well as selecting suitable gelling agents, is
important for achieving the desired texture.
Regulatory
compliance
Meeting
regulatory criteria for vitamin D3 concentrations, as well as guaranteeing the
safety and efficacy of the emulgel formulation, adds another degree of
complication. Compliance with health-care standards and regulations is critical
for market acceptance.
Consumer
Acceptance
The sensory attributes of the emulgel, such as color, odor,
and feel, are essential for consumer acceptance. Formulating a product that
meets consumer expectations in terms of appearance and usability is crucial for
market success. Addressing these challenges necessitates a comprehensive
understanding of the physicochemical properties of vitamin D3 and the
principles of emulsion and gel formulation. Experimentation and optimization
are often necessary to achieve a stable and effective vitamin D3 emulgel.
Steps involved in the formulation[13, 14, 15 ]
Emulgel
is formulated by following steps,
a.
Selection of components
b.
Preparation of emulsion
c.
Preparation of emulgel.
a.
Screening of components
Drug
Solubility was checked in various oils by excess addition of drug followed by
continuously stirred for 72 hours to achieve equilibrium. After that samples
centrifuged and supernatant was taken and solubility was determined by suitable
analytical methods. Then, excipients in each category with the highest
solubility of drug are selected for further studies.
Psuedoternary
phase diagram:
Surfactant
and co-surfactant were mixed in different ratios (2:1, 3:1 and 5:1). Every
ratio preferred in increasing amount of surfactant with respect to co
surfactant while studying on the phase diagrams. In most of the cases aqueous
phase.
(Distilled
water) used as dilution media. Oil along with Surfactant and co-surfactant was
mixed at different ratios from 9:1 to 1:9 in different vials for its each
mixture. Main importance of this is to cover the study which decide boundaries
of phases formed in the diagrams. Slow titration of oil and surfactant and
co-surfactant is performed and visually observed for transparency of emulsion.
b.
Preparation of emulsion: The drug is then
solubilized in oil and oil is mixed into mixture of surfactant and
co-surfactant, this mixture is then diluted with water to form emulsion of
known drug.
c.
Preparation of emulgel: Gel base is formulate
using 1g of the Carbopol with a required quantity of water and kept for
overnight soaking, then prepared emulsion is slowly added with continues
stirring. Triethanolamine is added to maintain the pH of formulation. Finally
required remaining volume is adjusted by distilled water.
Advantages of vitamin D3 emulgel[16, 17, 18]
Vitamin
D3 emulgel formulations offer several advantages, especially when compared to
traditional dosage forms. Here are some potential advantages:
Enhanced
Skin Absorption
Emulgels
are designed to improve the penetration and absorption of active ingredients
through the skin. Vitamin D3, when formulated as an emulgel, can potentially be
absorbed more efficiently through the skin.
Topical
Application
Emulgels
allow for the topical application of vitamin D3, which is particularly
beneficial for individuals who may have difficulty taking oral supplements.
This can be useful for people with gastrointestinal issues or those who prefer
non-oral methods of supplementation.
Localized
Delivery
Emulgels
enable the localized delivery of vitamin D3 to specific areas of the skin. This
can be advantageous in cases where targeted therapy is needed, such as for skin
conditions or joint pain.
Reduced
Systemic Side Effects
By
delivering vitamin D3 directly to the skin, the risk of systemic side effects
may be reduced compared to oral supplementation. This is because topical
application can limit the amount of the vitamin that enters the bloodstream.
Stability
and Shelf Life
Emulgels
can enhance the stability and shelf life of vitamin D3. The gel matrix can
protect the active ingredient from degradation, oxidation, or other factors
that may affect its efficacy over time.
Ease
of Application
Vitamin
D3 emulgels are typically easy to apply and spread evenly on the skin. This
ease of application can improve patient compliance, as individuals are more
likely to adhere to a treatment regimen that is convenient and user-friendly.
Reduced
Irritation
The
emulgel formulation can provide a smooth and non-irritating application, making
it suitable for individuals with sensitive skin. This is particularly important
for long-term use.
Customization
of Formulation
Emulgels
allow for flex19ibility in formulating the product with various additives, such
as moisturizers or skin-conditioning agents, to enhance the overall skin feel
and provide additional benefits.
Disadvantages of vitamin D3 emulgel [ 19]
While vitamin D3 emulgel formulations offer several
advantages, there are also potential disadvantages that should be considered.
Here are some possible drawbacks:
Skin
Irritation
Some individuals may be sensitive to the components of
emulgels, leading to skin irritation. This can be a concern, especially for
those with pre-existing skin conditions or allergies.
Potential
for Overdose
Topical
formulations may pose a risk of overdose if not used as directed. It's
important for users to follow the recommended dosage instructions to avoid
excessive absorption through the skin.
Limited
Absorption
While
emulgels are designed to enhance absorption, the skin still presents a barrier
that may limit the amount of vitamin D3 absorbed. This could be a concern if
high doses are required for therapeutic purposes.
Staining
and Residue
Some
emulgels may leave a residue on the skin, and certain formulations may have the
potential to stain clothing. This can be a cosmetic concern for users.
Complex
Formulation
The
formulation of emulgels can be complex, requiring careful consideration of
ingredients and their interactions. Achieving a stable and effective
formulation may be challenging, and variations in the manufacturing process
could impact product quality.
Cost
Emulgel
formulations may be more expensive to produce compared to traditional oral
supplements. This could result in higher costs for consumers.
Not
Suitable for Systemic Deficiency
Topical
formulations are generally more suitable for localized conditions or situations
where targeted therapy is needed. They may not be the best option for
individuals with systemic vitamin D deficiency, where oral supplementation may
be more appropriate.
Compliance
Issues
Some
individuals may find it less convenient to apply a topical emulgel regularly,
leading to issues with compliance. Oral supplements may be more convenient for
those who prefer a once-daily dosage.
Risk
of Contamination
Like
any topical product, emulgels may be at risk of contamination if proper hygiene
and storage practices are not followed. This could compromise the safety of the
product.The formulation of a vitamin D3 emulgel involves combining water, oil,
emulsifiers, and other ingredients to create a stable and effective product.
Here are the key formulation requirements for a vitamin D3 emulgel.
CHARACTERIZATION OF VITAMIN D3 EMULGEL
1.
Physical examination[20]
Physical
examination like Color, homogeneity, consistency are examined visually.
2.
Determination of pH:[21]
Numerous
Topical formulations have pH range in between of 5-6 measured by using pH
meter. For pH determination, take 1g of product and dissolve in 10ml water. pH
1% solution in water of emulgel subjected to measure pH by the digital pH
meter. pH of each formulation is done on triplicate to minimize error.
3.
Globules size measurement:
To
measure this parameter 1.0 gm of product was dissolved in water and stirred to
become dispersion and then sample was inserted into the photocell of Malvern
zetasizer.
4.
Swelling Index:
1
gm of prepared emulgel is taken on porous aluminum foil which is then dispered
in 10 ml of 0.1 N NaOH solutions. Sample removed on various time interval and
weight is noted till no further change in weight. It is calculated by using
following formula:
Swelling
Index (SW) % = [[Wt-Wo]/Wo] × 100
Where,
(SW)
% = Percentage swelling,
Wo
= Original weight of emulgel,
Wt
= Weight of swollen emulgel at time t.
5. Measurement of Bioadhesive strength:
Accurately
1 gm of emulgel is applied between slides containing rat’s hairless skin
pieces. Putting weight on single glass slide create some pressure to removed
sandwich of two slides. Adding extra weight is concidered as 200 mg/min to
until the detachment of the skin surface. Required weight to detach the emulgel
from skin will give bio adhesive strength.
It
is calculated by using following formula:
Bio
adhesive Strength = W / A
where,
W= Weight required (in gms) and A=Area (cm2)
6.
Determination of Rheological properties:[23]
20gm
of prepared emulgel filled in 25ml beaker was used to measure viscosity by
using Spindle number S64 by Brookfield viscometer.
7.
Accelerated stability studies:[22]
As
given in ICH guidelines, the formulations are kept in oven at 37±2°C, 45±2°C
and 60±2°C differently for 3 months. Drug content is examined every two week by
appropriate analytical method. Stability measurement is based on change in pH
of gel or degradation of drug.
8.
Determination of % drug content: [26]
1
g of prepared emulgel is mixed with 25 ml of methanol. This resultant solution
is sonicated for 30 min. Drug content was analyzed using the suitable
analytical method from this solution.
OR
1
gm of emulgel was dissolved in 50 ml of 0.1N NaOH kept aside for 2 hr. Then 5
ml of sample was withdrawn and absorbance was measured at 265 nm by UV visible
spectrophotometer (schimadzu).
9.
Determination of emulgel spreadability:[19]
It
can be determined by using Slip and Drag method, as suggested by Mutimer, For
this take 2gm of emulgel and applied on lower side slide which is mounted with
wooden block and sandwiched is prepared by using other glass slide having same
size which is bind with hook having 500mg weight placed. After 5 min additional
weight was placed on pan which connected with second slide. Time to cover 5cm
distance for upper slide was recorded and used to calculate spreadability by
using following formula:
Spreadability
(S) = M×L / T Where,
M
= Weight tied to upper slide,
L
= Length of glass slides
T
= Time taken to cover distance by upper slide.
10.
Skin irritation test:[27]
0.25
gm of prepared emulgel is applied to each different site (two to three
sites/rabbit). Rabbit skin sites are washed and wiped after 24 hours of
treatment, and any unfavorable morphological changes or changes in skin color
are noted.
11.
In-vitro Diffusion studies:[21]
Franz
diffusion cell is used to demonstrate diffusion study of prepared emulgel. A
cellophane membrane is used during the study and 0.5g of sample spread on
membrane and diffusion is conducted for 8 Hrs at 37±1°C using phosphate buffer
(pH 7.4). At the time interval of 1 Hr. 1 ml sample is collected and replaced
with fresh buffer solution. Collected samples are analyzed by using suitable
analytical method.
12.
Syneresis measurement test:[23]
Syneresis
measurement test on rest gel shrinks and little liquid is pressed out called
syneresis. This could be measured by means of centrifuge tubes in specific
apparatus.16
Syneresis(%) =
x 100
13.
Determination of Skin Permeation:[24]
Differential
scanning calorimetry is used to examine the structural and chemical alterations
in the epidermal layer (DSC). Using the DSC method, temperature changes in
rats' desiccated SC membranes are examined in order to evaluate the penetration
process. In order to guarantee reducing hydration to 20%, both treated and
untreated skin samples were previously hydrated on a 27% Sodium-Br solution for
at least 48 hours. Before being analyzed, the skin samples are kept in
desiccators for three days at silica gel. The skin layer is divided into
pieces, and 4 mg of weighted pieces are sealed in 10μL aluminum pans before
being added to an empty pan for comparison and put in the differential scanning
calorimetry equipment. Nitrogen flow is set to 20 milliliters per minute to act
as purge gas. Samples are heated steadily at a rate of 10°C per minute between
30 and 400°C, and any variations in the DSC graph are recorded and examined.
14.
Extrudability test (Tube test):[25]
Determines
force necessary for removal of emulgel from tube and necessary to evaluate
emulgel formulation for extrudability.
15.
Microbial assay of emulgel: [27]
Ditch
plate technique could be preferred for microbial assay, it is used for
evaluation of bacteriostatic or fungistatic activity of an antimicrobial agent
and mainly used for semisolid formulation. Zone of inhibition is calculated as
per the following equation.
% Inhibition =
× 100
CONCLUSION
In
summary, this review emphasizes formulation and thorough evaluation of the
vitamin D3 emulgel will present a promising approach for topical application.
The optimized emulgel will exhibits
favourable characteristics, including enhanced stability, efficient skin
permeation and controlled release of vitamin D3. These findings underscore the
potential of the emulgel as a viable and patient-friendly option for delivering
vitamin D3 through the skin. However, further investigations, including
clinical trials are imperative to confirm its efficacy and safety, paving the
way for its eventual incorporation into dermatological practice.
REFERENCES
1.
Ashara K,
Soniwala M, Shah K. Emulgel: A novel drug delivery system. Journal of Pakistan
Association of Dermatologists. 2016;26(3):244-9.
2.
Peneva P,
Andonova V, Pilicheva B, Kassarova M. In vitro survey of Ketoprofen release
from emulgels. Medicine. 2014;4(1):118-21.
3.
Khullar R,
Kumar D, Seth N, Saini S. Formulation and evaluation of mefenamic acid emulgel
for topical delivery. Saudi pharmaceutical journal. 2012 Jan 1;20(1):63-7.
4.
Mandal S,
Mandal SS, Sawant KK. Design and development of microemulsion drug delivery
system of atorvastatin and study its intestinal permeability in rats. International
Journal of Drug Delivery. 2010 Jan 1;2(1).
5.
Joshi B,
Singh G, Rana AC, Saini S, Singla V. Emulgel: a comprehensive review on the
recent advances in topical drug delivery. Int Res J Pharm. 2011;2(11):66-70.
6.
Bikle DD.
Vitamin D metabolism, mechanism of action, and clinical applications. Chemistry
& biology. 2014 Mar 20;21(3):319-29.
7.
Kim GK. The
rationale behind topical vitamin d analogs in the treatment of psoriasis: where
does topical calcitriol fit in?. The Journal of clinical and aesthetic dermatology.
2010 Aug;3(8):46.
8.
Vieth R,
Chan PC, MacFarlane GD. Efficacy and safety of vitamin D3 intake exceeding the
lowest observed adverse effect level. The American journal of clinical
nutrition. 2001 Feb 1;73(2):288-94.
9.
Shankar R,
Tiwari V, Mishra C, Singh C, Sharma D, Jaiswal S. Formulation and evaluation of
ketoconazole nanoemulsion gel for topical delivery. American Journal of
Pharmtech Reseatch. 2015;5(5):446-62.
10.
Modi JD,
Patel JK. Nanoemulsion-based gel formulation of aceclofenac for topical
delivery. International Journal of Pharmacy and Pharmaceutical Science
Research. 2011;1(1):6-12.
11.
Sailaja AK,
Supraja R. An overall review on topical preparation-gel. Innovat International
Journal Of Medical & Pharmaceutical Sciences. 2016 Nov;1(1):17-2.
12.
Cevc G, Schätzlein
A, Blume G. Transdermal drug carriers: basic properties, optimization and
transfer efficiency in the case of epicutaneously applied peptides. Journal of
Controlled Release. 1995 Sep 1;36(1-2):3-16.
13.
Shankar R,
Tiwari V, Mishra C, Singh C, Sharma D, Jaiswal S. Formulation and evaluation of
ketoconazole nanoemulsion gel for topical delivery. American Journal of
Pharmtech Reseatch. 2015;5(5):446-62.
14.
Modi JD,
Patel JK. Nanoemulsion-based gel formulation of aceclofenac for topical
delivery. International Journal of Pharmacy and Pharmaceutical Science
Research. 2011;1(1):6-12.
15.
Singh RP,
Parpani S, Narke R, Chavan R. Emulgel: A recent approach for topical drug
delivery system. Asian Journal of Pharmaceutical Research and Development. 2014
Mar 1:112-23.
16.
Vats S,
Saxena C, Easwari TS, Shukla VK. Emulsion based gel technique: Novel approach
for enhancing topical drug delivery of hydrophobic drugs. International Journal
for Pharmaceutical Research Scholars. 2014;3(2):649-60.
17.
Alexander
A, Khichariya A, Gupta S, Patel RJ, Giri TK, Tripathi DK. Recent expansions in
an emergent novel drug delivery technology: Emulgel. Journal of Controlled
Release. 2013 Oct 28;171(2):122-32.
18.
Bhowmik D.
Recent advances in novel topical drug delivery system. The Pharma Innovation.
2012 Nov 1;1(9).
19.
Ashara KC,
Paun JS, Soniwala MM, Chavada JR, Mori NM. Micro-emulsion based emulgel: a
novel topical drug delivery system. Asian pacific journal of tropical disease.
2014 Jan 1;4:S27-32.
20.
Modi JD,
Patel JK. Nanoemulsion-based gel formulation of aceclofenac for topical
delivery. International Journal of Pharmacy and Pharmaceutical Science
Research. 2011;1(1):6-12.
21.
Sumithapaul, Abhineshkumar, Pramod
Yadurkar, Kruthikasawant. Design and Development of multiple emulsions for the
enhancement of oral bioavailability of Acyclovir. Drug development and
Industrial pharmacy, 39(11), 2013, 1808-1817.
22.
Bonacucina
G, Cespi M, Palmieri GF. Characterization and stability of emulsion gels based
on acrylamide/sodium acryloyldimethyl taurate copolymer. Aaps Pharmscitech.
2009 Jun;10:368-75.
23.
Mandal S,
Mandal SS. Research paper microemulsion drug delivery system: a platform for
improving dissolution rate of poorly water soluble drug. Int J Pharm Sci
Nanotech. 2011;3(4):1214-9.
24.
Shakeel F,
Baboota S, Ahuja A, Ali J, Shafiq S. Skin permeation mechanism of aceclofenac
using novel nanoemulsion formulation. Die Pharmazie-An international journal of
pharmaceutical sciences. 2008 Aug 1;63(8):580-4.
25.
Charoenrein S, Tatirat O, Rengsutthi K,
Thongngam M. Effect of konjac glucomannan on syneresis, textural properties and
the microstructure of frozen rice starch gels. Carbohydr Polym. 2011;83: 291-6.
26.
Singla V, Sanini S, Rana AC, Singh G.
Development and evaluation of topical emulgel of lornoxicam using different
polymer bases. Int Pharm Sci. 2012;2(3):36-44.
27.
Murty SN, Hiremath SRR, Physical and
chemical enhancers in transdermal delivery of terbutaline sulphate, AAPS Pharm.
Sci. Tech 2001; 2:1–5.