Studies on Transdermal Delivery System of Electret Meloxicam Patch
Transdermal drug delivery system (TTDS) is a new formulation which treats
or prevents diseases by the skin administration. TTDS can maintain drug blood
level, avoid hepatic first-pass elimination, decrease side effects, and extend
drug effective time, facilitate and enhance long-term treatment of patients with
compliance. However, there are only limited number of chemicals, which have low
molecular weight (<500), low melting point (<200℃), low-dose (≤20mg·d-1)
and high lipophilicity (log P = 1~3), are
neodymium standard state suitable for TDDS due to the barrier
function of the outmost layer of the skin.Meloxicam is a small molecule and
lipophilic drug with the molecular weight of 351.41 and LogP=1.01. Its daily
dose is less than 10mg and melting point, determined in our experiment, is
247.1℃.As a whole, meloxicam is suitable for TDDS.However, it is difficult for
some drug to achieve therapeutic effect because of physiological barrier
function of the stratum corneum. Therefore, it is of much importance to overcome
barrier effect of skin and to promote penetration amount of drugs within a
certain period of time.Some strategies, consisting of chemical and physical
enhancers, have been investigated and developed in order to overcome the barrier
properties of the skin and thus enhance drug transdermal absorption.
Penetration enhancers, such as Azone, ethyl oleate, menthol, propylene
glycol, dimethyl sulfoxidend are commonly used. On the other hand, iontophoresis
is an enhancement technique that improves transdermal drug transport through the
application of a low-level electric current.Eelectret is the electrostatic
equivalent of a permanent magnet and can generate internal and external electric
fields. Our previous studies indicated that electret can improve the circulation
of blood, enhance the wound healing, regulate the cell growth and apoptosis,
modify the electret state of skin, and enhance the transdermal drug delivery.The
primary aim of this paper was to characterize enhancing effect of electret on
the maloxicam transdermal absorption through rat skin as compared with chemical
enhancers, to understand in detail the
magnetic materials possible mechanisms by which electret
enhances molecular transport across the skin, to investigate the possible
synergic effect of the application of chemical enhancers and electret, to
prepare a meloxicam electret patch formulation and to study its pharmacodynamics
for inflammation and pain.
The solubilities of meloxicam in octanol or phosphrte buffer solution (PBS)
with different pH were determined by UV method and the partition coefficient was
calculated accordingly. The results showed that (1) The octanol-water partition
coefficient of meloxicam logP was 0.97 which is similar to the reported value.
(2) The solubility of meloxicam increased with the increasing of pH of the
buffer solution. The in vitro permeation study indicated that (1) 1%, 3% and 5%
azones show a 1.18, 1.33, 1.26 times increase of the cumulated permeation amount
of meloxiam in 10h as compared with that of in control group(p<0.05).The
enhancing effect was ranged in following order: 3% azone >5% azone >1%
azone; (2) Most of the chemical enhancers used in this study were shown to have
enhancing effects except for 20% propylene glycol. Among them, 10% ethyl oleate
was proved to be the most effective one, showing a 1.86 times increase of the
cumulated permeation amount of meloxiam in 10h as compared with that of in
control group(p<0.05); (3) Negative electret was more effective than the
chemical enhancers used in this study in meloxicam trasdermal delivery, showing
a 2.16 times increase of the cumulated permeation amount of meloxiam in 10h as
compared with that of in control group(p<0.05); (4) Electret can improve the
enhacing effect of chemical enhancers in this study. The cumulated permeation
amount of meloxicam for chemical enhancer with electret patchs in 10h were 1.14
to 2.89 times that of the meloxicam patchs with chemical enhancers
only(p<0.05); (5) The cumulated permeation amounts of meloxicam for 10% ethyl
oleate with negative electret patch was the largest in all of the patchs,
showing a 4.53 times increase as compard with that of in control group (
p<0.01). In order to explain and explore the electret enhancing mechanism,
electron microscopy specimen was used to observe the rat skin’s ultrastructural
change and confocal laser scanning microscopy (CLSM) was used to study the
mechanisms of drug skin permeation enhancement after the rats skin was treated
with electret for 2h. The studies revealed that the enhancing effect of electret
on meloxicam transdermal delivery was not only through changing the structure of
the stratum corneum cells to achieve, but also to a large extent through
broadening the hair follicle to obtain.Based on the above findings, we prepared
meloxicam patch combining 10% ethyl oleate with negative electret. The effects
of the plasticizer and drug content on adhension of the patches were observed.
The study showed that the more the content of plasticizer, the stronger the tack
of the patch was, but the waker the cohesion of the patch was. The effect of
meloxicam was opposite to plasticizer.
Optimal formulation was achieved by orthogonal experiment on considering
the factors of cohesion of the patch and cumulated released amount of meloxicam
from the patch. The methodology for determination the quality of electret
meloxicam patch was studied. The results showed that electret meloxicam patch
was of uniform thickness, moderate adhension. The releasing rate, stability,
toxicity and irritability studies indicated that electret meloxicam patch was a
safe, nontocix and non irritant formulation.In addition, the mice retortion pain
models induced by acetic acid and mice auriculate tumefaction models caused by
xylene were established in the paper. The results showed that the inhibitory
ratio of retortion of mice induced by acetic acid in electret meloxicam patch
was 63.30% (p<0.01), which was higher than that in meloxicam patch (55.85%)
and oral meloxicam suspension (54.25%). the inhibitory ratio of auriculate
tumefaction of mice caused by xylene in electret meloxicam patch was 34.20%
(p<0.05), which was also higher than that in meloxicam patch (22.14%) and
oral meloxicam suspension (24.60% ).In this paper, the electret meloxicam patch
combined both the physical and chemical enhacing methods. Electret demonstrated
its unique effect as a new, non-toxic, safe physical method in this
Neodymium Magnets paper. The
studies proved that electret could be used as excellent enhancer in transdermal
permeation of meloxicam. Meanwhile, electret meloxicam patch was a kind of
multiple effective anti-inflammatory analgesic patch, which integrated chemical
and physical treatment into a one. It took advantage of the pharmacological
effects of meloxicam and characteristics of electret which can adjust skin in
biological electret state and weakened pain caused by injure and improved the
effect of the analgesic drug.