INTRODUCTION:
Transdermal drug delivery systems have gained interest in health care because of its potential, like ease of use, lack of first pass metabolism burdening liver, steady release profile and improved patient compliance.1-5
Physiotherapists use therapeutic ultrasound (TUS) for transdermal delivery of pharmaco-therapeutic drugs by enhancing skin permeability, a technique which is known as phonophoresis or Sonophoresis (PH).6-11
For its topical application, a pharmaco-therapeutic drug needs to be prepared in various topical formulations such as gel or cream mediums9 and in the Indian clinical practice, the same preparation available in the market is found to be used by the Physiotherapists for PH along with coupling gel.
Using gel-based coupling mediums for the application of TUS for its ultrasonic transmittivity is a common practice by physiotherapists.10-12 and many commonly used topical drug formulations, especially with more oil-based lipophilic medium like ointments and creams known for better permeability through skin, might be poor transmitters of ultrasound.9,13,14 Though gels are effortless and non-greasy, the effect of them are relatively slower but sustained.15,16 Phonophoresis use either a continuous mode (CTUS) or pulsed mode (PTUS) of TUS in phonophoresis. In thermal CTUS, the enhancement of drug molecule diffusion through the stratum corneum is believed to be because of an increase in the kinetic energy of the molecules, improved circulation, and dilation of points of entry such as the hair follicles and the sweat glands. But this route of entry is barely 1% of the total skin surface.9,14,17,18,19 In PTUS the thermal effect is eliminated because of an interruption in transmission and the application goal is achieved through its mechanical effects of cavitation, micro-streaming and acoustic effects.7,21
The literature available on phonophoresis mainly focuses on studies related to pharmacy and chemical engineering in which the ultrasound used is far different from TUS used by Physiotherapists i.e., the frequency is lower or higher than therapeutic 1-3 MHz22-30 duration of application is longer27,30,31 and most of the studies are conducted on in-vitro models23,28,31,32
Owning to the lack of evidence on effective medium and mode of TUS for PH, the Physiotherapist are observed to be using any mode or medium as per convenience. Therefore, an attempt to establish a most effective protocol of PH in terms of drug medium and mode of TUS is aimed at this study. The estimation of serum concentration of drug Diclofenac Sodium (DS) as the variable for the objective of comparison regarding media and modes used in this study because DS is a widely used in physiotherapy practice in both gel and cream-based preparations.
MATERIAL AND METHODS:
Animals:
Eight Healthy New Zealand white rabbits, approximately eight months to one year of age, weighing two to three kilograms, were used for the study. Prior to the study, the proposal was scrutinized by the Institutional Animal Ethics Committee (IAEC) appointed by The Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA) of India and ethical clearance obtained. The animals were procured from the National Institute of Biosciences, Pune (CPCSEA Reg. No. 1091/PO/07/abc/CPCSEA) and were housed in the Animal Lab of MGM Medical College, Kamothe, Navi Mumbai (CPCSEA Reg. No. 303/PO/Re/S/2000/CPCSEA). The rabbits were secured in a cage which were properly ventilated and ensured the safe handling of the animal as prescribed by CPCSEA.33
Drug Preparation:
In this study, DS formulations were prepared with 1% concentration in gel and cream medium. The formulations were prepared at the Dept. of Pharmaceutics, Bharati Vidyapeeth's College of Pharmacy, Belapur, Navi Mumbai. DS was used as an active ingredient in this study as it is used as NSAIDs in musculoskeletal conditions like osteoarthritis, rheumatoid arthritis, sprains and strains in muscles and ligaments etc. However oral administration of DS in prolong period can cause indigestion, constipation, diarrhea and even ulcer. Currently, the topical route offers more advantages, like prevention in first pass metabolism and damage the gastrointestinal tract.34,35
TUS Parameters for phonophoresis:
A dual frequency, 1 and 3 MHz digital ultrasound machine (Striker Biotech India) was used for the study which comprised CTUS as well as PTUSmode at 10%, 20%, 50% and 100% duty cycle and a power output of maximum 2.5W/cm2. The machine was inspected for proper output prior to the study.
Procedure:
Eight healthy adult rabbits were subjected to 6 experiments, which accounted for total 48 blood samples (Topical DS in gel or cream, DS gel or cream PH with CTUS and DS gel or cream PH with PTUS). For Phonophoresis, each animal received 1 MHz TUS of 1W/cm2 intensity and 8 minutes duration for CTUS and 20% PTUS, respectively. The dorsal thigh region of the rabbit was selected, hair removed from the region carefully without cut or visible damage to the skin. Drug preparation was then applied by spreading the gel/cream evenly over the target area. Each experiment was repeated after a wash-out period of one week. The animals were placed in a restrainer for blood collection. Ear was cleaned with 95% v/v alcohol. A 26G needle was used to collect blood from marginal ear veins or the central ear artery. After collecting blood, clean sterile cotton was kept on the collection site and finger pressure applied to cease the bleeding. Up to 5ml of blood was collected at each experiment. The samples were collected in EDTA tubes, transported to the MGM Central Laboratory, Kamothe and centrifuged to separate serum and refrigerated until being analyzed for serum concentration of an applied drug by High Performance Liquid Chromatography (HPLC) assay at Jubilant Pharma and Chemical Lab, New Panvel. The animals were not sacrificed at the end of the study.
Statistical Methods:
Sample size was calculated using G*Power software and the
base data for the same was from a previous study by Asano et al. (1997)36and
the values considered were for control 4.19±0.56 (SE), PTUS 5.53±0.37 (SE) and CTUS
9.44±1.31 (SE). The standard Deviations (SD) were then calculated from standard
error (SE) by the formula SD=SE x 
. Since the total n in Asano et al. study
was 4 for which 
was 2, SD for control was calculated as 1.12,
pulsed ultrasound 0.74 and continuous ultrasound 2.62. Finally, SD within each group
was calculated as mean SD i.e., 1.12+0.74+2.62/3 = 1.48 for sample size calculation.
For the expected method of One-way ANOVA, the output obtained was a total sample
size of 8 for an input details of effect size f of 1.50, α err prob 0.05 and
Power (1-β err prob) at 0.80.
The data obtained from HPLC were statistically analyzed using SPSS 21 software. For this study, the level of significance was set at 5%. All P values < 0.05 were considered as significant. Prior to statistical analysis, tests for normality using the Shapiro - Wilk test were conducted to determine the statistical method adopted. The null hypothesis was set as the distribution of phonophoretically applied drugs in blood are the same in both gel and cream mediums and in continuous and pulsed mode of TUS.
RESULTS:
Data were analyzed for descriptive statistics, such as mean and standard deviation. The descriptive statistics for mean and standard deviation of the data set are shown in Table 1.
Table 1: Descriptive statistics for plasma concentration of Methyl Salicylate and Diclofenac sodium (all in μg/ml).
|
|
N |
Mean |
Std. Deviation |
|
DS_G_Top |
8 |
.016469 |
.0073320 |
|
DS_G_Cont |
8 |
.027518 |
.0103140 |
|
DS_G_Puls |
8 |
.046452 |
.0078950 |
|
DS_C_Top |
8 |
.022357 |
.0068774 |
|
DS_C_Cont |
8 |
.093975 |
.0497784 |
|
DS_C_Puls |
8 |
.101759 |
.0448998 |
DS: Diclofenac sodium G: Gel. C: Cream. Top: Topical. Cont: Continuous ultrasound. Puls: Pulsed ultrasound.
Mann-Whitney U test was run to determine if there were differences in the drug penetrability of DS in gel and cream medium along with Rosenthal correlation (r) for effect size report. The test statistics are shown in Table 2 and graphical representation of means of two different media are shown in Figure 1. A Mann-Whitney U test for only TA of DS showed that the mean ranks for gel (mean rank = 6.75) and cream (mean rank = 10.75) mediums were not significantly different with a very low effect size, U (n1 = 8, n2 = 8) = 18.0, p =.161, r = 0.367, application of DS PH in continuous mode showed that the mean ranks for gel (mean rank = 4.50) and cream (mean rank = 12.50) mediums were significantly different with a large effect size, U (n1 = 8, n2 = 8) = 0.00, p = <.001, r = 0.840 and the application of DS PH in pulsed mode showed that the mean ranks for gel (mean rank = 5.25) and cream (mean rank = 11.75) mediums were significantly different with a moderately large effect size, U (n1 = 8, n2 = 8) = 6.00, p =.005, r = 0.682.
Table 2: Test Statisticsa
|
|
DS_Top |
DS_Cont |
DS_Puls |
|
Mann-Whitney U |
18.000 |
.000 |
6.000 |
|
Wilcoxon W |
54.000 |
36.000 |
42.000 |
|
Z |
-1.470 |
-3.361 |
-2.731 |
|
Asymp. Sig. (2-tailed) |
.141 |
.001 |
.006 |
|
Exact Sig. [2* (1-tailed Sig.)] |
.161b |
.000b |
.005b |
|
|
|||
a. Grouping Variable: Medium. b. Not corrected for ties. DS: Diclofenac sodium. Top: Topical. Cont: Continuous ultrasound. Puls: Pulsed ultrasound.
Figure 1: Mean comparison of drug concentration in plasma after DS phonophoresis through different medium. DS: Diclofenac Sodium. Top: Topical. Cont: Continuous. Puls: Pulsed. *: p <0.05 vs gel. **: p <0.05 vs gel.
For comparing different modes of TUS in PH of different medium, a Kruskal-Wallis test was conducted with an epsilon-squared (E2) estimate of effect size and post-hoc Dunn's test with Bonferroni correction for pair-wise comparisons with adjusted p-values. The test statistics is shown in Table 3 and mean comparison of drug concentration in plasma after CTUS and PTUS modes are shown in Figure 2. The Kruskal-Wallis test showed that the modes of TUS had a significant strong effect on the distribution of DS PH through gel medium, χ2 (2, N = 24) = 15.585, p= <.001, Ε2 =.678. A post-hoc test showed significant differences between topical (mean rank 6.00) and pulsed (mean rank 19.88) with p= <.001, no significant differences between topical (mean rank 6.00) and continuous (mean rank 11.2) with p=.335 and between continuous (mean rank 11.2) and Pulsed (mean rank 19.88) with p=.059. Also, there is a significant strong effect on the distribution of DS PH through cream medium, χ2 (2, N = 24) = 15.405, p= <.001, Ε2 =.670. A post-hoc test showed significant differences between topical (mean rank 4.50) and continuous (mean rank 16.12) with p=.003 and topical (mean rank 4.50) and pulsed (mean rank 16.88) with p=.001 but no significant differences between continuous (mean rank 16.12) and Pulsed (mean rank 16.88) with p=.832.
Table 3: Test Statistics from Kruskal-Wallis testa,b
|
|
DS_G |
DS_C |
|
Chi-Square |
15.585 |
15.405 |
|
df |
2 |
2 |
|
Asymp. Sig. |
.000 |
.000 |
a. Kruskal-Wallis Test. b. Grouping Variable: Mode. DS: Diclofenac sodium. G: Gel. C: Cream.
Figure 2: Mean comparison of drug concentration in plasma after continuous and pulsed modes of Ultrasound application. DS: Diclofenac Sodium. G: Gel. C: Cream. #: p <0.05 vs topical. *: p <0.05 vs topical. **: p <0.05 vs topical.
DISCUSSION:
Since this study involved repeated extraction of blood for analysis of DS concentration, the experiment was conducted on animals, and rodents were used for the same because physiotherapeutic ultrasound energy on rodents is safe without adverse side effects.36,37,38As per the outcome of our pilot study on identification of lag time, blood collection after each experiment was done 90 minutes after the application of drug. HPLC method for determination of DS was carried out based on published work by Emami J (2005).39
Though several studies have reported that PH can increase transdermal drug penetration under various parameters of TUS (e.g., frequency, time of application, on/off ratio, etc.), studies comparing the media used in this technique are rare. The results confirmed the higher availability of an applied drug in cream base when TUS is used for PH. Higher drug concentration with cream base could be explained in terms of lipophilic properties of stratum corneum, which is also known to provide resistance to penetration of hydrophilic medium.40,41,42,43
In this study, drug concentration after TA was comparable in both the media. We used same method to spread the drug on the skin during both TA and PH. Effectivity of cream medium also supported our next finding when DS after CTUS and PTUS modes of PH application were compared over TA along with the effect of PTUS mode confirmed over CTUS. PH seems to lower the skin resistance to enable effective transdermal delivery of drug for which, various mechanisms are responsible. Among these, cavitation is thought to be the primary effect responsible.7,8,28,44,45,46
Although there is significant difference found between TA and PH in both media, no change was found in the rate of absorption between CTUS and PTUS which supported the findings by Cagnie B et al. (2003) and Deniz et al. (2009)47,48 but showed conflicting results with studies by Ebrahimi S et al. (2012).49 Asano et al. (1997) found maximum penetration effect in 1:2 PTUS in transdermal absorption of indomethacin ointment with gel medium in rat experiment and they suggested that the on/off pulsed ratio, intensity, and the time of application play an important role in the transdermal phonophoresis delivery system.36 In PTUS, there can be disappearance of stable cavitation during the interval mode, whereas the transient cavitation, while collapsing, leading to more micro-bubbles which eventually contribute to the next 'on' phase, creating a cloud of bubbles. This leads to the amplified creation of shock waves and micro-jets to disrupt the tissue structure of the skin, enhancing drug transport.50,51,52 With an interval provided in pulsed US, there is a possibility of the bubbles to maintain their integrity longer until the critical stage of collapse with a stronger consequent shock wave energy conversion.53,54
Merino et al. concluded that approximately one fourth of enhancement was because of the increased temperature induced by ultrasound, but the mechanism, most probably cavitation, is responsible for the lowered skin barrier function they observed.24 Besides the change in drug penetration similar or better compared to continuous mode application, various authors argue about the enhanced safety of pulsed mode ultrasound compared to continuous ultrasound which can cause irreversible disruption such as detachment and necrotic changes of the epidermis, dermis, sweat ducts, capillaries and muscles.19,55
Though several studies have reported that PH can increase transdermal drug penetration under various parameters of TUS (e.g., frequency, time of application, on/off ratio, etc.), studies comparing the medium used in this technique are rare. Phonophoresis as a method of transdermal drug delivery can be considered because of the advantages such as sustained delivery of drug, reduced chances of side effects associated with overdose, avoids first pass metabolism due to bypassing of gastro-intestinal tract that can cause degradation of drug molecules and is more acceptable to patients who cannot take drugs orally such as in unconscious patients.
CONCLUSION:
In this comparative study on transdermal drug delivery, the cream medium was found to be more effective than gel. Comparison between mode of application of PH using CTUS and PTUS was found to be significantly higher drug concentration than TA alone. Both CTUS and PTUS showed comparable drug concentration.
ACKNOWLEDGMENT:
The authors would like to thank MGM Institute of Health Sciences, Navi Mumbai, Department of Pharmacology, MGM Medical College, Navi Mumbai, Bharati Vidyapeeth's College of Pharmacy, Belapur, Navi Mumbai, Jubilant Pharma and Chemical Lab, New Panvel for their support in different phases of this study and our never-ending gratitude to Dr. Vimal V(PT) for his assistance and support throughout.
CONFLICT OF INTEREST:
The authors declare that there was no conflict of interest.
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Received on 28.10.2021 Modified on 18.07.2022
Accepted on 10.12.2022 © RJPT All right reserved
Research J. Pharm. and Tech 2023; 16(4):1965-1970.
DOI: 10.52711/0974-360X.2023.00322