IMPROVEMENT IN PAIN RELIEF USING A DMSO BASED DICLOFENAC IN COMPARISON TO CONVENTIONAL DICLOFENAC GELS IN OSTEOARTHRITIS –A RANDOMIZED CONTROLLED TRIALHTML Full Text
IMPROVEMENT IN PAIN RELIEF USING A DMSO BASED DICLOFENAC IN COMPARISON TO CONVENTIONAL DICLOFENAC GELS IN OSTEOARTHRITIS –A RANDOMIZED CONTROLLED TRIAL
N. Senthil Kumar *, Anu Chacko, M. I. Jimshad, G. Yuva Srinivas and A. Tamilselvan
Department of Pharmacy Practice, JKKMMRF’s - Annai JKK Sampoorani Ammal College of Pharmacy, Komarapalayam, Namakkal - 638183, Tamil Nadu, India.
ABSTRACT: Background: Topical NSAIDs are the first line choice of drug for management Osteoarthritis elderly patients, which produce less systemic exposure compared with oral NSAIDs. Now a day’s several topical formulations are available. This study provides a comparison between two various topical diclofenac formulations. Methods: 12 weeks, randomized controlled trial to evaluate dimethyl sulfoxide (DMSO) based diclofenac solution and Linseed oil based diclofenac gel safety and efficacy profile. 43 men and women, age 40-65 years, with radiologically confirmed primary OA of the knee were included in this study. The included participants treated with DMSO based diclofenac solution; 40 drops 3 times daily directly to the painful knee without a massage (test group) and Linseed oil based diclofenac gel; 1 gram 3 times daily to the painful knee(control group). The primary outcome measure included the continuous variable pain relief and improved physical function measured by the Western Ontario McMaster Universities (WOMAC) Likert 3.1OA Index. Secondary efficacy measure was reduced stiffness. Safety assessment included adverse events and application site reactions. Results: DMSO based diclofenac solution group had a significantly greater mean change in score (final minus baseline) compared to the linseed oil based diclofenac gel group for pain (-9.8 vs. -6.9, p=0.032), stiffness (-3.7 vs. -2.4, p=0.048) and function, daily living (-26.4 vs. -15.9, p=0,019). Overall, each drug’s application was well tolerated, and no adverse event was reported. Conclusion: This DMSO based diclofenac solution group showed statistically significant improvement in pain, stiffness and physical function compared to the conventional diclofenac gels.
Topical NSAIDs, DMSO, Diclofenac, Osteoarthritis, Knee OA
INTRODUCTION: Osteoarthritis is characterized by pain, stiffness, cracking of the joints (crepitus) and loss of function of the joint which can lead to disability 1. OA affects about 4-6% of the elderly population, and it is the leading top 5 chronic diseases in India 2.
A survey-based study discloses that “India is forecast as chronic disease capital by 2025 has 60 million populations with arthritis”. 3 Now itself no specific treatment available to cure the osteoarthritis, only symptomatic relief from the pain and stiffness of the knee. Primary management of OA for all individuals’ medication is to reduce pain. Oral NSAIDs are recommended treatment for OA of the knee but have been associated with a higher risk in gastrointestinal, renal and cardiovascular systemic toxicity.
Current guidelines, Osteoarthritis Research Society International (OARSI) 2014 and National Institute for Health and Clinical Excellence 2014 for the management of knee osteoarthritis recommends topical NSAIDs considered alternative to oral NSAIDs, cox-2 inhibitors or Opioid with decreased systemic exposure to the active diclofenac.
Topical NSAIDs are the safest medication and first-line therapy to OA management, especially in the elderly population, and those with co-morbidities such as HTN, type 2 diabetes mellitus, cerebrovascular or cardiovascular disease 4.
Objectives: In this report, we present the efficacy and safety results from a 12 week controlled trial to find out if there a difference in pain relief between DMSO based diclofenac solution and linseed oil based diclofenac gel. Our secondary objectives were to assess improvement in pain, stiffness and physical function in both groups.
MATERIALS AND METHODS:
Study Design: This study was a randomized controlled trial conducted from March 2018 to August 2018 at Maaruthi Medical Centre Hospital (MMCH), Erode. The ethical clearance was approved from Institutional ethics committee, and hospital authority has sanctioned, IEC approval number - EC NO/PHARM D/2018-6.
Participants (Inclusion / Exclusion Criteria): Participants were recruited from the MMCH orthopedic outpatient department. At the screening visit, all the patients gave informed written consent before their inclusion in this study. Inclusion criteria specified either gender; aged 40-65 years with primary OA of the knee defined as standard radiographic criteria for OA based on recent (within 3 months) examination and pain with regular use of topical NSAIDs. Participants were excluded if they had secondary arthritis like wrist, hip, feet and multiple joint osteoarthritis and history of major surgery, patients already on oral NSAIDs/analgesics, any contraindication to diclofenac, patients with skin wounds at the site of application, concomitant skin disease at site of application and severe cardiac, renal, hepatic or other systemic diseases; and history of drug or alcohol abuse.
Interventions: The participants were randomly divided into two groups in which test group (n=22) who get DMSO based diclofenac solution and control group (n=21) who get linseed oil based diclofenac gel with methyl salicylate. Test group participants were applied a dose of 40 drops DMSO based diclofenac solution (about 1.2 ml) to the affected knee 3 times daily up to 12 weeks and they were instructed to apply 10 drops of solution to each side of the knee (front, back, medial and lateral) dripped directly on to the affected knee and then spread over the site without massage. Control group participants have applied a dose of 4gm (4.5 inches) of gel on to the affected knee 3 times daily up to 12 weeks.
Outcome Measures: The primary outcome measures were defined as the change in from baseline to the final assessment of the study, knee in the 3 continuous variables pain, stiffness and physical functions measured by the Western Ontario McMaster Universities (WOMAC) subscales. There was no intermediate assessment of efficacy. The WOMAC pain scale validated questionnaire consisting of 24 questions, 5 questions on pain, 2 on stiffness and 17 on physical functions.
Each questions scored on a 5 point Likert scale (0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = extreme problem) 5. Higher scores on the WOMAC indicate worse pain, stiffness and physical functions limitations 6.
Safety Analysis: Safety was assessed during every week clinic visit. Safety assessment included adverse event, application site dermatological reactions. Adverse events were identified using open questions and a checklist covering common oral NSAIDs side effects. Laboratory assessment was not done.
Randomization: A random number generator within Microsoft Excel will be used to generate the randomization sequence and maintained centrally by one of the investigators, who will not be involved in the assessment of participants.
Statistical Analysis: To find out the effectiveness of the drugs, the pain reduction between the two groups was compared by student independent “t” tests. To compare the two groups, they would be homogenous groups in respect of their demographic profiles. The homogeneity of discrete variables was tested by χ2 (Chi-square) test and continuous variables by independent “t” test. The above statistical procedures were performed with the help of the statistical package IBM SPSS statistics-20. The level of significance was fixed as P-values less than or equal to 0.05 (P≤0.05).
Participants Flow: 50 participants were randomized to treatment either DMSO based topical diclofenac solution (n = 26) or linseed oil based diclofenac gel (n = 24). All participants received their allocated intervention. Most of the participants completed this study (n = 43). The discontinuation rate due to non-availability during the study visit in both groups. Dropout due to lack of effect of treatment (n = 2), non-availability during the study visit (n = 5). Finally, n = 43 participants have completed this study in which test group (n = 22) and control group (n = 21) Fig. 1.
FIG. 1: FLOW OF PARTICIPANTS
Baseline Demographic Data: Table 1 states the description and homogeneity of the test and control groups. The demographic characteristics such as age, gender, BMI, number of knees affected, family history of OA, smoking status, co-morbid diseases, duration of OA, education status and occupation status of both groups were not statistically significantly differed (P>0.05). A summary of demographic data described in Table 1.
TABLE 1: DESCRIPTION AND HOMOGENEITY OF DEMOGRAPHIC PROFILES BETWEEN THE TEST AND CONTROL GROUP
n = 22
|Control group n=21||Results||Significant|
|Age group (years)||40-49||6||27.3||9||42.8||Mean ± SD||P = 0.936|
|50-59||10||45.4||3||14.4||53.4 ± 8.2|
|60-69||6||27.3||9||42.8||53.7 ± 9.1|
|Gender||Male||7||31.8||11||52.4||χ2 = 1.867
df = 1
|P = 0.172|
(Mean ± SD
|Weight||62.0||11.0||66.5||13.5||t = 1.198||P = 0.238|
|Height||156.6||9.4||158.1||13.0||t = 0.450||P = 0.655|
|BMI||25.5||4.7||26.7||5.4||t = 0.836||P = 0.408|
|No of knees affected||Both knees||7||31.8||7||33.3||χ2 = 0.011
df = 1
|P = 0.916|
|Family history of OA||Yes||6||27.3||4||19.0||χ2 = 0.407
df = 1
|P = 0.523|
|Smoking status||Yes||3||13.6||1||4.8||χ2 = 0.227
df = 1
|P = 0.634|
|Co morbid diseases||Yes||13||59.1||7||33.3||χ2 = 2.865
df = 1
|P = 0.091|
|Duration of OA (years)||Mean||6.5||5.3||t = 1.106||P = 0.275|
|Educational status||Illiterates||7||31.8||5||23.8||χ2 = 0.343
df = 1
|P = 0.558|
|Type of occupation||Sedentary||12||54.5||11||52.4||χ2 = 0.020
df = 1
|P = 0.887|
The Effectiveness of the Drugs on Pain Relief: The effectiveness of the two drugs in pain relief within and between the two groups was compared. Table 2 states the effectiveness of DMSO based diclofenac solution in pain reduction from baseline to last follow up. The mean pain on the baseline and last follow up was 11.1 ± 3.1 and 1.3 ± 0.7.
The mean stiffness on the baseline and last follow up was 3.9 ± 2.2 and 0.1 ± 0.4. The mean physical function on the baseline and last follow up were 34.8 ± 13.5 and 8.4 ± 6.3. The mean total pain on the baseline and last follow up was 49.8 ± 17.8 and 9.9 ± 6.7. The differences between the above means were statistically very highly significant (P<0.001).
TABLE 2: PAIN REDUCTION WITHIN THE TEST GROUP FROM BASELINE TO the LAST FOLLOW-UP
Table 3 states the effectiveness of conventional diclofenac gel in pain reduction from baseline to last follow-up. The mean pain on the baseline and last follow-up were 11.2 ± 4.3 and 4.3 ± 2.8. The mean stiffness on the baseline and last follow up was 3.8 ± 2.2 and 1.4 ± 1.3. The mean physical function on the baseline and last follow up were 32.7 ± 13.6 and 16.8 ± 9.2. The mean total pain on the baseline and last follow up was 47.7 ± 18.9 and 22.4 ± 10.6. The differences between the above means were statistically very highly significant (P<0.001).
Table 4 compares the pain reductions between the two groups. The mean decrease in the test group was 9.8 ± 3.3 and control group mean reduction was 6.9 ± 4.9. The difference between the reductions was statistically significant (P<0.05). The stiffness reductions of test and control groups were 3.7 ± 2.1 and 2.4 ± 2.2. The difference between them was statistically significant (P<0.05). The mean reductions of physical function of both groups were 26.4 ± 16.4 and 15.9 ± 11.2. The difference of reduction between the two groups was statistically significant (P<0.05).
The total mean pain reductions between the test and control group were 39.9 ± 21.1 and 25.3 ± 14.8. The difference between the total mean reductions was statistically significant (P<0.05).
TABLE 3: PAIN REDUCTION WITHIN THE CONTROL GROUP FROM BASELINE TO LAST FOLLOW-UP
TABLE 4: COMPARISON OF PAIN REDUCTIONS FROM BASELINE TO THE LAST FOLLOW-UP BETWEEN TEST AND CONTROL GROUPS
|Reductions||Test (n=22)||Control (n=21)||Difference
Safety Analysis: No adverse events were reported during the study period.
DISCUSSION: Published guidelines have incorporated topical NSAIDs as a recommended treatment for OA of the knee 5. However, there has been controversy surrounding the adequacy of data is supporting their benefit beyond 12 weeks.
Total of 43 patients was enrolled and divided into two groups. Patients enrolled in both groups were comparable with each other to age, gender, BMI, no of knees affected, family history of OA, smoking status, co-morbid diseases, duration of OA, educational and occupational status with p>0.05 in all the groups, so difference between the two groups were not statically significant.
This present randomized controlled study evaluated the efficacy of the topical DMSO based diclofenac solution and conventional gel in the symptomatic treatment of OA of the knee. Efficacy findings demonstrated that for the primary endpoint (i.e., WOMAC pain scale score from baseline to the final report of the pain scale score), patients reported significantly greater reductions in WOMAC pain scores with DMSO based diclofenac solution versus conventional gel (P=0.012). Moreover, improvement in the secondary outcome was also directionally and statistically significantly greater in the test group versus the control group as assessed under the study protocol; pain (p=0.032), stiffness (P=0.048), physical function (P=0.019). In general, the test group had a higher proportion of responders across the range of response levels shown compared with the control group. Analysis of all of the primary and secondary measures demonstrated that treatment with this topical diclofenac solution relieved the symptoms of primary knee OA at 12 weeks in this study population. Two other published trials using this DMSO based topical diclofenac solution showed it to be superior to vehicle control and placebo; a 4 week, non-flare trial 7 and a 12 week, flare trial 8.
The most common AEs with diclofenac topical solution analysis were application-site reactions 9. The incidence of application-site reactions (29.0%) was greater than in recent studies of diclofenac sodium gel (5%-6% incidence) 10, 11 but was similar to that observed in previous placebo-controlled trials of diclofenac topical solution 7, 8, 12. DMSO may produce skin dryness by dissolving lipids on the skin surface 13.
But in this study, no cutaneous AEs were reported because of the maximum of patients already exposed to topical diclofenac formulations. The safety analysis results in this study confirm topical NSAIDs had a lower incidence of gastrointestinal adverse events than the other formulations like oral tablets. The study has some limitations. It involved a small number of the population compared to the previous studies because there is no funding from another source. Trials were conducted over 12 weeks, which may not be including blood level safety analysis in this study.
Hence, only the efficacy data from these trials were reported here. No serious AEs were observed in this randomized trial in the general population.
However, confirmation of the CV safety of topical NSAIDs still warrants further study. Dosing compliance; Approximately 95% of patients self-reported >96% compliance by week 12; however, calculation of the difference between dispensed and returned study drug bottle weights showed that many patients administered lower than expected average doses in both treatment groups using the study drug dispensing system. Osteoarthritis is a major source of pain, disability and socioeconomic costs worldwide 24. The DMSO based diclofenac solution has reduced pain and improved functions in the patients with OA and it is cost-effective than the conventional diclofenac gel.
CONCLUSION: DMSO based topical diclofenac solution symptoms relief knee OA over the 12 weeks. DMSO based diclofenac lead to significant improvement in pain, stiffness, and physical function scores, since the DMSO diclofenac has high tissue penetration in comparison to conventional diclofenac gel. The data in this and previous reports provide substantial evidence for the efficacy and safety of DMSO based topical diclofenac solution in chronic osteoarthritis.
ACKNOWLEDGEMENT: Both the DMSO based diclofenac and conventional diclofenac gels were supplied by EDG Pharmaceuticals (India) limited for this study.
CONFLICT OF INTEREST: None declared.
- Yusuf E: Pharmacologic and Non-Pharmacologic Treatment of Osteoarthritis. Curr Treat Options in Rheum 2016; 2: 111-25.
- Arthritis India; Fight arthritis with knowledge and courage. Available at: http://www.arthritis-india.com/osteoarthritis. Html © 2014 arthritis-india.com. Assessed in 2014.
- Arthritis: Freedom from pain. Available at https:// completewellbeing.com/article/towards-a-joint-effort/. Assessed on13 Oct 2008.
- McPherson ML and Cimino NM: Topical NSAID Formulations. Pain Medicine 2013; 14: S35-S39.
- Baer PA, Thomas LM and Shainhouse Z: Treatment of osteoarthritis of the knee with a topical diclofenac solution: a randomized controlled, 6-week trial. BMC Musculoskeletal Disorders 2005; 6: 44.
- Ontario W: McMaster Universities Osteoarthritis Index (WOMAC); Available at: https://www.rheumatology.org/ I-Am A/Rheumatologist /Research/ Clinician-Researchers/ Western-Ontario-McMaster-Universities-Osteoarthritis-Index-WOMAC; Reviewed 2015 by ARHP Research Committee.
- Bookman AA, Williams KS and Shainhouse JZ: Effect of a topical diclofenac solution for relieving symptoms of primary osteoarthritis of the knee: a randomized controlled trial. CMAJ 2004; 171: 333-38.
- Roth SH and Shainhouse JZ: Efficacy and safety of a topical diclofenac solution (Pennsaid) in the treatment of primary osteoarthritis of the knee: a randomized, double-blind, vehicle-controlled clinical trial. Arch Intern Med 2004; 164: 2017-23.
- Roth SH and Fuller P: Diclofenac topical solution compared with oral diclofenac: a pooled safety analysis; Journal of Pain Research 2011; 4159-67.
- Barthel HR, Haselwood D, Longley S, Gold MS and Altman RD: Randomized controlled trial of diclofenac sodium gel in knee osteoarthritis. Semin Arthritis Rheum. 2009; 39(3): 203-12.
- Baraf HS, Gold MS and Clark MB: Safety and efficacy of topical diclofenac sodium 1% gel in knee osteoarthritis: a randomized controlled trial. Phys Sports med. 2010; 38(2): 19-28.
- Baer PA, Thomas LM and Shainhouse Z: Treatment of osteoarthritis of the knee with a topical diclofenac solution: a randomized controlled, 6-week trial [ISRCTN53366886]. BMC Musculoskelet Disord 2005; 6: 44.
- Simon LS, Grierson LM, Naseer Z, Bookman AA and Zev Shainhouse J: Efficacy and safety of topical diclofenac containing dimethyl sulfoxide (DMSO) compared with those of topical placebo, DMSO vehicle and oral diclofenac for knee osteoarthritis. Pain 2009; 143(3): 238-45.
- Baraf HSB, Gold MS, Petruschke RA and Wieman MS: Tolerability of topical diclofenac sodium 1% gel for osteoarthritis in seniors and patients with comorbidities. The American Journal of Geriatric Pharmacotherapy 2012; 10(1): 47.
- Galer BS: A comparative subjective assessment study of PENNSAID® and Voltaren Gel®, two topical formulations of diclofenac sodium. Pain Practice 2011; 11(3): 252-60.
- Simon LS, Grierson LM, Naseer Z, Bookman AM and Shainhouse JZ: Efficacy and safety of topical diclofenac containing dimethyl sulfoxide (DMSO) compared with those of topical placebo, DMSO vehicle and oral diclofenac for knee osteoarthritis. Pain 2009; 143: 238-45.
- Meng Z and Huang R: Topical Treatment of Degenerative Knee Osteoarthritis: Review. Am J Med Sci 2018; 355(1): 6-12.
- Stanos SP: Osteoarthritis guidelines: a progressive role for topical non-steroidal anti-inflammatory drugs. Journal of Multidisciplinary Healthcare 2013; 6: 133-37.
- Fuller P and Roth S: Diclofenac sodium topical solution with dimethyl sulfoxide, a viable alternative to oral non-steroidal anti-inflammatories in osteoarthritis: a review of current evidence. Journal of Multidisciplinary Healthcare 2011; 4: 223-31.
- Schuelert N, Russell FA and McDougall JJ: Topical diclofenac in the treatment of osteoarthritis of the knee. Orthopedic Research and Reviews 2011; 3: 1-8.
- Nair B and Taylor-Gjevre R: A review of topical diclofenac use in musculoskeletal disease: Pharmaceuticals 2010; 3: 1892-08.
- Altman R, Asch E and Bloch D: Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Arthritis Rheum 1986; 29: 1039-49.
- American Geriatrics Society Panel on Pharmacological Management of Persistent Pain in Older Persons. Pharmacological management of persistent pain in older persons. J Am Geriatr Soc 2009; 57: 1331-46.
- Glyn-Jones S, Palmer AJR and Agricola R: Osteoarthritis. The Lancet 2015; 386: 376-87.
- Narasimha BC, Ravish KS, Ranganath TS and Sri SN: A study on knee joint osteoarthritis among the women aged above 40 years, residing in the urban field practice area at the tertiary care centre, Bangalore, Karnataka, India: Int J Community Med Public Health 2016; 3(6): 1554-58.
- Baraf HS, Gold MS and Clark MB: Safety and efficacy of topical diclofenac sodium 1% gel in knee osteoarthritis: a randomized controlled trial. Phys Sports Med 2010; 38(2): 19-28.
- Baraf HS, Gold MS, Petruschke RA and Wieman MS: Tolerability of topical diclofenac sodium 1% gel for osteoarthritis in seniors and patients with comorbidities. Am J Geriatr Pharmacother 2012; 10(1): 47-60.
- Venkatachalam J, Natesan M, Eswaran M, Johnson AK, Bharath V and Singh Z: Prevalence of osteoarthritis of knee joint among the adult population in a rural area of Kanchipuram District, Tamil Nadu. Indian J Public Health 2018; 62: 117-22.
- Tugwell PS, Wells GA and Shainhouse JZ: Equivalence study of a topical diclofenac solution (pennsaid) compared with oral diclofenac in the symptomatic treatment of osteoarthritis of the knee: a randomized controlled trial. J Rheumatol 2004; 31(10): 2002-12.
- Srinivasan S, Jayasree TM, Felix AJW and Govindarajan PK: Prevalence of osteoarthritis of the knee joint among elderly population in a rural area. Int Journal of Biological & Pharmaceutical Research 2015; 6(11): 849-51.
- Maroo SKH, Patel KR and Bhatnagar A: Penetration of diclofenac from novel quick penetrating solution. A comparative scintigraphy study with gel. IJPSR 2015; 6(5): 1936-42.
- National Institute for Health and Clinical Excellence. Osteoarthritis: care and management-Guidance and guidelines=NICE [Internet] 2014. Available from: http://www.nice.org.uk/guidance/cg177. Cited January 12, 2017.
- Muthunarayanan L, Ramraj B and Russel JK: Prevalence of pain among rural adults seeking medical care through medical camps in Tamil Nadu. Indian J Pain 2015; 29: 36-40.
- March LM and Bachmeier CJ: Economics of osteoarthritis: a global perspective. Baillieres Clinical Rheumatology 1997; 11: 817-34.
- Nivsarkar M, Maroo SKH, Patel KR and Patel DD: Evaluation of skin penetration of diclofenac from a novel topical nonaqueous solution: a comparative bioavailability study. Journal of Clinical and Diagnostic Research 2015; 9(12): FC11-FC13.
- Wadsworth LT, Kent JD and Holt RJ: Efficacy and safety of diclofenac sodium 2% topical solution for osteoarthritis of the knee: a randomized, double-blind, vehicle-controlled, 4 week study. Current Medical Research and Opinion, 32:2, 241-50.
- Dipro JT, Talbert RL, Yee GC, Matzke GR, Wells BG and Posey LM: Pharmacotherapy: A pathophysiologic approach 7th McGraw-Hill Medical; 7 edition (1707).
- Hochberg MC, Altman RD, April KT, Benkhalti M, Guyatt G, McGowan J, Towheed T, Welch V, Wells G and Tugwell P: American College of Rheumatology 2012 recommendations for the use of non-pharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res 2012; 64: 465-74.
- Fernandes L, Hagen KB and Bijlsma JWJ: EULAR recommendations for the non-pharmacological core management of hip and knee osteoarthritis. Ann Rheum Dis 2013; 72: 1125-35.
- Doherty M, Jones A and Cawston T: Osteoarthritis. In: Oxford Textbook of Rheumatology, 3rd (Eds: Isenberg DA et al.,) Oxford University Press 2004: 1091-18.
- Dicesare PE and Abramson SB: Pathogenesis of osteoarthritis. In: Harris ED, Budd RC, Genovese MC et al., (editors) .Kelley’s Textbook of Rheumatology, volume II, 7th edition, Elsevier Saunders 2005: 1493-13.
- Pradhan CV, Talesara JM, Sharma AB, Panchal VH, Ramanathan S, Patel KR, Maroo SKH and Ojha RU: A novel quick penetrating solution of diclofenac (topical) for management of acute musculoskeletal pain. Int J Res Med 2013; 2(2): 103-08.
How to cite this article:
Kumar NS, Chacko A, Jimshad MI, Srinivas GY and Tamilselvan A: Improvement in pain relief using a DMSO based diclofenac in comparison to conventional diclofenac gels in osteoarthritis –a randomized controlled trial. Int J Pharm Sci & Res 2019; 10(9): 4384-90. doi: 10.13040/IJPSR.0975-8232.10(9).4384-90.
All © 2013 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.
N. S. Kumar *, A. Chacko, M. I. Jimshad, G. Y. Srinivas and A. Tamilselvan
Department of Pharmacy Practice, JKKMMRF’s - Annai JKK Sampoorani Ammal College of Pharmacy, Komarapalayam, Namakkal, Tamil Nadu, India.
29 December 2018
07 April 2019
19 April 2019
01 September 2019