Rationale and evidence for the incorporation of heparin into the diclofenac epolamine medicated plaster

Objective: The nonsteroidal anti-inflammatory drug (NSAID) diclofenac epolamine (DHEP) formulated as a topical patch has demonstrated efficacy and safety in the localized treatment of acute pain from minor strains, sprains and contusions, and for epicondylitis and knee osteoarthritis. The glycosaminoglycan heparin enhances the activity of topical NSAIDs formulated as a medicated plaster, even in the absence of any significant release of heparin. Therefore, DHEP plus, a new formulation of the DHEP medicated plaster containing a small amount of heparin sodium as excipient, has been developed.

Methods: We reviewed the pivotal and supportive studies of the clinical development program of the new patch and evaluated the role of heparin as an enhancer in the treatment of localized pain/inflammation of musculoskeletal structures, associated with post-traumatic and/or rheumatic conditions.

Results: The data was consistent with the concept that heparin increased the clinical activity of the DHEP plus medicated plaster versus the reference DHEP medicated plaster through improved bioavailability due to enhanced movement of diclofenac from the plaster. Both DHEP formulations have the same dissolution profile, indicating that heparin does not change the physical and chemical characteristics of the plaster. Permeation testing showed that heparin is not released from the DHEP plus medicated plaster. Efficacy studies showed that the DHEP plus medicated plaster was significantly more effective in reducing pain than the reference marketed DHEP medicated plaster.

Conclusions: The benefit/risk assessment of DHEP plus 180?mg medicated plaster is favorable, with a safety profile equal to placebo and improved efficacy over the reference marketed DHEP medicated plaster.     

Diclofenac epolamine medicated plaster in the treatment of minor soft tissue injuries: a multicenter randomized controlled trial

Abstract

Objective:

To investigate the efficacy and safety of a topical plaster containing diclofenac epolamine (DHEP) 1.3% in the treatment of patients with acute minor soft tissue injuries in China.     

Short-term treatment with topical diclofenac epolamine plaster in patients with symptomatic knee osteoarthritis: pooled analysis of two randomised clinical studies

ABSTRACT

Background: Data from two randomised, double-blind, placebo-controlled studies were considered in order to investigate the efficacy and safety of a bio-adhesive plaster for topical administration containing diclofenac epolamine (DHEP) in patients with symptomatic knee osteoarthritis (OA).

Methods: Patients with radiologically confirmed symptomatic knee OA were included. The 14‐day treatment consisted of two daily applications of either DHEP or placebo plaster. The algofunctional Lequesne index and pain intensity, measured by means of the Huskisson's visual analogue scale (VAS), were considered as main efficacy parameters. The main analysis of the pooled data was by intention-to-treat.

Results: Of the 258 patients included, 235 completed the study. At the end of the study, the mean decrease in the Lequesne index was 35% in the DHEP group and 15% in the placebo group (?p < 0.0001). The mean decrease in pain intensity was 59.5% in the DHEP group and 29.9% in the placebo group. No interaction resulted between treatment and study effects (?p ≥ 0.2 whatever the test). The non-parametric Hodges–Lehmann estimator of the treatment effect resulted in a reduction of 21.9% for the Lequesne index and of 30.0% in pain intensity.

The number needed to treat (NNT) for at least a 50% reduction of pain was 3.0 and the effect size for pain was 0.75.

Conclusions: Topical application of DHEP plaster was shown to be an efficacious and safe short-term treatment for symptomatic knee OA, reducing pain and increasing physical function and may be similar in efficacy to oral non-steroidal anti-inflammatory drugs (as indicated by relative benefit data and NNT value).     

An exploratory microdialysis study investigating the effect of repeated application of a diclofenac epolamine medicated plaster on prostaglandin concentrations in skeletal muscle after standardized physical exercise

Aim

Muscle injuries and extensive exercise are associated with cyclo-oxygenase dependent formation of inflammatory prostaglandins. Since the effect of topical administration of non-steroidal anti-inflammatory drugs (NSAIDs) on local cyclo-oxygenase is unknown, the present exploratory, open label, non-randomized study set out to measure exercise induced release of prostaglandins before and after epicutaneous administration of diclofenac.

Methods

Microdialysis was used to determine the local interstitial concentration of PGE₂ and 8-iso-PGF_2α as well as diclofenac concentrations in the vastus lateralis under rest, dynamic exercise and during recovery in 12 healthy subjects at baseline and after a treatment phase applying a total of seven plasters medicated with 180 mg of diclofenac epolamine over 4 days.

Results

At baseline PGE₂ concentrations were 1169 ± 780 pg ml⁻¹ at rest and 1287 ± 459 pg ml⁻¹ during dynamic exercise and increased to 2005 ± 1126 pg ml⁻¹ during recovery. After treatment average PGE₂ concentrations were 997 ± 588 pg ml⁻¹ at rest and 1339 ± 892 pg ml⁻¹ during exercise. In contrast with the baseline phase no increase in PGE₂ concentrations was recorded during the recovery period after treatment (PGE₂ 1134 ± 874 pg ml⁻¹). 8-iso-PGF_2α was neither affected by exercise nor by treatment with diclofenac. Local and systemic concentrations of diclofenac were highly variable but comparable with previous clinical pharmacokinetic studies.

Conclusions

We can hypothesize an effect of topical diclofenac epolamine plaster on limiting the increase of local concentrations of the pro-inflammatory prostaglandin PGE₂ induced in the muscle of healthy human subjects following standardized physical exercise. No effect of diclofenac treatment on 8-iso-PGF_2α concentrations was observed, mainly since isoprostane is produced by a free radical-catalyzed lipid peroxidation mechanism independent of cyclo-oxygenases.     

Review of the pharmaceutical properties and clinical effects of the topical NSAID formulation,diclofenac epolamine

ABSTRACT

Background: Topical formulations of non-steroidal anti-inflammatory drugs (NSAIDs), in particular diclofenac (DI), have become popular for treating various acute and chronic painful inflammatory conditions.

Objective: To perform a literature review of (1) the use of topical NSAIDs; (2) the pharmaceutical, pharmacokinetic and pharmacodynamic properties of a medicated plaster (patch) containing diclofenac epolamine (DI-EP, Flector Tissugel, Flector patch^*) compared with other formulations of topical NSAIDs; and (3) evaluation of the clinical findings from studies with this novel DI-EP patch.

Outcomes: (1) Pharmacokinetic studies involved determination of DI from DI-EP and separately epolamine (EP) and the epoxide metabolite (N-oxide-EP) in laboratory animals and humans; the latter being the major metabolite in humans. About 2% of DI is absorbed by the skin in humans and is excreted in the urine. Maximum plasma concentrations of 17.4?ng/mL DI are reached at 5.4 hours (approximate steady state conditions); the plasma elimination half-time (t_½) being 26.4 hours. Low systemic levels of DI and EP are produced from DI-EP. Pronounced accumulation of DI occurs in the muscle layers and in synovial fluids of arthritic patients; (2) No significant toxicity occurs from EP nor N-oxide-EP, while that of oral DI-EP was similar to that from DI; and (3) In acute musculoskeletal conditions (sprains, tendonitis and sports injuries) and osteoarthritis DI-EP patches control pain and signs of joint or physical injury compared with placebo controls by 3–5 days with almost complete pain relief at 14 days. DI-EP was shown to have equivalent therapeutic effect to another DI diethylammonium gel formulation (Voltaren Emulgel^?).

There were no reports of serious adverse events in the gastro-intestinal (GI) tract, kidneys or liver from DI-EP. Mild GI symptoms and skin reactions occur in 2 and10% of patients, respectively.

Conclusions: The patch delivery of DI in DI-EP affords controlled delivery of the active drug in contrast to that from application of gels or ointments of NSAIDs.     

Effect of lecithin on epicutaneous absorption of diclofenac epolamine

The epicutaneous application of nonsteroidal antiinflammatory drugs in localized rheumatic diseases results in a highly targeted antiinflammatory action and is associated with reduced systemic effects. The new diclofenac epolamine (DHEP) salt is much more soluble both in water and in lipid solvent than other diclofenac salts. The pharmaceutical addition of lecithin to DHEP leads to the formation of mixed micelles with high affinity to the cellular component, which guarantees the absorption of the active ingredient. We performed a bioavailability randomized, cross-over study to compare the plasma profiles of diclofenamic acid after repeated epicutaneous administration of the new topical formulation with those of the marketed DHEP formulation without lecithin. Based on a randomization list, 12 healthy volunteers were asked to apply one of the two formulations twice a day for 10 consecutive days. The other formulation was given after a washout period of 1 week. Blood samples were collected before the morning epicutaneous dose on days 1, 3, 5 and 8 of treatment and on day 10 at different sampling times until 24 h after the application. The pharmacokinetic analysis showed a significantly higher plasma concentration of diclofenamic acid after the application of DHEP lecithin, which indicates a better saturation of the subcutaneous tissues underlying the application site. This also indicates increased local availability of the active principle. In conclusion, the new DHEP formulation with lecithin should have a therapeutic advantage compared with the formulation without lecithin, even in cases of short- to medium-term treatments.     

Analgesic efficacy of a lecithin-vehiculated diclofenac epolamine gel in shoulder periarthritis and lateral epicondylitis: a placebo-controlled, multicenter, randomized, double-blind clinical trial

Diclofenac epolamine (2-hydroxyethyl-pyrrolidine) (DHEP) is a diclofenac salt endowed with enhanced cutaneous permeation. To optimize its absorption after topical application, a lecithin-enriched DHEP 1.3% gel has been developed (DHEP lecithin gel) and investigated in patients with shoulder periarthritis and lateral epicondylitis in a placebo-controlled, multicenter double-blind clinical trial. One hundred fifty-eight patients were randomized to a 10-day treatment with DHEP lecithin gel or placebo (5 g t.i.d. applied on the painful area). The efficacy criteria were pain measured by visual analog scale (VAS) while performing a specific standardized movement, intake of rescue medication (paracetamol), and the disabilities of the arm, shoulder and hand (DASH) questionnaire. VAS scores indicated a consistently higher analgesic activity of DHEP lecithin gel. At day 3, pain was reduced by -20.1 +/- 20.2 and -9.9 +/- 12.7 mm in the DHEP lecithin gel- and placebo-treated patients, respectively (p < 0.001); at day 6 of treatment, DHEP lecithin gel induced a pain reduction of -33.2 +/- 26.1 mm, while the reduction achieved with placebo was only -21.2 +/- 18.8 mm (p < 0.001). The mean changes in DASH questionnaire indicated that DHEP lecithin gel was more effective than placebo in improving patient well-being and reducing difficulties in performing the activities most severely impaired by rheumatism, while no difference was observed between the two treatments in consumption of rescue medication. In conclusion, these results indicate that DHEP lecithin gel is a topically effective analgesic product in patients with shoulder periarthritis or lateral epicondylitis and provide further evidence on the use of topical nonsteroidal anti-inflammatory drugs as an optimal approach to the treatment of localized musculoskeletal disorders.     

双氯芬酸羟乙基吡咯烷盐巴布剂制备及其体外透皮研究

目的 制备双氯芬酸羟乙基吡咯烷盐巴布剂,进行含量测定,并考察不同种类促渗剂对其体外透皮行为的影响.方法 以水溶性高分子材料基质,制备巴布剂,高效液相色谱法测定含量;添加不同种类、不同浓度促渗剂后采用改良的Franz扩散池法进行透皮实验.结果 巴布剂含量测定结果均在90%~110%范围内,符合制剂要求.不同种类促渗剂均能促进药物的经皮渗透,其中1%氮酮的促渗效果最显著,经皮渗透速率为18.98μg·cm-2·h-1,增渗倍数为2.38.结论 巴布剂制备工艺简单,成型性良好,1%氮酮具有良好的促渗效果,适宜作为促渗剂.     

消肿止痛膏在家兔中的药效学实验

目的：研究消肿止痛膏药的药效作用。方法：制作家兔股骨骨折和软组织损伤模型。进行治疗观察。结果：本药可促进家兔股骨骨折愈合，升高血清Ｃａ＾２＋；能改善损伤组织肿胀的消退速度，促进组织恢复正常。结论：本药有利于治疗股骨骨折和促进软组织损伤部位恢复正常。     

骨痹息痛巴布膏的质量标准研究

目的 建立骨痹息痛巴布膏的质量标准.方法 采用薄层色谱法对其中的青风藤和延胡索等药材进行了鉴别,高效液相色谱法对其中的盐酸巴马汀进行含量测定.色谱柱:InertSustain C18(5μm,4.6 mm×250 mm);流动相:乙腈-0.4%磷酸溶液(30:70);检测波长:345 nm;柱温:30℃;流速:1 mL·min-1.结果 制定了骨痹息痛巴布膏中青风藤和延胡索等药材的薄层鉴别方法和盐酸巴马汀的含量测定方法.结论 该分析方法简便可靠、重现性好,基本可控制骨痹息痛巴布膏的质量.     

Double-blind,randomized, controlled study on the efficacy and safety of a novel diclofenac epolamine gel formulated with lecithin for the treatment of sprains,strains and contusions

To evaluate the efficacy of the new diclofenac-N-(2-hydroxyethyl)-pyrrolidine gel formulated with lecithin (DHEP lecithin) compared with diclofenac-N-(2-hydroxyethyl)-pyrrolidine gel (DHEP gel) without lecithin in mild-to-moderate posttraumatic injuries (grade 1 ankle, knee and muscle injuries), a multicenter, double-blind, controlled study was carried out. A total of 100 patients were enrolled and randomly assigned to either DHEP lecithin (n = 52) or DHEP gel (n = 48) treatment. All patients concluded the treatment period except for five, who did not turn up to their respective investigational sites for the follow-up visits. According to an intention-to-treat approach, they were all included in the statistical analysis. As for the efficacy and safety analysis, the primary variable was "pain on movement" as measured by a Huskisson visual analog scale. During the first 3 days of treatment each group recorded a significant within-group decrease, but patients treated with DHEP lecithin showed a decrease in absolute value that was statistically greater than that obtained with DHEP gel (p = 0.025). At the end of the treatment period (day 10) the difference between groups was still statistically significant (p = 0.036). The statistical analysis of the secondary efficacy variables showed significant results in favor of DHEP lecithin treatment. These were superimposable on the results found for the primary variable. The global efficacy and tolerability judgments, reported either by patient or by physician, showed no statistical difference between treatment groups. Due to the presence of lecithin in the new gel formulation, DHEP lecithin showed a faster and significantly more marked therapeutic effect compared with that of DHEP gel.     

麝香壮骨膏致接触性皮炎

患者女,46岁。曾有青霉素过敏史。本次因右踝关节扭伤,疼痛,使用麝香壮骨膏7cm×5cm贴于患处。数小时后,患者右踝关节处出现肿胀、皮疹、瘙痒难忍。局部皮肤明显发红,皮温较高。考虑为药物过敏所致,立即揭去所贴膏药。采用醋酸曲安奈德氯霉素乳膏涂患处,每4h涂1次。1d后,肿胀瘙痒有所减轻,皮疹减少,继续治疗至3d后,上述症状消失。麝香壮骨膏为外用膏剂,含有麝香、豹骨、当归、生川乌、生草乌、吴茱萸、冰片、樟脑、薄荷脑等16味中药成分,具有镇痛、消炎的功能。用于风湿痛、关节痛、腰痛、神经痛、肌肉酸痛、扭伤、挫伤等症。本例提示有过敏…     

伤科止痛膏的基质配方研究

目的优选伤科止痛膏的基质组成比例。方法选用合成橡胶和氧化锌、松香、液体石蜡四种辅料的用量为因素．在4个水平上,以涂展性能、外观、含膏量和粘附性四项为考察指标,用正交试验法优选出最佳基质配方。结果以合成橡胶550g,氧化锌50g、松香93g和液体石蜡100g为最佳基质配方。结论筛选的基质配方所制备的伤科止痛膏稳定性良好。     

701跌打镇痛膏抗炎作用的实验研究

目的考察701跌打镇痛膏的抗炎作用,为其临床应用提供实验依据。方法通过角叉菜胶致大鼠足跖肿胀模型、二甲苯致小鼠耳肿胀模型、完全氟氏佐剂致大鼠关节炎模型,考察701跌打镇痛膏的抗炎作用。结果 701跌打镇痛膏单次腹部敷贴给药后能明显降低角叉菜胶致SD大鼠足肿胀的足容积和足肿胀度,药效达峰时间约为给药后4 h;连续腹部敷贴给药5 d后能明显降低二甲苯引起的小鼠耳廓肿胀度,抗炎作用具有明显的量效关系;对大鼠佐剂性关节炎模型未见明显作用。结论 701跌打镇痛膏对急性渗出性炎症具有明显的改善作用,但对免疫性炎症作用不明显。     

精制狗皮膏与狗皮膏治疗急性软组织损伤的临床观察比较研究

目的:观察精制狗皮膏与狗皮膏对于急性软组织损伤的临床疗效。方法:将59例急性软组织损伤患者随机分成两组,分别使用精制狗皮膏和狗皮膏治疗3周,结合临床疗效指标判定,比较在治疗前后两组的症状积分值以及疗效观察结果。结果:给药后两组患者的急性软组织损伤症状评分逐渐降低;给药3周后,精制狗皮膏组下降86.7%,狗皮膏组评分下降84.6%。结论:精制狗皮膏与狗皮膏均具有良好的抗炎镇痛作用,两者的疗效相当。