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PubMed1997

Contact allergy to oxidized d-limonene among dermatitis patients.

d-Limonene, obtained as a by-product from the citrus juice industry, was introduced on the market as a more environmentally friendly defatting and cleaning agent than the traditionally used organic solvents. Autoxidation of d-limonene readily occurs to give a variety of oxygenated monocyclic terpenes that are strong contact allergens. The aim of the present study was to investigate the prevalence of contact allergy to air exposed d-limonene among dermatitis patients. A fraction consisting of d-limonene hydroperoxides was also tested. Screening with oxidized d-limonene will detect cases of allergic contact dermatitis. Additional cases were detected when testing with the fraction of limonene hydroperoxides. The proportion of positive patch test reactions to oxidized d-limonene was comparable to that seen for several of the allergens within the standard series. An increased use of d-limonene containing allergenic oxidation products in industry where high concentrations are used, as well as in domestic exposure, might result in contact sensitization and dermatitis. Patients reacting to d-limonene often reacted to fragrance mix, balsam of Peru and colophony in the standard series.

Confidence Intervals↗
PubMed2006

Not only oxidized R-(+)- but also S-(-)-limonene is a common cause of contact allergy in dermatitis patients in Europe.

Limonene, one of the most often used fragrance terpenes in any kind of scented products, is prone to air-oxidation. The oxidation products formed have a considerable sensitizing potential. In previous patch test studies on consecutively tested dermatitis patients, oxidized R-limonene has been proven to be a good and frequent indicator of fragrance-related contact allergy. The current study extends these investigations to 6 European clinics of dermatology, where the oxidation mixture of both enantiomers of limonene (R and S) have been tested in 2411 dermatitis patients. Altogether, 63 out of 2411 patients tested (2.6%) reacted to 1 or both the oxidized limonene preparations. Only 2.3% reacted to the oxidized R-limonene and 2.0% to the oxidized S-limonene. In 57% of the cases, simultaneous reactions were observed to both oxidation mixtures. Concomitant reactions to the fragrance mix, colophonium, Myroxylon pereirae, and fragrance-related contact allergy were common in patients reacting to 1 or both the oxidized limonene enantiomers. Our study provides clinical evidence for the importance of oxidation products of limonene in contact allergy. It seems advisable to screen consecutive dermatitis patients with oxidized limonene 3% petrolatum, although this patch test material is not yet commercially available.

Cyclohexenes↗
PubMed2004

Inhibition of growth and metastasis of human gastric cancer implanted in nude mice by d-limonene.

AIM: To investigate the effects and mechanism of d-limonene on the growth and metastasis of gastric cancer in vivo. METHODS: Metastatic model simulating human gastric cancer was established by orthotopic implantation of histologically intact human tumor tissue into gastric wall of nude mice. One percent d-limonene was orally administered at dose of 15 ml/kg every other day for seven weeks. Eight weeks after implantation, tumor weight, inhibition rate, apoptotic index (AI), microvessel density (MVD), vascular endothelial growth factor (VEGF), variation of ultrastructure, and the presence of metastasis were evaluated, respectively, after the mice were sacrificed. RESULTS: The tumor weight was significantly reduced in 5-FU group (2.55+/-0.28 g), d-limonene group (1.49+/-0.09 g) and combined treatment group (1.48+/-0.21 g) compared with the control group(2.73+/-0.23 g, P<0.05). In 5-FU group, d-limonene group, combined treatment group, the inhibition rates were 2.60%,47.58% and 46.84% and 0, respectively; AI was (3.31+/-0.33)%, (8.26+/-1.21)%, (20.99+/-1.84)% and (19.34+/-2.19)%, respectively; MVD was (8.64+/-2.81), (16.77+/-1.39), (5.32+/-4.26) and (5.86+/-2.27), respectively; VEGF expression was (45.77+/-4.79), (41.34+/-5.41), (29.71+/-8.92) and (28.24+/-8.55), respectively. The incidences of peritoneal metastasis also decreased significantly in 5-FU group(77.8%), d-limonene group (20.0%) and combined group (22.2%) compared with control group (100%) versus 62.5%,30% and 22.2%) (P<0.05). Liver metastasis was also inhibited and the incidences decreased significantly in 5-FU group, d-limonene group and combined group than that in control group (87.5% vs 55.5%, 20.0% and 22.2% respectively)(P<0.05). The incidence of ascites in control group, 5-FU group, d-limonene group and combined group was 25.0%, 22.2%, 0, 0, respectively and 12.5%, 11.1% 0, 0, with respect to the metastasis rate to other organs. CONCLUSION: d-limonene has antiangiogenic and proapoptotic effects on gastric cancer, thereby inhibits tumor growth and metastasis. Combination of d-limonene with cytotoxic agents may be more effective.

Animals↗
PubMed2002

Pharmacokinetics of perillic acid in humans after a single dose administration of a citrus preparation rich in d-limonene content.

d-Limonene, a monoterpene, is widely distributed as a natural nonnutritive constituent of a variety of foods and volatile oils, particularly citrus oils. d-Limonene and its derived metabolites have been shown to possess cancer chemotherapeutic and chemopreventive efficacy in various preclinical model systems. In our previous work, we have found that lemonade prepared with the whole lemon (Mediterranean-style lemonade) contains high levels of d-limonene. The current study is designed to determine the systemic availability of perillic acid, a major and biologically active metabolite of d-limonene, after a single dose administration of Mediterranean-style lemonade. Healthy individuals were recruited to consume 30-40 oz of Mediterranean-style lemonade with a light breakfast. Blood samples were collected for up to 24 h after the completion of lemonade consumption. d-Limonene levels in the juice and perillic acid levels in plasma were determined by reversed-phase high-performance liquid chromatography with UV detection. It was found that 40 oz of lemonade contained 596 mg of d-limonene and 30 oz contained 447 mg of d-limonene. Plasma concentrations of perillic acid reached maximal levels at 1 h after the lemonade consumption and declined rapidly as a function of time with the terminal elimination half-life ranging from 0.82 to 1.84 h. The maximum plasma perillic acid concentration ranged from 2.08 to 13.98 micro M, and the levels were undetectable at 24 h after the lemonade consumption. The area under the plasma concentration-time curves of perillic acid ranged from 5.07 to 32.59 (micro M) x h. Our study illustrates that the major metabolite of d-limonene is bioavailable after oral consumption of a citrus preparation rich in d-limonene content.

Adult↗
PubMed2001

Biotransformation of (R)-(+)- and (S)-(-)-limonene by fungi and the use of solid phase microextraction for screening.

The biotransformation of (R)-(-)- and (S)-(-)-limonene by fungi was investigated. More than 60 fungal cultures were screened for their ability to bioconvert the substrate, using solid phase microextraction as the monitoring technique. After screening, the best fungal strains were selected for further study and were grown as sporulated surface cultures in conical flasks and as submerged liquid cultures. It was found that (+)- and (-)-limonene were converted by Penicillium digitatum to alpha-terpineol (main metabolite), cis- and trans-p-menth-2-en-1-ol, neodihydrocarveol and limonene oxide (minor metabolites) using liquid cultures. The bioconversion of (R)-(-)- and (S)-(-)-limonene by Corwespora cassiicola yielded (1S,2S,4R)- and (1R,2R,4S)-limonene-1,2-diol respectively. The bioconversions by liquid cultures were also monitored by solid phase microextraction as a function of time. The optimum conversion of limonene to alpha-terpineol by Penicillium digitatum was obtained after 8 hours (yield up to 100%). Since an important pH-decrease was noticed in some liquid broths, the stability of limonene under acidic conditions was investigated. No acid catalysed conversion products were recovered after 8 days from control flasks at pH 3.5 containing limonene.

Ascomycota↗
PubMed1998

Pharmacokinetics of d-limonene in the rat by GC-MS assay.

The naturally occurring monoterpene d-limonene has been found to inhibit various stages of tumorigenesis in a number of animal models and is now being evaluated as a chemopreventive agent in humans. To date, there are little or no preclinical pharmacokinetics available nor is there a sensitive assay methodology. In this study, d-limonene and its dideuterium-labeled internal standard, limonene-d2, in whole rat blood were extracted with n-pentane which was then concentrated on a Kuderna-Danish concentrator. The residue was analyzed by an ion-trap GC -MS under ammonia chemical ionization. The detection limit of d-limonene was 1.0 ng if injected in pure form; however, due to the presence of endogenous d-limonene levels (probably from diet), the routine quantitation limit was set at 1.0 microgram ml-1. The monitored assay linearity range from 1.0 to 30 micrograms ml-1 within-day CV values of 8.0%, 2.4%, and 2.0% at 1.0, 3.0 and 10.0 micrograms ml-1, respectively (all at n = 8), and corresponding accuracy of 100%, 100%, and 101%. The between-day CV values were 12.3, 8.0, and 7.5% at 1, 6, and 20 micrograms ml-1, respectively (all at n = 8). Using this assay, pharmacokinetics of d-limonene were studied in Sprague-Dawley rats following intravenous and oral administration at 200 mg kg-1 each. Blood concentration-time profiles after intravenous administration showed a biphasic decline with a mean initial t1/2 of 12.4 min and a terminal t1/2 of 280 min. The plasma:red blood cell partition was found to be 0.84. Plasma protein binding of d-limonene was found to be 55.3% at 20 microgram ml-1. The mean total clearance was 49.6 ml min-1 kg-1, the volume of distribution at steady-state 11.7 1 kg-1, and median residence time 263 min. The blood concentration-time decline following oral administration also showed a biphasic decline with a mean initial t1/2 of 34 min and terminal t1/2 of 337 min. The oral bioavailability of d-limonene was 43.0%.

Animals↗
PubMed2003

Involvement of YY1 and its correlation with c-myc in NDEA induced hepatocarcinogenesis, its prevention by d-limonene.

Anticarcinogenic activity of d-limonene has been well documented within last few years. We have also reported the anticarcinogenic activity of d-limonene in N-nitrosodiethylamine (NDEA) induced hepatocarcinogenesis. The involvement of oncogenes which adds to the mechanisms of d-limonene mediated chemprevention were also suggested in the same model system. The overexpression of c-myc oncoprotein in different durations of NDEA induced hepatrocarcinogenesis is observed which is inhibited completely when d-limonene was treated prior to and along with NDEA. To work further in this direction, an attempt has been made here to know the role of YY1 (Yin Yang 1) transcription factor in N-nitrodiethylamine (NDEA) induced hepatocarcinogenesis and its chemoprevention by d-limonene. Electrophoretic mobility shift assay results have clearly indicated the binding of YY1 in control liver tissue. But this binding is blocked in 60 days and 150 days NDEA treated liver tumors. Thus, it is assumed that there is deregulation of YY1 transcription factor in NDEA induced hepatocarcinogenesis. A similar type of binding to that of control liver tissue has also observed when limonene was given prior to NDEA administration. Western blot analysis has shown inhibition of YY1 protein in NDEA induced liver tumor samples in comparison to normal and both NDEA and limonene treated samples. On the otherhand RT-PCR analysis does not indicate any correlation between YY1 mRNA level and inhibition of YY1 protein. However, along with our earlier information about c-myc with the present study, clearly indicated the involvement of YY1 in NDEA induced hepatocarcinogenesis and d-limonene mediated chemoprevention which might be regulated by c-myc oncoprotein.

Animals↗
PubMed1987

Modulation of immune responses in mice by d-limonene.

The immunotoxicologic effects of d-limonene were determined. This naturally occurring substance is widely used in food flavorings and is a common additive in cosmetics. In the present study, BALB/c mice were treated with d-limonene for 9 wk. Effects on T- and B-cell responses were determined after 4 and 8 wk of treatment. Concanavalin-A responses at 8 wk, but not 4 wk, were suppressed in treated mice. A similar trend was observed for phytohemagglutinin and lipopolysaccharide responses. Evidence was presented that d-limonene had polyclonal activator action. Mice primed with keyhole limpet hemocyanin (KLH) prior to initiation of d-limonene treatment had suppressed primary and secondary anti-KLH responses. Mice treated with d-limonene prior to KLH priming produced significant increased antibody responses. Additional evidence for polyclonal stimulation was obtained by histopathologic examination of secondary lymphoreticular tissue. Significant secondary follicle development and prominent lymphoid nodules and aggregates were found in the pancreas and intestinal mucosa, particularly apparent in mice receiving the highest d-limonene dosage. A subchronic LD50 study was conducted wherein BALB/c mice received 16 daily doses of d-limonene. An LD50 of approximately 0.0850 mg d-limonene/kg (corrected for 82% purity) was determined.

Animals↗
PubMed2000

Effects of R-(+)- and S-(-)-limonene on the respiratory tract in mice.

The effects of airborne R-(+)- and S-(-)- limonene were studied in conscious BALB/c mice by continuous monitoring respiratory rate (f), tidal volume (VT) and mid-expiratory flow rate (VD) during an exposure period of 30 min. Both enantiomers decreasedf from a trigeminal reflex, i.e., due to sensory irritation. The exposure concentration decreasing f by 50% (RD50) in the first 10 min of the exposure period was estimated to be 1,076 ppm for R-(+)-limonene and 1,467 ppm for S-(-)-limonene. Results for sensory irritation of R-(+)-limonene in BALB/c mice and humans are in close agreement. The reported sensory irritation threshold is above 80 ppm in humans while the no-observed-effect level was estimated to be 100 ppm in mice. The enantiomers were devoid of pulmonary irritation or general anesthetic effects with R-(+)-limonene < or =1,599 ppm and S-(-)-limonene < or =2,421 ppm. R-(+)-limonene did not influence VT below 629 ppm. S-(-)-limonene increased VT above 1,900 ppm. Both enantiomers induced a mild bronchoconstrictive effect above 1,000 ppm.

Administration, Inhalation↗
PubMed1998

Biosynthesis of the monoterpenes limonene and carvone in the fruit of caraway. I. Demonstration Of enzyme activities and their changes with development

The biosynthesis of the monoterpenes limonene and carvone in the fruit of caraway (Carum carvi L.) proceeds from geranyl diphosphate via a three-step pathway. First, geranyl diphosphate is cyclized to (+)-limonene by a monoterpene synthase. Second, this intermediate is stored in the essential oil ducts without further metabolism or is converted by limonene-6-hydroxylase to (+)-trans-carveol. Third, (+)-trans-carveol is oxidized by a dehydrogenase to (+)-carvone. To investigate the regulation of monoterpene formation in caraway, we measured the time course of limonene and carvone accumulation during fruit development and compared it with monoterpene biosynthesis from [U-14C]Suc and the changes in the activities of the three enzymes. The activities of the enzymes explain the profiles of monoterpene accumulation quite well, with limonene-6-hydroxylase playing a pivotal role in controlling the nature of the end product. In the youngest stages, when limonene-6-hydroxylase is undetectable, only limonene was accumulating in appreciable levels. The appearance of limonene-6-hydroxylase correlates closely with the onset of carvone accumulation. At later stages of fruit development, the activities of all three enzymes declined to low levels. Although this correlates closely with a decrease in monoterpene accumulation, the latter may also be the result of competition with other pathways for substrate.

Journal Article↗
PubMed2002

Species differences in the metabolism of (+)- and (-)-limonenes and their metabolites, carveols and carvones, by cytochrome P450 enzymes in liver microsomes of mice, rats, guinea pigs, rabbits, dogs, monkeys, and humans.

(+)-Limonene is shown to cause renal toxicity in male rats, but not in female rats and other species of animals including mice, guinea pigs, rabbits, and dogs. We have previously shown that male-specific rat CYP2C11 (but not female-specific CYP2C12) is able to convert limonenes to carveols and perillyl alcohols (M. Miyazawa, M. Shindo, and T. Shimada: Chem. Res. Toxicol., 15, 15-20, 2002). Here, we investigated whether (+)- and (-)-limonene enantiomers are differentially metabolized by P450 enzymes in liver microsomes of mice, rats, guinea pigs, rabbits, dogs, monkeys, and humans. Limonene enantiomers were converted to respective carveols, perillyl alcohols, and carvones (oxidative metabolites of carveols) by liver microsomes of dogs, rabbits, and guinea pigs. Mice, rats, monkeys, and humans produced carveols and perilly alcohols, but not carvones. Reconstituted monooxygenase systems containing purified rabbit CYP1A2 and 2B4 and NADPH-P450 reductase were found to catalyze (+)-limonene to (+)-carveol, (+)-carvone, and (+)-perillyl alcohol, being more active with CYP2B4. When (+)-carveol and (+)-carvone were used as substrates, dogs, rabbits, and guinea pigs metabolized them to (+)-carvone and (+)-carveol, respectively. Again humans, monkeys, rats, and mice did not convert (+)-carveol to (+)-carvone, but metabolized (+)-carvone to (+)-carveol, with male rats having the highest rates. CYP2C enzymes were suggested to play major roles in metabolizing (+)-carveol to (+)-carvone and (+)-carvone to (+)-carveol by liver microsomes, since the activities were inhibited significantly by anti-human CYP2C9 antibodies in these animal species. Studies with recombinant P450 enzymes suggested that CYP2C9 and 2C19 in humans and CYP2C11 in untreated male rats were the major enzymes in metabolizing (+)-carvone. These results suggest that there are species-related differences in the metabolism of limonenes by P450 enzymes, particularly in the way from (+)-carveol to (+)-carvone. However, it remains unclear whether these differences in limonene metabolism by these animal species explain species-related differences in limonene-induced renal toxicity.

Journal Article↗
PubMed1998

Phase I and pharmacokinetic study of D-limonene in patients with advanced cancer. Cancer Research Campaign Phase I/II Clinical Trials Committee.

PURPOSE: D-Limonene is a natural monoterpene with pronounced chemotherapeutic activity and minimal toxicity in preclinical studies. A phase I clinical trial to assess toxicity, the maximum tolerated dose (MTD) and pharmacokinetics in patients with advanced cancer was followed by a limited phase II evaluation in breast cancer. METHODS: A group of 32 patients with refractory solid tumors completed 99 courses of D-limonene 0.5 to 12 g/m2 per day administered orally in 21-day cycles. Pharmacokinetics were analyzed by liquid chromatography-mass spectrometry. Ten additional breast cancer patients received 15 cycles of D-limonene at 8 g/m2 per day. Intratumoral monoterpene levels were measured in two patients. RESULTS: The MTD was 8 g/m2 per day; nausea, vomiting and diarrhea were dose limiting. One partial response in a breast cancer patient on 8 g/m2 per day was maintained for 11 months; three patients with colorectal carcinoma had prolonged stable disease. There were no responses in the phase II study. Peak plasma concentration (Cmax) for D-limonene ranged from 10.8+/-6.7 to 20.5+/-11.2 microM. Predominant circulating metabolites were perillic acid (Cmax 20.7+/-13.2 to 71+/-29.3 microM), dihydroperillic acid (Cmax 16.6+/-7.9 to 28.1+/-3.1 microM), limonene-1,2-diol (Cmax 10.1+/-8 to 20.7+/-8.6 microM), uroterpenol (Cmax 14.3+/-1.5 to 45.1+/-1.8 microM), and an isomer of perillic acid. Both isomers of perillic acid, and cis and trans isomers of dihydroperillic acid were in urine hydrolysates. Intratumoral levels of D-limonene and uroterpenol exceeded the corresponding plasma levels. Other metabolites were trace constituents in tissue. CONCLUSIONS: D-Limonene is well tolerated in cancer patients at doses which may have clinical activity. The favorable toxicity profile supports further clinical evaluation.

Adult↗
PubMed1995

The inhibition of protein prenyltransferases by oxygenated metabolites of limonene and perillyl alcohol.

The monoterpenes limonene and perillyl alcohol are effective therapeutic agents against advanced rat mammary cancer. Limonene is currently undergoing clinical testing in cancer patients. These monoterpenes and their oxygenated metabolites have been previously shown to inhibit protein prenylation in cultured cells. Since farnesylation of ras protein is critical for its ability to cause oncogenic transformation, inhibition of protein prenylation may be the basis of the anti-tumor effects of limonene and perillyl alcohol. In this study we test the ability of limonene and its oxygenated analogs to inhibit protein prenylation enzymes in vitro. Limonene and perillyl alcohol and their major in vivo metabolite, perillic acid, are weak inhibitors of both mammalian and yeast protein farnesyl transferase (PFT) and protein geranylgeranyl transferase (PGGT). In contrast, a minor metabolite of both limonene and perillyl alcohol, perillic acid methyl ester, is a potent inhibitor of both enzymes. Perillic acid methyl ester is a competitive inhibitor of yeast PFT with respect to farnesyl pyrophosphate. These studies suggest that if the inhibition of protein prenylation is a mechanism for limonene's and perillyl alcohol's anti-cancer activities, these monoterpenes may be prodrugs that are converted into pharmacologically-active substances by metabolic modification.

Animals↗
PubMed2005

Effect of D-limonene on immune response in BALB/c mice with lymphoma.

The monoterpene D-limonene and its metabolites have been shown to exert chemopreventive and chemotherapeutic activities against different tumors in animal models and clinical trials. However, it is unknown whether these compounds modulate the immune response in tumor-bearing mice. We evaluated the survival of lymphoma-bearing mice fed with a diet with D-limonene. To assess the cell immune response, we sensitized and challenged BALB/c mice with 2,4-dinitrofluorobenzene (DNFB) and evaluated the T-cell subpopulations by flow cytometry. We also examined phagocytosis, microbicidal activity and chemotactic function in peritoneal macrophages. In order to know the role of D-limonene and its metabolites, macrophage NO production and lymphocyte proliferation studies were performed in vitro with D-limonene, perillic acid and perillyl alcohol. The results showed that D-limonene increased the survival of lymphoma-bearing mice, delayed hypersensitivity reaction to DNFB, phagocytosis and microbicidal activity. In vitro studies indicate that D-limonene increased NO production in peritoneal macrophages obtained from tumor-bearing mice. Our data suggest that in addition to reported properties, D-limonene modulates the immune response with significant potential for clinical application.

Animals↗
PubMed2005

Influence of carrot psyllid (Trioza apicalis) feeding or exogenous limonene or methyl jasmonate treatment on composition of carrot (Daucus carota) leaf essential oil and headspace volatiles.

The effect of carrot psyllid (Trioza apicalis Förster) feeding and limonene and methyl jasmonate (MeJA) treatments on the essential oil composition and headspace volatiles of carrot (Daucus carota ssp. sativus), cvs. Parano and Splendid, leaves was studied. Carrot psyllid feeding significantly increased the concentrations of sabinene, beta-pinene, and limonene, whereas limonene treatment increased the concentration of (Z)-beta-ocimene in the leaves of both cultivars. The limonene treatment significantly increased the concentration of total phenolics in the leaves of both cultivars, and MeJA treatment increased phenolic concentration in the leaves of Parano. Exogenous limonene spray did not decrease the number of carrot psyllid eggs laid either 2 or 24 h after treatment. The results suggest that carrot psyllid feeding induces changes in the endogenous monoterpene pool in the carrot leaves. Limonene and MeJA treatments affect some induced defenses of the carrot, but the exogenous limonene spray is not an effective oviposition deterrent against carrot psyllid.

Animals↗
PubMed2005

In vivo evaluation of limonene-based transdermal therapeutic system of nicorandil in healthy human volunteers.

Hydroxypropyl methylcellulose (HPMC) gel drug reservoir system prepared with 70:30 v/v ethanol-water solvent system containing 6% w/w of limonene was effective in promoting the in vitro transdermal delivery of nicorandil. The objective of the present study was to fabricate and evaluate a limonene-based transdermal therapeutic system (TTS) for its ability to provide the desired steady-state plasma concentration of nicorandil in human volunteers. The in vitro permeation of nicorandil from a limonene-based HPMC gel drug reservoir was studied across excised rat skin (control), EVA2825 membrane, adhesive-coated EVA2825 membrane and adhesive-coated EVA2825 membrane-excised rat skin composite to account for their effect on the desired flux of nicorandil. The flux of nicorandil from the limonene-based HMPC drug reservoir across EVA2825 membrane decreased to 215.8 +/- 9.7 microg/cm(2).h when compared to that obtained from control, indicating that EVA2825 was effective as a rate-controlling membrane. The further decrease in nicorandil flux across adhesive-coated EVA2825 membrane and adhesive-coated EVA2825 membrane-excised rat skin composite showed that the adhesive coat and skin also controlled the in vitro transdermal delivery. The limonene-based drug reservoir was sandwiched between adhesive-coated EVA2825-release liner composite and a backing membrane. The resultant sandwich was heat-sealed as circle-shaped patch (20 cm(2)), trimmed and subjected to in vivo evaluation in human volunteers against immediate-release tablets of nicorandil (reference formulation). The fabricated limonene-based TTS of nicorandil provided a steady-state plasma concentration of 21.3 ng/ml up to 24 h in healthy human volunteers. It was concluded that the limonene-based TTS of nicorandil provided the desired plasma concentration of the drug for the predetermined period of time with minimal fluctuations and improved bioavailability.

Administration, Cutaneous↗
PubMed2002

Effect of limonene on the in vitro permeation of nicardipine hydrochloride across the excised rat abdominal skin.

The aim of the present investigation was to study the effect of limonene on in vitro permeation of nicardipine hydrochloride across the excised rat abdominal skin from a 2% w/w hydroxypropyl cellulose (HPC) gel. The HPC gel formulations containing 1% w/w of nicardipine hydrochloride and selected concentrations of limonene (0% w/w to 12% w/w) were prepared, and subjected to in vitro permeation of the drug through excised rat abdominal epidermis. The drug content in the gels was found to be uniform and the drug was found to be stable in the HPC gel formulations. The permeation flux of nicardipine hydrochloride across rat epidermis was increased markedly by the addition of limonene to the HPC gels. A maximum flux was observed (246 +/- 1 micrograms/cm2/h) with an enhancement ratio of about 8 when limonene was incorporated at a concentration of 4% w/w. However, there was no further increase in the permeability of nicardipine hydrochloride beyond 4% w/w of limonene. The DSC and FT-IR data indicated that limonene increased the permeability of nicardipine hydrochloride across the rat epidermis by partial extraction of lipids in the stratum corneum. The results suggest that limonene may be useful for enhancing the skin permeability of nicardipine hydrochloride from transdermal therapeutic system containing HPC gel as a reservoir.

Administration, Cutaneous↗
PubMed2004

In vitro percutaneous permeability enhancement of nimodipine by limonene across the excised rat abdominal skin.

The purpose of the present study was to investigate the effect of limonene on the in vitro permeation of nimodipine across the excised rat abdominal skin from a 2% w/w hydroxypropyl methylcellulose (HPMC) gel drug reservoir system. The HPMC gel formulations containing 1.5% w/w of nimodipine and selected concentrations of limonene (0% w/w to 8% w/w) were prepared, and subjected to in vitro permeation of the drug through excised rat abdominal epidermis. The drug content in the gels was found to be uniform, and the drug was found to be stable in HPMC gel formulations. The flux of nimodipine across rat epidermis was markedly increased by the addition of limonene to the HPMC gels. A maximum flux of nimodipine was observed (203+/-0.6 microg/cm2 x h) with an enhancement ratio of about 5.7 when limonene was incorporated in HPMC gel at a concentration of 4% w/w. However, there was no further increase in the permeability of nimodipine beyond 4% w/w of limonene in the HPMC gel. FT-IR data indicated that limonene increased the permeability of nimodipine across the rat epidermis by partial extraction of lipids in the stratum corneum. The results suggest that limonene is useful for enhancing the skin permeability of nimodipine from transdermal therapeutic systems containing HPMC gel as a reservoir.

Algorithms↗