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To overcome the problems associated with bioavailability and systemic side effects of the drug by oral administration, monolithic matrix type transdermal patches containing cinnarizine (CNZ) were developed. For this purpose, films based on hydroxypropyl methylcellulose and polyvinylpyrrolidone as matrix-forming polymers were designed. Physical characteristics of transdermal films and drug-excipient compatibility were investigated. Factors affecting in vitro drug release and ex vivo skin penetration and permeation of the drug were studied. It was confirmed that films displayed sufficient flexibility and mechanical strength for application onto the skin for a long time period. Ex vivo penetration experiments gave satisfactory results for transdermal drug delivery through rat skin. The parameters determining good skin penetration were also evaluated. The highest drug permeation rate was obtained with incorporation of Transcutol® (0.102 mg/cm2/h) into the base CNZ formulation, followed by propylene glycol (0.063 mg/cm2/h), menthol (0.045 mg/cm2/h), and glycerin (0.021 mg/cm2/h) as penetration enhancers (p < 0.05). As a result, the developed transdermal patches of CNZ may introduce an alternative treatment for various conditions and diseases such as idiopathic urticarial vasculitis, Ménière's disease, motion sickness, nausea, and vertigo. Thus, the risk of systemic side effects caused by the drug can be reduced or eliminated
Subject(s)
Administration, Oral , Cinnarizine , Histamine Agonists/adverse effects , Cholinergic Antagonists , Anesthetics/classification , Skin , In Vitro Techniques/methods , Pharmaceutical Preparations/analysis , Hypromellose Derivatives/adverse effects , Drug LiberationABSTRACT
Objective: To compare the penetration-enhancing effect and composition changes of fresh ginger and dried ginger essential oil. Methods: The essential oil was extracted before and after fresh ginger being processed into dried ginger, and the penetration- enhancing effect of them was compared by skin electrical resistance and transdermal test of ibuprofen in vitro. The main mechanism of penetration-enhancing effect of the essential oil was studied by ATR-FTIR. The skin cytotoxicity of the essential oils was compared by skin cytotoxicity test, and the composition changes were analyzed by GC-MS. Results: Thepenetration-enhancing effect of dried ginger essential oil was much better than the fresh ginger essential oil. The mechanism was mainly due to the skin stratum corneum lipids extraction. The skin cytotoxicity of fresh ginger and dried ginger essential oil was much lower than that of azone. The sesquiterpenes content of dried ginger essential oil was higher than that of fresh ginger essential oil. The intradermal sesquiterpenoids of dried ginger essential oil group after transdermal treatment were higher than those in the fresh ginger essential oil group. Conclusion: The transdermal absorption promotion effect of the processed dried ginger essential oil was much better than that of fresh ginger essential oil, which verified the existence of the rule of “hot herbs with better efficacy”.
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To compare the penetration-enhancing effect of cinnamon oil and its main components (cinnamaldehyde) on ibuprofen and their self-percutaneous absorption behavior in vitro. Firstly, cinnamon oil was extracted by steam distillation, then the compositions were analyzed by gas chromatography mass spectrometry (GC-MS) and the cinnamaldehyde content in cinnamon oil was determined by high performance liquid chromatography (HPLC). With azone as positive control, ibuprofen as model drug, cinnamon oil and cinnamaldehyde as penetration enhancers (PE) were prepared and administered to the SD rat's abdominal skin. The penetration-enhancing effects of cinnamon oil and cinnamaldehyde and their own transdermal absorption properties were compared. The results showed that yield of cinnamon oil was (3.55±0.36)% (=3), and the cinnamaldehyde content in cinnamon oil was (73.48±0.21)% (=3). As compared with blank group, the enhancing rate (ER) of cinnamon oil, cinnamaldehyde, and azone was 3.56, 1.13, 2.47 respectively. The cumulative penetration rate of cinnamaldehyde in cinnamon oil and cinnamaldehyde monomer in 24 h was (63.30±0.98)%, (51.03±3.34)% (=4) respectively. The penetration-enhancing effect of cinnamon oil was significantly better than that of cinnamaldehyde, indicating the existence of muti-component synergy. The penetration rate of cinnamaldehyde in cinnamon oil was higher than that of cinnamaldehyde monomer, suggesting that a "pull effect" may be present.
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The critical problem to be solved in the study of transdermal drug delivery system is to improve the transdermal penetration of drugs through the skin. Most essential oils from Chinese material medica, considered as a large class of penetration enhancers, possess enhanced percutaneous absorption, minor skin irritation, certain therapeutic efficacy, and a synergistic effect with transdermal drugs. However, the essential oils have poor solubility and unstable problems. Some special preparations, including patch, clathrate, gel plasters, gels, microemulsion, and so on, can increase the solubility of the essential oils, improve the effect of permeability, and can significantly boost the stability of the essential oils. In this paper, the techniques of the related preparations on essential oil from Chinese materia medica should be reviewed, and the research direction of the later stage should be discussed.
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Objective To prepare naloxone hydrochloride nasal spray and evaluate the ciliotoxicity and pharmacokinetics of the formulation. Methods The stability of naloxone hydrochloride was studied in pH3.5-5.5. Penetration promoting effects of absorp-tion enhancers on the naloxone hydrochloride were evaluated. Nasal ciliotoxicity studies were carried out using isolated toad palate. Rats were treated with naloxone hydrochloride solution by intramuscular injection of nasal drops to evaluate the pharmacokinetics. Results Naloxone hydrochloride solution was stable in pH3.5-5.5. Disodium ethylenediaminetetraacetic acid(0.2%,W/V)had the best penetration promoting effect on naloxone hydrochloride. Naloxone hydrochloride nasal spray did not exhibit obvious nasal ciliotox-icity compared to the negative control. The nasal spray had a faster therapeutic effect and its bioavailability was similar to that of the in-tramuscular injection. Conclusion Naloxone hydrochloride nasal spray prepared in this research is stable with no obvious nasal cilio-toxicity,has faster therapeutic effect,and good bioavailability,so may have a broad application prospect.
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Objective: To screen the best transdermal enhancers of naringenin in Premna fulva extract. Methods: Using abdominal skin of rats as experimental barrier, the in vitro percutaneous absorption experiment was established by modified Franz diffusion cell method. The cumulative infiltration and permeation rate of naringenin in three different penetration enhancers were determined by HPLC. Results: The borneol, menthol, and azone could enhance transdermal absorption of naringenin in different degree. Several penetration enhancers were increased in the following order: borneol > menthol > azone. The average percutaneous rate of naringenin was 0.136 8 mg/(cm2∙h), using 5% borneol as penetration enhancer. Conclusion: The 5% borneol is an effective transdermal enhancer for naringenin in P. fulva extract.
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Objective: To optimize the matrix prescription of Compound Qingfengteng Cataplasm (CQC). Methods: Taking the comprehensive senses as evaluation index, the types and dosage of the matrix were investigated by single factor. Further combined with the initial viscosity and holding viscosity index to optimize the matrix prescription of CQC by orthogonal test, and in vitro transdermal absorption experiments were carried out by Franz diffusion pool method to screen penetration enhancers. Results: The optimal formulation of CQC was as follows: 2.5 g of NP-700, 11 g of glycerin, 0.08 g of glycine aluminum, 0.08 g of tartaric acid, 0.8 g of PVP K90, 0.5 g of PVPP, 20 g of water, and 4.2 g of dry extract. 3% nitrile as a penetration agent could enhance penetration action. Conclusion: The preferred matrix prescription is practicable; CQC adhesion is moderate, no residue, paste traits, skin followability are good.
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Penetration enhancers (PE) were usually applied as the optimum strategy to improve the percutaneous absorption of active components from pharmaceutical preparations. Essential oils (EOs) were a kind of PE with satisfactory characteristics. Only 34 of among more than 300 EOs are reported to be used as PE. That is to say, about 90% EOs have not been applied until now and EOs possess great potential to act as PE. However, the research of EOs from Chinese materia medica (CMM) mainly followed the strategy of chemical PE. A large amount of studies were carried out to evaluate the transdermal penetration enhancing efficacy and pharmacological activity, resulting in the limited efficiency. EOs of CMM were also the key material basis of CMM pungent flavor. In the theory of traditional Chinese medicines (TCM), it was accepted that the pungent flavor could open the striae and interstice. The results of literature investigation revealed that the penetration enhancing efficacy of EOs directly related with drug property characteristics of CMM. Therefore, in the present paper, it was proposed that a rule existed between the penetration enhancing efficacy of EOs and drug property characteristics of CMM. A series of studies were then designed to reveal the rule with the aid of data analysis. The resultant rule will help to find the effective PE from various EOs. Moreover, to facilitate the high-throughput screening of EOs, liposomal artificial skin membrane was prepared and applied to the evaluation of in vitro penetration enhancing efficacy of EOs with optimization of the evaluation parameters. Finally, the results of the study will provide a novel strategy for the research of EOs as PE and the research of the application of TCM theory to the modern pharmaceutical study. In addition, the application of microemulsion technique will be the future trends of EOs as PE to solve the stability problems.
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The study was carried out to investigate the pharmacokinetics and in vitro/in vivo correlation of ibuprofen with essential oils as penetration enhancers (PE) following transdermal administration. With Azone as the positive control, ibuprofen hydrogels containing Chuanxiong oil, Angelica oil or Cinnamon oil as PE were prepared and administered to the rat abdominal skin. Then the pharmacokinetics of ibuprofen following transdermal administration were investigated and compared. In comparison with negative control (no PE was added), the relative bioavailability values with the addition of Chuanxiong oil, Angelica oil, Cinnamon oil and Azone as PE were determined to be 161.87%, 171.05%, 151.37% and 148.66%, respectively. In vitro/in vivo correlation analysis was performed by deconvolution method and the results demonstrated a good correlation between in vitro and in vivo percutaneous absorption studies. The correlation coefficients were measured to be 0.999 7, 0.995 2 and 0.999 4 for Chuanxiong oil, Angelica oil and Cinnamon oil respectively. In summary, Chuanxiong oil, Angelica oil and Cinnamon oil as PE could significantly enhance the bioavailability of ibuprofen following transdermal administration. A satisfactory in vitro/in vivo correlation could be obtained by using hydrogel as the dosage form.
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Objective:To study the effect of caprylic/capric acid glycerides (Lab), propylene glycol (PG) and Azone on the transdermal behavior of ketoconazole and miconazole nitrate in compound ketoconazole gel, to screen appropriate penetration enhanc-ers. Methods:Using a RYJ-6A-type transdermal drug diffusion tester, the effects of Lab, PG and Azone at different concentrations on the transdermal behavior of ketoconazole and miconazole nitrate in compound ketoconazole gel were studied. Results:3% PG showed the most obvious penetration enhancement, which could increase the permeation of ketoconazole by 2. 004 times, and increase the pen-etration of miconazole nitrate by 1. 795 times, and the differences were statistically significant (P<0. 05). Conclusion:The penetra-tion effect of 3% PG is obvious, which can be applied in compound ketoconazole gel.
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Objective: To investigate the effects of common peneration enhancers on the transdermal permeation of total flavones and six flavonoid components from Scutellariae Radix Gel-unguentum (SRGU), thus to provide the experimental evidence for the selection of optimal penetration enhancers. Methods: In vitro diffusion cell method was used to evaluate the changes of the transdermal pemeation parameters by azone (AZ), menthol (MT), and propylene glycol (PG), separately or in combination. Results: When applied individually, AZ and MT showed the best enhancing effect on the transdermal permeability and cumulative permeation of flavonoids and their aglycons, respectively. PG, in contrast, produced poor enhancement. When applied in combination, the permeation enhancing effects were generally more remarkable than those of single enhancer. In particular, 3% AZ + 5% PG could achieve the most effective enhancement effect on the transdermal permeation of flavonoids. Conclusion: Penetration enhancers could significantly affect the transdermal permeation of total flavones and flavonoid components from SRGU in vitro, and 3% AZ + 5% PG may serve as the most effective enhancer.
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Because TCM transdermal medicine delivery preparations are hot spots in domestic researches, the rational application of penetration enhancers in prescriptions and the evaluation methods become increasingly important. This article reviewed the recent application of natural penetration enhancers and synthetic penetration enhancers in the prescription design of TCM transdermal medicine delivery preparations, and analyzed the existing problems and development prospects.
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Objective To investigate the effects of volatile oil of Fructus Evodia, mustar d oil and total anthraquinone in Rheum on the transcutaneous permeability of paeoniflorin. Methods Using intelligent transdermal diffusion cell and excised mice skin in vitro as transdermal barrier, the kinetics parameters such as cumulative permeation quantity, permeation rate and permeation lagged time of the three kinds of penetration enhancers on paeoniflorin were determined by HPLC in 12 hours. Results The penetration rate of volatile oil of Fructus Evodia, mustard oil and total anthraquinone in Rheum were 8.188 6, 3.411 7, 1.230 3 μg/(cm2?h), respectively, the enhancement ratios were 22.6, 9.40, 3.40, respectively, and the permeation lagged times were 0.93, 0.51, 0.83 h, respectively. Conclusion Three penetration enhancers all can enhance previously percutaneous absorption of paeoniflorin, which provides reference for the selection of the penetration enhancers of transdermal delivery.
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Application of penetration enhancers (PE) is one of the most commonly used strategies to improve the percutaneous absorption. Most essential oils from Chinese materia medica (CMM) possess the good ability to enhance percutaneous absorption, minor skin irritation, and certain therapeutic efficacy. Therefore, the research on essential oils as PE has good prospects. In the present paper, the percutaneous absorption enhancing effects, mechanism of action, safety, and transdermal absorption of essential oils from CMM are reviewed. Moreover, the existing main problems, namely the confusing application of pharmaceutical preparations and the limitation of in vitro percutaneous absorption evaluations, are summarized and analyzed. Then the research ideas are proposed on the basis of the analysis results. The application scope, dosage forms, and mechanism of action of essential oils from CMM as PE should be further studied and standardized. More attention should be paid to the guiding role of CMM theory.
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Objective: To study the effect of different penetration enhancers on the percutaneous absorption of nine active components in Shaofu Zhuyu Transdermal Patches (SZTP) across skin of mice and optimize the proper penetration enhancers in order to provide the scientific basis for SZTP research, clinical medication, and reform of the traditional forms. Methods: Using improved Franz diffusion cells and taking isolated rat abdomen skins as transdermal barrier, the concentration of these components was determined by UPLC-MS/MS, then the total factor scores of the concentrations at different time were calculated using PCA and employed instead of the concentration to compute the cumulative amounts and steady fluxes. Results: The results showed that compared to the control group, the steady fluxes of the other groups increased significantly, and furthermore, 2.5% azone with 2.5% propylene glycol manifested the best effect. The nine components could penetrate through skin well under the action of penetration enhancers. Conclusion: Azone and propylene glycol could significantly promote the percutaneous penetration effect of the nine active components in SZTP, and it could provide a scientific basis for the preparation research of SZTP.
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Objective: To study the transdermal penetration absorption of Salviae Miltiorrhizae Radix et Rhizoma, the monarch drug in Xiaoyan Zhentong Cataplasm and to optimize the transdermal penetration enhancers of Xiaoyan Zhentong Cataplasm. Methods: The Franz diffusion cell was used to study the in vitro permeation behavior, and salvianolic acid B and Tanshinone IIA were chosen as indexes. Samples with different penetration enhancers were assayed by HPLC method to determine the cumulative permeation quantity and permeation rate of salvianolic acid B and Tanshinone IIA. Results: When azone - propylene glycol (1:1), the permeation rates of salvianolic acid B and Tanshinone IIA through rat skin in vitro were 3.62 and 1.35 μg/(cm2·;h), respectively, and the 24 h permeated amounts were 88.72 and 16.12 μg/cm2, respectively. Compared with the Xiaoyan Zhentong Cataplasm without penetration enhancers, the permeation rates increased by 6 and 10 times, respectively. Conclusion: The combination of Azone - propylene glycol (1:1) is an effective penetration enhancer both to water-soluble salvianolic acid B and liposoluble Tanshinone IIA.
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glycerol,and the best penetrable concentrations for it were 0.5%,0.5% and 0.2%,respectively.No obvious penetration efficacy was noted for glycerol.CONCLUSIONS: 4 kinds of penetrations enhances can increase the percutaneous absorption of DH under the certain concentration.
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IPA.Skin permeation was significantly enhanced by increasing the loading concentration of OA or NMP,larger IPA amount(8%) or PG amount(20%) could inhibit the permeation of artesunate.Conclusion Oleic acid was found to be the most efficient enhancer for artesunate,10% is the most effective concentration.
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Azone. PG combined with azone showed a higher synergic effect of enhancing effectiveness. Conclusion National Starch polyacrylate pressure-sensitive adhesive was the most effective pressure-sensitive adhesive matrix, PVP-K30 was the most effective crystallization inhibitor, PG combined with azone were the most effective penetration enhancers.
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Objective To optimize the formulation of Dihydroartemisinin ointment and study its characteristics of penetration enhancers.Method A method of transdermal experiment in vitro was established for DHA.The penetration rate in vitro was examined by HPLC,and coincided the DHA cumulative permeation curve with the Higuchi equation.Result The penetration rate of DHA from DHA ointment made up of water-soluble carbopol and Azone was the highest in all formulations,up to 27.262 ?g/(h?cm2).The cumulative permeation curve which coincided with the Higuchi equation was better.Conclusion The formulation which made up of water-soluble carbopol and Azone was optimized.