齐墩果酸和熊果酸环糊精包合物的研究
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摘要
齐墩果酸(Oleanolic Acid)和熊果酸(Ursolic Acid)是在植物界中广泛存在的五环三萜类同分异构体。它们有很多药理活性,如肝保护、化疗辅助等,但临床应用受到了低水溶性的限制。
环糊精(Cyclodextrin)是一类拥有亲水性的外表面和亲脂性的中央腔的环状低聚糖,在制药工业中常被作为络合剂用于提高难溶性药物的溶解度,进而提高生物利用度。环糊精还可以提高药物的稳定性、掩盖药物的不良性质、降低药物对胃的刺激性、使液体药物转化为微晶或无定型粉末、防止药物与药物或药物与辅料的相互作用。
本文采用环糊精包合技术提高难溶性药物齐墩果酸和熊果酸的溶解度。测定了环糊精与齐墩果酸、熊果酸作用时溶液紫外吸收图谱和~1H NMR图谱的变化;利用相溶解度的方法考察了pH值、温度和环糊精的取代度对环糊精与齐墩果酸、熊果酸包合作用的影响,并计算了包合过程中的热力学参数;考察了水溶性高分子材料及乙醇对包合过程的影响,并利用Yalkowsky等建立的潜溶剂与环糊精联合增溶的数学模型对乙醇-环糊精-药物的相互作用进行了解释和评价;考察了包合物的制备工艺,制备了固体包合物,并利用红外、差示扫描热分析、X-射线衍射和核磁共振对样品进行了分析。
环糊精的加入会使齐墩果酸和熊果酸的紫外吸收图谱产生减色效应,并伴随轻微的红移;环糊精的加入还会使齐墩果酸和熊果酸的核磁图谱产生变化,其中β-环糊精的变化最大,可使药物的羧基峰消失。以上结果表明,在溶液中齐墩果酸和熊果酸可与环糊精发生相互作用,提示有包合物形成。随着HP-β-环糊精中羟丙基取代度的增加,环糊精对药物的包合效率(CE)降低;随着包合介质pH值的升高,药物的溶解度增大,环糊精的包合效率提高。药物与环糊精的包合过程均为放热过程(ΔH＜0),且包合过程的吉布斯自由能(ΔG)均为负值,表明包合过程在常温下均可自发进行;熊果酸与HP-β-环糊精的包合过程为熵值减小的过程(ΔS＜0),而齐墩果酸与β-环糊精和HP-β-环糊精的包合过程及熊果酸与β-环糊精的包合过程为熵值增加的过程(ΔS＞0)。Yalkowsky等建立的数学模型可被用于解释和预测齐墩果酸和熊果酸在不同浓度的乙醇和环糊精溶液中的溶解度。水溶性高分子(PVP k30和HPMC E5)的加入并不能提高环糊精的包合效率,相反,有拮抗作用,且作用的大小与高分子的浓度不成线性相关。齐墩果酸和HP-β-环糊精的包合物在制备过程中加入少量的乙醇不但可以提高产品的载药量还可以进一步提高齐墩果酸在水中的溶解度,但其它样品在制备过程中加入乙醇或氨水只会显著提高样品的载药量,并不能进一步提高药物在水中的溶解度,该现象可利用Yalkowsky等建立的数学模型解释。在对固体样品的鉴定中,药物与β-环糊精形成的包合物与含有同浓度药物的物理混合物有较明显的差异;而药物与HP-β-环糊精形成的包合物可能是由于样品的载药量过低,在有些样品中,包合物、物理混合物和单纯环糊精的图谱没有显示出很明显的差异。
Oleanolic Acid and Ursolic Acid are ubiquitous pentacyclic triterpenoid isomers in plant kingdom.They have lots of pharmacological abilities,such as hepatoprotection and chemotherapy,but their clinical use is limited by poor aqueous solubility.
Cyclodextrin are cyclic oligosaccharides with a hydrophilic outer surface and a lipophilic central cavity.They have mainly been used as complexing agents in the pharmaceutical industry to increase aqueous solubility and bioavailability of poorly soluble drugs.In addition, cyclodextrin can also be used to increase the stability of drugs or mask their disadvantageous properties,reduce gastrointestinal drug irritation, convert liquid drugs into microcrystalline or amorphous powder,and prevent drug-drug and drug-excipient interactions.
In this paper,the solubility of Oleanolic Acid and Ursolic Acid is increased by forming complex with Cyclodextrin.The change in UV spectra and ~1H NMR spectra of Oleanolic Acid and Ursolic Acid with cyclodextrin in aqueous solution was studied.Phase-solubility study was used to evaluate the influence of pH value,temperature and the degree of substitution of hydroxypropyl moiety in HP-β-Cyclodextrin on the complexation of Oleanolic Acid and Ursolic Acid with Cyclodextrin. Thermodynamic parameters during the inclusion process were also determined.The influence of water-soluble polymers and concentration of ethanol on the complex behavior were also studied,and the interaction of cyclodextrin,ethanol and drugs was evaluated and explained according to a mathematical model established by Yalkowsky.The preparation technologies of complexes were also investigated.The solid complexes were prepared and then identified use IR,DSC,X-ray and ~1H NMR method.
The existence of cyclodextrin can cause hypochromic effect and a little red shift in the UV spectra of Oleanolic Acid and Ursolic Acid.The addition of cyclodextrin can also change the 1H NMR spectra of Oleanolic Acid and Ursolic Acid,especiallyβ-Cyclodextrin which can mask the peak of carboxy group of Oleanolic Acid and Ursolic Acid in the NMR spectra.There is interaction between drugs and cyclodextrin in aqueous solution which indicated the formation of complex.The solubility of the two drugs increased with the increasing pH value and the complexation efficiency(CE)decreased when the degree of substitution of hydroxypropyl moiety in HP-β-Cyclodextrin increased.The enthalpy (ΔH)and the Gibbs free energy(ΔG)in the complexations gave negative values which indicate that the inclusion could proceed spontaneously. The entropy(ΔS)of formation of Ursolic Acid with HP-β-Cyclodextrin gave negative value,but in other cases,the entropy gave positive values. The mathematical modle established by Yalkowsky can be used to explain and predict the combined solubilization of Oleanolic Acid and Ursolic Acid in different cosolvent systems.The addition of water-soluble polymers(PVP k30 and HPMC E5)doesn't increase the complexation efficiency,they show an antagonistic action and the intensity of the antagonism was independent upon the concentration of water-soluble polymers.The existence of a little ethanol in Oleanolic Acid-HP-β-cyclodextrin complexing media will raise both the drug loading dosage of product and the aqueous solubility of Oleanolic Acid. In other cases,the addition of ethanol or ammonia water into the complexing media will raise the drug loading dosage of products,but it has no help on increasing the solubility of drugs in aqueous solution.The phenomena can be explained useing the mathematical modle established by Yalkowsky.The solid complex of drugs withβ-cyclodextrin show great difference from physical mixtrue containing the same concentration of drugs.But some solid complex samples of drugs with HP-β-cyclodextrin didn't show difference from physical mixtrue containing the same concentration of drugs,it is may be because of the low drug loading dosage.
环糊精(Cyclodextrin)是一类拥有亲水性的外表面和亲脂性的中央腔的环状低聚糖,在制药工业中常被作为络合剂用于提高难溶性药物的溶解度,进而提高生物利用度。环糊精还可以提高药物的稳定性、掩盖药物的不良性质、降低药物对胃的刺激性、使液体药物转化为微晶或无定型粉末、防止药物与药物或药物与辅料的相互作用。
本文采用环糊精包合技术提高难溶性药物齐墩果酸和熊果酸的溶解度。测定了环糊精与齐墩果酸、熊果酸作用时溶液紫外吸收图谱和~1H NMR图谱的变化;利用相溶解度的方法考察了pH值、温度和环糊精的取代度对环糊精与齐墩果酸、熊果酸包合作用的影响,并计算了包合过程中的热力学参数;考察了水溶性高分子材料及乙醇对包合过程的影响,并利用Yalkowsky等建立的潜溶剂与环糊精联合增溶的数学模型对乙醇-环糊精-药物的相互作用进行了解释和评价;考察了包合物的制备工艺,制备了固体包合物,并利用红外、差示扫描热分析、X-射线衍射和核磁共振对样品进行了分析。
环糊精的加入会使齐墩果酸和熊果酸的紫外吸收图谱产生减色效应,并伴随轻微的红移;环糊精的加入还会使齐墩果酸和熊果酸的核磁图谱产生变化,其中β-环糊精的变化最大,可使药物的羧基峰消失。以上结果表明,在溶液中齐墩果酸和熊果酸可与环糊精发生相互作用,提示有包合物形成。随着HP-β-环糊精中羟丙基取代度的增加,环糊精对药物的包合效率(CE)降低;随着包合介质pH值的升高,药物的溶解度增大,环糊精的包合效率提高。药物与环糊精的包合过程均为放热过程(ΔH＜0),且包合过程的吉布斯自由能(ΔG)均为负值,表明包合过程在常温下均可自发进行;熊果酸与HP-β-环糊精的包合过程为熵值减小的过程(ΔS＜0),而齐墩果酸与β-环糊精和HP-β-环糊精的包合过程及熊果酸与β-环糊精的包合过程为熵值增加的过程(ΔS＞0)。Yalkowsky等建立的数学模型可被用于解释和预测齐墩果酸和熊果酸在不同浓度的乙醇和环糊精溶液中的溶解度。水溶性高分子(PVP k30和HPMC E5)的加入并不能提高环糊精的包合效率,相反,有拮抗作用,且作用的大小与高分子的浓度不成线性相关。齐墩果酸和HP-β-环糊精的包合物在制备过程中加入少量的乙醇不但可以提高产品的载药量还可以进一步提高齐墩果酸在水中的溶解度,但其它样品在制备过程中加入乙醇或氨水只会显著提高样品的载药量,并不能进一步提高药物在水中的溶解度,该现象可利用Yalkowsky等建立的数学模型解释。在对固体样品的鉴定中,药物与β-环糊精形成的包合物与含有同浓度药物的物理混合物有较明显的差异;而药物与HP-β-环糊精形成的包合物可能是由于样品的载药量过低,在有些样品中,包合物、物理混合物和单纯环糊精的图谱没有显示出很明显的差异。
Oleanolic Acid and Ursolic Acid are ubiquitous pentacyclic triterpenoid isomers in plant kingdom.They have lots of pharmacological abilities,such as hepatoprotection and chemotherapy,but their clinical use is limited by poor aqueous solubility.
Cyclodextrin are cyclic oligosaccharides with a hydrophilic outer surface and a lipophilic central cavity.They have mainly been used as complexing agents in the pharmaceutical industry to increase aqueous solubility and bioavailability of poorly soluble drugs.In addition, cyclodextrin can also be used to increase the stability of drugs or mask their disadvantageous properties,reduce gastrointestinal drug irritation, convert liquid drugs into microcrystalline or amorphous powder,and prevent drug-drug and drug-excipient interactions.
In this paper,the solubility of Oleanolic Acid and Ursolic Acid is increased by forming complex with Cyclodextrin.The change in UV spectra and ~1H NMR spectra of Oleanolic Acid and Ursolic Acid with cyclodextrin in aqueous solution was studied.Phase-solubility study was used to evaluate the influence of pH value,temperature and the degree of substitution of hydroxypropyl moiety in HP-β-Cyclodextrin on the complexation of Oleanolic Acid and Ursolic Acid with Cyclodextrin. Thermodynamic parameters during the inclusion process were also determined.The influence of water-soluble polymers and concentration of ethanol on the complex behavior were also studied,and the interaction of cyclodextrin,ethanol and drugs was evaluated and explained according to a mathematical model established by Yalkowsky.The preparation technologies of complexes were also investigated.The solid complexes were prepared and then identified use IR,DSC,X-ray and ~1H NMR method.
The existence of cyclodextrin can cause hypochromic effect and a little red shift in the UV spectra of Oleanolic Acid and Ursolic Acid.The addition of cyclodextrin can also change the 1H NMR spectra of Oleanolic Acid and Ursolic Acid,especiallyβ-Cyclodextrin which can mask the peak of carboxy group of Oleanolic Acid and Ursolic Acid in the NMR spectra.There is interaction between drugs and cyclodextrin in aqueous solution which indicated the formation of complex.The solubility of the two drugs increased with the increasing pH value and the complexation efficiency(CE)decreased when the degree of substitution of hydroxypropyl moiety in HP-β-Cyclodextrin increased.The enthalpy (ΔH)and the Gibbs free energy(ΔG)in the complexations gave negative values which indicate that the inclusion could proceed spontaneously. The entropy(ΔS)of formation of Ursolic Acid with HP-β-Cyclodextrin gave negative value,but in other cases,the entropy gave positive values. The mathematical modle established by Yalkowsky can be used to explain and predict the combined solubilization of Oleanolic Acid and Ursolic Acid in different cosolvent systems.The addition of water-soluble polymers(PVP k30 and HPMC E5)doesn't increase the complexation efficiency,they show an antagonistic action and the intensity of the antagonism was independent upon the concentration of water-soluble polymers.The existence of a little ethanol in Oleanolic Acid-HP-β-cyclodextrin complexing media will raise both the drug loading dosage of product and the aqueous solubility of Oleanolic Acid. In other cases,the addition of ethanol or ammonia water into the complexing media will raise the drug loading dosage of products,but it has no help on increasing the solubility of drugs in aqueous solution.The phenomena can be explained useing the mathematical modle established by Yalkowsky.The solid complex of drugs withβ-cyclodextrin show great difference from physical mixtrue containing the same concentration of drugs.But some solid complex samples of drugs with HP-β-cyclodextrin didn't show difference from physical mixtrue containing the same concentration of drugs,it is may be because of the low drug loading dosage.
引文
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[10]Jun L,Liyan Q,Jianqing G,Yi J.Preparation,Characterization and in vivo evaluation of formulation of baicalein with hydroxypropyl-β-cyclodextrin.INT J PHARM 2006;312(1-2):137-143.
[11]Chao JB,Tong HB,Liu DS,Huang SP.Preparation and characterization of inclusion complexes of pefloxacin mesylate with three kinds of cyclodextrins.SPECTROCHIM ACTA A 2006;64(1):166-170.
[12]Cinzia AV,Ignazio G,Donatella P,Venerando P,Antonino C,Giovanni P.Preparation of celecoxib-dimethyl-β-cyclodextrin inclusion complex:characterization and in vitro permeation study.EUR J MED CHEM 2005;40(7):624-631.
[13]Zingone G.Rubessa F.Preformulation study of the inclusion complex warfarin-β-cyclodextrin.INT J PHARM 2005;291(1-2):3-10.
[14]AL-Marzouqi AH,Jobe B,DowaidarA;Maestrelli F,MuraR P.Evaluation of supercritical fluid technology as preparative technique of benzocaine-cyclodextrin complexes-Comparison with conventional methods.J PHARMACEUT BIOMED 2007;43(2):566-574.
[15]Thorsteinn T,Mason M.The effects of water-soluble polymers on cyclodextrinsand cyclodextrin solubilization of drugs.J DRUG DEL SCI TECH 2004;14:35-43.
[16]Paola M,M.Teresa F,Gian PB.The influence of polyvinylpyrrolidone on naproxen complexation with hydroxypropyl-β-cyclodextrin.EUR J PHARM SCI 2001;13(2):187-194.
[17]Enrico R,Lajos S,Jozsef S.Cyclodextrin complexes of salts of acidic drugs,Thermodynamic properties,structural features,and pharmaceutical applications.J PHARM SCI 2001;90:979-986.
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[21]Yan H,Ping L,Yalkowsky SH.Solubilization of Fluasterone in cosolvent/cyclodextrin combinations.INT J PHARM 2003;264:25-34.
[22]Rao VM,Stella VJ.When can cyclodextrins be considered for solubilizing purposes.J PHARM SCI 2003;92:927-932.
[23]Lipinski CA,Lombardo F,Dominy BW,Feeney PJ.Experimental and computatorial approaches to estimate solubility and permeability in drug discovery and development settings.ADV DRUG DELIVER REV 2001;46:3-26.
[24]Thorsteinn T,Masson M.Cyclodextrins in topical drug formulations:theory and practice.INT J PHARM 2001;225:15-30.
[25]Thorsteinn T,Sigfusson SD,Sigurdsson HH,Masson M.The effects of cyclodextrins on topical delivery of hydrocortisone:the aqueous diffusion layer.STP PHARMA SCI 2003;13:125-131.
[26]Marttin E,Verhoef JC,Merkus FW.Efficiency,safety and mechanism of cyclodextrins as absorption enhancers in nasal delivery of peptide and protein drugs.J DRUG TARGET 1998;6:17-36.
[27]Dotsikas Y,Loukas YL.Kinetic degradation study of insulin complexed with methyl-β-cyclodextrin.Confirmation of complexation with electrospray mass spectrometry and ~1H NMR.J PHARMACEUT BIOMED 2002;29(3):487-494.
[28]Jumma M,Chimilio L,Chinnaswamy S,Silchenko S,Stella VJ.Degradation of NSC-281612(4-[bis[2-[(methylsulfonyl)- oxy]ethyl]amino]-2-methylbenzaldihyde),and experimental antineoplastic agent:effects of pH,solvent composition,(SBE)7m-β-CD and HP-β-CD on stability.J PHARM SCI 2004;93:532-539.
[29]Jumma M,Chimilio L,Chinnaswamy S,Silchenko S,Stella VJ.Stabilizing and solubilizing effects of sulfobutylether β-cyclodextrin on prostaglandin El analogue.PHARM RES 2002;18:1578-1585.
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[1]崔福德.药剂学.北京:人民卫生出版社.2003.350-356.
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[4]Ling W,Xuehua J,Weijuan X,Chenrui L.Complexation of tanshinone ⅡA with 2-hydroxypropyl-β-cyclodextrin:Effect on aqueous solubility,dissolution rate,and intestinal absorption behavior in rats.INT J PHARM 2007;341(1-2):58-67.
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[8]Thorsteinn T,Auour M,Mar M,Johanna FS.Self-association and cyclodextrin solubilization of drugs.J PHARM SCI 2002;91:2307-2316.
[9]Thorsteinn T,Mar M,Marcus EB.Self-association of cyclodextrins and cyclodextrin complexes.J PHARM SCI 2004;93:1091-1099.
[10]Jun L,Liyan Q,Jianqing G,Yi J.Preparation,Characterization and in vivo evaluation of formulation of baicalein with hydroxypropyl-β-cyclodextrin.INT J PHARM 2006;312(1-2):137-143.
[11]Chao JB,Tong HB,Liu DS,Huang SP.Preparation and characterization of inclusion complexes of pefloxacin mesylate with three kinds of cyclodextrins.SPECTROCHIM ACTA A 2006;64(1):166-170.
[12]Cinzia AV,Ignazio G,Donatella P,Venerando P,Antonino C,Giovanni P.Preparation of celecoxib-dimethyl-β-cyclodextrin inclusion complex:characterization and in vitro permeation study.EUR J MED CHEM 2005;40(7):624-631.
[13]Zingone G.Rubessa F.Preformulation study of the inclusion complex warfarin-β-cyclodextrin.INT J PHARM 2005;291(1-2):3-10.
[14]AL-Marzouqi AH,Jobe B,DowaidarA;Maestrelli F,MuraR P.Evaluation of supercritical fluid technology as preparative technique of benzocaine-cyclodextrin complexes-Comparison with conventional methods.J PHARMACEUT BIOMED 2007;43(2):566-574.
[15]Thorsteinn T,Mason M.The effects of water-soluble polymers on cyclodextrinsand cyclodextrin solubilization of drugs.J DRUG DEL SCI TECH 2004;14:35-43.
[16]Paola M,M.Teresa F,Gian PB.The influence of polyvinylpyrrolidone on naproxen complexation with hydroxypropyl-β-cyclodextrin.EUR J PHARM SCI 2001;13(2):187-194.
[17]Enrico R,Lajos S,Jozsef S.Cyclodextrin complexes of salts of acidic drugs,Thermodynamic properties,structural features,and pharmaceutical applications.J PHARM SCI 2001;90:979-986.
[18]Enrico R,Lajos S,J6zsef S.Drug/cyclodextrin/hydroxy acid multicomponent systems:Properties and pharmaceutical applications.J PHARM SCI 2000;89:1-8.
[19]Thorsteinn T,Sigurdsson HH,Masson M,Schipper N.Preparation of solid drug/cyclodextrin complexes of acidic and basic drugs.PHARMAZIE 2004;59:25-29.
[20]Thorsteinn T,Matthiasson K,Masson M.The effects of organic salts on the cyclodextrin solubilization of drugs.INT J PHARM 2003;262:101-107.
[21]Yan H,Ping L,Yalkowsky SH.Solubilization of Fluasterone in cosolvent/cyclodextrin combinations.INT J PHARM 2003;264:25-34.
[22]Rao VM,Stella VJ.When can cyclodextrins be considered for solubilizing purposes.J PHARM SCI 2003;92:927-932.
[23]Lipinski CA,Lombardo F,Dominy BW,Feeney PJ.Experimental and computatorial approaches to estimate solubility and permeability in drug discovery and development settings.ADV DRUG DELIVER REV 2001;46:3-26.
[24]Thorsteinn T,Masson M.Cyclodextrins in topical drug formulations:theory and practice.INT J PHARM 2001;225:15-30.
[25]Thorsteinn T,Sigfusson SD,Sigurdsson HH,Masson M.The effects of cyclodextrins on topical delivery of hydrocortisone:the aqueous diffusion layer.STP PHARMA SCI 2003;13:125-131.
[26]Marttin E,Verhoef JC,Merkus FW.Efficiency,safety and mechanism of cyclodextrins as absorption enhancers in nasal delivery of peptide and protein drugs.J DRUG TARGET 1998;6:17-36.
[27]Dotsikas Y,Loukas YL.Kinetic degradation study of insulin complexed with methyl-β-cyclodextrin.Confirmation of complexation with electrospray mass spectrometry and ~1H NMR.J PHARMACEUT BIOMED 2002;29(3):487-494.
[28]Jumma M,Chimilio L,Chinnaswamy S,Silchenko S,Stella VJ.Degradation of NSC-281612(4-[bis[2-[(methylsulfonyl)- oxy]ethyl]amino]-2-methylbenzaldihyde),and experimental antineoplastic agent:effects of pH,solvent composition,(SBE)7m-β-CD and HP-β-CD on stability.J PHARM SCI 2004;93:532-539.
[29]Jumma M,Chimilio L,Chinnaswamy S,Silchenko S,Stella VJ.Stabilizing and solubilizing effects of sulfobutylether β-cyclodextrin on prostaglandin El analogue.PHARM RES 2002;18:1578-1585.
[30]Martins PS,Ochoa R,Pimenta AMC,Ferreira LAM,Melo AL,Silva JBB,Sinisterra RD,Demicheli C,Frezard F.Mode of action of β-cyclodextrin as an absorption enhancer of the water-soluble drug meglumine antimoniate.INT J PHARM 2006;325(1-2):39-47.
[31]Jinjiang L,Yushen G,Zografi G.The solidstate stability of amorphous quinapril in the presence of β-cyclodextrin.J PHARM SCI 2002;91:229-243.
[32]Wu WM,Wu J,Bodor N.Effect of 2-hydroxypropyl-β-cyclodextrin on the solubility,stability,and pharmacological activity of the chemical delivery system of TRH analogs.PHARMAZIE 2002;57:130-134.
[33]Waleczek KJ,Cabral MHM,Hempel B;Schmidt PC.Phase solubility studies of pure (-)-α-bisabolol and camomile essential oil with β-cyclodextrin.EUR J PHARM BIOPHARM 2003;55:247-251.
[34]Kang F,Jiang G,Hinderliter A,DeLuca PP,Singh J.Lysozyme stability in primary emulsion for PLGA microsphere preparation: effect of recovery methods and stabilizing excipients. PHARM RES 2002; 19:629-633.
[35] Jarho P, Veldedv DV, Stella VJ. Cyclodextrin-catalyzed deacetylation of spironolactone is pH and cyclodextrin dependent. J PHARM SCI 2000; 89:241-249.
[36] Angela MA, Francesco B, Valentina DP, Bruno G, Diego LM, Giuseppe L, Salvatore S, Barbara T, Enrico R, Graziella V. Synthesis and antioxidant activity of new homocamosine P-cyclodextrin conjugates. EUR J MED CHEM 2007; 42:910-920.
[37] Puskás I, Csempesz F. Influence of cyclodextrins on the physical stability of DPPC-liposomes. COLLOID SURFACE B 2007; 58:218-224.
[38] Washington N, Washington C, Prof Wilson C. Physiological pharmaceutics: barriers to drug absorption. Routledge, UK (2001):249-270.
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