吡罗昔康自微乳化给药系统的研究
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摘要
提高难溶性药物生物利用度是一直以来药剂学面临的问题。自微乳化给药体系(SMEDDS)是由药物、油相、表面活性剂和辅助表面活性剂组成的均一、透明的溶液,在特定温度和温和搅拌的条件下,遇水自发乳化形成粒子在150nm以下的乳剂。与常规乳剂相比,微乳是一种热力学稳定体系,具有更高的分散度(通常在10～140nm之间),并且由于一些特殊表面活性剂的作用,自微乳化给药体系(SMEDDS)可以通过多种渠道达到提高药物生物利用度的目的。研发难溶性药物的自微乳化给药体系的关键在于发现合适的药物载体(油相、表面活性剂、助表面活性剂以及适当的增溶剂)。因此,对于材料的了解和筛选显得尤为重要。自微乳化给药体系(SMEDDS)主要研发手段是采用伪三元相图以及对微乳的理化性质分析。其中着重要考虑的因素有载体对药物的溶解能力、自微乳化体系在伪三元相图区域特点、形成微乳后药物的溶出度和微乳粒径的大小。这些都是影响药物生物利用度的重要因素。
本课题以难溶性药物吡罗昔康为模型药物,吡罗昔康(Piroxicam)又名炎痛昔康,是辉瑞公司研发出来的解热镇痛类非甾体抗炎药,文献报道,吡罗昔康难溶于水、生物利用度低。本课题对吡罗昔康自微乳化给药体系(SMEDDS)进行了探索性研究,本研究建立了高效液相色谱法梯度洗脱测定吡罗昔康含量的方法:对15种常用自微乳化辅料进行了筛选,优选出以辛酸甘油酯为油相、月桂酸聚乙二醇甘油酯为乳化剂、二乙二醇单乙基醚为助表面活性剂的吡罗昔康自微乳化给药系统,并对其进行了体内外评价。体外溶出结果表明,5min内药物的溶出大于80%,平均粒径在33nm左右;在以吡罗昔康Tmax未发生明显改变,Cmax提高4.8倍。相对生物利用度为466%.
The enhancement of oral bioavailability of poorly water soluble active pharmaceutical ingredients (APIs) or new chemical entities (NCEs) remains one of the most challenging aspects of drug development. Although salt formation, solid dispersion, cyclodextrin inclusion, liposome, solubilisation and micronization have commonly been used to enhance the in vitro dissolution rate and thereby oral absorption and bioavailability, there are practical difficulties. The use of very fine powders may still be problematic to handle due to poor wettability. Lipid-based drug delivery systems have gained an important place in the formulation of poorly soluble drugs for oral administration. Lipid-based formulations are typically administered in liquid form, generally in soft-gel capsules. This can offer favorable dissolution, release, and bioavailability properties. Self emulsifying drug deliver system (SEDDS) and self micro-emulsifying drug deliver system (SMEDDS) is one of the technologies to improve poorly water soluble APIs or NCEs wettability, dissolution rate, bioavailability.
There are a number of characteristics of lipid-based delivery systems which make them an important tool to formulate drugs with dissolution-rate limited absorption. Advantages include solubilisation of hydrophobic drugs in the lipid matrix, absorption enhancement, and avoidance of the food effect. Components of these formulations include triglycerides, which can be long chain (14-18 carbons), or medium chain (6-12). The latter are less viscous and generally have higher solubilisation ability than long chain analogues. Mono-/diglycerides are more hydrophilic than corresponding triglycerides, and have higher solubilisation ability and dispersibility. Fatty acids (e.g. oleic acid), co-solvents, and surfactants may also be important components of lipid-based formulations. Surfactants can be categorised into either high hydrophilic-lipophilic balance (HLB), such as polysorbates, polyoxyl castor oils (Cremophor(?)), Gelucire(?) 44/14, Labrasol(?), poloxamers, and Vitamin E TPGS, or low HLB (e.g. SPAN(?), Labrafil(?), lecithins); both high and low HLB surfactants are useful in formulating lipid-based drug delivery systems. When added to water, those with higher levels of surfactants and co-solvents will disperse into smaller droplet size, which will aid absorption of drugs in the intestinal lumen due to the larger available droplet surface area. Nevertheless, even those lipid formulations with low surfactant and cosolvent content (and thus relatively large initial droplet size after dispersion) will often afford adequate absorption of poorly soluble drugs. This is due to the fact that in the gastrointestinal (GI) tract, triglycerides will be digested by lipases into mono- and di-glycerides, glycerol, and fatty acids, which will themselves act as surfactants and reduce the particle size. These will be further solubilised by bile salts and phospholipids to form mixed micelles of low particle size, favoring partitioning and diffusion of drug molecules to the surface of the enterocytes for absorption. The process of digestion is crucial for drug absorption for lipid formulations with low surfactant content, while those with high surfactant and co-solvent content will have less dependence on digestion products for their emulsification. A useful tool for understanding the phase structure and properties of lipid-based drug delivery systems is the phase diagram . The types of structures formed can be identified as a function of oil/surfactant/water ratios. This will aid in understanding changes encountered over the dilution path, and thus serve as a tool for choosing the formulation composition .
This paper presents the use of vehicle/excipient screening for judicious selection of type and concentration of each excipient in formulating a SMEDDS of a poorly soluble drug (Piroxicam). This paper will outline the general concepts of solubilisation and bioavailability enhancement with lipid-based formulations; compare liquid and solid dosage forms. Finally, chemical and physical stability considerations for lipid-based drug delivery systems will be discussed. The pros and cons of the various approaches for lipid-based formulations will be outlined in order to guide the formulator in choosing an appropriate dosage form based on drug profile and application requirements. The dissolution rate and particle size of Piroxicam SMEDDS was evaluated in vitro. The bioavailability of Piroxicam SMEDDS in rabbit showed 4.8 times Cmax and 466% bioavailability compared with suspention dosage form.
本课题以难溶性药物吡罗昔康为模型药物,吡罗昔康(Piroxicam)又名炎痛昔康,是辉瑞公司研发出来的解热镇痛类非甾体抗炎药,文献报道,吡罗昔康难溶于水、生物利用度低。本课题对吡罗昔康自微乳化给药体系(SMEDDS)进行了探索性研究,本研究建立了高效液相色谱法梯度洗脱测定吡罗昔康含量的方法:对15种常用自微乳化辅料进行了筛选,优选出以辛酸甘油酯为油相、月桂酸聚乙二醇甘油酯为乳化剂、二乙二醇单乙基醚为助表面活性剂的吡罗昔康自微乳化给药系统,并对其进行了体内外评价。体外溶出结果表明,5min内药物的溶出大于80%,平均粒径在33nm左右;在以吡罗昔康Tmax未发生明显改变,Cmax提高4.8倍。相对生物利用度为466%.
The enhancement of oral bioavailability of poorly water soluble active pharmaceutical ingredients (APIs) or new chemical entities (NCEs) remains one of the most challenging aspects of drug development. Although salt formation, solid dispersion, cyclodextrin inclusion, liposome, solubilisation and micronization have commonly been used to enhance the in vitro dissolution rate and thereby oral absorption and bioavailability, there are practical difficulties. The use of very fine powders may still be problematic to handle due to poor wettability. Lipid-based drug delivery systems have gained an important place in the formulation of poorly soluble drugs for oral administration. Lipid-based formulations are typically administered in liquid form, generally in soft-gel capsules. This can offer favorable dissolution, release, and bioavailability properties. Self emulsifying drug deliver system (SEDDS) and self micro-emulsifying drug deliver system (SMEDDS) is one of the technologies to improve poorly water soluble APIs or NCEs wettability, dissolution rate, bioavailability.
There are a number of characteristics of lipid-based delivery systems which make them an important tool to formulate drugs with dissolution-rate limited absorption. Advantages include solubilisation of hydrophobic drugs in the lipid matrix, absorption enhancement, and avoidance of the food effect. Components of these formulations include triglycerides, which can be long chain (14-18 carbons), or medium chain (6-12). The latter are less viscous and generally have higher solubilisation ability than long chain analogues. Mono-/diglycerides are more hydrophilic than corresponding triglycerides, and have higher solubilisation ability and dispersibility. Fatty acids (e.g. oleic acid), co-solvents, and surfactants may also be important components of lipid-based formulations. Surfactants can be categorised into either high hydrophilic-lipophilic balance (HLB), such as polysorbates, polyoxyl castor oils (Cremophor(?)), Gelucire(?) 44/14, Labrasol(?), poloxamers, and Vitamin E TPGS, or low HLB (e.g. SPAN(?), Labrafil(?), lecithins); both high and low HLB surfactants are useful in formulating lipid-based drug delivery systems. When added to water, those with higher levels of surfactants and co-solvents will disperse into smaller droplet size, which will aid absorption of drugs in the intestinal lumen due to the larger available droplet surface area. Nevertheless, even those lipid formulations with low surfactant and cosolvent content (and thus relatively large initial droplet size after dispersion) will often afford adequate absorption of poorly soluble drugs. This is due to the fact that in the gastrointestinal (GI) tract, triglycerides will be digested by lipases into mono- and di-glycerides, glycerol, and fatty acids, which will themselves act as surfactants and reduce the particle size. These will be further solubilised by bile salts and phospholipids to form mixed micelles of low particle size, favoring partitioning and diffusion of drug molecules to the surface of the enterocytes for absorption. The process of digestion is crucial for drug absorption for lipid formulations with low surfactant content, while those with high surfactant and co-solvent content will have less dependence on digestion products for their emulsification. A useful tool for understanding the phase structure and properties of lipid-based drug delivery systems is the phase diagram . The types of structures formed can be identified as a function of oil/surfactant/water ratios. This will aid in understanding changes encountered over the dilution path, and thus serve as a tool for choosing the formulation composition .
This paper presents the use of vehicle/excipient screening for judicious selection of type and concentration of each excipient in formulating a SMEDDS of a poorly soluble drug (Piroxicam). This paper will outline the general concepts of solubilisation and bioavailability enhancement with lipid-based formulations; compare liquid and solid dosage forms. Finally, chemical and physical stability considerations for lipid-based drug delivery systems will be discussed. The pros and cons of the various approaches for lipid-based formulations will be outlined in order to guide the formulator in choosing an appropriate dosage form based on drug profile and application requirements. The dissolution rate and particle size of Piroxicam SMEDDS was evaluated in vitro. The bioavailability of Piroxicam SMEDDS in rabbit showed 4.8 times Cmax and 466% bioavailability compared with suspention dosage form.
引文
1. T. Vilhemsen, H. Eliasen, T. Schaefer. Effect of a melt agglomeration process on agglomerates containing solid dispersions. Int J Pharm 2005; 303(1-2) 132-142.
2. K. Schamp, S.A. Schreder, J. Dressman. Development of an in vitro/in vivo correlation for lipid formulations of EMD 50733, a poorly soluble, lipophilic drug substance. Eur J Pharm Biopharm 2006; 62(3) 227-234.
3. S. Shimpi, B. Chauhan, K. Mahadik, A. Paradkar. Stabilization and Improved in Vivo Performance of Amorphous Etoricoxib using Gelucire~(?) 50/13. Pharm Res 2005; 22(10) 1727-1734
4. J.D. Schulze, E.E. Peters, A.W. Vickers et al. Excipient effects on gastrointestinal transit and drug absorption in beagle dogs. Int J Pharm 2005; 300(1-2) 67-75.
5. O. Chambin, V. Jannin, S. Clerc, Y. Pourcelot. Interest of carriers for the development of solid self-emulsifying drug delivery systems. 5th World Meeting on Pharmaceutics Biopharmaceutics and Pharmaceutical Technology 2006; Geneva (Switzerland) 1-2.
6. B. Chauhan, S. Shimpi, A. Paradkar. Preparation and evaluation of glibenclamide-polyglycolized glycerides solid dispersions with silicon dioxide by spray drying technique. Eur J Pharm Sci 2005; 26(2) 219-230.
7. M.D. Taylor, Improved passive oral drug delivery via prodrugs, Adv. Drug Delivery Rev. 19 (1996) 131-148.
8. B.J. Aungst, Novel Formulation strategies for improving oral bioavailability of drugs with poor membrane permeation or presystemic metabolism, J. Pharm. Sci. 82 (1993) 979-87.
9. M. Devani, M. Ashford, D.Q. Craig. The emulsification and solubilisation properties of polyglycolysed oils in self-emulsifying formulations. J Pharm Pharmacol 2004; 56(3) 307-316
10. M.J. Devani, M. Ashford, D.Q.M. Craig. The development and characterisation of triglyceride-based 'spontaneous' multiple emulsions. Int J Pharm 2005; 300(1-2) 76-8
11. K. Schamp, S.A. Schreder, J. Dressman. Development of an in vitro/in vivo correlation for lipid formulations of EMD 50733, a poorly soluble, lipophilic drug substance. Eur J Pharm Biopharm 2006; 62(3) 227-234.
12 . K. Iwanaga, T. Kishibiki, M. Miyazaki, M Kakemi. Disposition of Lipid-based Formulation in the Intestinal Tract Affects the Absorption of Poorly Water-soluble Drugs. Biol Pharm Bull 2006; 29(3) 508-512
13. L. Wei, P. Sun, S. Nie, W Pan. Preparation and evaluation of SEDDS and SMEDDS containing carvedilol. Drug Dev Ind Pharm 2005; 31(8) 775-784.
14. S. Cui, C. Zhao, D. Chen, Z. He. Self-microemulsifying drug delivery systems (SMEDDS) for improving in vitro dissolution and oral absorption of pueraria lobata isoflavone. Drug Dev Ind Pharm 2005; 31(4-5) 349-356
15. B. Chauhan, S. Shimpi, A. Paradkar. Preparation and Characterization of Etoricoxib Solid Dispersions Using Lipid Carriers by Spray Drying Technique. AAPS Pharm Sci Tech 2005; 6(3) E405-E412
16. Mueller EA ,Kovarik JM ,Van B , et al . Improved dose linearity of cyclosporin pharmacokinetics from a microemulsion formulation. Pharm Res, 1999 ,11 (3) :301
17. Kovarik JM ,Mueller EA ,Van B , et al . Reudced inter- and intra-individual variability in cyclosporin pharmacokinetics from a mi2 crioemulsion formulation. J Pharm Sci ,1994,83 (3) :444
18. K. Bogman, F. Erne-Brand, J. Alsenz and J. Drewe, The role of surfactants in the reversal of active transport mediated by multidrug resistance proteins, J. Pharm. Sci. 92 (2003) 1250 -1261.
19. B.D. Rege, J.P. Kao and J.E. Polli, Effects of nonionic surfactants on membrane transporters in Caco-2 cell monolayers, Eur.J. Pharm. Sci. 16 (2002) 237 - 246.
20. Constantinides ,PP. Lipid microemulsions for improving drug dissolution and oral absorption : physical and biopharaceutical aspects. Pharm Res ,1995 ,12 (11) :1561
21. Charman SA ,Charman WN ,Rogge MC , et al . Self-emulsifying drug delivery systems :formulation and biopharmaceutic evaluation of an investigational lipophilic compound. Pharm Res ,1992 ,9(1) :87
22. J.Y. Hong, J.K. Kim, Y.K. Song, J.S. Park, C.K. Kim. A new self-emulsifying formulation of itraconazole with improved dissolution and oral absorption. J Control Release 2006; 110(2) 332-338.
23.Y.W.Choy,N.Khan,K.H.Yuen.Significance of lipid matrix aging on in vitro release and in vivo bioavailability.Int J Pharm 2005;299(1-2) 55-64.
24 N.Venkatesan,J.Yoshimitsu,Y.Ito,N.Shibata,K.Takada.Liquid filled nanoparticles as a drug delivery tool for protein therapeutics.Biomaterials 2005;26(34) 7154-7163.
25.J.B.Brubach,M.Ollivon,V.Jannin et al.Structural and thermal characterization of mono- and diacyl polyoxyethylene glycol by infrared spectroscopy and X-ray diffraction coupled to differential calorimetry.J Phys Chem B 2004;108(46) 17721-17729.
26 O.Chambin,V.Jannin.Interest of multifonctional lipid cxcipients:Case of Gelucire(?)44/14.Drug Dev Ind Pharm 2005;31(6) 527-534.
27 C.K.Kim and J.S.Park,Solubility enhancers for oral drug delivery:Can chemical structure manipulation be avoided? Am.J.Drug Deliv.2(2)(2004) 113-130.
28 M.Grove,A.Mullertz,J.Logsted Nielsen and G.Pommergaard Pedersen,Bioavailability of seocalcitol Ⅱ:Development and charactedsation of self-microemulsifying drug delivery systems (SMEDDS) for oral administration containing medium and long chain triglycerides,J.Pharm.Sci(2006).
29 S.Prabhu,D.R.Brocks,B.G.Vetageri,Enhancement of dissolution of ethopropazine using solid disperisions prepared with phospholipid and/or polyethylene glycol,Drug Dev.Indus.Pharm.27(2001)413-418.
30 S.M.Khoo,C.J.Porter,W.N.Charman,Formulation of halofantrine as either nonsolubilizing PEG 6000 or solubilizing lipid based solid dispersions:physical stability and absolute bioavailability assessment,Int.J.Pharm.205(2000) 65-78.
31 中华人民共和国药典 2000版:二部 化学工业出版社:285-288
32 陈雪玲,奚念珠,戈顺娣,等.高效液相色谱法测定炎痛喜康血药浓度及人体药物动力学参数.药学学报,1986,21(9):692.
33 张英,刺桂荣.吡罗昔康片制备工艺的改进研究.西北药学杂志,2006,18(6):263-264.
34 孙体健,刁海鹏,王如林,等.吡罗昔康与环糊精包合作用的研究.中国药物与临床 2007,7(1):13-14
35 胡鹏翼,翼以木,固体分散技术和包合技术对吡罗昔康溶出度的影响,医药导报,2007,26(5):530-531
36 James EF,Reynolds,Katnleen P,and Anne VP et al Martindale,31ed Royal Pharmaceutical Society 1996:92-93
35 李英剑.吡罗昔康经皮贴剂的研究:[硕士学位论文].辽宁沈阳:沈阳药科大学,2002
2. K. Schamp, S.A. Schreder, J. Dressman. Development of an in vitro/in vivo correlation for lipid formulations of EMD 50733, a poorly soluble, lipophilic drug substance. Eur J Pharm Biopharm 2006; 62(3) 227-234.
3. S. Shimpi, B. Chauhan, K. Mahadik, A. Paradkar. Stabilization and Improved in Vivo Performance of Amorphous Etoricoxib using Gelucire~(?) 50/13. Pharm Res 2005; 22(10) 1727-1734
4. J.D. Schulze, E.E. Peters, A.W. Vickers et al. Excipient effects on gastrointestinal transit and drug absorption in beagle dogs. Int J Pharm 2005; 300(1-2) 67-75.
5. O. Chambin, V. Jannin, S. Clerc, Y. Pourcelot. Interest of carriers for the development of solid self-emulsifying drug delivery systems. 5th World Meeting on Pharmaceutics Biopharmaceutics and Pharmaceutical Technology 2006; Geneva (Switzerland) 1-2.
6. B. Chauhan, S. Shimpi, A. Paradkar. Preparation and evaluation of glibenclamide-polyglycolized glycerides solid dispersions with silicon dioxide by spray drying technique. Eur J Pharm Sci 2005; 26(2) 219-230.
7. M.D. Taylor, Improved passive oral drug delivery via prodrugs, Adv. Drug Delivery Rev. 19 (1996) 131-148.
8. B.J. Aungst, Novel Formulation strategies for improving oral bioavailability of drugs with poor membrane permeation or presystemic metabolism, J. Pharm. Sci. 82 (1993) 979-87.
9. M. Devani, M. Ashford, D.Q. Craig. The emulsification and solubilisation properties of polyglycolysed oils in self-emulsifying formulations. J Pharm Pharmacol 2004; 56(3) 307-316
10. M.J. Devani, M. Ashford, D.Q.M. Craig. The development and characterisation of triglyceride-based 'spontaneous' multiple emulsions. Int J Pharm 2005; 300(1-2) 76-8
11. K. Schamp, S.A. Schreder, J. Dressman. Development of an in vitro/in vivo correlation for lipid formulations of EMD 50733, a poorly soluble, lipophilic drug substance. Eur J Pharm Biopharm 2006; 62(3) 227-234.
12 . K. Iwanaga, T. Kishibiki, M. Miyazaki, M Kakemi. Disposition of Lipid-based Formulation in the Intestinal Tract Affects the Absorption of Poorly Water-soluble Drugs. Biol Pharm Bull 2006; 29(3) 508-512
13. L. Wei, P. Sun, S. Nie, W Pan. Preparation and evaluation of SEDDS and SMEDDS containing carvedilol. Drug Dev Ind Pharm 2005; 31(8) 775-784.
14. S. Cui, C. Zhao, D. Chen, Z. He. Self-microemulsifying drug delivery systems (SMEDDS) for improving in vitro dissolution and oral absorption of pueraria lobata isoflavone. Drug Dev Ind Pharm 2005; 31(4-5) 349-356
15. B. Chauhan, S. Shimpi, A. Paradkar. Preparation and Characterization of Etoricoxib Solid Dispersions Using Lipid Carriers by Spray Drying Technique. AAPS Pharm Sci Tech 2005; 6(3) E405-E412
16. Mueller EA ,Kovarik JM ,Van B , et al . Improved dose linearity of cyclosporin pharmacokinetics from a microemulsion formulation. Pharm Res, 1999 ,11 (3) :301
17. Kovarik JM ,Mueller EA ,Van B , et al . Reudced inter- and intra-individual variability in cyclosporin pharmacokinetics from a mi2 crioemulsion formulation. J Pharm Sci ,1994,83 (3) :444
18. K. Bogman, F. Erne-Brand, J. Alsenz and J. Drewe, The role of surfactants in the reversal of active transport mediated by multidrug resistance proteins, J. Pharm. Sci. 92 (2003) 1250 -1261.
19. B.D. Rege, J.P. Kao and J.E. Polli, Effects of nonionic surfactants on membrane transporters in Caco-2 cell monolayers, Eur.J. Pharm. Sci. 16 (2002) 237 - 246.
20. Constantinides ,PP. Lipid microemulsions for improving drug dissolution and oral absorption : physical and biopharaceutical aspects. Pharm Res ,1995 ,12 (11) :1561
21. Charman SA ,Charman WN ,Rogge MC , et al . Self-emulsifying drug delivery systems :formulation and biopharmaceutic evaluation of an investigational lipophilic compound. Pharm Res ,1992 ,9(1) :87
22. J.Y. Hong, J.K. Kim, Y.K. Song, J.S. Park, C.K. Kim. A new self-emulsifying formulation of itraconazole with improved dissolution and oral absorption. J Control Release 2006; 110(2) 332-338.
23.Y.W.Choy,N.Khan,K.H.Yuen.Significance of lipid matrix aging on in vitro release and in vivo bioavailability.Int J Pharm 2005;299(1-2) 55-64.
24 N.Venkatesan,J.Yoshimitsu,Y.Ito,N.Shibata,K.Takada.Liquid filled nanoparticles as a drug delivery tool for protein therapeutics.Biomaterials 2005;26(34) 7154-7163.
25.J.B.Brubach,M.Ollivon,V.Jannin et al.Structural and thermal characterization of mono- and diacyl polyoxyethylene glycol by infrared spectroscopy and X-ray diffraction coupled to differential calorimetry.J Phys Chem B 2004;108(46) 17721-17729.
26 O.Chambin,V.Jannin.Interest of multifonctional lipid cxcipients:Case of Gelucire(?)44/14.Drug Dev Ind Pharm 2005;31(6) 527-534.
27 C.K.Kim and J.S.Park,Solubility enhancers for oral drug delivery:Can chemical structure manipulation be avoided? Am.J.Drug Deliv.2(2)(2004) 113-130.
28 M.Grove,A.Mullertz,J.Logsted Nielsen and G.Pommergaard Pedersen,Bioavailability of seocalcitol Ⅱ:Development and charactedsation of self-microemulsifying drug delivery systems (SMEDDS) for oral administration containing medium and long chain triglycerides,J.Pharm.Sci(2006).
29 S.Prabhu,D.R.Brocks,B.G.Vetageri,Enhancement of dissolution of ethopropazine using solid disperisions prepared with phospholipid and/or polyethylene glycol,Drug Dev.Indus.Pharm.27(2001)413-418.
30 S.M.Khoo,C.J.Porter,W.N.Charman,Formulation of halofantrine as either nonsolubilizing PEG 6000 or solubilizing lipid based solid dispersions:physical stability and absolute bioavailability assessment,Int.J.Pharm.205(2000) 65-78.
31 中华人民共和国药典 2000版:二部 化学工业出版社:285-288
32 陈雪玲,奚念珠,戈顺娣,等.高效液相色谱法测定炎痛喜康血药浓度及人体药物动力学参数.药学学报,1986,21(9):692.
33 张英,刺桂荣.吡罗昔康片制备工艺的改进研究.西北药学杂志,2006,18(6):263-264.
34 孙体健,刁海鹏,王如林,等.吡罗昔康与环糊精包合作用的研究.中国药物与临床 2007,7(1):13-14
35 胡鹏翼,翼以木,固体分散技术和包合技术对吡罗昔康溶出度的影响,医药导报,2007,26(5):530-531
36 James EF,Reynolds,Katnleen P,and Anne VP et al Martindale,31ed Royal Pharmaceutical Society 1996:92-93
35 李英剑.吡罗昔康经皮贴剂的研究:[硕士学位论文].辽宁沈阳:沈阳药科大学,2002