The role of dissolution testing in complementary and African traditional medicines: development of methods and applications. Isadore (Izzy) Kanfer

Transcription

1 The role of dissolution testing in complementary and African traditional medicines: development of methods and applications Isadore (Izzy) Kanfer RHODES UNIVERSITY Where leaders learn DISSOLUTION WORKSHOP CHALLENGES IN DISSOLUTION TESTING: EQUIVALENCE AND SURROGATES 9-10 DECEMBER 2009 Barratt Lecture Complex, Rhodes University, Grahamstown South Africa, Dissolution Testing A QC Tool or Bioequivalence Predictor? 1

2 Dissolution This test is used to measure the release of an active substance (usually single ingredient) from the product in solid oral, tablet or capsule dosage forms. It is one of the most important and useful in vitro tests for assuring product quality In vitro dissolution often aids in guiding the selection of prototype formulations It helps to determine optimum amounts of ingredients needed to achieve requisite drug release profiles It is one of the most important and useful in vitro tests for assuring product quality batch-batch consistency Provides information on the impact of changes in composition, process or site of manufacture Can help identify potential problems of In vivo release and bioavailability/absorption following administration 2

3 In vitro dissolution is a valuable tool to assess drug product stability and shelf-life As products age, the formulation s properties may change and alter the dissolution characteristics of the product over time For example: 1) moisture levels may increase or decrease over time and this can result in altered tablet hardness and subsequent possible changes in drug release rates 2) Polymorphic transformations affect solubility and dissolution Disintegration Deaggregation Dissolution Drug in Blood 3

4 Factors Affecting Dissolution Rate Over the past 30 years or so, dissolution testing is probably the most important in vitro test that can be used to assess and control variables associated with formulation excipients, design and manufacturing which may alter the release characteristics of the active moiety from the dosage form. In vitro In vivo L Shargel and ABC Yu, Applied Biopharmaceutics & Pharmacokinetics, 4th Edition,

5 Banker et al, Lieberman and Lachman (eds)pharmaceutical Dosage Forms: Tablets Volume1, 1980 Banker et al, Lieberman and Lachman (eds)pharmaceutical Dosage Forms: Tablets Volume1,

6 Guidelines For Dissolution Testing of Oral Dosage Forms (Orthodox Medicines) Developed USA FDA (Guidance for industry: Dissolution testing of immediate release solid oral dosage forms. U.S. Dept of Health and Human Services, Food & Drug Administration, Center for Drug Evaluation and research (CDER), Rockville, USA, 1977) FDA recommends use of buffers in the range for dissolution media and initial iti method development Unlike orthodox medicines, specific guidelines for dissolution testing of complementary/alternate (CAMs) and traditional medicines (TMs) have not been developed Also, there are no dissolution testing requirements for the quality control of such products. 6

7 Application of dissolution testing as a quality control tool in complementary & alternative medicines (CAMs) and traditional medicines (TMs) CAMs/TMs, unlike conventional pharmaceutical products, which usually consist of one or two well- characterized active ingredients, are complex, consisting of multiple components that may be active individually or in combination What should be measured? i.e. in contrast to chemically defined components, the actives in CAMs/TMs are generally defined to be the whole herbal preparation, e.g. the extract in its entirety Chemical composition and classification of active pharmaceutical ingredients (API s) in CAMs/TMs Suggested that since the whole herbal product, e.g. extract, is regarded as the API, several extract types, depending on the pharmaceuticalanalytical, pharmacological-toxicological and clinical findings, can be identified: A B1 B2 extracts containing constituents (single or groups) that are solely responsible for the activity (standardized extracts) extracts containing chemically defined constituents (single or groups) known to contribute to pharmacological or synergistic activity (quantified extracts) extracts containing no constituents documented as being determinant or relevant for efficacy, or having pharmacological or clinical relevance. 7

8 C unknown active ingredients for which no individual active ingredients have been identified but have a traditional place in therapy of certain diseases. Use of chemical markers which may not contribute to any activity, e.g. Valerian CASE STUDY St John s Wort Products Components in St John s Wort known, or suspected, to play a role in its antidepressant activity include phloroglucinols, naphthodianthrones and flavonoids, hence B1 category Hyperforin is purported to contribute to the antidepressive activity 8

9 Roles of other components in St John s Wort? e.g.naphthodianthrones (medium polarity)? Flavonoids (hydrophilic)? CONTENT UNIFORMITY and COMPLIANCE WITH THE LABEL CLAIM are standard quality criteria that need to be tested! What about dissolution testing? 5 St John s Wort products were selected by Westerhoff et al. (2002), J.Pharm Pharmacol., 54: Dissolution of hyperforin, naphthodianthrones (hypericin & pseudohypericin) and flavonoids (isoquercitrin, quercitrin, rutin and hyperoside) were characterized to cover the entire spectrum of polarities present in the products. FaSSIF=Fasted state simulated intestinal fluid; ph 6.5 FeSSIF=Fed state simulated intestinal fluid; ph 5.0 SGF=Simulated gastric fluid; ph 1.5 Westerhoff et al; (2002), J Pharm Pharmacol; 54;

10 Westerhoff et al; (2002), J Pharm Pharmacol; 54; Biflavonoid Purported to be pharmacologically active. 10

11 Coated tablet (St.John s Wort) Tap water? N.B. Phenolic glycosides better dissolved than flavone aglycones Jürgenliemk and Nahrstedt 11

12 Pharmacological synergism and/or Physicochemical synergism? Flavonoids (other included components) increase dissolution of hypericin? What about synergistic effects on bioavailability? Pharmaceutical quality of different Ginkgo biloba brands Kressmann et al; J Pharm Pharmacol; 54: (2002) 12

13 Consider African Potato (AP): a commonly used African Traditional Medicine (ATM) Apart from its perceived nutritional value used for: Immuno-boosting properties urinary diseases prostrate hypertrophy cancer? In South Africa African Potato gained prominence as an alternative medicine for nutritional use in the daily diet of HIV/AIDS patients recommended by the previous South African Minister of Health 13

14 AP contains as it s most important component, a norlignan di-glucoside, namely hypoxoside It is also purported to contain a sterol, β-sitosterol (BSS) Currently, assay methods for quality control of AP products include: Hypoxoside (HPLC UV 1 and dcze 2 ) 1 Nair & Kanfer, J Agric Food Chem, 54: , Nair & Kanfer, Phytochem Anal, 18: , 2007 Stigmasterol, β-sitosterol and stigmastanol (HPLC with evaporative light-scattering detection 3 ) 3 Nair, Kanfer & Hoogmartens, J Pharm Biomed Anal, 41: ,

15 Approaches used for the development of a suitable dissolution method for products containing AP: Phytochemical composition? - Hypoxoside - Sterols & sterolins but which? First step = Assay! Assay results: β-sitosterol major component Hypoxoside Used as markers for Quality Control 15

16 List of AP Products: Initial dissolution tests: Products A,B,D,E,F & G - all capsules USP-1 (Basket) Product C - the only tablet t dosage form - USP-2 (Paddle) Dissolution Conditions: Volume 900 ml Rotation speed 100 rpm Temperature 37 ± 0.5 ºC Dissolution media as per USA FDA Guidance buffered dissolution media (ph ) 16

17 Hypoxoside relatively unstable at higher phs, hence used acidic dissolution media only, i.e. ph 1.2 and 4.5 Product B used since it contained highest content of hypoxoside β-sitosterol relatively insoluble in aqueous media Dissolution performed at phs 1.2, 4.5, 6.8 and 7.8 NO β-sitosterol detected even after 12 hours - i.e confirmation of aqueous insolubility Choice of alternate dissolution media necessary FaSSIF (fasted state simulation - generally ph 6.5) FeSSIF (fed state simulation - generally ph 5.0) 17

18 Dissolution of product D for BSS in FaSSIF & FeSSIF at various phs Dissolution comparison of Products A, B and C at ph

19 Dissolution profiles of Products D, E, F & G showing profiles of BSS at ph 5.0 in FeSSIF Issues with African Traditional Medicines (ATMs) Sceletium Species - example 19

20 Reference substances: Example Sceletium Alkaloids OCH 3 OCH 3 OCH 3 OCH 3 5' 4' 3' OCH3 OCH3 OCH3 OCH3 3 6' 1' 3a 2' 4 5 HCl 2 N 6 7a 7 O N O N O N O CH 3 CH 3 CH 3 Mesembrine (Major alkaloid) 7 Mesembrenone Mesembrenone CH 3 Mesembrine hydrochloride crystals OCH 3 OCH 3 OCH3 OCH3 OCH 3 OCH3 N CH 3 H OH N CH 3 H OH N CH3 H OH Mesembranol crystals Epimesembranol Mesembrenol Dissolution profile of Sceletium capsules in Buffer ph Mean P rofiles AP 0001/09 Test Product Sceletium C apsule NNNNN % Released Time (Hours) 20

21 Summary Complexity of CAMS/TMs Role of dissolution as a quality control tool for CAMS/TMs What to monitor? Bio-relevance of dissolution testing? 21