STANDARISASI OBAT HERBAL. Mae Sri Hartati Wahyuningsih Dept. Of Pharmacology and Therapy Faculty of Medicine UGM

Transcription

1 STANDARISASI OBAT HERBAL Mae Sri Hartati Wahyuningsih Dept. Of Pharmacology and Therapy Faculty of Medicine UGM

2 TUJUAN PEMBELAJARAN 1. Mengetahui definisi standarisasi herbal medicine. 2. Mengetahui jenis, parameter dan cara standarisasi herbal medicine 3. Mengetahui manfaat standarisasi herbal medicine

3 STANDARISASI Serangkaian parameter, prosedur dan cara pengukuran yang hasilnya merupakan unsur-unsur terkait paradikma mutu kefarmasian Memenuhi syarat standar Jaminan stabilitas produk Proses yang menjamin bahwa produk akhir (obat, ekstrak, produk ekstrak) mempunyai nilai parameter tertentu yang konstan (ajeg) dan ditetapkan (dirancang dalam formula) terlebih dahulu.

4 TUJUAN STANDARISASI 1. Memberikan perlindungan kepada Masyarakat melalui Safety, Quality dan Efficacy (SQE) 2. Menjamin konsistensi bahan penelitian. 3. Menjamin konsistensi produk dalam hal SQE

5 Herbal medicine Development Process Phytomedicine integrated in health care system Clinical study 1. Phase I 2. Phase II 3. Phase III Formulation development Simple standardization 1. Identity 2. Purity 3. Content or assay Present (traditional medicine) Preclinical study Toxicological study Pharmacodynamics study Information of safety and effects on animal

6 APA YANG DISTANDARISASI 1. Proses dan metodologi 2. Produk termasuk bahan baku 3. Label termasuk klaim

7 Quality Control and Standardization of A Manufactured Herbal Product QUALITY CONTROL HERBAL MEDICINE RAW MATERIALS PROCESS PROCESSING METHOD FINISHED PRODUCT SPECIFICATIONS AND STANDARDIZATION QUALIFICATIONS Building (CPOTB), Machine Tools, environment (energy, Water, air) personnel TECHNOLOGY AND FORMULATION, CONTROL FEED BACK PARAMETERS (Temperature, Pressure, Homogeneity, Stability) SPECIFICATIONS AND CERTIFICATION VALIDASI

8 In general, quality control is based on three important pharmacopoeial definitions: 1. Identity : is the herb the one it should be? 2. Purity : are there contaminants, e.g., in the form of other herbs which should not be there? 3. Content or assay: is the content of active constituents within the defined limits?

9 Several problems not applicable to synthetic drugs influence the quality of herbal medicine: 1. Herbal medicines are usually mixtures of many constituents. 2. The active principle(s) is (are), in most cases unknown. 3. Selective analytical methods or reference compounds may not be available commercially. 4. Plant materials are chemically and naturally variable. 5. The source and quality of the raw material are variable. 6. The methods of harvesting, drying, storage, transportation, and processing (for example, mode of extraction and polarity of the extracting solvent, instability of constituents, etc.) have an effect.

10 Quality Control & Standardization of A Plant Material Control Quality & Standardization of A Plant Material

11 PHYSICO - CHEMICAL Ash Values ph Optical Rotation Specific Gravity Hardness Disintegration Time Elemental Composition QC & Standardization of A Plant Matrial PHYTOCHEMICAL Extractive Values Chemical Profiling TLC Fingerprinting Markers - Bio-active - Biologically - Chemical HPTLC/HPLC Based Quantifications

12 Parameters for Standardization of Herbal Medicine (Non Spesifik) 1. Macroscopic evaluation 2. Microscopic evaluation 3. Determination of foreign matter 4. Determination of Ash 5. Determination of heavy metals 6. Determination of microbial contaminants & aflatoxins 7. Determination of pesticide residues 8. Determination of radiative contaminations 9. Analytical methods

13 1. Macroscopic examination Organoleptic evaluation of refers to the evaluation of a herbal by colour, odour, size, shape, taste and special features including touch, texture etc.

14 Macroscopic of Curcuma domestica L (kunyit) Pieces: Mild, crumbly, brownish orange yellow color; almost circular shape to elliptical, sometimes branched; width of 0.5 cm to 3 cm long, 2 cm to 6 cm, thickness 1mm to 5mm; generally curved irregular, sometimes there is a base (upih leaves and roots). Limit cortex and central cylinder is sometimes unclear. File fault: rather flat, dusty, yellow orange to reddish-brown

15 1. C. longa 2. C. xanthorrhiza

16 2. Microscopic examination Today microscopic evaluation is indispensable in the initial identification of herbs, as well as in identifying small fragments of crude or powdered herbs, and detection of foreign matter and adulterants. At other times, microscopic analysis is needed to determine the correct species and/or that the correct part of the species is present.

17 Microscopic Curcuma domestica (Turmeric) The epidermis: a single layer of cells, flat polygonal shape, cell wall into the cork. Hair coverings: conical, straight or slightly curved; length of 250 µm to 890 µm, thick walls. Hypodermis: consists of several layers of cells stretched tangentially, menggabus cell wall. Periderm: consists of 6 layers up to 9 layers of cell shaped rectangular, cell wall into the cork. Cortex and central silibder: parenchimatic, composed of large cells, filled with starch. Starch grains: single, oval or ovoid shape with one end having a round bulge or until almost triangle with one side rounded; lamella is less clear; less clear hilum contained in the bulge at the end point; length of 10 µm and 60 µm, generally 20 µm to 40 µm, 10 µm wide and 28 µm, generally 14 µm to 20 µm. Cell secretion:... ect.

18 Microscopic of Berberis aristata DC. T.S. of the root (x 100) T.S. cellular structure of stem (x 100) TLS of the root (x100) Powder study (x400)

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20 3. Determination of Foreign Matter Herbal medicine should be made from the stated part of the plant and be devoid of other parts of the same plant or other plants. They should be entirely free from harmful foreign matters such as fungus, insects, sand, stones, poisonus, chemical residues, microbial contaminants, ect. For chemical residues: TLC, HPTLC, HPLC is often used to detect the contaminants.

21 4. Determination of Ash To determine ash content the plant material is burnt and the residual ash is measured as total and acid-insoluble ash. Total ash is the measure of the total amount of material left after burning and includes ash derived from the part of the plant itself and acid-insoluble ash.

22 5. Determination of Heavy Metals Contamination by heavy metals such as mercury, lead, copper, cadmium, and arsenic in herbal drugs can be attributed to environmental pollution, and clinically relevant dangers for the health and should therefore be limited. The main methods commonly used are atomic absorption spectrophotometry (AAS), inductively coupled plasma (ICP) and neutron activation analysis (NAA).

23 6. Determination of microbial contaminants & aflatoxins Medicinal plants may be associated with a broad variety of microbial contaminants, represented by bacteria, fungi, and viruses. Herbal medicine normally carry a number of bacteria and molds, often originating in the soil. Poor methods of harvesting, cleaning, drying, handling, and storage may also cause additional contamination. While a large range of bacteria and fungi are from naturally occurring microflora, aerobic spore-forming bacteria frequently predominate.

24 The European Pharmacopoeia also specifies that E. coli and Salmonella spp. should be absent from herbal preparations. However it is not always these two pathogenic bacteria that cause clinical problems. For example, a fatal case of listeriosis was caused by contamination of alfalfa tablets with the Gram positive bacillus Listeria monocytogenes. Aflatoxin-producing fungi sometimes build up during storage. Procedures for the determination of aflatoxin contamination in herbal drugs are published by the WHO. After a thorough clean-up procedure, TLC is used for confirmation.

25 7. Determination of pesticide residues Herbal medicine are liable to contain pesticide residues, which accumulate from agricultural practices, such as spraying, treatment of soils during cultivation, and administering of fumigants during storage.. Many pesticides contain chlorine in the molecule, which, for example, can be measured by analysis of total organic chlorine. In an analogous way, insecticides containing phosphate can be detected by measuring total organic phosphorus.

26 8. Determination of radioactive contaminations There are many sources of ionization radiation, including radionuclides, occurring in the environment. Hence a certain degree of exposure is inevitable. Dangerous contamination, however, may be the consequence of a nuclear accident. The WHO, in close cooperation with several other international organizations, has developed guidelines in the event of a widespread contamination by radionuclides resulting from major nuclear accidents.

27 9. Analytical methods The quantitative determination of constituents has been made easy by recent developments in analytical instrumentation. Recent advances in the isolation, purification, and structure elucidation of naturally occurring metabolites have made it possible to establish appropriate strategies for the determination and analysis of quality and the process of standardization of herbal preparations. Classification of plants and organisms by their chemical constituents is referred to as chemotaxonomy.

28 TLC, HPLC, GC, quantitative TLC (QTLC), and highperformance TLC (HPTLC) can determine the homogeneity of a plant extract. Over-pressured layer chromatography (OPLC), infrared and UV-VIS spectrometry, MS, GC, liquid chromatography (LC) used alone, or in combinations such as GC/MS, LC/MS, and MS/MS, and nuclear magnetic resonance (NMR), are powerful tools, often used for standardization and to control the quality of both the raw material and the finished product.

29 STANDARISASI EKSTRAK 1. Parameter Non Spesifik a. Susut pengeringan Tujuan: Rentang besarnya senyawa yang hilang pada proses pengeringan b. Kadar air Rentang besarnya kandungan air didalam bahan

30 c. Kadar abu Gambaran kandungan mineral yang berasal dari proses awal sampai terbentuk ekstrak. d. Sisa pelarut Jaminan selama proses tidak meninggalkan sisa pelarut e. Residu pestisida Jaminan bahwa ekstrak tidak mengandung pestisida melebihi nilai yang ditetapkan

31 f. Cemaran logam berat Jaminan bahwa ekstrak tidak mengandung logam berat tertentu melebihi nilai yang ditetapkan g. Cemaran mikroba Jaminan bahwa ekstrak tidak mengandung mikroba patogen dan tidak mengandung mikroba non patogen melebihi batas yang ditetapkan

32 2. Parameter Spesifik a. Identitas ekstrak Memberi identitas obyektif dari nama dan spesifik dari senyawa identitas b. Organoleptik Pengenalan awal yang sederhana seobjektif mungkin c. Senyawa terlarut dalam pelarut tertentu Memberikan gambaran awal jumlah senyawa kandungan.

33 New standardization of herbal medicine True standardization, a definite phytochemical or group of constituents is known to have activity. Ginkgo with its 26% ginkgo flavones and 6% terpenes is a classic example. These products are highly concentrated and no longer represent the whole herb, and are now considered as phytopharmaceuticals. In many cases they are vastly more effective than the whole herb. Not true standardization is based on manufacturers guaranteeing the presence of a certain percentage of marker compounds; these are not indicators of therapeutic activity or quality of the herb.

34 Misal: AKAR KUNING (Fibraurea chloroleuca Lour.) Secara tradisional Mengobati berak darah, sakit mata dan penurun panas badan Sistematika tumbuhan Divisi Kelas Bangsa Suku Marga Jenis : Spermatophyta : Dicotyledonae : Ranunculales : Menispermaceae : Fibraurea : Fibraurea chloroleuca Miers. Sinonim : Fibraurea tinctoria Lour. Nama Indonesia: Akar kuning

35 Organoleptik Warna : kuning Bau : tidak berbau aromatik Rasa : pahit

36 SENYAWA IDENTITAS 4 5 O O N 8 O Struktur kimia OCH OCH 3 8-oksoprotoberberina Bagian batang yang digunakan

37 CARA PERHITUNGAN RF A RF = B = 2,3 = 0,32 A 7,2 B

38 - Pola kromatogram - Kadar total golongan senyawa - Kadar kandungan kimia tertentu 3. Uji Kandungan Kimia Ekstrak Fase diam : Silika gel GF254 Fase gerak {N-Heksan:Etil asetat (1:1 v/v)} Deteksi : a. Sinar UV254 nm b. Sinar UV366 nm c1. Serium(iv) sulfat c2. Dragendorff Pembanding: 8-oksoprotoberberina

39 References book Chinese Pharmacopoeia: 1997 edition has 647 traditional drugs. European Pharmacopoeia: 2000 edition contains monographs on 152 crude drugs. Indian Pharmacopoeia: 1996 edition number shrinked to 57 including only 12 crude drugs. Materia Medica Indonesia : 224 monographs Indonesian Herbal Pharmacopoeia : 98 monographs of herbs and extracts.

40 THANK YOU