Development of biopharmacy

Transcription

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2 Development of biopharmacy Expression biopharmaceutics was composed By Gerhard Levy and it was written down by John G. Wagner in a publication from 1961 for the first time. Gerhard Levy Knowledge accumulated from the field of biopharmacy reached a level which was able to be functionable as a separate discipline. Wagner later declared the birth of the biopharmacy as: a body of knowledge which needed a name Wagner, J.G.: Biopharmaceutics: Absorption aspects, J. Pharm. Sci., 50, p /10/2017 2

3 What is biopharmacy? Biopharmacy is a pharmaceutical discipline which could be used by the modern drug discovery, quality control and pharmaceutical attendance. Biopharmacy investigates the connection between the medicine and the livingorganism. 31/10/2017 3

4 Development of biopharmacy Investigates the characteristics and behaviour of the API and the medicine in the human body. Biopharmaceutics: -models theprocesses accompanying the interactions of themedicine and the human body -reveals the main physical, chemical and pharmacological characteristics of the medicines - examines the pharmacodynamic and/or toxicologic reactions of the human body and the development of the effect 31/10/2017 4

5 LADME system liberation absorption invasion distribution disposition metabolism excretion elimination 31/10/2017 5

6 Liberation Liberation means the relase of the API from the dosage form. 31/10/2017 6

7 Arthur Amos Noyes Willis Rodney Whitney 31/10/2017 7

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9 Intestinosolvent coated granules Capsule containing a tablet with three layers Coated tabletwith immediate effect. Inner matrix releases the API slowly Osmotic tablet with zero order kinetics Matrix tablet with controlled release Tablet composed by compressed micropellets 31/10/2017 9

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11 Dissolution testers (1,2,3,4) 11

12 Dissolution run 12

13 Place of sampling It should be in the middle of the medium level and upper level of the paddle/basket. It should be at least 10 mm from the container. Sampled and analysed medium should be injected back, or substituted with clean medium, or taken intoaccount the eliminatedamount. 13

14 Transdermal drug dissolution 14

15 Evaluation of drug release 1.) model-independent 2.) model-dependent evaluation

16 Evaluation of dissolution tests Pairwise comparison of dissolution data by appropriate staticstical methods

17 Model-independent methods fit factors (f 1, f 2 ) Method compares the reference dissolution data to the test preparation. f 1 difference factor f 2 similarity factor f n ( R i i i= 1 1 = n i= 1 T R i ) 100 f 2 = 50 lg n n 0,5 ( R i T i ) * 100 i= 1 n R i T i no. of samples, dissolution % at i time of the reference preparation, dissolution % at i time of the test preparation

18 Evaluation of drug release tests 1. ) With theoretically valid background 2. ) Without theoretical background, based on experiences

19 Model-dependent methods Zero order dissolution kinetics m = kt m c = V m m = kt m API amount at t time t time c API % at t time k rate constant t

20 Model-dependent methods First order kinetics ln m dm = km dt m = m e o kt (lnm lnm o ) = kt t

21 Model-dependent methods General model: Weibull model m / m / m m = = 1 exp{ [( t t 1 e t t [ τ o ] β o ) / τ β ]} m dissolved API % at t time m dissolved API % at t= time t time t 0 lag time τ time of 63,2% API dissolution β shape factor

22 Absorption The API enters the systemic circulation There is no absorption at iv. medicines There are several factors affecting the absorption at per os administration 31/10/

23 Transcellular transports summary Characteristics Passive diffusion Facilitated diffusion Active transport needs carrier molecule no yes yes selective no yes yes can be saturated no yes yes can be inhibited no yes yes against concentration gradient no no yes needs energy (ATP) no no yes 23

24 Passisve diffusion The most frequent type of transport of APIs. Apolar, non-ionised APIs can cross the membrane according to the concentration gradient. This type of transport lasts until the equilibrium in concentration, it does not need energy. 24

25 Ionisation Degree of ionisation of molecules is calculated by the Henderson-Hasselbalch equation. Using this formula the ratio of ionised and non-ionised amount of molecules can be determined which highly depends on the ph of environment. In case of weak bases: ph pk a = lg C C non ionised ionised In case of weak acids: ph pk a = C lg C ionised non ionised 25

26 Ionisation Degree of ionisation 100% 50% bases acids pk a =3,5 pk a =7,0 pk a =10,5 3,5 7,0 10,5 14 ph

27 GI tract ph values 27

28 Distribution API(s) enter the tissues fromthe systemic circulation APIs are usually distributed unequally between different tissues, they can accumulate in different organs ie. Penicillin cannot enter through the blood-brain barrier Compartment models 31/10/

29 Metabolism Biotransformation of the API Medicines are xenobiotics (foreign material) for the human body Decreases or terminates the effect of the drug On the contrary it can accelerate the effect 31/10/

30 Excretion Terminal disposal of the API or its decayed forms Kidney Bile Lungs Any humour 31/10/

31 Biopharmacy based Pharm. Technology Aim is to produce a preparation which is able to release the API at the proper - - site of action, - - amount (concentration), - release rate In order to suit these rerquirements, it is important to get acquanted with the biopharmaceutical characteristics of the medicine. Biopharmaceutical basics 31/10/

32 2017. október

33 Gordon L. Amidon, Amidon et al. published the importance of Biopharmaceutical Clasification System (BCS) in 1995, which is an important characteristic of the preparation s bioavailability. According totheir suggestion APIs can be categorized into four groups regarding the gastrointestinal absorption by their solubility and permeability characters.

34 APIs can be categorized into four groups accordingto their solubility and permeability: Class I Class II Human intestinal absorption Permeability High solubility High permeability Class III High solubility Low permeability Low solubilitiy High permeability Class IV Low solubility Low permeability Solubility Volume of water required to dissolve the highest dose streght across the physilogical ph range (1.2 ; 4.5; 6.8 )

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36 Literature shows that there is an increasing number of poorly soluble compounds in the drug discovery pipeline including 70 per cent BCS Class II compounds although only about 30 per cent are BCS Class II in the existing top 200 market New chemical entities Top 200 marketed drugs in USA IV. 20% I. 1,5% IV. 6% Unclassified 10% I. 31% III. 5% III. 23% II. 70% II. 30%

37 Sources of pharmaceutical technology to increase the bioavailability of drug delivery systems accourding to the BCS Permeability Class I Class III lipophilic capsules, GI motility enhancers mucoadhesion, absorption-enhancer efflux inhibitors Solubility Cass II micronisation, nanoparticles, solubilisation, solid dispersion, salt forming, self emulsifying systems, complexes, buffers, surfactants, liquid-filled capsules Class IV solubilisation, submicroscopic particles, nanoparticles, co-solvents, salt forming, solid dispersion, amorphous form, self emulsifying systems, complexes, buffers, liquid-filled capsules with absorptionenhancer

38 Thank you for your attention! 31/10/