Biopharmaceutics Dosage form factors influencing bioavailability Lec:5

Transcription

1 Biopharmaceutics Dosage form factors influencing bioavailability Lec:5 Ali Y Ali BSc Pharmacy MSc Industrial Pharmaceutical Sciences Dept. of Pharmaceutics School of Pharmacy University of Sulaimani 09/01/2019 1

2 Biopharmaceutics Physicochemical properties Bioavailability (Rate & Extent) Dosage form Route of Administration 2

3 Overview Dosage form factors influencing bioavailability Type of dosage form Aqueous solutions and suspensions Capsules; liquid- and powder-filled Tablets; uncoated, coated and enteric-coated Excipients Diluents Surfactants Lubricants Disintegrants Viscosity-enhancing agents Biopharmaceutical classification scheme 3

4 Introduction Bioavailability of drug in a dosage form can be affected by : Formulation Production Nowadays, dosage forms are designed and changed to influence of the release and absorption of drugs. 4

5 Possible steps between administration and appearance of drug in SOLUTION in GI fluids Aqueous solution Aqueous suspension Suspension of fine particles of drug in GI fluids Dissolution Solution of drug in GI fluids Absorption Deaggregation Immediate release solid dosage form Disintegration Aggregate or granules Dissolution 5

6 Aqueous Solution Drugs soluble and stable in the aqueous solution Formulation as solution eliminates the dissolution step in vivo in the absorption process. 6

7 Poorly soluble drugs Cosolvency Complex formation Aqueous Solution Dilution by GI fluids might lead to precipitation Exposure of salt of acidic drug to the acidic environment of the stomach also precipitates the drug as it will be in the free from. 7

8 However, in general the fine nature of the precipitate allows fast redissolution of the drug particles compared to other dosage forms Aqueous suspension Hard gelatin capsule and tablet. 8

9 Formulation factors of Aqueous Solution affecting bioavailability Chemical stability: Dosage form and GIT Complexation: drug-excipints Increase aqueous solubility Increase viscosity of the dosage form Solubilisation Incorporation into micelles in order to increase the aqueous solubility Viscosity of the dosage form Viscosity enhancing agents 9

10 Aqueous Suspension Insoluble and poorly soluble drugs Dissolution rate limited 10

11 Particle size & effective surface area of dispersed drug If increase total surface area then increase dissolution rate For a given mass of drug, smaller particles have a higher effective surface area If absorption of drug is dissolution-rate limited, then increase absorption by decreasing particle size 11

12 Aqueous suspensions: factors affecting bioavailability Particle size and effective surface area of dispersed drug Crystal form of drug Polymorph; amorphous vs. crystalline Possible complexation with excipient Inclusion of surfactant as wetting, flocculating or deflocculating agent Viscosity 12

13 Viscosity-enhancing agents and drug Liquid dosage forms absorption 1. Complex formation 2. Increase viscosity of GI contents 1. Decreased dissolution rate of solid particles 2. Decreased rate of diffusion of drug molecules 13

14 Liquid filled capsules Liquid can be filled into hard or soft gelatin capsules Advantages: Unit dosage form Rapid absorption Dissolved Suspended 14

15 Liquid filled capsules Non-toxic, non-aqueous vehicles Water miscible (hydrophilic) Polyethylene glycols some non-ionic surfactants (polysorbate-80) Water immiscible (lipophilic) Vegetable oils (digestible or non-digestible) Release of contents: Dissolution and splitting of the shell 15

16 Types of Vehicle of Liquid filled capsules Water miscible vehicle: disperses and/or dissolves in GIT, releasing the drug as either suspension or solution, respectively. Allows rapid absorption Water Immiscible: Solution or suspension Release of the drug from the dosage form followed by dispersion Solution, emulsion, suspension 16

17 Water Immiscible Water immiscible (lipophilic): Vehicle is digestible oil and drug is highly soluble in the vehicle: In GIT it is possible that the drug remain in solution in the dispersed oil phase and absorbed along with the oil droplet, by fat absorption mechanisms 17

18 Water Immiscible Drug is less soluble in the oily vehicle or the drug is dissolved in the non-digestible oil: The drug must partition from the oily phase or into the aqueous GI fluids Absorption depends on this partition Increase interfacial (oil/aqueous) will increase dissolution rate 18

19 Suspension Suspension in oily phase : Dissolution in the vehicle Diffusion to the oil/aqueous interface Partition across the interface 19

20 Poorly soluble drugs with improved Digoxin: bioavailability Formulated as soft gelatin showed faster absorption compared to tablets Saquinavir Antiviral Peptidomimetic Soft glatin (fortovase) showed improvement in bioavailability compared to hard gelatin powder filled 20

21 Liquid-filled capsules: factors affecting bioavailability Solubility of drug in vehicle (and GI fluids) Particle size of drug (if suspended in vehicle) Nature of vehicle (hydrophilic or lipohilic) Inclusion of surfactant Inclusion of suspending agent Complexation 21

22 Powder-filled Capsules Dissolution of hard gelatin shell Penetration of GI fluids into encapsulated mass excipients and packing density important Dispersion of encapsulated mass in GI fluids Dissolution of dispersed drug particles Good bioavailability? 22

23 Only hydrophobic drug particles Hydrophobic drug particles Hydrophilic diluent particles Shell dissolves 23

24 Powder-filled capsules: factors affecting bioavailability Surface area and particle size of drug Use of salt form Crystal form of drug Chemical stability of drug Composition and properties of capsule shell (including enteric capsules) Interactions between capsule shell and contents 24

25 Tablets Uncoated Coated ( enteric-coated) The most widely used dosage form Characterised by large reduction in the surface area owing to the production methods used Granulation Compaction 25

26 Tablet Reduction in the surface area can be solved by formulation, this is by addition of excepients that serve to increase surface area upon administration 26

27 Release and absorption of a drug from a tablet?? Tablet Granules Fine particles? Stomach Transit Small intestine Drug in solution A B S O R P T I O N? Fine suspension 27

28 Uncoated tablets: factors affecting bioavailability of a poorly soluble drug Physicochemical properties of liberated drug particles in GI fluids Nature and quantity of excipients Diluent, binder, disintegrant, lubricant, wetting agent Drug-excipient interactions Manufacturing factors Granule size, compaction pressure and speed Storage and age of tablet 28

29 Coated tablets Coating presents physical barrier between tablet core and GI fluids Problems of uncoated tablets PLUS Problems of coating Coating must dissolve/disrupt 29

30 Types of coating Poorly water-soluble coating Can delay and or reduce rate of drug release Shellac, cellulose acetate phthalate, ethylcellulose Water-soluble coating No significant effect on drug release Hydroxypropylmethylcellulose (HPMC) 30

31 Enteric-coated tablets Resists low ph of gastric fluids Dissolves at higher ph of duodenal fluids (ph 5) Coatings include: Cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, copolymers of methacrylic acid and their esters, poly vinyl acetate phthalate 31

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33 Enteric coating Delays drug release to improve bioavailability Can protect stomach Types EC tablet (monolith) Onset of action dependent on gastric emptying time EC granules or pellets (< 1 mm) Gradual release from stomach with liquids 33

34 Diluents Increased incidence of phenytoin intoxication in Australia from phenytoin?? Changing the diluent in the capsules from calcium sulphate dihydrate to lactose. This is because of forming non absorbable complex between Ca-phenytoin 34

35 Surfactants Emulsifying agent Solubilising agent Suspension stabilisers Wetting agent Inert? Increase Decrease No effect 35

36 Surfactants Inhibition of absorption : drugs normally soluble in the GIT fluids: presence of surfactants in micellar concentration decrease absorption by incorporation of the drug in the micelles 36

37 Surfactants Increase absorption: Poorly soluble drugs, increase dissolution by solubilisation (Cs), this leads to rapid absorption Disrupting biological membranes increases membrane permeability 37

38 Lubricants Added to reduce friction between solid particles and metal parts of machinery in the manufacturing of solid dosage forms Hydrophobic Mg stearate: retard penetration of GI fluids 38

39 Solution Overcome Wetting agent Hydrophilic diluent Decrease Mg stearate content 39

40 Disintegrants Break up tablet capsules and granules into primary particles Disintegration failures Incomplete absorption Delay in onset Tolbutamide 40

41 Biopharmaceutical Classification Scheme Solubility Class III High solubility Low permeability Class I High solubility High permeability Class IV Low solubility Low permeability Class II Low solubility High permeability Permeability 41

42 Biopharmaceutical Classification Scheme Considers aqueous solubility (Dose and Solubillity) and permeability via oral route of delivery (90%) Class I high solubility, high permeability rapid absorption, good bioavailability e.g. propanolol, metaprolol Class II low solubility, high permeability drug controls absorption; potential for particle size effects on bioavailability e.g. ketoprofen, carbamazepine 42

43 Biopharmaceutical Classification Scheme Class III - high solubility, low permeability drug dissolves rapidly but poorly absorbed require rapid drug release to maximise absorption e.g. ranitidine, atenolol Class IV - low solubility, low permeability challenging molecules, likely to exhibit low bioavailability e.g. hydrochlorothiazide, `` option to increase permeability - modify drugs as prodrugs 43

44 Any Questions 44

45 Further Readings Shargel L, Yu AB, (Eds.), Applied Biopharmaceutics and Pharmacokinetics. Aulton's Pharmaceutics: The Design andmanufacture of Medicines, M.E.Aulton, Churchill Livingstone,

46 Thank You 46