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2. Design in Product Development and Choice of Formulation 1.

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Presentation on theme: "2. Design in Product Development and Choice of Formulation 1."— Presentation transcript:

1 2. Design in Product Development and Choice of Formulation 1

2 Design & Selection of Drug Substance 2

3 High Failure Rate For every 10,000 NCE’s in Discovery  10 enter pre-clinical development  5 enter human trials  1 is approved Interestingly…..  Winning the lottery1 in 5,200,000  A Royal Flush in Poker1 in 650,000  Struck by lightning1 in 600,000  Appear on the Tonight Show1 in 490,000  Discovery to Market1 in 10,000  A son who will play pro football1 in 8000 3 Make, screen & push more compounds into the pipeline!

4 ‘HITS’ Developability Screens In Silico Screening Optimisation DRUG PRODUCT Lead Compounds Combinatorial Chemistry High Throughput Screening 4

5 Combinatorial Chemistry & HTS: Poor Solubility Drug Discovery Before 1990 lead compounds - drug like potency improved by adding lipophilic moieties low mol. weights circa.300 Drug Discovery After 1990 advent of HTS uses organic solvents to screen in vitro potency lead optimisation occurs by –increasing mol. weight – lipophilicity 5 40 % of compounds made each year are abandoned due to poor solubility- Giovani Sala, Elan Pharma Brick Dust !

6 hundreds of compounds evaluated in parallel using rapid, high throughput predictive assays Combinatorial Library Potency Selectivity Kinetics Tissue penetration Carcinogenicity Physicochemical Properties Drug candidate Increase choiceImprove selection Preformulation and Developability Screening 6

7 Solubility: Double Edged Sword Relative difficulty in formulation design* –poor permeability –high first pass metabolism –poor chemical stability –low solubility –instability in GI fluids –high dosage More flexibility in altering physical chemistry than physiology –absorption rate can vary from 0.001 - 0.05 min -1 i.e. x 50 –solubility can vary from 0.1 µg - 100 mg/ml i.e. x 1000,000 –target solubility is 1mg/ml (covers 1 mg to 500 mg oral dose) 7 Taken from a survey of formulation scientists from 12 companies in Japan least most

8 GIT Physiology Potential for chemical degradation under different pH’s Changes in mucosal SA, presence of specific absorption windows Influence of endogenous secretion along the GI-tract Influence of gastric emptying, transit time and food dependency Influence of hydration state and water availability along GI-tract Pre-systemic availability – membrane/faecal binding & metabolism 8

9 Gastro Intestinal Tract conditions Absorbing surface area of the colon (~0.3m 2 ) very small c.f. rest of GIT (120-200m 2 ) High viscosity of lumen contents can compromise drug diffusion and therefore absorption Long residence times (up to 16 hrs) Densely populated with microbial flora 9

10 Predicting good oral absorption Increasing dose Increasing permeability 250500100010000100000 Volume (ml) required to dissolve the dose 5000 10 1 0.1 Predicted Permeability in Humans (cm/sec x10 -4 ) Class I Good solubility and permeability Class III Good solubility, poor permeability Class IV Poor solubility and permeability Class IIa (dissolution rate limited) Class IIb (solubility limited) Jejunal solubility (e.g.FaSSIF) Poor solubility, good permeability Good Difficult Poor Very poor Particle size reduction or other bio-enhancement required Increasing solubility Dose/solubility ratio Butler & Dressman, JPharmSci. Vol 99, Issue 12, pp 4940–4954, Dec 2010Vol 99, Issue 12,

11 Physico-chemical methods for Boosting Oral Absorption* Use a Form with higher solubility more soluble salt more soluble polymorph amorphous c.f. crystalline form Formulate so drug is in solution Increase rate of dissolution particle size 11 *many principles applicable for parenteral delivery

12 Use a form with higher solubility 12

13 Crystal Form Depending on crystallising conditions, actives may exhibit: –different habits –different polymorphs –solvates (solubility: organic > non solvate > aqueous solvate) Polymorphs with lowest free energy (lowest solubility) tend to be more thermodynamically stable –metastable (more soluble) form less soluble form –smaller the difference in free energy the smaller the difference in solubility –could we use metastable form for safety assessment? 13

14 Serum Levels: Chloramphenicol Palmitate Effect of Polymorph Type 14

15 Amorphous forms Amorphous forms afford better solubility & faster dissolution rates c.f. crystalline forms –e.g. novobiocin, troglitazone Amorphous forms can transform to a more stable, but less soluble crystalline state –tendency to transform is related to T g & storage temp –T g > 80 o C for amorphous solids to remain stable at RT –for investigative studies low temperature storage to retain amorphous form is viable –can stabilise by formulating with excipients of higher T g PVP (T g, 280 o C) inhibits crystallisation of Indomethacin melt-extrusion with PVP to form granules or tablets 15

16 Granulator Shaping Device Tablets Polymer Excipient Drug Granulation Pellets Schematic view of Melt Extrusion 16

17 17

18 pH adjustment & Salt Form Any drug moiety with a pKa between 3-11 can potentially be solubilised by pH modification Salt-Formation is an extension of pH adjustment. Most common forms are as follows: –acidic drugs: sodium>potassium>calcium –basic drugs: hydrochloride>sulphate>mesylate >chloride>maleate>tartrate>citrate Salt-form requires agreement from all development parties –highly soluble form might be hygroscopic & unstable choose the best ‘all-rounder’ 18

19 pH Solubility Profiles Intrinsic solubility (S 0 ) region – pH range in which compound is completely unionized and has the lowest solubility. Ionized region – region around pK a of compound. At pK a are equal amounts of ionized and unionized forms of the compound in solution. For every pH unit change either side of the pK a gives a 10- fold change in amount of ionized drug in solution. Implications for lab measurements (pH control), & GI pH/ absorption. Compound precipitating in this region can be as free base or salt (depends upon the strength of solid-state interactions). pH max – the region where compound has maximum solubility (equilibrium solid state form will be a salt i.e. completely ionized drug associated with oppositely charged counter-ions). Salt plateau – pH range in which the molecule is fully ionized and the salt solubility of the compound predominates. Solubility value is dependent upon strength of solid-state interactions with the counter-ion forming the salt. (Common ion effects & solvent can impact solubility.) 19 Weak Base Solubility=S 0 (1+10 (pKa-pH) ) S 0 =intrinsic, solubility of free acid/base S 0 = 0.528  g/ml pKa5.54

20 Classical pH-Solubility profile S 0 =intrinsic, solubility of free acid/base

21 Salt Form 21 Aqueous solubilities of RPR-127963 salts Sulphate was progressed into development Could use a more soluble form for investigative studies?

22 22

23 Formulate so drug is in solution 23

24 Solubilising Vehicles: organic solvents 24 Organic solvents used in commercial parenteral formulations

25 Solubilising Vehicles Solvent/CosolventIssue Polyethylene glycolLaxative, LMW residues Propylene GlycolDose limitation EthanolEffect of chronic dosing Dimethyl AcetamideIrritation Oily VehiclesSolubilising limitations 25

26 Complexation: Cyclodextrins Enhance the Drug’s Water Solubility Increase Drug’s Aqueous Solution Stability Improve Solubility & Dissolution: Improve Oral Bioavailability Effective Delivery Drug:CD Complex Lipophilic Cavity Hydrophilic Exterior OH CH 2 OH HO CH 1:1 Complex Lipophilic Drug 26

27 27

28 Increase rate of dissolution 28

29 Solubility & Dissolution Rate Dissolution Rate D.A e.Cs R Where D = Diffusion Coefficient A e = Effective Surface Area Cs = Saturation Solubility R = Thickness of Diffusion Layer 29

30 Danazol Bioavailability (Dog) 30

31 31 Take Home Message Biology occurs in aqueous solution Regardless of route a drug needs to dissolve first!

32 Modified Release Technologies TerminologyDefinition (USP) Controlled (including sustained/ prolonged release) A Controlled Release (CR) dosage form is one in which the drug is released at a constant rate and therefore produces blood drug levels which remain invariant with time Extended releaseAn Extended Release (ER) dosage form allows a two-fold reduction in the frequency of dosing or increase in patient compliance or therapeutic performance Modified releaseA Modified Release (MR) dosage form is one in which the drug release characteristics and/or location of release are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms NB: Ph. Eur. uses extended release as denominator rather than modified release 32

33 Technical argument How does MR drug delivery modulation add value? Reduced dosing frequency, thus promote patient compliance Reduced potential for side-effects (lessen peak/trough ratio) Customised profile, link drug level to efficacy performance Targeted delivery to specific GI regions for improved “delivery” opportunities 33

34 Drug properties IdealChallenging Dose 10-250mg<10mg potential homogeneity issues >250mg payload and physical dosage size issues Dose/solubility ratio * 1-100ml100-1000ml challenging may need solubilisation >1000ml practically impossible Permeability Abs > 70% Rat K a > 0.01min -1 (P apps >15cm/s) P apps 5-15cm/s absorption unpredictable P apps < 5cm/s practically impossible Stability 48hr in gut content @ 37°C Interpretation can be complex – many facets to stability i.e., physical (binding, adsorption) and chemical * Dose/solubility ratio calculated using the highest dose and lowest solubility in the pH range of 1 to 7.5. 34

35 Other considerations IdealChallenging Plasma half-life 2 – 8 hr< 2hr high dependency on delivery rate to maintain steady state concentration >>10hr may not require MR delivery Presystemic/first pass metabolism No pre- systemic/low 1 st pass metabolism Pre-systemic drug loss increases overall dose requirements. CYP3A4 substrate introduces dose-dependent metabolism Efflux and dose linearity BA/BA ratio < 1.8 fold Dose linear Efflux issues difficult to handle if dominant over therapeutic dose range Therapeutic window > 4-fold< 4-fold challenging, reliant on very precise control of drug plasma level 35

36 Modes of Oral Modified Drug Delivery Most popular systems classified as follows:  Osmotic pumps: Oros  Swellable systems: HPMC matrix, Geomatrix etc  Erosion controlled systems: Egalet Major issues still revolve around  Choice of a suitable animal model  Poor understanding of PK/PD relationships  Chronotherapeutics  Polypharmacy What is the ideal in vivo release profile? 36

37 Osmotic pump systems Cross-section of typical oral therapeutic system (OROS) Delivery orifice Drug solution Semipermeable membrane Delivery orifice Drug compartment Osmotic core containing active substance Water Osmotic propellantFlexible partition 37

38 Process complexity Process complex involving multiple steps Bi-layer compression requires good control Coating critical to meet dissolution target GranulationMill Blend and lubricate Bi-layer tabletting CoatingDrilling Granulation DRUG LAYER SWELLER LAYER Mill Blend and lubricate 38

39 Chronotherapy Covera-24 was the first oral MR product approved for chronotherapeutic treatment for angina & hypertension Dose at night & release starts between 0200 - 0300 & counters the surge in blood pressure between 0400 - 0500 Constant release continues to cover events during the day 39

40 Product Development Design Case Study 40

41 Case Study Product Line extension Your company markets an oral product for migraine – you are the PLE department and the commercial team have asked you to design a faster acting product. The product development team is asked to ‘brainstorm’ options for this development You have 20 minutes to discuss before feeding back your best concept to the Product Development Board What do you need to know about the patient population? What do you need to know about the disease? What do you need to know about the properties of the drug? What formulation technology will you use? 41

42 Formulating the drug substance into a Product 42

43 Requirements of a Dosage Form Contains an Accurate Dose. Makes drug available for absorption (oral dosage). Is stable (retains quality). Convenient to take or administer. Is produced economically by an acceptable process. 43

44 Effect on Drug “Know your Dosage Form” Optimise Levels of Excipients Addition of other materials Engineering Technologies Physical Modifications Compensate for Deficiencies Meet patient needs “Know your Drug & Patient” Formulation Development 44

45 Functions of Excipients Aid function of the dosage form Aid manufacture of the dosage form Quality assurance and maintenance Identity, patient acceptability –colour –taste “Target” the drug to site of activity –absorption –site-specific delivery 45

46 Factors affecting performance of oral dosage forms particle size of active granulation –granulating agents –mode of granulation lubricant –type –degree of mixing compression force film coat 46 All need to be evaluated: CMC section of regulatory submission

47 Dosage Forms for Clinical Programmes 47 Phase OneFlexibility of Dose - powder in bottle - capsule - tablet Phase TwoRange of Doses in “look-alike” units - tablet - capsule Phase ThreeFormulation for Marketing FDA will not consider tablets & capsules as bioequivalent! Tablets more popular than capsules (smaller & more stable)

48 What does a dose look like? 48 Preclinical stage Phase 1 stage Phase 2 stage Phase 2/3 Phase 4 stages

49 Why do Formulations Change ? Technical problems Different doses Nature of clinical programmes 49

50 Formulation and the Stock Market 50 “To Merck’s dismay, Monsanto completed its clinical studies first. Among the reasons was a dosage glitch at Merck. The company found that, instead of 1000mg, the proper dose was 12.5-25mg. The pills that resulted were so tiny that Merck was afraid that Arthritis patients wouldn’t be able to pick them up. It enlarged them with edible filler but that caused another problem. The fiber turned out to slow the drug’s absorption. Three months were lost while researchers worked to fix this” Wall Street Journal January 10th 2001

51 Impact of changing dose! Very difficult to accommodate large changes in dose, as it will influence processing & manufacturing on scale-up 51


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