2. Design in Product Development and Choice of Formulation

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

2. Design & Selection of Drug Substance

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 lottery 1 in 5,200,000 • A Royal Flush in Poker 1 in 650,000 • Struck by lightning 1 in 600,000 • Appear on the Tonight Show 1 in 490,000 • Discovery to Market 1 in 10,000 • A son who will play pro football 1 in 8000 Make, screen & push more compounds into the pipeline!

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

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 BrickDust ! 40 % of compounds made each year are abandoned due to poor solubility-Giovani Sala, Elan Pharma

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

7. most least 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) • Taken from a survey of formulation scientists • from 12 companies in Japan

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

9. Gastro Intestinal Tract conditions • Absorbing surface area of the colon (~0.3m2) very small c.f. rest of GIT (120-200m2) • High viscosity of lumen contents can compromise drug diffusion and therefore absorption • Long residence times (up to 16 hrs) • Densely populated with microbial flora

10. Predicting good oral absorption Volume (ml) required to dissolve the dose Dose/solubility ratio 250 500 1000 5000 10000 100000 Increasing permeability Jejunal solubility (e.g. FaSSIF ) Class I Class IIa Class IIb Good Difficult 10 (solubility limited) (dissolution rate limited) Good solubility and permeability Poor solubility, good permeability Particle size reduction or other bio-enhancement required Predicted Permeability in Humans (cm/sec x10-4) 1 Class IV Class III Poor solubility and permeability Good solubility, poor permeability Very poor Poor 0.1 Increasing solubility Increasing dose Butler&Dressman, JPharmSci. Vol 99, Issue 12, pp 4940–4954, Dec 2010

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 *many principles applicable for parenteral delivery

12. Use a form with higher solubility

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?

14. Serum Levels: Chloramphenicol Palmitate Effect of Polymorph Type

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 Tg & storage temp • Tg > 80oC 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 Tg • PVP (Tg, 280oC) inhibits crystallisation of Indomethacin • melt-extrusion with PVP to form granules or tablets

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

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’

19. pH Solubility Profiles Weak Base Solubility=S0(1+10(pKa-pH) ) • Intrinsic solubility (S0) region – pH range in which compound is completely unionized and has the lowest solubility. • Ionized region – region around pKa of compound. At pKa are equal amounts of ionized and unionized forms of the compound in solution. For every pH unit change either side of the pKa 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). • pHmax – 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.) S0= 0.528mg/ml pKa5.54 S0=intrinsic, solubility of free acid/base

20. Classical pH-Solubility profile S0=intrinsic, solubility of free acid/base

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

23. Formulate so drug is in solution

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

25. Solubilising Vehicles Solvent/Cosolvent Issue Polyethylene glycol Laxative, LMW residues Propylene Glycol Dose limitation Ethanol Effect of chronic dosing Dimethyl Acetamide Irritation Oily Vehicles Solubilising limitations

26. Hydrophilic Exterior HO OH CH CH CH2OH Lipophilic Cavity • 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 Drug 1:1 Complex

28. Increase rate of dissolution

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

30. Danazol Bioavailability (Dog)

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

32. Modified Release Technologies NB: Ph. Eur. uses extended release as denominator rather than modified release

33. 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 Technical argument

34. Drug properties * Dose/solubility ratio calculated using the highest dose and lowest solubility in the pH range of 1 to 7.5.

35. Other considerations

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?

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

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

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

40. Product Development Design Case Study

41. Case StudyProduct 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?

42. Formulating the drug substance into a Product

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.

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

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

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 All need to be evaluated: CMC section of regulatory submission

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

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

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

50. Formulation and the Stock Market “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