Unigel TM Case Study: Extending Soft Gelatin Capsule Benefits to Novel Fixed Dose Combinations

Transcription

1 Unigel TM Case Study: Extending Soft Gelatin Capsule Benefits to Novel Fixed Dose Combinations Diego Monterroza, H. M. Sc, Corporate Manager, R&D Procaps S.A. Stand # 30A46

2 OUTLINE

3 Fixed Dose Combinations Fixed-dose combination (FDC) A combination of two or more actives in a fixed ratio of doses. This term is used generically to mean a particular combination of actives irrespective of the formulation or brand. It may be administered as single entity products given concurrently or as a finished pharmaceutical product. Fixed-dose combination finished pharmaceutical product (FDC-FPP or FDC-DP) A finished pharmaceutical product that contains two or more actives. Source: World Health Organization WHO Technical Report Series, No. 929, 2005

4 Fixed Dose Combinations FDCs have advantages when: There is an identifiable patient population for whom treatment with a particular combination of actives in a fixed ratio of doses has been shown to be safe and effective. All of the actives contribute to the overall therapeutic effect. There can be real clinical benefits in the form of increased efficacy and/or a reduced incidence of adverse effects. Other Advantages: Improved patient compliance. Simplified and cost effective handling & distribution. Development costs. Life Cycle Management (LCM) extension.

5 Fixed Dose Combinations Includes new combinations, indications, formulations, and territories Excludes generics, OTC, and approvals. N=230

6 Fixed Dose Combinations Some presentation of oral FDC-DPs: TABLETS HARD GELATIN CAPSULES Oral fixed dose combinations can be Swallowable Chewable Oral disintegrating Immediate-release Immediate-release + sustained-release Other And now

7 OUTLINE

8 What is Unigel? A new patented technology for combining multiple delivery systems in a single dosage Unigel is the only technique for fixed dose combinations which incorporates the benefits of the soft gelatin capsule dosage form.

9 Main Advantages: Fast and sustained-release in a single dose Gastric or intestinal release in the same dose Fewer intakes to be administrated Reduces number of prescriptions prescribed by Physician What is Unigel? Reduces liability issues related to physicians prescriptions Smaller number of presentations to maintain Simplicity of regimen reduces mistakes Impossible to be falsified The big challenge is that can t be used for inner soft capsules or hard dose greater than 1/3 the size of the outer soft capsule. In those cases must use two inner solid dose.

10 OUTLINE

11 3.1. Rationale About the combination: Omega-3 fatty acids, can be used in combination with statins to achieve more global improvements in lipid profiles Am.J Cardiol Oct 15;102(8): doi: /j.amjcard Epub 2008 Jul 31: Effectiveness of combined statin plus omega-3 fatty acid therapy for mixed dyslipidemia. Combination of Prescription Omega-3 With Simvastatin (COMBOS) About the finished dosage form: A combination of 1 g of Omega-3-fatty acids (mainly EPA and DHA) with one immediate release 20 mg Atorvastatin tablet, in one dosage form. Unigel is the ONLY fixed dose combination dosage form that you can use for feasible products where at least one of the API is liquid or semisolid.

12 3.2. Quality Target Product Profile (QTPP) QTPP Element Target Justification Dosage Form Dosage Design Route of Administration Drug Product Quality Attributes Dosage Strength Pharmacokinetics Physical attributes Atorvastatin dissolution Capsules rupture Degradation products Assay Atorvastatin residues in the oil Container Closure System Soft capsule IR tablet and IR capsule Oral SGC: 840mg/g Tablet: 20 mg/tab Immediate release enabling same T max for ATV; Bioequivalent to RLD Pharmaceutical equivalence requirement: same dosages forms of the individual single products IR tablet and IR capsule release according to individual labels Pharmaceutical equivalence requirement: same route of administration of the individual products Pharmaceutical equivalence requirement: same strength of the individual products Bioequivalence requirement for atorvastatin Pharmaceutical equivalence requirement of the individual products Container closure system qualified as suitable for this Container closure system qualified as suitable for this drug product

13 3.3. RESULTS: Tablet shape and size Tablet shape and size affects dramatically Unigel filling process. ATV tablet had to be formulated in a suitable shape and size. Depend on drug load, amount of drug substance should be divide in more than one inside dosage form.

14 3.3. RESULTS: coating selection Tablet coating affect both: tablet release and physicochemical stability of the Unigel. Selected coating should avoid oil affect tablet but with low influence on tablet release/dissolution.

15 % Dissolved 3.3. RESULTS: coating selection 120 ATV Tablet Dissolution Profiles Lipitor - Not-encapsulated tablets Rupture Time was about Rupture 13 minutes Time was about 6 minutes Test product tablets in oil Sampling (minutes) Optimized shell was achieved by varying factors related to both gelatin raw material and manufacturing process!!!

16 3.4. Next Steps We have 3 months accelerated data meeting all CQAs and we should complete six months by 12/13. Those stability studies are performed in PVDC blisters and we are prompt to initiate them in HDPE bottles. BE study of the proposed formulation against Lipitor. New combinations are also under development: Fish Oil & Aspirin Rosuvastatin & Fenofibrate (2 tablets) Ibuprofen & Hyoscine Ibuprofen & methocarbamol We have recently filed in Colombia applications for Fish oil & Atorvastatin and Fish oil & Aspirin. Scaling-up the process to more than 1 million Unigel batches.

17 OUTLINE

18 4. Conclusions We have developed a FDC drug product for a combination od a liquid API (fish oil 84%) plus a tablet containing 20 mg of Atorvastatin. A QbD approach was followed for this development and all CQAs proved to be satisfactory with the proposed specification after 3 months at accelerated (40 C/75%RH) in the propose container closure system (Aluminum/PVDC blisters). A fast dissolution gelatin shell was necessary to be developed in order to avoid the in vitro delayed effect of the gelatin shell on the ATV tablet.

19 GRACIAS! THANK YOU! Please visit us at stand 30A46