Development of Nanotechnology -Based Drugs and its Guidance

1. Development of Nanotechnology -Based Drugs and its Guidance Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph.D Department of Pharmaceutics KLE University College of Pharmacy BELGAUM-590010 E-mail: nanjwadebk@gmail.com Cell No: 00919742431000 FDP on Nanotechnology, VTU, Belgaum.

2. CONTENTS • Nanotechnology • Nanoparticle • Dendrimer • Liposomes • Micelles • Nanoemulsions • Nanocrystals • Primary Particle • Metal Colloids • Guidance for Industry Nontechnology Based Products FDP on Nanotechnology, VTU, Belgaum.

3. Definitions • Nanomaterial/Nanoscale Material: Any material with at least one dimension smaller than 100 nm. • Nanomedicine: The use of nanoscale materials for medical applications • Characterization: Physicochemical evaluation of relevant drug properties FDP on Nanotechnology, VTU, Belgaum.

4. Nanotechnology Commercialization • Consumer product applications, including cosmetics and sunscreens • Food applications, including dietary supplements • Medical applications, including drugs and drug delivery devices. FDP on Nanotechnology, VTU, Belgaum.

5. Medical Applications FDP on Nanotechnology, VTU, Belgaum.

6. Nanotechnology • The understanding and control of matter at dimensions between approximately 1 to 100 nanometers, where unique phenomena enable novel applications. • (Source: National Nanotechnology Initiative Definition) FDP on Nanotechnology, VTU, Belgaum.

7. Types of pharmaceutical nanosystems FDP on Nanotechnology, VTU, Belgaum.

8. Nanoparticle • Nano-object with all three external dimensions at the nanoscale that is the size range from approximately 1 nm to 100 nm. • Polymeric nanoparticle platforms are characterized by their physicochemical structures including solid nanoparticles, nanoshell, dendrimer, polymeric micelle, and polymer-drug conjugates. FDP on Nanotechnology, VTU, Belgaum.

9. Nanoparticle TEM (a, b, and c) images of prepared mesoporous silica nanoparticles with mean outer diameter: (a) 20nm, (b) 45nm, and (c) 80nm. SEM (d) image corresponding to (b). The insets are a high magnification of mesoporous silica particle FDP on Nanotechnology, VTU, Belgaum.

10. Dendrimer A polymer in which the atoms are arranged in many branches and subbranches along a central backbone of carbon atoms. FDP on Nanotechnology, VTU, Belgaum.

11. Dendrimer FDP on Nanotechnology, VTU, Belgaum.

12. Liposomes Vesicles composed of one or more bilayers of amphiphatic lipid molecules enclosing one or more aqueous compartments. FDP on Nanotechnology, VTU, Belgaum.

13. Liposomes FDP on Nanotechnology, VTU, Belgaum.

14. Micelles Self-assembling nanosized colloidal particles with a hydrophobic core and hydrophilic shell currently used for the solubilization of various poorly soluble pharmaceuticals. FDP on Nanotechnology, VTU, Belgaum.

15. Micelles FDP on Nanotechnology, VTU, Belgaum.

16. Nanoemulsions • Emulsions with droplet size in the nanometer scale. • Emulsion is a thermodynamically unstable system consisting of at least two immiscible liquid phases, one of which is dispersed as globules (the dispersed phase), in the other liquid phase (the continued phase), stabilized by the presence of an emulsifying agent. FDP on Nanotechnology, VTU, Belgaum.

17. Nanoemulsions FDP on Nanotechnology, VTU, Belgaum.

18. Nanocrystals Nanoscale solid formed with a periodic lattice of atoms, ions, or molecules. FDP on Nanotechnology, VTU, Belgaum.

19. Nanocrystals FDP on Nanotechnology, VTU, Belgaum.

20. Primary Particle Smallest identifiable subdivision in a particulate system. FDP on Nanotechnology, VTU, Belgaum.

21. Primary Particle FDP on Nanotechnology, VTU, Belgaum.

22. Metal Colloids • Metal nanoparticles in colloidal systems where the term colloidal refers to a state of subdivision. • This implies that the molecules or polymolecular particles are dispersed in a medium and have at least in one direction a dimension roughly between 1 nm and 1μm or, in a system, have discontinuities at distances of that order. • For example, silver, gold, titanium dioxide, zinc oxide, and iron oxide. FDP on Nanotechnology, VTU, Belgaum.

23. Metal Colloids FDP on Nanotechnology, VTU, Belgaum.

24. Polymer Colloids FDP on Nanotechnology, VTU, Belgaum.

25. Guidance for Nano-Industry • Chemistry Manufacturing and Control II. Human Pharmacokinetics and Bioavailability III. Labeling FDP on Nanotechnology, VTU, Belgaum.

26. I. Chemistry Manufacturing and Control • Description and Composition • Physicochemical Properties • Description of Manufacturing Process and Process Control • Control of Excipients: Lipid Components • Description and Characterization • Manufacture • Specifications • Stability E. Control of Drug Product: Specifications F. Stability G. Changes in Manufacturing FDP on Nanotechnology, VTU, Belgaum.

27. Description and Composition • The components of liposome drug products are the drug substance, the lipids, and other inactive ingredients. • The pharmacological and toxicological properties and the quality of these drug products can vary significantly with changes in the formulation, including the lipid composition. FDP on Nanotechnology, VTU, Belgaum.

28. Physicochemical Properties • Morphology of the liposome, including lamellarity determination, if applicable • Volume of entrapment in liposomal vesicles • Particle size (mean and distribution profile) • Phase transition temperature • Spectroscopic data, as applicable • In vitro release of the drug substance from the liposome drug product • osmotic properties • light scattering index FDP on Nanotechnology, VTU, Belgaum.

29. Description of Manufacturing Process and Process Control • Liposome drug products are sensitive to changes in the manufacturing conditions, including changes in scale. • If there are changes in critical manufacturing parameters, complete characterization of the liposome drug product is recommended and in vivo studies may be warranted. FDP on Nanotechnology, VTU, Belgaum.

30. Control of Excipients: Lipid Components • Description and Characterization • Manufacture • Specifications • Stability FDP on Nanotechnology, VTU, Belgaum.

31. Control of Drug Product: Specifications • Physicochemical parameters of the liposome determined to be critical to product quality for each batch. • Assay for encapsulated and unencapsulated (i.e., free) drug substance. • Degradation products related to the lipids. • Assay of lipid components. • In vitro test for release of drug substance from the liposome. FDP on Nanotechnology, VTU, Belgaum.

32. Stability • The physical stability of liposome drug products is a function of the integrity and the size distribution of the lipid vesicles. • Liposomes are susceptible to fusion, aggregation, and leakage of the encapsulated drug substance during storage. • Liposome drug products should be evaluated for stability of the encapsulated drug substance as well as stability of the lipids that compose the liposomal bilayer. FDP on Nanotechnology, VTU, Belgaum.

33. Changes in Manufacturing • Liposome drug products are a relatively new dosage form, it is not possible to provide recommendations on the type of information that should be generated to demonstrate that the change has not adversely affected the quality of the drug product. • The extent of the information and documentation to be developed and submitted to support a change should depend on the types of manufacturing changes and the stage of manufacturing at which the changes occur. FDP on Nanotechnology, VTU, Belgaum.

34. II. Human Pharmacokinetics and Bioavailability • Bioanalytical Methods • In Vivo Integrity (Stability) Considerations • Protein Binding • In Vitro Stability • Pharmacokinetics and Bioavailability • Mass Balance Study • Pharmacokinetic Studies • Additional Pharmacokinetic Studies • Food-Effect Studies • Drug Interactions and /or Special Populations • Exposure-response Studies FDP on Nanotechnology, VTU, Belgaum.

35. Bioanalytical Methods • Validated bioanalytical methods should be used when evaluating the pharmacokinetics and bioavailablity of a drug substance. • For liposome drug products the bioanalytical method should also be capable of measuring encapsulated and unencapsulated drug substance. FDP on Nanotechnology, VTU, Belgaum.

36. In Vivo Integrity (Stability) Considerations • In addition to the general stability considerations of the drug substance in a biological fluid, the stability of the liposome in vivo should be considered. • A single-dose study is recommended to assess the in vivo stability of the liposome. • The concentration-time profile should be evaluated at multiple time points over an adequate period of time. • The concentration of encapsulated and unencapsulated drug substance should be determined at each sampling time point. FDP on Nanotechnology, VTU, Belgaum.

37. Protein Binding • The stability of liposomes in vivo can be affected by interactions with lipoproteins and other proteins in the blood. • Interactions of liposomes with serum proteins and lipoproteins can be dependent on the type of lipids used in formulating the liposomes. • The protein (including lipoprotein) binding of the drug substance and liposome drug product should be determined over the expected therapeutic concentration range. • The major binding proteins should be identified. FDP on Nanotechnology, VTU, Belgaum.

38. In Vitro Stability • An in vitro test that measures the release of the drug substance from the liposome can be important for assessing the (1) Quality of a liposome drug product, (2) Adequacy of the process controls, (3) Release characteristics of the product over time, and (4) The effect of CMC changes e.g., minor manufacturing process changes or change in site of manufacture. FDP on Nanotechnology, VTU, Belgaum.

39. Pharmacokinetics and Bioavailability • Mass Balance • Pharmacokinetic Studies • Additional Pharmacokinetic Studies a. Food-Effect Studies b. Drug Interaction and /or special Populations c. Exposure-Response Studies FDP on Nanotechnology, VTU, Belgaum.

40. III. Labeling • Product Name • Cautionary Notes and Warning • Dosage and Administration FDP on Nanotechnology, VTU, Belgaum.

41. Product Name • The product name should include the established name, dosage form, terminology to describe that it is a liposome drug product, and, if desired, a proprietary (i.e., brand) name. • The descriptive terminology should include the term liposome and, when appropriate, such terms as Type A, Type B, and Type C, to distinguish one liposome product from other liposomal formulations of the same drug substance that are not therapeutically equivalent. • Forexample: BrandX (Acetaminophen) Liposome-Type A For Injection FDP on Nanotechnology, VTU, Belgaum.

42. Cautionary Notes and Warning • A cautionary note should be included in the description section of the labeling regarding the fact that liposome drug products may behave differently from nonliposome drug products. • A warning should be included in the labeling that the liposome drug product is not equivalent to or cannot be substituted for other drug products containing the same drug substance. FDP on Nanotechnology, VTU, Belgaum.

43. Dosage and Administration • This information should be provided for both unloaded lyophilized liposomes that are reconstituted with a drug substance-containing solution at the time of use, as well as products in which the drug substance is loaded into the liposome by the manufacturer and then lyophilized. • Other issues that should be addressed, as warranted, include storage conditions for the reconstituted drug, robustness of the liposome drug product under varied reconstitution conditions (e.g., degree of shaking), and appropriateness of using in-line filters. FDP on Nanotechnology, VTU, Belgaum.

44. Nanotechnology Product Evaluating Questions FDP on Nanotechnology, VTU, Belgaum.

45. Nanotechnology Product Evaluating Questions FDP on Nanotechnology, VTU, Belgaum.

46. Template for CDER Nanotechnology Drug Product Database Entry FDP on Nanotechnology, VTU, Belgaum.

47. Nanotechnology Product Review Flow Chart FDP on Nanotechnology, VTU, Belgaum.

48. Nanotechnology Product Review Flow Chart FDP on Nanotechnology, VTU, Belgaum.

49. Common Techniques for Characterization • Morphology • Surface • Chemical • Others FDP on Nanotechnology, VTU, Belgaum.

50. Morphology FDP on Nanotechnology, VTU, Belgaum.