Nanosuspension

1. Seminar on Nanosuspensions By : Ms. Rutuja Dhorje M.Pharm First Year (Pharmaceutics) SEMESTER – I Roll no. 05

2. Content • What are Nanosuspensions? • Need of Nanosuspensions • Major Advantages of Nanosuspensions • Advantages of Nanosuspensions over Conventional Formulations • Stability Issues • Formulation considerations • Preparation Techniques of Nanosuspensions • Characterization and Evaluation • Application • Marketed Preparation • Case Study • Conclusion • Bibliography

3. What Are Nanosuspensions? • A pharmaceutical nanosuspension is defined as : “Very finely colloid biphasic, dispersed and solid drug particles in aqueous vehicle, size below 1um without any matrix material stabilized by surfactant and polymers and prepared by suitable methods for drug delivery applications through various routes of administration.” • Average particle size ranges from 200-600 nm. (The diameter of suspended particle is usually less than 1 μm in size). • An increase in the dissolution rate of micronized particles (particle size < 10 μm) is related to an increase in the surface area and consequently the dissolution velocity.

4. Need Of Nanosuspensions • Major issues associated with poorly water soluble drugs: • Poor bioavailability. • Inability to optimize lead compound selection based on efficacy and safety • Fed/fasted variation in bioavailability • Lack of dose-response proportionality • Suboptimal dosing • Use of harsh excipients, i.e., excessive use of co-solvents and other excipients • Use of extreme basic or acidic conditions to enhance solubilization • Nanosuspension is the only approach universally applicable to overcome these issues by enhancing solubility of drug in aqueous as well as lipid media. • Thus preferred suitable for compounds with high log P value high melting point high dose

5. Major Advantages • Applicable for the poorly water soluble drugs. • Reduced tissue irritation in case of subcutaneous/intramuscular administration. • Rapid dissolution and tissue targeting can be achieved by IV route of administration. • Oral administration provide rapid onset, reduced fed/fasted ratio and improved bioavailability. • Higher bioavailability and more consistent dosing in case of ocular administration and inhalation delivery. • Improvement in biological performance due to high dissolution rate and saturation solubility of the drug. • Long term physical stability (Due to absence of Ostwald ripening). • Nanosuspensions can be incorporated in tablets, pellets, hydrogel and suppositories are suitable for various routes of administration. • Increasing the amorphous fraction in the particles, leading to a potential change in the crystalline structure and higher solubility. • Possibility of surface-modification of nanosuspension for site specific delivery.

6. Advantages of Nanosuspensions over Conventional Formulation

7. Stability issues a- deflocculated suspension b- deflocculated suspension c- open-flocs based suspension

8. Formulation Considerations

9. Preparation techniques • Homogenization in water (DissoCubes) • Media Milling (Nanocrystals or Nanosystems) • Homogenization in non-aqueous media (Nanopure) • Combined precipitation and homogenization (Nanoedge) • Nanojet Technology • Emulsification-Solvent Evaporation Technique • Hydrosol Method • Supercritical Fluid Method • Dry Co-grinding • Emulsion as template • Microemulsion as template

10. In bottom-up Technology, the drug is dissolved in an organic solvent and this solution is mixed with a miscible anti-solvent. In the water-solvent mixture, the solubility is low and the drug precipitates. Basic challenge is that during the precipitation procedure growing of the crystals need to be controlled by addition of surfactant to avoid formation of microparticles. In Top-down Technology, the nano size range of particles is obtained by reduction in size of larger particles.

11. Most commonly, Media Milling and High Pressure Homogenization are used for Large Scale Production Of Nanosuspensions

12. Media Milling (Nanocrystals) • This patent-protected technology was developed by Liversidge et al. (1992). Formerly, the technology was owned by the company NanoSystems but recently it has been acquired by Élan Drug Delivery. • The milling chamber charged with polymeric media is the active component of the mill. • Operated in batch or recirculation mode. • Crude slurry consisting of drug, water and stabilizer is fed into the milling chamber and processed into nano-crystalline dispersion and the milling media or pearls are then rotated at a very high shear rate. • The typical residence time generated for a nanometer-sized dispersion with a mean diameter of <200nm is 30–60 min. • Principle: The high energy and shear forces generated as a result of the impaction of the milling media with the drug provide the energy input to break the microparticulate drug into nano-sized particles.

13. Elan Lab Scale NanoMill TM for batch production of Nanosuspensions. Schematic of wet bead milling process used for production of drug nanoparticles

14. ADVANTAGES • Drugs that are poorly soluble in both aqueous and organic media can be easily formulated into nanosuspensions. • Ease of scale-up and little batch-to-batch variation. • Narrow size distribution of the final nanosized product. • Flexibility in handling the drug quantity, ranging from 1 to 400mg/mL, enabling formulation of very dilute as well as highly concentrated nanosuspensions • DISADVANTAGES • Generation of residues of milling media, which may be introduced in the final product as a result of erosion. • Scale up is not easy due to mill size or weight. • Time consuming

15. High pressure homogenization • Most widely used method for preparing nanosuspensions of many poorly soluble drugs, • Basically involves three steps: • Initially, drug powders are dispersed in stabilizer solution to form pre-suspensions. • Secondly, the pre-suspension is homogenized in High Pressure Homogenizer at a low pressure for pre-milling. • Finally it is homogenized at high pressure for 10-25 cycles until the nanosuspensions of desired size are formed. • DissoCubes technology is an example of this technology developed by R.H. Muller in 1999 e.g. Omeprazole.

16. Scanning electron microscope image of a nanosuspension prepared with High Pressure Homogenization

17. Basic principle: Particle size reduction is based on the cavitation principle. The dispersion contained in 3cm diameter cylinder; suddenly passes through a very narrow gap of 25µm. This leads to increase in dynamic pressure and decrease of static pressure below the boiling point of water at room temperature. Due to this, water starts boiling at room temperature and forms gas bubbles, which implode when the suspension leaves the gap (called cavitation) and normal air pressure, are reached. Factors affecting size of drug nanocrystals: Temperature Number of homogenization cycles Power density of Homogenizer Homogenization pressure

18. ADVANTAGES • It does not cause the erosion of processed materials. • Very dilute as well as highly concentrated nanosuspensions can be prepared by handling 1mg/ml to 400mg/ml drug quantity. • It is applicable to the drugs that are poorly soluble in both aqueous and organic media. • It allows aseptic production of nanosuspensions for parenteral administration. • DISADVANTAGES • Pre-processing like micronization of drug is required. • High cost instruments are required that increases the cost of dosage form.

19. Characterization • Nanosuspensions are characterized for appearance, color, odour, assay, related impurities, particle size, zeta potential, crystalline status, dissolution studies and in vivo studies.

21. applications

22. Oral drug delivery system • The efficacy or performance of the orally administered drug generally depends on its solubility and absorption through the GIT. • Nano-sizing of such drugs can lead to a dramatic increase in their oral absorption and subsequently bioavailability. • The amelioration in oral bioavailability can be attributed to the adhesiveness of the drug nanosuspension, increased surface area (due to reduction in particle size by 10–50 fold), and increased saturation solubility, leading to an increased concentration gradient between the gastrointestinal tract lumen and blood, and increased dissolution velocity. • This enhancement in bioavailability will lead to a subsequent reduction in drug dose, rendering the therapy cost-effective and obliterating any undue drug dumping in the body. • Danazole, a poorly bioavailable gonadotropin inhibitor, showed a drastic improvement in bioavailability when administered as a nanosuspension as compared to the commercial Danazole macrosuspension Danocrine. Danazole nanosuspension led to an absolute bioavailability of 82.3%, whereas the marketed Danazole suspension Danocrine was 5.2% bioavailable. In addition, Danazole nanosuspension resulted in a reduction in the inter-subject variability and fed/fasted ratio of Danazole.

23. Parenteral drug delivery • Nanosuspensions overcome the problems of solubilization capacity, parenteral acceptability, physical instability, high manufacturing cost and difficulties in scale-up as in other parenteral formulations. • Nanosuspensions reduce the cost of therapy and improve therapeutic performance of drug by improving the parentally tolerable dose of drug. • Clofazimine nanosuspension shows improved stability and efficacy when compared to the liposomal Clofazimine in M. avium-infected female mice. PULMONARY DRUG DELIVERY • Drugs that are poorly soluble in pulmonary secretions can be administered by the formulation of the nanosuspensions. • These drugs are delivered as suspension aerosols or as dry powders by means of dry powder inhalers. • Nebulized form of the aqueous nanosuspensions is used for the delivery of drugs to lung. • Bupravaquone nanosuspensions formulated by nebulization. Nanosuspension of Budesonide has also been prepared successfully for pulmonary delivery.

24. Ocular DRUG DELIVERY • Nanosuspension is an ideal approach for ocular delivery of hydrophobic drugs as they improve the saturation solubility of the drug. • Nanosuspensions of glucocorticoid drugs; hydrocortisone, prednisolone and dexamethasone show improved shelf-life and the bioavailability after ophthalmic application due to enhanced rate of drug absorption. DRUG TARGETTING • As the surface properties and in-vivo behaviour of nanosuspensions can be altered easily by changing either the stabilizer or the milieu, so they are good candidates for targeted delivery. • Brain targeting of peptide Dalargin has been done successfully by the modification of the nanoparticle surface using poly-isobutyl cyanoacrylate.

25. Marketed preparations Parenteral Liquid Nanosuspension Johnson & Johnson High Pressure Homogenization For schizophrenia Lyophilized powder for injectable suspensions Abraxis Bio-sciences nab™ Metastatic Breast cancer Oral Liquid Nanosuspension Par Pharmaceutical Media Milling Appetite Stimulant

26. Marketed preparations

27. Overview of the technologies and patents / patent applications on which the various homogenization processes are based

28. Case study 1 • Title: Development and Characterization of Mucoadhesive Nanosuspension of Ciprofloxacin • Reference: VIKAS JAIN*, PRADEEP KARE, DEEPIKA JAIN and RANJIT SINGH, Development and Characterization of Mucoadhesive Nanosuspension of Ciprofloxacin, Acta Poloniae Pharmaceutica - Drug Research, Vol. 68 No. 2 pp. 273- 278. • Abstract: Mucoadhesive nanosuspension of ciprofloxacin was designed to improve its solubility, bioavailability and efficacy in the treatment of typhoid fever. After development, characterization of ciprofloxacin nanosuspension was performed to conclude that it exhibited satisfactory physical stability and can be effectively formulated as novel gastroretentive drug delivery systems . • Result: The system exhibited enhanced dissolution rate due to decreased particle size. The incorporation mucoadhesive polymers can increase the gastric residence time of the ciprofloxacin resulting in an efficient system. The enhanced residence time in gastrointestinal tract may decrease the dosing frequency as well as dose of drug.

29. Case study 2 • Title: Analytical Evaluation of formulated Occular Nanosuspension of Pilocarpine Nitrate • Reference: Kalpana Anumolu*, Vijay Amritharaj R, Suchetha Reddy Aleti and N. Senthil Kumar, Analytical Evaluation of Formulated Occular Nanoasuspension of Pilocarpine Nitrate, International Journal Of Research In Pharmacy And Chemistry. • Abstract: Ophthalmic nanosuspension of Pilocarpine nitrate was prepared by quassi emulsion method using Eudragit S 100 and was evaluated for pH, entrapment efficiency, UV, Drug polymer compatibility by FT-IR and DSC. The readings obtained showed that the percentage drug entrapment efficiency was ranged between 65-80%. DSC studies were carried out for pure drug and physical mixture of pure drug with polymer; data from DSC study conclude that there were no drug polymer interactions between the drug and polymer combinations. • Result: Results obtained were within the limits indicating the proposed method for the formulation is good for single dosing and validation results were accurate and precise. Also the prepared ocular nanosuspension have a pH of 6.4-7.4 (Eye have a tolerable capacity of 5-7.4 pH)

30. conclusion • Despite of stability problems, Nanosuspensions appears to be a unique and yet commercially viable approach to combating various problems such as poor bioavailability that are associated with the delivery of hydrophobic drugs, including those that are poorly soluble in aqueous as well as organic media. • Attractive features, such as increased dissolution velocity, increased saturation solubility, improved bio-adhesiveness, versatility in surface modification and ease of post-production processing, have widened the applications of nanosuspensions for various routes.

31. bibliography • NANOSUSPENSION: A PROMISING DRUG DELIVERY SYSTEM Geeta Vikram Yadav* and Sushma R. Singh. http://www.pharmacophorejournal.com/ • Katteboinaa S, Drug nanocrystals: A novel formulation approach for poorly Soluble drugs, International journal of pharmtech research, 1(3), 2009, 682-694. • Dineshkumar B, Nanosuspension Technology in Drug Delivery System, Nanoscience and Nanotechnology: An International Journal, 3(1), 2013, 1-3. • Patel AP, A review on drug nanocrystal a carrier free drug delivery, IJRAP, 2(2), 2011, 448-458. • Dhiman S, Nanosuspension: a recent approach for nano drug delivery system, International journal of current pharmaceutical research, 3, 2011, 96-101. • Basics about nanosuspensions and current research in the field - for pharmacy, Rahil Dalal, Published in: Health & Medicine, www.slideshare.net.