NANOSUSPENSIONS 1
CONTENTS
Introduction
Characteristics
Merits
Stability issues
Methods of Manufacture
High-pressure homogenizat...
Introduction
3
Introduction
Theformulationofpoorlywater-solubledrugshasalwaysbeenachallengingproblemfacedbypharmaceuticalscientists
T...
Introduction…
“Nanosuspensionsrefertothedispersesystemscontainingdrugparticlesofsubmicronsize,alsoknownasdrugnanoparticl...
Characteristics
6
7
Instability
Improved water-and lipid- solubility
Characteristics
8
Characteristics…
Merits
9
Merits
Applicabletopoorlywater-solubleaswellaspoorlywater-andlipid-solubledrugs
Increasedbioavailability
Increasedsa...
Merits
Usefulindrugtargeting–passivetargeting
Easeofmanufactureandscale-up
Decreaseindose
Decreaseinfoodeffect
11
Stability issues
12
Stability issues 13
Issue
Reason
Solution
Agglomeration
large surface area of nanoparticles → hightotal surfaceenergy...
Stability issues… 14
Methods of Manufacture
15
Methods of Manufacture 16
In-situ formation
Emulsion template
Microemulsiontemplate
High-pressure homogenization
Medi...
High-pressure homogenization 17
Principle:
Cavitation
High-shear forces
Inter-particle collisions
High-pressure homogenization 18
Processed to micro size in colloid mill
High-pressure homogenization 19
In the homogenization gap, according to Bernoulli’s equation, the dynamic pressure of th...
High-pressure homogenization 20
Media/Pearl Milling 21
Principle:
the impaction of the milling media with the drug
high energy and shear forces genera...
Media/Pearl Milling 22
Glass/zirconium oxide/
Highly crosslinkedpolystyrene
Formulation
23
Formulation 24
Stabilizer
Stabilizerplaysanimportantroleintheformulationofnanosuspensions.Intheabsenceofanappropriates...
Formulation 25
Organicsolvents
Organicsolventsmayberequiredintheformulationofnanosuspensionsiftheyaretobepreparedusing...
Formulation 26
Otheradditives
Nanosuspensionsmaycontainadditivessuchasbuffers,salts,polyols, osmogentandcryoprotectant...
Evaluation
27
Evaluation 28
BIOMOLECULES
Applications
29
Applications 30
Topical formulations:
Incorporation of Nanosuspensions into topical formulation → supersaturated system...
Applications… 31
Parenteral formulations:
For administration by the parenteral route, the drug either has to be solubil...
Applications… 32
Pulmonary formulations:
Thedrugsusedinsuspensionaerosolsanddrypowderinhalersareoftenjetmilledandhavepa...
Applications… 33
Ocular formulations:
Nanosuspensions can prove to be a boon for drugs that exhibit poor solubility in ...
Applications…(targeted delivery) 34
Recent Advances
35
Recent advances 36
Shegokaret. al. reported surface-modified nevirapinenanosuspensionsto target the viral reservoirs of ...
Recent advances… 37
Kayseret. al. reported enhanced delivery of amphotericin B to brain in the form of Nanosuspensions d...
Marketed Formulations 38
Brand name
API
Manufacturer
Use
Oncospar
PEG –L– Asparaginase
Enzon
Acute lymphoidleukemi...
Conclusion 39
Despiteproblemsofstabilitynanosuspensionsappeartobeauniqueandyetcommerciallyviableapproachtocombatingproble...
References 40
1.PatravaleVetal.Nanosuspensions:apromisingdrugdeliverystrategy. JournalofPharmacyandPharmacology.2004;56:8...
THANK YOU
41
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Nanosuspensions

Basics about nanosuspensions and current reaseach in the field - for pharmacy
Published on: Mar 3, 2016
Published in: Health & Medicine      
Source: www.slideshare.net


Transcripts - Nanosuspensions

  • 1. NANOSUSPENSIONS 1
  • 2. CONTENTS Introduction Characteristics Merits Stability issues Methods of Manufacture High-pressure homogenization Media-milling Formulation 2 Evaluation Applications Recent advances Marketed formulations References Conclusion
  • 3. Introduction 3
  • 4. Introduction Theformulationofpoorlywater-solubledrugshasalwaysbeenachallengingproblemfacedbypharmaceuticalscientists Theproblemisevenmoreintensefordrugssuchasitraconazole,astheyarepoorlysolubleinbothaqueousandorganicmedia,andfordrugshavingalogPvalueof2 Thereisagrowingneedforauniquestrategythatcantackletheformulation- relatedproblemsassociatedwiththedeliveryofhydrophobicdrugs. Nanosuspensionsduetotheiruniquefeatureshaveshownthepotentialtofillthislacuna. 4
  • 5. Introduction… “Nanosuspensionsrefertothedispersesystemscontainingdrugparticlesofsubmicronsize,alsoknownasdrugnanoparticlesornanocrystals,asthedispersedphaseinanaqueousmedium.” 5
  • 6. Characteristics 6
  • 7. 7 Instability Improved water-and lipid- solubility Characteristics
  • 8. 8 Characteristics…
  • 9. Merits 9
  • 10. Merits Applicabletopoorlywater-solubleaswellaspoorlywater-andlipid-solubledrugs Increasedbioavailability Increasedsaturationsolubilityduetolargersurfaceareaofnanoparticles Increaseddissolutionrate–relatedtoincreasedsaturationsolubilityaccordingtoNoyes-Whitneyequation Absorbedbyendocytosis Adhesiveness–comparedtomicrocrystal Canbegivenbyvariousroutesofadministration–I.Vroute 10
  • 11. Merits Usefulindrugtargeting–passivetargeting Easeofmanufactureandscale-up Decreaseindose Decreaseinfoodeffect 11
  • 12. Stability issues 12
  • 13. Stability issues 13 Issue Reason Solution Agglomeration large surface area of nanoparticles → hightotal surfaceenergy → thermodynamicallyunfavourable → particles tend toagglomerate to minimizethe surface energy. Stabilizers: Ionic (electrostatic) –SDS, SLS, Lecithin Non-ionic (steric) – Poloxamer, PEG, HPMC, PVA Sedimentation (rare due to small particle-size) Mainly due to agglomeration Prevent agglomeration, Open-flocs Change in crystalline state Due to high-energy top- down processes Stabilizers depending on suspension Stability during solidification (spray/freeze-drying) drug nanocrystalgrowth or agglomeration during drying process matrix formers, such as mannitol, sucrose andcellulose, intonanosuspensionsprior todrying
  • 14. Stability issues… 14
  • 15. Methods of Manufacture 15
  • 16. Methods of Manufacture 16 In-situ formation Emulsion template Microemulsiontemplate High-pressure homogenization Media milling Sonoprecipitation Dry co-grinding Bottom-up approaches Top-down approaches Solubility problem- drug must be soluble in atleastone solvent
  • 17. High-pressure homogenization 17 Principle: Cavitation High-shear forces Inter-particle collisions
  • 18. High-pressure homogenization 18 Processed to micro size in colloid mill
  • 19. High-pressure homogenization 19 In the homogenization gap, according to Bernoulli’s equation, the dynamic pressure of the fluid increases with the simultaneous decrease in static pressure below the boiling point of water at room temperature. In consequence, water starts boiling at room temperature, leading to the formation of gas bubbles, which implode when the suspension leaves the gap (called cavitation)and normal air pressure is reached again. The implosion forces are sufficiently high to break down the drug microparticlesinto nanoparticles. Additionally, the collision of the particles at high speed helps to achieve the nano-sizing of the drug.
  • 20. High-pressure homogenization 20
  • 21. Media/Pearl Milling 21 Principle: the impaction of the milling media with the drug high energy and shear forces generated energy input to break the microparticulatedrug into nano-sized particles
  • 22. Media/Pearl Milling 22 Glass/zirconium oxide/ Highly crosslinkedpolystyrene
  • 23. Formulation 23
  • 24. Formulation 24 Stabilizer Stabilizerplaysanimportantroleintheformulationofnanosuspensions.Intheabsenceofanappropriatestabilizer,thehighsurfaceenergyofnano-sizedparticlescaninduceagglomerationoraggregationofthedrugcrystals. Themainfunctionsofastabilizeraretowetthedrugparticlesthoroughly,andtopreventOstwald’sripeningandagglomerationofnanosuspensionsinordertoyieldaphysicallystableformulationbyprovidingstericorionicbarriers. Thedrug-to-stabilizerratiointheformulationmayvaryfrom1:20to20:1andshouldbeinvestigatedforaspecificcase.Stabilizersthathavebeenexploredsofarincludecellulosics,poloxamers,polysorbates,lecithinsandpovidones. Lecithinisthestabilizerofchoiceifoneintendstodevelopaparenterallyacceptableandautoclavablenanosuspension.
  • 25. Formulation 25 Organicsolvents Organicsolventsmayberequiredintheformulationofnanosuspensionsiftheyaretobepreparedusinganemulsionormicroemulsionasatemplate. Co-surfactants Thechoiceofco-surfactantiscriticalwhenusingmicroemulsionstoformulatenanosuspensions.Sinceco-surfactantscangreatlyinfluencephasebehaviour,theeffectofco-surfactantonuptakeoftheinternalphaseforselectedmicroemulsioncompositionandondrugloadingshouldbeinvestigated.
  • 26. Formulation 26 Otheradditives Nanosuspensionsmaycontainadditivessuchasbuffers,salts,polyols, osmogentandcryoprotectant,dependingoneithertherouteofadministrationorthepropertiesofthedrugmoiety.
  • 27. Evaluation 27
  • 28. Evaluation 28 BIOMOLECULES
  • 29. Applications 29
  • 30. Applications 30 Topical formulations: Incorporation of Nanosuspensions into topical formulation → supersaturated systems (increased saturation solubility) → increased diffusion pressure of drug into skin Oral-cavity formulations (paste, gel, patches): For drugs that did not have sufficiently high bioavailability in traditional oral formulations → small particles → increased adhesion and prolonged residence time Peroralformulations: Reduction in inter-subject variation, improved dose proportionality and increased availability due to increase in bioadhesion.
  • 31. Applications… 31 Parenteral formulations: For administration by the parenteral route, the drug either has to be solubilized or have particle/globule size below 5μm to avoid the capillary blockade. The current approaches for parenteral delivery include salt formation, solubilizationusing co-solvents, micellarsolutions, complexationwith cyclodextrinsand liposomes. However, there are limitations on the use of these approaches because of limitations on their solubilizationcapacity and parenteral acceptability. In this regard, liposomes are much more tolerable and versatile in terms of parenteral delivery but, they often suffer from problems such as physical instability, high manufacturing cost and difficulties in scale-up.
  • 32. Applications… 32 Pulmonary formulations: Thedrugsusedinsuspensionaerosolsanddrypowderinhalersareoftenjetmilledandhaveparticlesizesofmicrons.Becauseofthemicroparticulatenatureandwideparticlesizedistributionofthedrugmoietypresentinsuspensionaerosolsanddrypowderinhalers, thefollowingdisadvantagesareencountered: 1.limiteddiffusionanddissolutionofthedrugatthesiteofactionbecauseofitspoorsolubilityandmicroparticulatenature,whichmayaffectthebioavailabilityofthedrug 2.rapidclearanceofthedrugfromthelungsbecauseofciliarymovements 3.lessresidencetimeforthedrugs,leadingtoabsenceofprolongedeffect 4.unwanteddepositionofthedrugparticlesinpharynxandmouth Nanosuspensionscansolvetheproblemsassociatedwithconventionalsystemsbecauseoftheirversatilenature.
  • 33. Applications… 33 Ocular formulations: Nanosuspensions can prove to be a boon for drugs that exhibit poor solubility in lachrymal fluids. For delivery of such drugs, approaches such as suspensions and ointments have been recommended. Also, reduction in irritation can be achieved Targeted drug delivery: Nanosuspensions can be used for targeted delivery as their surface properties and in-vivo behaviour can easily be altered by changing either the stabilizer or the milieu. Their versatility and ease of scale-up and commercial production enables the development of commercially viable nanosuspensionsfor targeted delivery.
  • 34. Applications…(targeted delivery) 34
  • 35. Recent Advances 35
  • 36. Recent advances 36 Shegokaret. al. reported surface-modified nevirapinenanosuspensionsto target the viral reservoirs of HIV: 1.Surface-modification with PEG → decreased cellular uptake 2.Surface-modification with dextran → increased cellular uptake as compared to bare nanosuspension. Garg et. al. reported that nanosuspensionof asulacrineshowed a prolonged release with a decrease in the Cmaxvalue due to uptake of slow-dissolving nanoparticles by RES and then release over a period of time due to increased solubility resulting from the change in pH inside the cell.
  • 37. Recent advances… 37 Kayseret. al. reported enhanced delivery of amphotericin B to brain in the form of Nanosuspensions due to increased adsorption of apolipoprotein-E on the nanoparticle surface. Recently, paclitaxel nanosuspensioncoated with P-gpinhibitory surfactants was prepared with a 5-fold increase in tumor- inhibition rate as compared to solution. Increased cutaneous delivery of tretinoinin nanosuspensionform as compare to solution and nanoemulsionforms reported by Faddaet. al.
  • 38. Marketed Formulations 38 Brand name API Manufacturer Use Oncospar PEG –L– Asparaginase Enzon Acute lymphoidleukemia (ALL) MegaceES Megestrolacetate PARpharmaceuticals Weightloss PICN Paclitaxel Sun Pharma Anti-cancer Rapamune Sirolimus Wyeth Immunosuppresant Emend Aprepitant Merck Anti-emetic
  • 39. Conclusion 39 Despiteproblemsofstabilitynanosuspensionsappeartobeauniqueandyetcommerciallyviableapproachtocombatingproblemssuchaspoorbioavailabilitythatareassociatedwiththedeliveryofhydrophobicdrugs,includingthosethatarepoorlysolubleinaqueousaswellasorganicmedia.
  • 40. References 40 1.PatravaleVetal.Nanosuspensions:apromisingdrugdeliverystrategy. JournalofPharmacyandPharmacology.2004;56:827-40 2.L.Wuetal.Physicalandchemicalstabilityofdrugnanoparticles. AdvancedDrugDeliveryReviews.2011;63:456-69 3.Mulleretal.Nanpsuspensions:Aformulationapproachforpoorlysolubleandpoorlybioavailabledrugs.Handbookofpharmaceuticalcontrolledreleasetechnology,1stEdition(2005),publishedbyMarcelDekker,pg345-56 4.DasSetal.Nanosuspension:anewvehiclefortheimprovementofthedeliveryofdrugstotheocularsurface.ApplicationtoamphotericinB. Nanomedicine:Nanotechnology,BiologyandMedicine.2011;7:242-47 5.Gargetal.Formulationandpharmacokineticevaluationofanasulacrinenanocrystallinesuspensionforintravenousdelivery.InternatoinalJournalofPharmaceutics.2009;367:179-86 6.SinghKetal.Surfacemodifiednevirapinenanosuspensionsforviralreservoirtargeting:Invitroandinvivoevaluation.InternatoinalJournalofPharmaceutics.2011;421:341-52
  • 41. THANK YOU 41

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