DRUG RELEASE METHODOLOGIES FOR NANOMEDICINES ADDRESSING CHALLENGES - - PowerPoint PPT Presentation

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DRUG RELEASE METHODOLOGIES FOR NANOMEDICINES ADDRESSING CHALLENGES - - PowerPoint PPT Presentation

Nov 09, 2023 111 likes •517 views

DRUG RELEASE METHODOLOGIES FOR NANOMEDICINES ADDRESSING CHALLENGES PROF. PADMA V. DEVARAJAN Dept. of Pharmaceutical Sciences and Technology Institute of Chemical Technology (ICT) Deemed University, Elite status and Centre of Excellence (GOM),

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DRUG RELEASE METHODOLOGIES FOR NANOMEDICINES ADDRESSING CHALLENGES

  • PROF. PADMA V. DEVARAJAN
  • Dept. of Pharmaceutical Sciences and Technology

Institute of Chemical Technology (ICT) Deemed University, Elite status and Centre of Excellence (GOM), Mumbai 400 019, INDIA E-mail: pvdevarajan@gmail.com

DISSO EUROPE – ROMANIA, OCTOBER 20-21, 2016

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NANOMEDICINES

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NANOCARRIERS IN NANOMEDICINE

Microemulsion

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ADVANTAGE - NANOMEDICINE

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TARGETTED DELIVERY ENHANCED EFFICACY DECREASED SYSTEMIC TOXICITY

SUCCESS STORIES

INFECTIOUS DISEASES CANCER

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Nanosystems and Need for in vitro Dissolution testing

Nanosystems are promising Urgent Need to develop Standardized Testing Methods Unavailability of standardized in vitro dissolution method

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OFFICIAL USP DISSOLUTION APPARATUS

Type I Type II Type III Type IV Type VII

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CHALLENGES IN DISSOLUTION METHOD FOR NANOMEDICINES

Size & Separation

  • Difficulty in Separation of NP

from medium Complex System

  • Complexity of System type
  • Target specific release
  • Environment specific release

(pH, temperature)

  • Programmed Release
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DISSOLUTION METHODS FOR NANOMEDICINES

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 Sample & Separation methods  Membrane Diffusion (Dialysis Sac) methods  Others (Micro dialysis, Dynamic dissolution & 2 stage reverse dialysis)

DISSOLUTION METHODS

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MODIFIED OFFICIAL APPARATUSES

 Constant Volume  Continuous Flow Methods

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Ultrafiltration Ultracentrifugation Key parameters : Sample separation technique Agitation conditions

SAMPLE & SEPERATION METHODS

  • NP directly added in medium & separation techniques applied
  • Drug content in supernatant or filtrate is analyzed
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Pressure Ultrafiltration

  • Completely separate Nanoparticles

from release media within 5 min

  • Prevent Clogging of filter pores

Syringe Filtration

  • Use of Syringe filters with smaller

pore size (0.1 to 0.02 µm) has been used

SAMPLE & SEPARATION METHODS

SCHEMATIC

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Difficulty in separation of NP from media though high external energy applied Long-time & High speed can result in destabilization

  • f system (e. g. Nanoemulsion & Liposome)

Drug release continues during separation process, which can lead to erroneous results

DISADVANTAGES OF SAMPLE & SEPARATION METHODS

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DYNAMIC DISSOLUTION ADVANCED SAMPLE AND SEPARATE METHOD

Utilize ion-

  • r

drug-selective electrodes to monitor the dissolution/release profiles of electroactive drugs Not suitable for non-electroactive drugs

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DIALYSIS METHODS FIXED VOLUME

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Nanosystems separated from the release medium through dialysis membranes that are permeable to the free drug but impermeable to the nanosystems Side-by-Side- Dialysis Dialysis Sac Method Reverse Dialysis Sac Method

MEMBRANE DIFFUSION METHODS (DIALYSIS BAG)

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DEVELOPMENTS IN DISSOLUTION METHOD

Dialysis Bag

Stirring Magnet inside the bag

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ROTATING DIALYSIS CELL FOR PARENTERAL DEPOT FORMLATIONS

BASKET MODIFIED INTO A DIALYSIS CELL

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ADAPTATION OF DIALYSIS AND USP TYPE I

BASKET MODIFIED INTO A DIALYSIS CELL

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ADAPTATION OF DIALYSIS AND USP TYPE I & II (Phamatest)

  • Pharma Test offers the “dispersion releaser”
  • High sensitivity for fluctuations in release rate
  • Works well for compounds with poor, moderate and good solubility
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ADAPTATION OF DIALYSIS AND USP TYPE I & II (Phamatest)

SCHEMATIC STIRRING ELEMENT

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Agitation Conditions Ratio between Donor & acceptor cell Volume

Inside Volume 6 to 10 fold less than medium volume

Molecular Weight Cut-Off (MWCO) of membrane

MWCO 100 times more than drug MW

KEY PARAMETERS INFLUENCING DRUG RELEASE IN DIALYSIS METHODS

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ADAPTATION OF DIALYSIS AND CONTINUOUS FLOW CELL

A a flask containing fresh release medium B a peristaltic pump C the proposed release device D a sampling flask 1 rubber seals 2 glass lid 3 release medium outlet 4 release medium inlet 5 release device

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ADAPTATION OF DIALYSIS AND CONTINUOUS FLOW CELL FOR NLC

Conventional Dialysis bag method with Proposed flow apparatus

In vitro CP (Clobetasol Propionate) release CONVENTIONAL DIALYSIS SAC TECHNIQUE SIGNIFICANT DIFFERENCE BASED ON SITE OF SAMPLING

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Disadvantages

  • f Dialysis

Methods

Hindrance to drug diffusion through membrane Lack of adequate agitation inside membrane Violation of sink condition

(fixed volume)

Reverse system causes high dilution

  • f Nano system

thus medium loses its discriminatory ability

DISADVANTAGES OF DIALYSIS METHODS

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CONTINUOUS FLOW THROUGH CELL TYPE IV

This method has been widely used to investigate drug release from microspheres But Nanoparticulate systems have very small particle size (<100nm), challenging to test their release in USP IV. CHALLENGE:

  • NP clog the filter leading to slow flow rates and high pressure build-

up in the system

  • Pass through filters, thus resulting in erroneous data.

SOLUTION: novel Dialysis Adaptor is introduced in USP type IV

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CONTINUOUS FLOW THROUGH CELL TYPE IV

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CONTINUOUS FLOW THROUGH CELL TYPE IV

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High Discriminative power Avoided Filter clogging Avoided violation of sink conditions Avoided lack of agitation

CONTINUOUS FLOW THROUGH CELL TYPE IV - DIALYSIS CELL

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CASE STUDIES USP APPARATUS IV WITH DIALYSIS CELL

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  • 98 % of SCT high molecular weight drug (MW ~3000) in 1 hr

indicates dialysis membrane not rate limiting

  • Sustained release seen with SCT NPs

INORGANIC NANOPARTICLES OF SALMON CALCITONIN USP IV

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BUPARVAQUONE SLN USP TYPE I vs IV

Parameters USP IV USP I Volume of media(5%sls) 100ml 500ml Speed 120rpm 100rpm Flow rate 6ml/min

  • Sample volume

1ml 5ml Aliquot volume 1ml 5ml

  • 20

20 40 60 80 100 120 0.00 20.00 40.00 60.00 80.00 %Cumulative release Time(hrs)

Plot of %Cumulative release vs Time

IN SITU SLN Drug suspension 0.00 10.00 20.00 30.00 40.00 50.00 60.00

  • 50.0

0.0 50.0 100.0 %Cumulative release Time(hrs)

Plot of %Cumulative release Vs Time

sln release drug suspension

USP I

USP I – LOWER DRUG RELEASE DUE TO ABSENCE OF SINK CONDITION USP IV – COMPLETE RELEASE AND LOWER STANDARD DEVIATIONS

USP IV

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5 10 15 20 25 30 35 40 45 50 2 4 6 8 10 12 14 16 18 20 22 24 26 %Cumulative drug release Time (h) In vitro drug release from SLN and Lipomer in 7.4 pH buffer

PGDS- SLN

5 10 15 20 25 30 35 40 45 2 4 6 8 10 12 14 16 18 20 22 24 26

% Cumulative drug release Time (h) In vitro drug release from SLN and Lipomer in 4.8 pH buffer PGDS- SLN PGDS- Lipomer

AMPHOTERICIN B NANOSYSTEM USP TYPE IV- LIPOMER vs SLN

Volume of Media-100mL Sample volume-1mL Flow rate-6mL/min Aliquot volume-1mL

  • SLN - 26.26±2.70% AmB release after 24h
  • Lipomer - 41.38±0.45% AmB release after 24h
  • SLN - 23.50±3.22% AmB release after 24h
  • Lipomer - 39.98±5.74 % AmB release after 24h

DISCRIMINATION BETWEEN TWO NANOSYSTEMS OBSERVED

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FUTURE PERSPECTIVES

  • USP IV WITH DIALYSIS CELL APPEARS PROMISING
  • USP II MODIFIED APPARATUS ALTHOUGH

PROMISING COULD LACK SINK CONDITION FOR POORLY SOLUBLE DRUGS

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  • SYSTEMS THAT ADDRESS SPECIFIC

REQUIREMENTS OF NANOSYSTEMS

– No release in circulation – Release prediction at site of delivery

  • COST EFFECTIVE STRATEGIES MAY BE EXPLORED

FUTURE PERSPECTIVES

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  • PROF. DEVARAJAN’S RESEARCH

GROUP

36

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INSTITUTE OF CHEMICAL TECHNOLOGY

Deemed University , Elite status and Centre of Excellence (GOM)

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ACKNOWLEDGEMENTS

  • WORLD BANK – TEQIP- ICT, FOR FINANCIAL

SUPPORT

  • SOTAX INDIA PVT. LTD., FOR USP IV WITH

DIALYSIS CELL

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