Nanotechnology and Insulin: A Perfect Marriage?

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NANOTECHNOLOGY AND INSULIN A PERFECT
MARRIAGE ????
Awanish Kumar, Ashwini Kumar Department of
Biotechnology NIT Raipur
Presented By Ashwini Kumar Doctoral Research
Scholar Department of Biotechnology National
Institute of Technology (NIT) Raipur C.G
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Diabetes..

• gt 550 million by 2030 (WHO)
• IDDM and NIDDM
• Hyperglycemia
• CVD, Retinopathy, Neuropathy, Nephropathy,
  Pulmonary Disorders, Infections..
• Oral Sulfonylureas, Biguanides, TZDs,
  a-glucosidase inhibitors, Incretin analogs, DPP-4
  inhibitors, SGLT2 inhibitors, GSK-3
  inhibitors..
• Parenteral Subcutaneous Insulin

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Insulin..

• Peptide hormone (51 a.a) secreted by ß-cells of
  the pancreas.
• Regulates the blood glucose level by transporting
  glucose inside adipocytes and skeletal muscles
  for further use.
• Recombinant Human Insulin (rHI) is currently the
  final answer to the uncontrolled diabetes (type 1
  and type 2).
• Formulations Short acting, Intermediate acting,
  Long acting, Ultra long acting.
• Regulates pre-prandial and post-prandial blood
  glucose.
• Parenteral (sub-cutaneous) administration.
• Injection site morbidity comes as resistance.

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Alternatives..
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Inhaled Insulin Formulations

• Lungs are highly vascularized, surface area
  50-140 m2 .
• Thin alveolar-capillary barrier, rapid
  absorption.
• No peptidases or proteases
• No pH variation
• Enhanced absorption with particle size 1-3µm in
  diameter larger particles are often swollowed
  through upper respiratory tract.
• Dry powder (Exubera and Technosphere) and Liquid
  (AERx iDMS).

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A. Exubera

• Pfizer/Nektar Pharmaceuticals
• Dry powder formulation
• First ever non-parenteral insulin reached market
  in 2006 withdrawn in late 2007
• Peak insulin concentration more quickly than
  sub-cutaneous route (45 minutes vs. 105 minutes).
• Spray-dried (lyophilized) excipients were
  mannitol, glycine, sodium citrate.
• 1 unit (3 mg) insulin or 3 units insulin per
  blister particle diameter lt 5 µm.

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Drawbacks of Exubera

• Not suitable for smokers, asthamatic patients
  COPD patients.
• Lung deposition.
• Decreased the respiratory volumes.
• A few patients were diagnosed with pulmonary
  malignancy (IGF-1 activity)
• Low market acceptibility

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B. Afrezza

• Developed by MannKind Corp. CA (USA) Approved by
  USFDA in June 2014.
• Technosphere Insulin (TI) rHI combined with
  fumaryl diketopiperazine.
• Technosphere particles were prepared by pH
  controlled crystallization of FDKP, polysorbate
  80, acetic acid and water.
• Median particle size 2-2.5 micron (µm)
• FDKP and Insulin are absorbed independently
  former excreted unchanged in urine.

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Contd..

• Insulin release mimics the pancreatic release
  pattern.
• Median Tmax from lungs to blood is 15 minutes.
• TI was found to ne non-cytotoxic to the bronchial
  cell lines (no membrane or tight junction
  damage).
• Hypoglycemic and weight gain events lesser than
  the SC injection.
• Better result in COPD and pulmonary patients as
  compared to Exubera, but still should be used
  with utmost precaution.

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Advantages..

• Better bioavailibility no 1st pass metabolism
• Ease of access
• Easy storage and transportaion
• No chance of microbial contamination

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Oral Insulin Formulations..

• Insulin is a peptide !!!!
• PROTEASE INHIBITORS (trypsin, chymotrypsin,
  elastase, carboxypeptidase, aminopeptidase,
  insulin degrading enzymes).
• pH variation, chemical degradation (1-7.5)
• Must adhere to the mucus layer..MUCOADHESIVE
• Intestinal cell permeability (hydrophillic
  large MW)..ABSORPTION and PERMEATION ENHANCERS
  (ZOT 4-CNAB).

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Oral Insulin Formulations..
OI FORMULATION COMPANY PHASE
ORMD 0801 Enteric coated, Protease inhibitors, Absorption Enhancers, Capsule Oramed Pharmaceuticals Israel III
IN-105 Conjugated at B29 lysine with PEG via acetyl chain, tablet Biocon Bristol Myers III
CAPSULIN Enteric coated capsules Diabetology UK IIa
DIASOME Hepatic Directed Visecles (HDV) liposomes loaded with Insulin and Hepatocyte Target Molecule (HTM) attached Diasome, USA II
NN1954 GIPET Technology medium chain fatty acids, Novo Nordisk Merrion Pharmaceuticals II
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Advantages..

• Easiest way of delivery.
• Low immunogenecity
• Low mitogenecity
• Low dosage forms and good bioavailibility

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NIDDK Study
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On-going Experiments..

• Chitosan, Alginate, Chitosan-Alginate, Liposomes,
  Dextran, Pectin, Cyclodextrin
• PLGA (FDA approved), PLA, PCL, Poly Acrylic Acid
  (PAA)
• Thiolated chitosan, better mucoadhesive and
  extended drug release.
• PAA-Cys Mucoadhesive, permeation enhancer,
  protease protection.
• PolyElectrolyte Complexes (PECs) by mixing
  oppositely charged ions

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C. Buccal Insulin

• Aerosol spray in the oralpharyngeal cavity.
• Presystemic metabolism in GIT and Liver is
  avoided.
• Better accessibility
• Low pH variation
• Good surface area
• Only animal for test is pig

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Oral- Lyn

• Generex Biotechnology, Ontaraio, Canada
• Aerosol insulin preparation.
• Average produced micelles is gt 10 µm so cant go
  to lungs.
• Each puff 10 U insulin stable at RT for approx 6
  months
• Surfactant, solubilizer, micelles forming agent.
• Appear in circulation within 5-10 minutes after
  administration.
• Short Tmax and faster time to peak glucose
  uptake than SC route.

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Withdrawn !!!!

• AutoImmune, Biosante, Coremed, Eligen, Nobex in
  phase II trials.
• Aerodose (by Aerogen)
• Unknown (by Abott)
• HIIP (Eli Lilly)
• Alveair (Coremed)
• BioAir (Biosante)
• Unknown (Epic Therapeutics)
• Spiros (Elan Pharmaceuticals)

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Why Nanotechnology ????

• Better than conventional drug loading, delivery
• Large diabetic population and increasing
• Large scope
• Easy for difficult molecules (peptides and
  proteins)

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• THANK YOU