Newer drug delivery systems

1. NEWER DRUG
DELIVERY SYSTEMS
- Dr. Chandini
- Moderator: Dr. Princy Pallatty
1

2. Introduction -
• Drug delivery systems refers to approaches,
formulations, technologies, and systems for transporting
a pharmaceutical compound in the body as needed to
safely achieve its desired therapeutic effect.
• Based on two basic parameters:
(A) Route of entry
(B) Dosage form
2

3. • Method of drug delivery - significant effect on efficacy
• Slow progress in Rx of severe diseases  growing
need for multidisciplinary approach to delivery of
therapeutics
• Current trend:
Targeted delivery
&
Sustained release formulations
3

4. • Any drug delivery system comprises of:
a) Drug formulation
b) Medical device/dosage form/technology to
carry the drug inside the body
c) Mechanism for the release
• Limitations of Conventional drug delivery:
- requires higher dosage
- lower effectiveness
- toxicity & A/E
4

5. • New drug delivery systems
(Targeted DDS & Controlled drug release systems)
1) ↑ efficacy
2) Site specific delivery
3) ↓ toxicity/side effects
4) ↑ convenience
5) Viable treatments for previously incurable diseases
6) Potential for prophylactic applications
7) Better patient compliance
5

6. Various Drug Delivery Systems
1. Carrier-based Drug Delivery System
2. Transdermal DDS
3. Mucoadhesive DDS
4. Osmotically-controlled DDS
5. Drug devices
6

7. Drug Delivery Carriers
• Special molecule or system, which encapsulates the
drug (both hydrophobic & hydrophilic) within
biocompatible polymers.
• Adv –
1) Targeted & controlled release (maintaining
therapeutic drug levels)
2) Biodegradable, non-immunogenic, biocompatible &
high chemical stability
3) Avoidance of 1st pass metabolism
4) Minimal drug leakage during transit
7

8. Types -
8
1. Micelles
2. Liposomes
3. Niosomes
4. Ethosomes
5. Transferomes
6. Virosomes
7. Cochleates
8. Cubosomes
9. eLiposomes
10. Cyclodextrins
11. Dendrimers
12. Nanoparticles
13. Immunoconjugates
14. Microspheres
15. Resealed erythrocytes

9. Micelles
• Formed by aggregates of
amphiphilic molecules.
• Hydrophobic core –
encapsulates poorly water soluble drugs,
Hydrophilic exterior
• Estradiol (Estrasorb™) - only FDA-approved micelle,
- topical Rx for vasomotor symptoms of menopause.
• BIND-04 : iv administered micellar system for prostate
ca Rx, under trial
9

10. Liposomes
10

11. Some commercially available marketed liposomal products -
11
Trade Name Drug Name Indication
Ambisome Amphotericin B Systemic fungal
infectionsAbelset
Amphotec
Doxil
Doxorubicin Breast cancerMyocet
DaunoXome Daunorubicin Kaposis sarcoma
DepoCyt Cytarabine Lymphomatous
meningitis
Oncaspar PEGasparaginase ALL

12. Under trial
Trade
Name
Drug Name Indication Phase
Onco-TCS Vincristine NHL I/II
LEP-ETU
EndoTAG-1
Paclitaxel Breast/Ovarian/ I/II
Aroplatin Cisplatin Colorectal cancer I/II
OSI-211 Lurtotecan Lung cancer/recurrent
ovarian cancer
II
12

13. Niosomes
13
• Non-ionic surfactant-based
vesicle
• Stabilized by cholesterol &
anionic surfactant.
• Specially designed for skin delivery
– facilitated fusion with membranes
- can be superficially modulated (eg. Rx of Herpes)
- full dermal penetration (eg. Transdermal delivery of
insulin)

14. 14
Eg. nimesulide, flurbiprofen, piroxicam, ketoconazole
bleomycin
Preferred over liposomes (expensive, chemically unstable)

15. Ethosomes & Transferosomes
• ↑ flexibility d/t addition of ethanol or surfactant.
• Skin delivery
• Ethosomes –
eg. Minoxidil, Acyclovir
15
Transferosomes –
eg. Estradiol, Norgestrel,
Insulin

16. Virosomes
• Liposomes carrying viral proteins.
• Route: Mucosal (nasal, vaginal etc), ID & IM
• Proposed in immunization.
• Eg. HIV1
16

17. Cochleates
• Liposomal derivative
• More stable than other lipidic particles
• composed mainly of
charged
phosphatidylserine
• no internal aqueous
space
• Amphotericin B,
F VIII, proteins,
peptides & DNA
17

18. Cubosomes
• Similar to cochleates
• Novel lipid delivery
systems
• Cube-like appearance
• Bio-compatible & bioadhesive
• eg. Oral administration of cubosomes loaded with
Insulin  hypoglycemic effect in rats
18

19. eLiposomes
• Liposome with internal emulsion droplets.
• Ability to further control the location and time of release
from liposome with ultrasound.
• Eg. Doxorubicin.
19

20. Cyclodextrins
• Composed of sugar molecules bound together in a ring
• 3 types: α, β and ϒ
• β cyclodextrin is ideal – d/t large cavity size
• Act as permeation enhancer to improve drug absorption
• Eg: dexamethasone, nitroglycerin, nimesulide, iodine
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21. Dendrimers
21
• Nanometer-sized,
highly branched
macromolecules
• Consist of
– central core
- branching units
- terminal functional groups
• Ligands attached at the external surface  Targeting
effectiveness
• PEG chains  Stability & protection from MPS

22. Nanoparticles
• Nanometer scale materials (10-200 nm)
- display different physicochemical properties
(small size, surface structure & high surface area)
- able to adsorb or encapsulate drugs, protecting it
against chemical and enzymatic degradation.
• Biodegradable polymeric nanoparticles
– Potential drug delivery devices
- DNA carriers (Gene Rx)
22

23. 1. Nanopores
23
• Cancer research & Rx
• Pores tiny enough to pass
only single strand of
DNA through them
 highly precise &
efficient DNA sequencing
• Can control rate of drug
diffusion in body.

24. 3. Carbon nanotubes –
• Circulates well within the body
(covalent or non covalent bonding)
• Enter readily into the cells.
• To deliver prodrugs to cancer cells
eg. Cisplatin
• No significant toxicity in body fluids
24

25. 4. Quantum dots –
• Miniscule semi-conductor particles containing a
radioactive substance (Cadmium) in their core that emit
diff wavelengths of radiations
• Applications –
Delivery siRNA (Gene Rx) Folic acid-QD complexes
25

26. 2. Bucky balls –
(Buckminster fullerene)
• Extremely stable & withstand
high temperature
• Drug delivery vehicles for cancer therapy
• Bucky ball- Antibody combination
- delivers antitumor drugs.
• To fight allergy.
• As powerful antioxidants and also inhibitor of HIV.
26

27. 5. Gold nanoshells (AuNS) –
• Hollow silica spheres covered with gold
• Both diagnostic and therapeutic applications,
• Able to deliver antitumor drugs (doxorubicin,
paclitaxel) into cancer cells
& siRNA, and ss DNA (Gene Rx)
Eg. Aurimmune (TNF α)
AuroShell
- head & neck Ca 27

28. 28

29. Trade Name Drug Name Indication
Abraxane Albumin-bound
Paclitaxel np
Breast Ca
NSCLC
Pancreatic Ca
Emend Aprepitant Vomiting
Tricor Fenofibrate Hyperlipidemia
Venofer Iron sucrose IDA in CKD
Ryanodex Dantrolene sodium Malignant
hyperthermia
Ostim Hydroxyapatite Bone substitue
29

30. Issues/Drawbacks
1) Potential toxicity – major concern (NPs can cross
biological membranes)
2) Surface interactions  become ineffective
3) Specific issues: In Cancer Rx,
NPs cannot extend upto core of tumor
↓
aggregates at periphery
↓
Does not fully eliminate tumor
4) Degradation by lysosomes 30

31. Immunoconjugates
• Ab-drug conjugates
• Recomb mAbs covalently bound to a drug.
• Uses specificity of mAbs to target drugs @ specific site.
• Eg.
Gemtuzumab ozogamicin (Mylotarg)
– 1st approved, for Rx of AML.
Naptumomab estafenatox – Advanced renal disease.
Brentuximab vedotin – HL
* Immunonanoparticles & Immunoliposomes
31

32. Microspheres
• Free flowing powders
- proteins or synthetic polymers
- biodegradable in nature
- particle size < 200 μm.
• Contain both hydrophilic & hydrophobic drugs
• Polymers classified into two types:
o Synthetic Polymers
o Natural polymers 32

33. Synthetic polymers
33
Non-biodegradable Biodegradable
• Eg. PMMA,
glycidyl
methacrylate
• Carrier toxicity
(parenteral use)
• Poly alkyl cyano acrylates
- parenteral, ophthalmic, oral prepns
• Poly lactic acid
- sustained release of narcotic
antagonist,
- Anti cancer agents (cisplatin,
cyclo phosphamide, & doxorubicin).
• Not seen (degrade to non-toxic
products) – suitable for parenteral
use

34. Natural polymers
• Sources:
Proteins – Albumin (TDD for tumor cells)
Gelatin microspheres (delivery of IFNs to
phagocytes),
Collagen
Carbohydrates - Agarose, Chitosan, Starch
Chemically modified carbohydrates - Polydextran,
Poly starch.
34

35. Resealed erythrocytes
• Erythrocytes - potential carrier capability
• Eg. Erythrocyte-encapsulated L-asparginase - enhanced
ALL therapy
35

36. • Advantages:
1) Bio-degradable, biocompatible, posses long
circulation t1/2
2) Entrapment of drug does not require the chemical
modification
3) Prolong the systemic activity of drug.
4) Larger amount of drug can be encapsulated
• Disadvantage:
1) Limited as carrier to non-phagocyte target tissue
2) Clumping of cells and dose dumping 36

37. Transdermal Drug Delivery System
• Self contained, discrete dosage forms,
applied to skin  delivers drug at controlled rate
• Adv:
1) Avoidance of first pass metabolism & GI
incompatibility
2) Greater patient compliance.
3) Enhance therapeutic efficacy
4) Termination of therapy is easy
37

38. Transdermal patches
38
Scopolamine patch
- Motion sickness
Hydrogel transdermal
patch
- Rx of burns
Insulin patch

39. Sonophoresis
• Localized, non‐invasive, convenient and rapid method
of delivering LMW drugs & macromolecules into the
skin by ultrasonic energy.
• US (20kHz-16MHz)
 ↑ skin permeability
• Reverse US technology
- extraction of fluid or
compounds out of the skin 39

40. Laser assisted Transdermal DDS
• New technology of drug delivery
• Effective drug permeation-enhancement approach for
facilitating drug delivery into or across the skin.
• Laser  controlled disruption and ablation of the
stratum corneum
• Eg. LAD of Mtx
LAD of drugs to treat
facial scars
40

41. Mucoadhesive DDS
41
• Mucosal membranes – Oral MDDS, ocular, nasal,
vaginal drug delivery systems

42. 42
Buccal
Nasal (methylcellulose, vaccines)
Ocular
(eg. LB HCl + PAA)
Vaginal

43. Osmotically controlled DDS
43
• Osmotic pressure – driving force to release drug in
controlled manner
• Widely accepted technique
• Oral –
eg. GI therapeutic systems (GITS)
Parenteral –
eg. Implantable pumps
• Mono-/bi-/multilayer systems

44. GastroIntestinal Therapeutic Systems
(GITS)
• Eg. Once-daily Nifedipine GITS tablet
• Based on Osmotic push–pull technology
• Approved for Rx of HTN & Px of angina
44

45. Commercially available oral osmotic systems -
Trade name Drug name Indication
Nifediac
Afeditab
Nifedipine
HTNAlpress LP
Minipress XL
Prazocin
Calan SR
Covera HS
Verapamil
Efidac/24 Pseudoephedrine Cold medication
Glucotrol XL Glipizide Diabetes
Volmax Albuterol Bronchospasm 45

46. Implantable pumps
Rose-Nelson pump
46
Higuchi-Leeper osmotic pump
Pulsatile release
osmotic pump

47. Drug devices
47

48. Drug eluting stents
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• 1st drug eluting stent approved
(Europe & USA)
- coated with Paclitaxel/Sirolimus
• Coronary stent –
slow release of drug to block
cell proliferation
↓
prevents fibrosis & clot formation
↓
Restenosis

49. Drug eluting micro stents
49
• Implanted in angle of iris & cornea
• Coated with polymer-
drug compound
• Diffusion-controlled
release of Paclitaxel or
Mitomycin –
- to avoid blockade of
stent

50. Ocusert
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• Eg. Pilocarpine
• Sandwiched b/w 2 layers of
ethylene-vinyl acetate
membrane
• Used in Rx of glaucoma
• Placed in the Cul de sac (floats with tears)
• Tears penetrate the microporous membrane & release
Pilocarpine.

51. Hormone releasing devices
513
rd
Gen IUCDs Norplant

52. Microchips
• Hold drug in a reservoir
• Implanted into the body under LA
• Released with the help of hand held wireless device
• Chronic conditions requiring careful monitoring &
precise therapy
• Compliance is
improved
• Eg: PTH for
osteoporosis
52

53. Iontophores
 Use of an electric current
to introduce ions of a
medicament into
bodily tissues
• Depending upon the
dose & energy
- act locally or
carried into blood
stream
 Eg: pilocarpine
53

54. PCA pump
• Computerized pump – allows patient to control their pain
• Patients recovering from surgery
• Children (4-6 yrs)
54

55. Insulin delivery devices
1. Open loop delivery
• Patient administering insulin to
his or herself at different times
of the day.
• Eg. SC insulin inj (M/C)
Insulin pens, jets, inhalers,
open loop pumps etc
• Requires >/= 3 inj daily,
serial blood glucose
measurement. 55

56. Insulin pens:
• NovoPen
• Composed of Insulin
cartridge, dial & a
needle
• Adv –
Less injection pain
Convenient & easy to handle
More accurate dosing
56
• Disadv –
Expensive
2 diff insulins cannot
be mixed

57. Insulin jets –
• Delivers insulin subcutaneously without using needle
• By pressurizing the liquid through a small orifice
↓
high speed jet
↓
penetrate the skin &
underlying tissue.
57

58. Micropump Insulin delivery system –
• Computerized syringe - delivers insulin into the
subcutaneous tissue every few minutes in tiny amount
24 hours a day through a canula placed in the
subcutaneous tissue
58

59. Insulin inhalers –
• Contains powdered form of insulin,
• Delivered with a nebulizer into the lungs,
• Absorbed more rapidly than subcutaneous
insulin.
• Exubera – 1st product (2006)
discontinued.
• Afrezza – only FDA approved
inhaled insulin (2014)
Rapid-acting human insulin
59

60. Recent trends in Nanomedicine
Nanorobotics –
• deals with nanometer scale robots
Applications -
 Target & destroy Cancer cells
60

61. Diagnosis, testing and
monitoring of microorganisms,
tissues and cells in the blood
stream
61
In Surgery – diagnosis &
correction by nanomanipulation
Gene Rx

62. References –
1) R R Bhagwat, I S Vaidhya. Novel Drug Delivery Systems: An
overview. International Journal of Pharmaceutical Sciences &
Research. 0975-8232.4(3).970-82
2) N Martinho, C Damgé, C P Reis. Recent Advances in Drug
Delivery Systems. Journal of Biomaterials and
Nanobiotechnology, 2011, 2, 510-526
3) Shaikh R, Raj Singh TR, Garland MJ, Woolfson AD, Donnelly
RF. Mucoadhesive drug delivery systems. Journal of Pharmacy
and Bioallied Sciences. 2011;3(1):89-100.
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