New drug delivery system

1. New Drug Delivery
System
Dr. Ashishkumar Baheti
MD Pharmacology

2. Introduction
A therapeutic system is defined as a drug
containing preparation or a device that
releases one or more drugs continuously in
a predetermined pattern for a fixed period
of time either systemically or to a specified
target organ.

3. Classical drug delivery
Problems associated with this approach
1. Reduced potencies because of partial degradation.
2. Toxic levels of administration.
3. Increase costs associated with excess dosing.
4. Compliance issue due to administration pain.
5. Show significant fluctuations in drug levels.

4. Why newer drug delivery system ?
1. Deploy to a target site to limit side effects.
2. Shepard drugs through specific areas of the body without degradation.
3. Maintain a therapeutic drug level for prolonged periods of time.
4. Predictable controlled release rates.
5. Reduce dosing frequency and increase patient compliance.

5. Classification
1) Nonbiological DDS
a) Oral DDS
b) Transdermal DDS
c) Ophthalmic DDS
d) Intranasal Drug Delivery system
e) Respiratory DDS

6. Cont.
2) Biological DDS
a) Liposomal DDS
b) Transfersome
c) Monoclonal Antibodies
d) Microspheres

7. OROS (Oral Osmotic System)
 Osmotic core containing drug surrounded by a semipermeable membrane with
a delivery orifice
 Safe and effective delivery of theophylline (treatment of asthma)
 Other example:
Metoprolol
Nifedipine

8. ADVANTAGES
1. Continuous and constant rate of drug delivery.
2. Drug with shorter T1/2 can be used.
3. GIT mucosa not damaged.
4. Gastric enzyme degradation can be overcome.
5. Good compliance.

9. Disadvantages
 Subject to dose dumping if membrane breaks
 [e.g. someone chews it]
 Slightly more expensive to formulate than
coating tablets
 Possible hole plugging

10. GITS
 Slowly releases drug into the intestinal tract over a 24 hour period.
 Based on Push Pull Method.
 Example : Nifedipine , Doxazosin

11. Intragastric floating tablets
 Contains drug
homogenously
dispersed in
hydrocolloid
 Action: Hydrocolloid
absorbs fluid –colloid
gel formed –drug
released by diffusion
 Eg: Valium tab 
Drug


12. pH sensitive DDS
 Targeted drug delivery at selected pH range in GIT
 Prepared by coating drug with pH sensitive polymer like Ethyl cellulose
 Eg: Nisoldipine

13. Transdermal DDS
 A transdermal drug delivery device, is a device which provides an
alternative route for administering medication, allowing for
pharmaceuticals to be delivered across the skin barrier
 In 1979 first transdermal scopolamine patch for motion sickness was
approved by USFDA.

14. Basic Components of Transdermal
Systems
The components of transdermal devices include:
1. Polymer matrix or matrices.
2. The drug to be delivered
3. Permeation enhancers
4. Other excipients

15. Advantages
 First pass metabolism avoided.
 Maintains constant blood drug levels.
 Improves bioavailability.
 reduced frequency of drug administration.
 Reduced side effects.
 Easy to discontinue the drug.
 Increased patient compliance.
 Noninvasive.

16. Mechanism of action
Transdermal permeation of a drug involves the following steps:
1. Penetration of stratum corneum.
2.Permeation of drug through viable
epidermis
3. Uptake of the drug by the capillary
network in the dermal papillary layer.

17. Routes
 Transappendageal
 Transepidermal
1. Intracellular
2. Intercellular

18. Factors affecting transdermal DDS
1) Biological factors
• Thickness and integrity of stratum corneum
• Site of application
• Skin hydration
• Blood flow in that region

19. Contd.
2) Physicochemical
 Size of drug molecule
 Membrane permeability
 pH of the drug
 Drug metabolism by skin flora
 Lipid solubility
 Drug depot

20. Polymer Matrix
The Polymer controls the release of the drug from the device.
polymers for transdermal devices are:
a) Natural Polymers:
 e.g. Cellulose derivatives, Zein, Gelatin, Shellac, Waxes, Proteins, Gums and
their derivatives, Natural rubber, Starch etc.
b) Synthetic Elastomers:
 e.g. Polybutadieine, Hydrin rubber, Polysiloxane, Silicone rubber, Nitrile,
Acrylonitrile, Butyl rubber, Styrenebutadieine rubber, Neoprene etc.
c) Synthetic Polymers:
 e.g. Polyvinyl alcohol, Polyvinyl chloride, Polyethylene, Polypropylene,
Polyacrylate, Polyamide, Polyurea, Polyvinylpyrrolidone,
Polymethylmethacrylate, Epoxy etc.

21. Drug
 Physicochemical properties
1. The drug should have a molecular weight less than approximately 1000
daltons.
2. 2. The drug should have affinity for both – lipophilic and hydrophilic
phases.
3. The drug should have low melting point.

22. Permeation Enhancers
classified as:
 a) Solvents
water alcohols – methanol and ethanol; alkyl methyl sulfoxides
 b) Surfactants
 Anionic Surfactants: e.g. Dioctyl sulphosuccinate,
 Nonionic Surfactants: e.g. Pluronic F127, Pluronic F68, etc.
 Bile Salts: e.g. Sodium ms taurocholate, Sodium deoxycholate,
 Biary system:. Propylene glycol-oleic acid and 1, 4-butane diol-linoleic
acid.

23. TYPES OF TRANSDERMAL PATCHES
1. Single-layer Drug-in-
Adhesive
This system is characterized
by inclusion of drug
directly within the skin-
contacting adhesive. . The
rate of release of drug
from this type of system is
dependent on the
diffusion across the skin.

24. Multi-layer Drug-in-Adhesive
This is similar to Single-
layer Drug-in-Adhesive
in that drug is
incorporated directly
into the adhesive but
has addition of a
membrane between
two layers or addition
of multiple drug-in-
adhesive layers under a
single backing film.

25. Drug Reservoir-in-Adhesive
The system design has
inclusion of a liquid
compartment
containing a drug
solution/suspension
separated from release
liner by semi-
permeable membrane
and adhesive.

26. Drug Matrix-in-Adhesive
The system has
inclusion of semi-solid
matrix containing drug
solution/ suspension
which is in direct contact
with the release liner.

27. Transdermal Drug Delivery (TDD)

28. Examples of transdermal patch
 Scopolamine for motion sickness.
 Nicotine for tobacco cessation.
 Estrogen for menopausal symptoms.
 Nitroglycerin for angina.
 Lidocaine to relieve peripheral pain for shingles( Herpes Zoster).
 Fentanyl for cancer pain control.

29. OCUSERT
 Pilocarpine, a parasympathomimetic agent for glaucoma
 Acts on target organs in the iris, ciliary body and trabecular meshwork
 Ethylene-vinyl acetate copolymer
 Carrier for pilocarpine : alginic acid in the core of Ocusert
 White annular border :EVA membrane with titanium dioxide (pigment) (easy for
patient to visualize)

30. Fig. 6. Schematic diagram of the Ocusert.

31. Contd.
Advantages
1) Drug application convenient (Once a week)
2) Stabilization of Diurnal variation in IOT.
3) Guard against dangerously high IOT due to irregularly
instilled drops.
Disadvantages
1) Foreign body sensation
2) Difficulty in retention of the device
3) Increased cost
4) Detailed instruction.

32. Lacrisert
Patients with dry eyes (keratitis sicca)
A substitute for artificial tears
Placed in the conjunctival sac and softens within 1
h and completely dissolves within 14 to 18 h
Stabilizes and thickens the precorneal tear film and
prolongs the tear film break-up time

33. Intranasal Drug Delivery
 Nasal delivery
 Ayurvedic system of East India
 Psychotropic drugs and hallucinogens in South America
 Proteins and peptides delivery
 Advantages of nasal delivery
 Lower doses
 More rapid attainment of therapeutic blood levels
 Quicker onset of pharmacological activity
 Fewer side effects

34. Examples of Intranasal Drug Delivery
Systems
 Intranasal sustained-release formulation
 Nasal absorption with Clofilium tosylate, enkephalin analogs
 Tobispray
 Dry, metered-dose nasal aerosol
 Vasoconstrictor (tramazoline), steroid (dexamethasone isonicotinate), antibiotic
(neomycin sulfate)

35. RESPIRATORY DDS
 ADVANTAGES
 AVOIDS FIRST PASS METABOLISM
 RAPID ONSET OF ACTION
 CONTROLLED RATE OF ADMINISTRATION POSSIBLE

36. Aerosol drug delivery system
 The ideal size for a therapeutic aerosol should not be more than 5 µm to
penetrate into the tracheo-bronchial tree and smaller airways if peripheral
deposition is required.
 It includes:
1)Metered dose inhaler
2) Dry powder inhaler
3) Jet nebulizer

37. Pharmaceutical Aerosols:
Cromolyn Sodium Aerosol
Use: Anti-asthmatic ;Anti-allergic
Amyl nitrite inhalant :
Use: Vasodilator
Propylhexadrine inhalant :
Use: Nasal Decongestants
Metaproterenol sulfate inhalation aerosol :
Use: Bronchodilator
Tuaminoheptane inhalant :
Use: Vasoconstrictor

38. Inhaled Insulin
 approved in January 2006 by FDA.
 approved for those over 18 years of age with diabetes
 short-acting powder form of insulin that is inhaled before
each meal
 Side effect -coughing, shortness of breath, sore throat
and dry mouth

39. What is a liposome?
A liposome is a spherical vesicle with a
membrane composed of a phospholipid and
cholesterol bilayer.
hydrophilic
Hydrophobic

40. Modes of Liposome/Cell Interaction
Adsorption Endocytosis
Fusion Lipid transfer

41. Why Use Liposomes in Drug Delivery?
 Drug Targeting can be achieved.
 Pharmacokinetics - efficacy and toxicity.
 Decrease harmful side effects.
 Increases duration of action and decrease frequency
of administration.
 Protects drug

42. Classes of Liposomes
Conventional Long circulating
Immuno Cationic

43. Problems with conventional liposomes
 Tendency of liposome to localize in the RES may cause RES impairment
 Short circulation time
 Rapid uptake by liver and spleen prevents specific targeting

44. Immuno liposomes
 Antibodies or ligands are
attached to the liposome surface
to increase the binding to specific
epitopes/ receptors on target
cells
 Stealth liposomes:
Formulated to escape RES and
increase the circulation time.
Polymers, polyethylene
glycols,synthetic phospholipids
are used to coat liposomes

45. Uses of stealth liposomes
 Targeting anticancer drugs to cancer sites.
 Depot applications for prolonged therapy periods.
 For diseases of vascular origin e.g.- haematological malignancies.

46. Liposomes Help Improve
 Rapid metabolism
 Therapeutic index
 Unfavorable pharmacokinetics
 Low solubility
 Irritation
 Lack of stability

47. Doxil
Chemotherapy drug doxorubicin
Anemia, damage to veins and tissue at injection, decrease
platelet and WBC count, toxic to
Treats Kaposi’s sarcoma lesions or cancer tumors
Modifications of liposome “stealth”
keeps doxorubin in blood for 50 hours instead of
20 minutes
concentrates at KS lesions and tumors

48. Amphotericin B
Side effects: nephrotoxicity, chills, and fever
Systemic fungal
infections in immune compromised patients
AmB - kills ergosterol-containing fungal cells, also
kills cholesterol-containing human cells

49. No decrease in effectiveness of drug against fungi
Liposomal Formulation of AmB
Decrease in toxicity
Exact Mechanism of liposomes not understood
Diffusion
Lipid transfer
AmB
Lipid

50. Problems with Liposomal Preparations of
Drugs
 cost
 Lack long term stability (short shelf life)
Physical and chemical instability
Freeze dry and pH adjustment
 Low “Pay Load” - poor encapsulation
 Possibility of new side effects
Doxil “hand and foot syndrome”
 Efficacy
CFTR

51. CFTR
Gene Therapy
Delivers cDNA of Cystic Fibrosis Transmembrane Conductance
Regulator (CFTR) to epithelial tissue of respiratory system
Fuse to cell membrane and
incorporate cDNA into cell
Clinical trials - no significant
change in symptoms
Now trying adeno associated
virus
Cationic liposome

52. Uses
 Anticancer Drugs-
 Anti bacterial-
 Antiviral-
 DNA material-
 Enzymes-
 Radionuclide-
 Fungicides-
 Vaccines -
Duanorubicin
Triclosan, Clindamycin
AZT
cDNA – CFTR
Hexosaminidase A
In-111, Tc-99m
Amphotericin B
Hepatitis B antigen,
Rabies virus
glycoprotein

53. • Studies with insulin show that liposomes may
be an effective way to package proteins
and peptides for use
• Clinical Trials for several liposomal formulations
• More studies on the manipulation of liposomes
Future

54. Transfersomes
 Deformable and ultraflexible artificial lipid vesicle.
 It delivers drugs or genetic material into a cell.
 Its bounding membrane is more flexible than that of a liposome.
 penetrates the skin when applied nonocclusively.
 Affinity to bind and retain water.

55. Monoclonal Antibodies
 Antibodies that are identical because they are produced by one type of
immune cell, all clone of a single parent cell.
 These monoclonal antibodies specifically bind to particular substance.
 They can then serve to detect or purify that substance.

56. The types of mAb designed
A. Murine source mAbs: rodent mAbs with excellent
affinities and specificities. may lead to allergic or
immune complex hypersensitivities.
B. Chimeric mAbs: chimers combine the human
constant regions with the intact rodent variable
regions. Also cause human antichimeric antibody
response (30% murine resource)
C.Humanized mAbs: contained only the CDRs of the
rodent variable region grafted onto human variable
region framework

57. Evolution of Therapeutic Antibodies

58. Types of monoclonal antibodies
1) Naked monoclonal antibodies -- those with no drug or
radioactive material attached to them
Most widely used at present.
1) Conjugated monoclonal antibodies --those joined to
chemotherapy drugs, radioactive particles or toxins

59. Rituximab
 Chimeric monoclonal antibody that targets the CD20 B-
cell antigen.
 This antigen is expressed on 90% of B-cell neoplasms
 This antibody thus leads to the elimination of all B-cells
from the body (including cancerous ones), allowing new,
healthy B-cells to be produced from lymphoid stem cells.

60. Trastuzumab
 Humanized monoclonal antibody
 Acts on HER2/neu (erbB2) receptor, which is overexpressed
in breast cancer.
 Such cells, when treated with Herceptin, undergo arrest in
the G1 phase of the cell cycle and experience a reduction in
proliferation.
 This can reduce the rate of relapse of breast cancer by 50%
during the first year.

61. Other monoclonal antibodies
Monoclonal
antibodies
Antigen Target Type
Alemtuzumab CD52 Humanized
Daclizumab CD25 α subunit Humanized
Gemtuzumab CD33 Humanized
Cetuximab EGFR (ErbB - 1) chimeric
Bevacizumab VEGR Humanized

62. Obstacles to the use of monoclonal
antibodies in cancer treatment
 Antigen distribution of malignant cells is highly heterogeneous, so some
cells may express tumor antigens, while others do not.
 Tumor blood flow is not always optimal
 High interstitial pressure within the tumor can prevent the passive
monoclonal antibody from binding.

63. Monoclonal antibodies- cytotoxic
conjugate
Gemtuzumab ozogamicin (Mylotarg):
 Humanized monoclonal antibody against CD33.
 Covalently linked to caicheamicin, a potent antitumour
antibiotic.
 Following binding to CD33, Gemtuzumab ozogamicin
undergoes endocytosis with cleavage of caicheamicin
within the lysosome which then enter the nucleus.

64. Radioimmune conjugates
 They provide monoclonal antibody targeted delivery
of radioactive particles to tumour cells
 I -131 is commonly used isotope.
 The gamma particles emitted by I -131 can be used
for both imaging and therapy
Immunotoxin
 Denileukin deftitox – made from the genetic
recombination of IL – 2 and the catalytically active
fragment of diphtheria toxin.
 Approved for the treatment of recurrent T- cell
lymphoma.

65. Microspheres
 They are roughly
cellular but not living,
molecules similar to a
cell
 They are mainly used
for cancer therapy and
targeted drug delivery

66. Contd.
 Essentially solid porous particles (1 - 100 micrometer
diameters).
 Can be made from a broad range of polymeric materials,
including proteins, polysaccharides, polyesters and lipids.
 Can both target their drug cargo by physical trapping in
blood vessels (chemoembolisation) and sustain the action
of a therapeutic agent through controlled release.
 Doxorubicin, mitomycin C, cisplatin and 5-fluorouracil

67. Drug-Eluting Stents (DESs)
 Bare metal stent coated with a drug-polymer matrix
 Local and controlled delivery of drugs to stop restenosis
 So far, only TWO FDA approved DESs in USA
1) CYPHER Sirolimus-eluting Coronary Stent
2) TAXUS Paclitaxel-Eluting Coronary Stent

68. How Sirolimus Works ?
 Lipophilic
 Rapidly crosses smooth
muscle cell membranes
 Solubility in blood very low
 Binds to intracellular
receptor proteins FKBP12,
FRAP,mTOR
 Reduces T – Cell
proliferation and
macrophage function

69. Paclitaxel
 Used as a anti-proliferative drug in Cancer treatment
 Highly lipophilic and diffuses extremely well into arterial tissues
 Smooth muscle cells are more sensitive to paclitaxel than endothelial
cells
 Paclitaxel is dosed to block smooth muscle cell proliferation and
migration

70. Viral vectors
• Viruses have evolved a way of encapsulating and
delivering genes to human cells in a pathogenic
manner.
• Scientist are attempting to take advantage of natures
delivery system.
• Viruses would be genetically altered to carry the
desired normal gene and turn off the natural occurring
disease within the virus.

71. THANK YOU