Novel& nano drug delivery systems

1. Novel Drug Delivery Systems
• Oral controlled release delivery systems.
• Parenteral controlled drug release delivery systems.
• Target drug delivery systems
• Nanoparticles.

2. Oral Controlled release drug delivery systems
• Modified release indicates:
• Modified to control time.
• Modified to control location of delivery.
• Two types of modified release dosage forms:
• Extended release: allows at least two-fold reduction in the dosing
frequency.
• Delayed release: releases the drug at a time other than immediate.

3. Rationale of controlled drug delivery:
To alter the pharmacodynamics and pharmacokinetics of drug by using novel drug
delivery systems.
Terminology:
Controlled release systems, which can provide some control whether of temporal or spatial
structure or both of drug release in the body. Attempt to control drug concentration in the
target tissue or cell.
Controlled drug delivery systems attempts to:
1/ Sustain drug action at a predetermined rate by maintaining a relatively constant, effective
drug level in the body with concomitant minimizing of undesirable side effects associated
with saw-tooth kinetic pattern.
2/ localize drug action by spatial placement of a controlled release system adjacent to or in
the desired tissue or organ.
3/ target drug action by using carriers or chemical derivatives to deliver drug to a particular
target cell type.

5. Modified release categories:
• Delayed release.
• Sustained release
• Site specific targeting.
• Receptor targeting

6. • Delayed release systems:
• Are those that use repetitive, intermitted dosing of a drug from one
or more immediate –release unit incorporated into a single dosage
form. Repeat action tablets, capsules and enteric coating tablets
where timely release is achieved by barrier coating.
• Sustained release systems:
• Includes any drug delivery system that achieves slow release of drug
over an extended period of time. The system maintains constant drug
level in the target tissue or cell. It is considered as controlled release.
• Site –specific targeting:
• Targeting drug to a certain specific biological location.
• Receptor targeting:
• Targeting to a particular receptor for a drug within an organ or tissue.

7. Uses:
• When less frequent administration is desired for drugs that are
eliminated rapidly from the body.
• When high peak blood levels due to rapid drug absorption from
conventional dosage forms are associated with adverse side effects.
• In the conventional dosage forms the physiologic factors are often
rate controlling and in controlled release the formulation is the rate
controlling factor.

8. Advantages of sustained and controlled release dosage
forms:
• Patient compliance.
• Reduced see-saw fluctuation (peak and valley).
• Reduced total dose and use of less amount of drug.
• Improved efficiency in treatment; better management of treatment in targeting
formulation.
• Economy in the cost and cost of hospitalization.
Disadvantages:
• Dose dumping.
• Less flexibility in accurate dose adjustment; the dose cannot be divided.
• Poor in vitro-in vivo correlation due to the so called absorption window.
• Individual variation.

9. Factors to be considered in designing sustained/controlled dosage forms:
• Biopharmaceutical factors:
• Dose size (0.5 – 1 gm)
• Dissociation constant pka
• Partition coefficient.
• Drug stability.
• Protein binding.
• Pharmacokinetic factors:
• Absorption.
• Distribution
• Metabolism
• Elimination t½

10. Requirements for a drug to be formulated in sustained /
controlled release dosage form:
• Desirable half-life 3-4 hours.
• High therapeutic index.
• Small dose.
• Desirable absorption and solubility characteristics.
• Desirable absorption window, drugs that exhibiting absorption
window is unsuitable for controlled release drugs.

11. Design and formulation of oral controlled release drug delivery systems
• Diffusion controlled systems
- Reservoir type.
- Matrix type.
• Dissolution controlled systems
- Reservoir type.
- Matrix type
• Methods using ion-exchange
• Methods using osmotic pressure.
• pH independent formulations. altered density formulations.
• Mucoadhesive systems.
• Intestinal release systems
• Colonic release systems

12. Diffusion controlled systems:
Release of drug is dependent on its diffusion through an inert membrane barrier.
• Reservoir devices:
• The core of drug, the reservoir, is surrounded by a polymeric membrane. The rate of
release of drug depends on the nature of this polymeric membrane. The polymer may be
used as coating to achieve sustained release in this case the polymer should not be
dissolved but should allow diffusion of drug to the outside.
• Matrix devices:
• The drug is dispersed homogeneously throughout the polymer matrix. Drug in the outer
layer dissolves firstly and then diffuses out the matrix. This process continues moving to the
interior. The rate dissolution of the drug particles must be much faster than the diffusion
rate of the dissolved drug leaving the matrix.
• Types of matrices:
• Hydrophilic matrices: (swelling, gelling)
• Cellulose derivatives as methyl cellulose 400, hydroxyethyl cellulose, hydroxypropylmethyl
cellulose and sodium carboxymethyl cellulose.
• Non-cellulose : Agar agar, alginates, mannose and glactose or modified starch.
• Lipid matrices: carnauba wax with sterylalcohol or stearic acid.
• Manufacturing:
• Direct compression of blend or granulation then compression.

13. Dissolution controlled System:
• Slow dissolution rate
will demonstrate
sustained properties.
To achieve this
appropriate salts or
derivatives, coating the
drug with a slowly
dissolving material or
incorporate the drug
into a tablet With
slowly dissolving
carrier.

14. Ion –exchange system:
• The drug is bound to the resin and released with an appropriately
charged ions in contact with ion exchange groups.
• Resin+-drug + X- resin+= X- + drug-
• Resin--drug + y+ resin-= y+ + drug+
• The free drug diffuses out of resin.

15. Osmotic controlled systems:
• Semipermeable membrane, water will flow from the body fluid to
inside the tablet owing to the osmotic pressure difference. Electrolyte
may be incorporated to provide the required osmotic pressure.
•

16. Swelling and expansion system (hydrogel):
• Conventional hydrogels swell slowly upon contact with water up to
100 times becoming too large to pass the pylorus and thus retained in
the stomach.

17. Muco ( bio) adhesive drug delivery systems:
• - Site – specific targeting, less
frequent dosing and
maintaining effective plasma
concentration. Bioadhesion may
be defined as state in which two
materials at least one of which
is a biological nature are held
together for expanded period of
time by interfacial forces.
Attachment of drug carrier to
specific location. Mucoadhesion
means attachment to mucous of
the GIT, urogenital, ear, nose,
eye and vaginal mucosa.

18. Gastroretentive drug delivery systems
• To increase the gastric residence of drug
delivery systems. Approaches include
floating, swelling or expansion,
mucoadhesive, modified shape, high –
density systems. The most commonly used is
floating as gastrorentive drug delivery system
GRDDS which retain the drug reservoir above
the absorption area and release the drug in a
controlled manner.
• Used for pathologies located in the stomach,
the duodenum or small intestine. It improves
bioavailability, reduces drug waste and
improve solubility for drugs that are less
soluble in high pH environment.

19. Colon specific drug delivery systems:
• Beneficial for Ulcerative colitis or Crohns disease or irritable bowel
syndrome.
• Protects the drug from delivery in the acidic medium and release it
only at the colonic environment.
• Requires longer release period and slower rate achieved by enteric
coating or use of slow release matrix.
• Hydrophilic gums which degrade in the colon help in release of drug
from the formulation.
• (chondroirtin sulphate, Guar gum, Pectin, and dextran are commonly
used.)

20. Parenteral Controlled Drug Delivery Systems
• Properties of parenteral controlled drug delivery system:
• a. safe from accidental release.
• b. simple to administer and remove.
• c. inert.
• d. biocompatible.
• e. mechanically strong.
• f. comfortable for the patient.
• g. capable of achieving high drug loading
• h. readily processable.
• i. easy to fabricate and sterilize.
• j. free from leachable impurities
Biodegradable polymers as:
• Polylactide / polyglycolide, polyanhydrides, polycaprolactone, polyorthoesters,
pseudopolyamino acid, polyphosphazenes, and natural polymers.

21. A- Injectables (Depot)
• 1. solution.
• 2. Colloidal dispersion
• a. Liposomes
• b. Noisomes
• c. Polymeric/ mixed
micelle
• d. Nanoparticle
• Nanosuspension
• Nanoemulsion
• Solid- lipid nanoparticle.
3. Microparticles
a. microsphere
b. microcapsule
c. microemulsion.
4. Released erythrocytes
5. Implants.
6. Infusion devices
a. Osmotic pumps
b. vapor pressure powdered
pump.
c. Battery powdered pumps.

22. Depot Systems:
• Long acting parenteral drug formulation, designed ideally to provide slow
constant, sustained and prolonged action.
• Control of drug release:
• Diffusion of drug through the polymer.
• Erosion of the polymer surface with concomitant release of physically
entrapped drug.
• Cleavage of the covalent bond between the polymer bulks or the surface
followed by diffusional drug loss.
• Diffusion controlled release at the physically entrapped drug with
bioadsorption of the polymer until drug depletion.

23. Approaches used in depot formulation:
• 1. use of low aqueous soluble salt.
• 2. use of large particle with crystallinity.
• 3. use of substances such as aluminium monasteries produce
prolonged absorption for the drug suspended in vegetable oil and
especially for gels.

24. 1. Dissolution controlled depot formulation:
• The rate limiting step of absorption is the dissolution and can be
achieved by:
• Formulation of salt complexes with low aqueous solubility
(benzathine penicillin)
• Suspension of macrocrystals (testosterone)

25. 2. Adsorption type depot formulations:
• Formed by binding drug molecule to an adsorpent. Only the unbound
drug molecule will be available for absorption. As soon as the
unbound drug absorbed a fraction of the bound drug will be released
to maintain equilibrium. ( vaccine preparation in which the antigen is
dispersed in aluminium gel to sustain their release and hence prolong
the duration.

26. 3. Encapsulation type depot formulation:
• Encapsulation of a drug solid within a permeation barrier or
dispersing drug particles in a diffusion matrix. The release of drug is
controlled by the rate of permeation across the permeation barrier
and rate of biodegradation of the barrier. ( gelatin, dextran, polylactic
acid, lactayl-glycolide copolymer, phospholipids, long chain fatty acids
and glycerides)

27. 4. Esterification depot type formulation:
• Esterifying a drug to form a bioconvertible prodrug ester and then
formulating it in an injection formulation. This will be the reservoir,
the rate of absorption limiting step is the partitioning of the esters
from the reservoir to the tissue fluid and the rate of the
bioconversion of drug ester to the active form.

28. Classification of depot systems:
1- Injectables 2- Implants
a. Solutions a. Solid implants
b. Colloidal dispersion
i. Liposomes
ii. Niosomes
iii.Polymeric/mixed micelles
iv.Nanparticles
b. In situ forming implants
i. Osmotic pumps
ii. Vapor pressure powdered pump
iii.Battery powdered pump
c. Microparticles
d. Resealed erythrocytes

29. 1- Injectables – Solutions:
• Aqueous being administered IM, the drug release may be controlled
by three ways:
• Increasing the viscosity of the vehicle by MC, CMC, or PVP and thus
decreasing the molecular diffusion and localizing the injected drug.
• By forming complex with macromolecules (MC, CMC or PVP) from
which the free drug releases on controlled rate of dissociation.
• By forming complex that reducing the solubility of the parent drug;
protamine insulin.

30. 2. Injectables – Colloidal dispersion
a. Liposomes
• liposomes are formed by the self-assembly of phospholipids molecules in an
aqueous environment. The molecules form a closed bilayer sphere in an
attempt to shield their hydrophobic groups from the aqueous environment
while still maintaining contact with the aqueous phase via the hydrophilic
groups.
• When suitably dispersed, they consist of a series of concentric bilayers
alternating with the aqueous compartment.
• Substances can be entrapped within their aqueous or lipid layer according to
their solubility.
• Depending on the phospholipid used and the ionic composition of the
medium, liposomes of various sizes and shapes can be obtained.
• Antibodies can be covalently coupled to liposomes to enhance their cell
specificity.

32. • Applications:
• Liposomal anticancer agents ( Doxorubicin)
• Liposomes as vaccine adjuvants.
• Liposomal anti infective agent ( Amphotericin)
• Methods of preparation:
• Sonication.
• High pressure homogenization.
• Detergent dialysis.
• Lipid-alcohol-water injection.
• Reverse phase evaporation.
• Dehydration-rehydration.

33. b. Niosomes:
• Niosomes are non-ionic surfactant vesicles obtained on hydration of
synthetic non-ionic surfactant of alkyl or dialkyl polyglycerol ether
class with or without incorporation of cholesterol or other lipids.

34. c. Polymeric/mixed Micelles:
• Nanosized core / shell assembles of amiphilic block copolymer as
polyethylene oxide. The hydrophobic core of polymeric micelle
provides an excellent host for the incorporation and stabilizing
anticancer agent. Nanosize of these micelles enable them to escape
the phagocytic effect of the reticuloendothelial system, enhance their
circulation life and penetration into the tumor tissue.

35. d. Nanoparticles - Nanosuspension:
• Nano-sized drug particles which is finely dispersed in an aqueous vehicle for either oral or topical
or parenteral and pulmonary administration. Particle size 200 – 600 nm.
• They ususlly contain 0.5 – 5% solid having particle size less than 5 microns for IM or Sc
administration.
• Preparation of nanosuspension:
• a. Buttom-up technology: precipitation method. The growing of microcrystals is controlled by
addition of surfactant.
• b. Top-down technology:
• Media milling ( nanocrystals)
• High pressure homogenization in non-aqueous media (nanopure)
• Combination of precipitation and high pressure homogenization ( nanoedge)
• Emulsion solvent diffusion method and microemulsion templete.
• Nanojet
• Drug cogrinding.
• Applications of Nanosuspension:
• Intera- articular or IV route, globules should be less than 5 microns to avoid capillary blockage.
(Pactitaxel anticancer)

36. Nanoemulsion/Microemulsion:
• Water and oil are made homogeneous, transparent and thermodynamically
stable by the addition of surfactant and having droplet diameter 10 – 100
nm.
• Oil, like myristic acid isopropyl ester
• Method of preparation:
• High – pressure homogenization.
• Microfluidization.
• Applications:
• IV for fat soluble vitamins and lipids for parenteral nutrition.
• Can be Intra-arterial, intrathecal, intraperitoneal IM or SC.

37. Solid- Lipid nanoparticles:
• Colloidal particles composed of a biocompatible / bidegradable lipid
matrix that is solid at body temperature and exhibit size range 100 –
400 nm. Prepared by hot high-pressure homogenization.
• Applications:
• Treatment of cancer.
• Transfection (DNA)
• Liver targeting
• Targeting the CNS
• Treatment of cardiovascular disease
• Treatment of parasitic disease
• Treatment of rheumatoid arthritis.

38. 2. Implants
• Cylindrical devices injected in the subcutaneous tissue by large
needle.
• Manufacture:
• Under temperature of 80 – 175 ˚C by melt-extrusion method, melt –
compression or injection molding.
• Applications:
• Local delivery of anesthetics.
• Antibiotics
• Controlled delivery LH-RH agonist (Zoladex and profact for prostate
cancer)

39. Mechanism of drug release from implant:
• a. Controlled drug release by diffusion:
• - membrane permeation.
• - matrix diffusion
• - microreservoir.
• b. Controlled drug release by activation:
• - osmotic pressure.
• - magnetism
• - ultrasound
• - vapor pressure
• - hydrolysis.
• Polymers used :
• Silicon polymers: Norplant: a subdermal implant to deliver levonorgestril for contraception.
A dual release vaginal ring.
• Polyethelyene vinyl acetate copolymer : IUD reservoir type system (Progestasert)
• Cellulose acetate

40. NANOPARTICLES
• They are submicron sized polymeric colloidal particles. The
therapeutic agent is encapsulated within their polymeric matrix or
adsorbed or conjugated on the surface. The particle size range from
10-1000 nm. The nm is 0.001 of the micron.

42. • Formulated nanoparticles may be nanocapsules in which the drug is
confined to a cavity surrounded by unique polmer membrane or
nanosphere which is a matrix in which the drug is physically and
uniformly dispersed.

43. Polymers used in nanoparticles:
• A- natural polymers as gums, gelatin and alginates, Chitosan, Gelatin.
• B- synthetic nonbiodegradable as celluloses, PVP and polyethylene glycol.
• C- synthetic biodegradable as polylactides, polyanhydrides and polycaprolactone.
Mechanisms of drug release:
• Swelling of the polymer followed by diffusion.
• Rupture of the polymer followed by release of entrapped drug.
• Dissociation of the drug from the polymer and deadsorption from the swelled
nanoparticles.

44. Types of Nanoparticles
1. Gold nanoparticles:
• Gold nanoparticles can provide effective carrier for biomolecules as DNA and
RNA, proteins and drugs protecting them from degradation and transporting
them across the cell membrane without toxicity.
2- Magnetic nanoparticles:
• Composed of magnetic iron, cobalt, cobalt ferrite and chromium dioxide.
Application in target drug delivery, gene delivery cell separation and cell
labeling.
3- Ceramic nanoparticles:
• Nanoparticles of silica, titanium, aluminia. They are simple and no affected by
change in pH or temperature.

45. 4- Nanogels:
• Made of flexible hydrophilic polymers. They are soluble in water and processes
large surface area and network to allow incorporation of molecules of drugs,
DNA/RNA and inorganic molecules. They are pH dependent release.
(cholesteroyl pullulan, cholesteroyl dextran and agarose cholesterol)
5- Solid lipid nanoparticles:
• These are submicron lipid emulsion where the oil had been substituted by solid
lipid. They are colloidal drug carrier for IV administration (TPN)
6- Protein nanoparticles:
• Albumin, gelatin and legumin. They are biodegrable, nanoantigenic,
metabolizable and amenable for surface modificationto allow covalent
attachment of drug and ligands.
7- Nanoshellls:
• Spherical core made from eilica surrounded by metal thin coat (gold or silver).
Antibodies or biomolecules are attached to the coat surface to target at tumor
site.

46. 8- Polymeric nanoparticles:
• Synthetic and semisynthetic degradable polymers as PLA, PGA,PLGA and
polmethacrylate.
9- Dendrimes:
• Demdrimes are unimolecular, monodisperse, micellar nanostructures with
regulary branched and symmetrical structure and highly functional end
groups. They contain three regions ( core, branches and surface). They are
similar in size to many proteins and biomolecules like insulin, Cytochrome C
and haemoglobin
10- Carbon nanotubes:
• Carbon nanotubes are hexagonal network of carbon atoms 1nm in diameter
and 1-100 nm in length. They can enter living cells without damage and can
transport drug molecule, proteins and nucleotides. Application include
immunoresponse, gene and RNA delivery.
• Carbon nanohornes are similar to nanotubes but they are closed at one end.

47. 11- Nanodiamonds:
• Diamond nanoparticles used to immobilize proteins and drug molecules and in cell
tracking and imaging.
12- Cyclodexrin nanosponges:
• Complex networks of cross-linked cyclodexrins with channels and pores inside. Used
to carry protein and drug molecules.
13- Implantable thin film:
• Nanoscale thin films carrying drug that can be controlled to release chemical agent
by applying an electrostatic field. Can be implanted in the body and useful in
chemotherapy.

48. Technology of preparation:
Nanoparticle from dispersion of
preformed polymer.
Nanoparticles from polymerization of
monomers.
a Solvent evaporation Emulsion
b Nanoprecipitation Miniemulsion
c Emulsification/solvent diffusion Microemulsion
d Salting out Interfacial polymerization
e Dialysis Controlled/ radical polymerizatio
f Supercritical fluid technology
•Nanoparticle from dispersion of preformed polymer.
• Nanoparticles from polymerization of monomers.

49. Nanoparticle from dispersion of preformed polymer.
1. Solvent evaporation:
• Polymer solution + volatile solvent = w/o emulsion, high speed
homogenization or ultrasonication the evaporation of the solvent by
continuous magnetic stirring at room temperature. Solidified
nanoparticles can be collected by ultracentrifugation, washed and
lyophilized.

51. 2. Nanoprecipitation:
• Principle: Precipitation of a preformed polymer from an organic solution
and the diffusion of the organic solvent in the aqueous medium in the
presence or absence of a surfactant.
• PLA ( water-insoluble) is dissolved in water-miscible organic solvent of
intermediate polarity, injected in stirred aqueous solution of surfactant,
this will cause precipitation of the polymer in the interface due to the
rapid diffusion of the solvent into the aqueous phase. Colloidal
suspension will be formed.
• To prepare nanocapsules, incorporation of nontoxic oil in the organic
phase.
• This method is suitable for lipophilic drugs. ( Cyclosporin A, clotrimazole

53. 3- Salting- out method:
• adding under stirring electrolyte saturated solution containing
polyvinyl alcohol to acetone solution of polymer forming oil in water
emulsion.
• sufficient water or aqueous PEG is added, this will make complete
diffusion of acetone into the aqueous phase leading to formation of
nanospheres.

55. 4- Emulsification/solvent diffusion Method:
This method is suitable for lipophilic drugs, doxorubicin, cyclosporine A nanopartic
Solvent as propylene carbonate.

56. 5- Dialysis Method:
• Polymer is dissolved in an organic solvent in a dialysis tube. Dialysis
took place between miscible and nonmiscible solvents leading to
formation of nanoparticles of the polymer.

57. 6- Supercritical fluid technology:
• high purity particles of no traces of organic solvent.
• Rapid production process.
• Formation of dry particles.
• Involves the use of environment friendly gas as carbon dioxide and nitrogen.

58. A- Rapid Expansion of Supercritical Solution RESS:
Generally produces nano and micro sized particles.

59. B- Rapid Expansion of Supercritical Solution
into liquid Solvent RESOLV:

60. RESOLV

61. Nanoparticles by polymerization of monomer:

62. 2- Dispersion polymerization:
Used for preparation of biodegradable polyacrylamide and polymethyl
methacrylate.
- The monomer is dissolved in the aqueous phase
- Polymerization by Ꝩ-radiation or chemical combined with
heating above 65 ˚C.
- The oligomer formed subsequently aggregate and above
certain molecular weight precipitate in the form of
nanoparticles.

63. Equipment for nanotechnology:
• Homogenizer
• Ultrasonicator
• Mills
• Spray milling
• Supercritical technology
• Electroscopy
• Ultracentrifugation
• Nanofiltration

71. Advantages of nanoparticles:
• Applications in controlled and target delivery e.g for gene therapy.
• Excellent administration performance via different routes.
• Enhanced bioavailability.
• Can be stabilized to give long shelf lives.
Disadvantages:
• Small size and large surface area may lead to particle aggregation.
• Physical handling is difficult.
• Limited drug loading.
• Toxic metabolite may be formed

74. ‫هللا‬ ‫بحمد‬ ‫المقرر‬ ‫تم‬