This document presents information on parenteral depot systems for long acting drug formulations. It discusses various approaches for controlled drug release including the use of viscous vehicles, polymeric microspheres, and drug derivatives. Common polymers used in depots are described as well as desirable characteristics. The main types of depot formulations are discussed - dissolution controlled, adsorption, encapsulation, and esterification. Examples of specific long acting preparations are provided for antibiotics, insulin, vitamin B12, and contraceptives. Evaluation methods and the development of depots are outlined.

1. Presented by-
Miss Shraddha M.
Kumbhar
M. Pharm (Pharmaceutics)
Satara college of
Under the guidance of -
Dr. Ajit S. Kulkarni
Vice-Principal
Satara college of Pharmacy,
Satara
A
Colloquium
on
1

2. Introduction
•Parenteral route: most effective
•To achieve constant drug level in the systemic
circulation, two strategies can be employed:
1)To control the rate of absorption of a drug.
2)To control the rate of excretion i. e. by modifying
physiology of body.
Depot: Long acting parenteral drug formulation is
designed, ideally to provide slow, constant,
sustained, prolonged action.
The release can either be continuous or pulsatile
depending on the structure of the device and the
polymer characteristics.
2

3. Parenteral depot system:
Properties:
• Safe from accidental release
• Simple to administer and remove
• Inert and Biocompatible
• Comfortable for the patient
• Capable of achieving high drug loading
• Easy to fabricate and sterilize
• Free of leachable impurities
3

4. Approaches used…
• Use of viscous, water miscible vehicles – aq.
Solution of gelatin
• Use of water immiscible vehicles – vegetable oils +
aluminium monosterate
• Formation of thixotropic suspension
• Preparation of water insoluble drug derivatives –
salts, complexes and esters
•Dispersion in polymeric microspheres and
microcapsules like- lactide-glycolide
homopolymers/ co-polymers.
• Co-administration of vasoconstrictors
4

5. Polymers used……
Generally, Biodegradable polymers are used as it
get degraded in the body.
•Natural- albumin, starch, dextran, gelatin,
fibrinogen, hemoglobin.
•Synthetic- poly ethyl-polyalkyl cynoacrylates, poly
amides, poly acryl amides, poly amino acid, poly
urethane.
5

6. Desirable characteristics of an ideal
Parenteral drug carrier
• Versatile
• High capacity to carry a sufficient quantity of
drug
• Uniform distribution
• Restricting drug activity at the target site over a
prolonged period.
• Protecting drug from inactivation by plasma
enzymes.
• Biocompatible and minimally antigenic.
• Undergoing biologic degradation with minimal 6

7. TYPES OF DEPOT
FORMULATION
1. Dissolution controlled depot formulation
2. Adsorption type depot formulation
3. Encapsulation type depot formulation
4. Esterification type depot formulation
7

8. Dissolution controlled depots
RDS of drug absorption is dissolution of drug.
• Approaches :
 Formation of salt or complexes with low aqueous
solubility.
Example:
penicillin G procaine (Cs = 4 mg/ml) and
penicillin G benzathine (Cs = 0.2 mg/ml).
 Suspension of Macrocrystals:
to control the rate of drug dissolution.
Example: aqueous suspension of testosterone
isobutyrate for intramuscular administration. 8

9. Adsorption type depots
This depot preparation is formed by the binding of
drug molecules to adsorbents.
Example: vaccine preparations in which the
antigens are bound to highly dispersed aluminum
hydroxide gel to sustain their release and hence
prolong the duration of stimulation of antibody
formation.
9

10. Encapsulation-type depots
prepared by encapsulating drug solids .
-The release is controlled by the rate of
permeation across the permeation barrier and the
rate of biodegradation.
Biodegradable or bio absorbable macromolecules
are used, e. g. gelatin, dextran, poly lactic acid,
lactide-glycolide copolymers, phospholipids, and
long-chain fatty acids and glycerides.
Example:
naltrexone pamoate –
releasing biodegradable microcapsule, 10

11. Esterification-type depots
produced by esterifying a drug to form a
bioconvertible prodrug-type ester.
The rate of drug absorption is controlled by
the interfacial partitioning of drug esters from
the reservoir to the tissue fluid and the rate of
bioconversion.
Example: fluphenazine enanthate,
nandrolone decanoate in oleaginous solution.
11

12. Parenteral Controlled Drug
Delivery System
A. Inject able drug delivery
B. Implantable drug delivery
system
C. Infusion devices
D. Recent advances
12

13. Injectable Drug Delivery
1. Thermoplastic pastes
2. In situ cross linked systems
3. In situ polymer precipitation
4. Thermally induced gelling
system
5. In situ solidifying organogels.
13

14. Thermoplastic pastes
•In this semisolid polymers are injected as a melt
and form a depot upon cooling to body temperature.
•having a low melting point (25-65˚C) intrinsic
viscosity (0.05-0.8 dl/g).
•Drugs are incorporated into the molten polymer by
mixing without the application of solvents.
•Polymers: D, L-lactide, glycolide, E-caprolactone,
dioxanone orthoesters etc.
•polycaprolactone (PCL) requires injection
temperature at least 60˚C i.e. painful injections and
necrosis at the injection site,POE have good
biocompatibility, relatively low softening14

15. In situ polymer precipitation
water-insoluble,
biodegradable polymer
+ biocompatible organic
solvent + drug
solution
or
suspensio
n after
mixing.
When this
formulation is
injected into
the body, the
water miscible
organic solvent
dissipates and
water
penetrates into
the organic
phase.
This leads to
phase
separation
and
precipitation
of the
polymer
forming the
depot at the
site of
injection
15

16. Thermally induced gelling system
•Environmental temperature causes change in
solubility of thermo sensitive polymers.
•Example:
Poly (NIPAAM) exhibit sharp lower critical solution
temperature, LCST at about 32˚C, poly NIPAAM
based gels with salt and surfactant shows release
over 10-20d.
16

17. Injectables
• Solid Lipid Nanoparticle (SLN)
• Nanodispersions
• Suspensions
• Niosomes
• Liposomes
• Microspheres
• Emulsomes
• Resealed Erythrocytes
• Cyclodextrins
• Aquasomes
• Dendrimers
17

18. SLN
•SLN are submicron colloidal particles composed of
a biocompatible/biodegradable lipid matrix that is
solid at body temperature.
•size range : 100-400 nm.
•Generally physiological lipid dispersed in water or in
aqueous surfactant solution. SLNs combine
advantages of polymeric nanoparticles, fat
emulsions and liposomes.
Advantages:
•Particulate nature
•encapsulate hydrophilic and hydrophobic drugs
•Ability to sustain the release, to prevent chemical,
photochemical, or oxidative degradation of drug 18

19. Nanodispersions
Nanoemulsions / miniemulsions / submicron emulsions:
These are transparent or translucent oil-in-water (o/w) or
water-in-oil droplets with a mean droplet diameter in the
range between 100 and 500 nm. great stability due to their
small droplet size.
Nanosuspensions:
Nanosuspensions of drugs are submicron colloidal dispersions
of drug particles which are stabilized by
surfactants. Nanocrystals are crystals of poorly water soluble
drug in nanosize.
Advantages: Used to formulate drugs that are insoluble in both
water and oil, have higher loading (upto 90% of crystalline
particle is drug).
Used when drug have high melting point.
19

20. Suspensions
•Drug release dependent upon both the intrinsic
aqueous solubility of the drug and the dissolution
of the drug particles.
•Example: Abbott laboratories developed aqueous
thixotropic suspension of penicillin procaine (40-
70%w/w), such as Duracillin (Lilly), Crystacillin
(Squibb) which on intramuscular injection
produces therapeutic blood level of penicillin in
both animal and human for 162hr
20

21. Niosomes
These are nonionic surfactant vesicles obtained on
hydration, with or without incorporation of cholesterol
or other lipids.
•These are bilayered structure which can entrap both
hydrophilic and lipophilic drugs.
•Drug is incorporated into by….
Ether injection-Doxorubicin,
Hand shaking- Methotrexate,
Sonication- Vasopressin
21

22. Liposomes
•Liposomes are formed by the self-assembly of
phospholipids molecules in an aqueous
environment.
•Drug incorporated in alternating aqueous and lipid
compartments ,
•Sustained release
•lasting over several days to weeks.
•Example: myelopoietin (Leridistim)
22

23. Microspheres
•Contains dispersed molecules either in solution or in
crystalline form, biodegradable polymers are used.
Magnetic microspheres increases target site
specificity & non-toxic and non-reactive with blood
components.
Examples:
Minocycline Arestin® Orapharma,
Bromocriptine Parlodel LAR ™ Novartis
23

24. EMULSOMES
•Emulosomes are lipid based drug delivery
systems, which are poorly water soluble.
• Emulosome particles are basically consisting of
microscopic lipid assembly with a polar core.
•Prepared by- melt expression/ emulsion solvent
diffusive extraction.
•Used as adjuvants for vaccines, as carrier
container for targeted drug delivery to liver, brain
and RES rich organs
24

25. Resealed Erythrocytes
•Here erythrocytes lose their haemoglobin content
when they are processed by various methods i.e.
osmolysis, electrical breakdown/electro-encapsulation,
endocytosis etc.
•Hb loss provides intracellular space for drug
incorporation. Erythrocytes membrane can be
resealed by restoring tonicity of the media and
incubating them at 37°C.
•t1/2= 60-120 days.
•biodegradable, biocompatible, and non-immunogenic.
25

26. Cyclodextrins
• Cyclodextrins are water soluble cyclic
carbohydrate compounds with
hydrophobic cavity.
• forms inclusion complexes with
hydrophobic molecules
• Example:
• Sulphobutyl β- cyclodextrin
Nimodipine aq. suspension –the
relative solubility of the drug is
increased with no change in drug
AUC.
26

27. AQUASOMES
• Aquasomes are 3-layered self assembling
composition.
• solid or glassy particles dispersed in an aq.
Environment & MOA is controlled by their
surface chemistry.
• For gene therapy, a 5- layered composition of
Aquasome comprised of the ceramic mono
crystalline core, the polyhydroxyl oligomeric film
coating, the noncovalently bound layer of
therapeutic gene segment, an additional
conserve viral membrane proteins have been
proposed for gene therapy
27

28. Dendrimers
• Dendrimers are highly branched 3-D-
macromolecules with highly controlled structures
with all bounds emanating from a central core.
• Methods-
Divergent method-
one branching unit after another is successfully
attached to the core molecule.
Convergent method-
where the skeleton in built stepwise starting from
the end group towards the inside and finally
treated with a core molecule to produce the
Dendrimer. 28

29. Implantable drug delivery system
• Implant systems are indicated in case of chronic
therapy, such as hormone replacement therapy.
Parenteral implants can be highly viscous liquids
or semisolid formulations.
• Polymers used – polysaccharides, polylactic
acid coglycolic acid (no need for surgical
removal of the implant after treatment) and non
degradable methacrylates.
• Types:
1. Solid implants
2. In situ forming implants 29

30. Infusion devices
• Osmotic pumps(alzet):
After implantation, water from the surrounding tissue
fluids is imbibed through the semi permeable
membrane.
Drug release osmotic pressure difference.
Ionized drugs macromolecules, steroids, and
peptides (insulin) can be delivered by such a device.30

31. • Vapour pressure powered pumps
(Infusaid):
After implantation, the volatile liquid vaporizes at the
body temperature and creates a vapor pressure.
Example:
Insulin for diabetics and morphine for terminally ill
cancer.
shows back flow of infusate.
• Battery powered pumps:
Types:
1. Peristaltic pump
2. Reciprocating pump,
both with electronic controls.
Do not show back flow of the infusate. 31

32. Evaluation of depots
Viscosity
Drug Content
In vitro release study
Sterility testing
32

33. Development of depots:
• Long acting antibiotic preparations:
aqueous solubility of penicillin is reduced by
converting to penicillin G procaine (aq. Solubility
4mg/ml) e.g. Duracillin (Lilly)
• Long acting insulin preparations:
Plasma t1/2 of insulin = 40 min
insulin-protamine complex has isoelectric point at
pH 7.3 and therefore it is insoluble in body fluid
which shows sustained release upto 24 hrs,
stability issues arises but solved by adding zinc
chloride.
33

34. Development of depots:
• Long acting vit.B12 preparations:
Vit.B12–zinc-tannate complex is suspended in
sesame oil gelled with aluminium-monostearate
having significant prolonged effect.
• Long acting adrenocorticotropic hormone
preparations:
when given parenterally ACTH gets disappeared
cause of plasma t1/2 15 min. addition of partially
hydrolyzed gelatin solution into injectable ACTH
solution shows prolonged release. Gelatin inhibits
protein binding of ACTH and enhances response. 34

35. Development of depots:
• Antipsychotic depots:
Example:
Piportil-Pipothiazinepalmitate up to 200 milligrams 1
injection every 4 weeks
• Long acting anti-narcotic preparations:
Gelled oleaginous suspension of narcotic antagonist
–salt complex shows sustained release for 72 hrs
• Long acting contraceptive preparations:
Norethindrone in a biodegradable polymer beads.
Norgestrel 17β-fatty acid esters in oleaginous
solution.
35

36. Conclusion
Parenteral controlled drug delivery system is
designed to achieve a desired
pharmacological response in a sustained
manner at a selected site without
undesirable interactions at the other sites.
Extended release parenteral products are
complex dosage forms, requiring careful
development of test methods and
acceptance criteria for the specifications
36

37. References
• Bari H.(July-Aug2010)A Prolonged Release Parenteral
Drug Delivery System- An Overview, ISSN(vol 3,p.1-11)
• Chien Y. W., Novel Drug Delivery Systems; Drugs and
Pharmaceutical Sciences(2nded, vol-50) Parenteral Drug
Delivery (pp-381-528),New York: Marcel Dekker.
• David A. S. & Adams C.(2001) Depot antipsychotic
medication in treatment of patients with schizophrenia,
Health Technology Assessment (vol 5, 34), Basingstoke:
Queen’s printer and controller of HMSO
• Gothoskar A. V. (March 2004),Resealed erythrocytes: A
review, Pharmaceutical technology (pp.140-158)
• Kempe S. & Mader K.(July 2012),In-situ forming
implants-an attractive formulation principle for parenteral
depot formulation, Journal of Controlled Release
(pp.668-679)
37

38. References
• Lachman L. & Libberman H. & Kanig J.(2007) Sterile
products(pp.653-654),Bombay: Varghese Publishing
House.
• M. Kalyani & P.Surendra & V. Sirisha(2013).Parenteral
Controlled Drug Delivery System, International Journal
Of Research In Pharmaceutics & Nanosciences (pp.572-
580)
• Malik K. & Sigh I. & Nagpal M. & Arrora S.(2010),
Atrigel: A potential Parenteral control Drug delivery
system, pelagia research lab der pharmacia sinica
(pp.74-81)
• Mischel N. & Cox L.(2012),Allergen Immunotherapy
Extract Preparation Manual, AAAAI Practice
Management Resource Guide(pp.1-39) 38

39. References
• Vyas S. P. & Khar R. K.(2006), Targeted and
Controlled Drug Delivery Novel Carrier Systems(pp.3-
38;173-279; 387-457) New Delhi: CBS Publishers and
Distributors.
• Wheeler A. M. & Newland B. Advantages of L-tyrosine
as a depot adjuvant for formulation of therapeutic
allergy vaccines; Allergy therapeutics: transforming
allergy treatment
• www.pharmatutor.org/articles/aquasomes-potential-
approach-novel -drug-delivery
• www.pharmatutor.org/articles/information-and-article-
on-erythrocytes-as-a-drug carrier.
• www.pharmatutor.org/articles/review-parenteral-
controlled-drug -delivery-system
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