Parenteral Controlled release drug delivery system- approaches, mechanism-Dissolution controlled depot formulation, Adsorption type depot formulation, Encapsulation type depot formulation, Esterification type depot formulation, In situ forming drug delivery systems (ISFD)-Thermoplastic pastes, In situ cross linked systems, In situ polymer precipitation, Thermally induced gelling system, In situ solidifying organogels, examples; Long acting contraceptives: Injectables -Depo-Provera C-150 (Depot Medroxyprogesterone acetate injection), Deladroxate, Norethindrone releasing biodegradable polymer based suspension, Norethindrone enanthate in oleaginous solutions, Norgestrel 17 beta fatty acid esters; Sub dermal- Hormonal intrauterine device (Mirena - also known as IUC or IUS), Nonhormonal intrauterine device with copper (US -Paragard), Subdermal contraceptive implant (US - Nexplanon/ Implanon/ Implanon NXT); internationally– Norplant- Jadelle; Implants: mechanism-Controlled drug release by diffusion(Membrane permeation-controlled release system, Matrix diffusion-controlled release system, Micro-reservoir dissolution-controlled release system, Membrane matrix hybrid type-controlled release system), Controlled drug release by activation (Osmotic pressure activated eg.- Alzet pump, Vapour pressure activated eg.- Infusaid pump, Magnetically activated, Phonophoresis, Hydrolysis activated eg.- for control release of levonorgestrel (poly ortho esters used) Hydration activated eg.- Hydron implant; Controlled drug delivery by feedback regulated: mechanism-Bioerosion regulated drug delivery system, Bioresponse activated drug delivery system; examples; case study- atrigel, References

1. Parenteral Controlled Release System
Seminar By: Varsha Phirke
M Pharm (Pharmaceutics)
Guided by: Mrs. Pallavi Chaudhari
Padm. Dr. D. Y. Patil College of Pharmacy, Akurdi1

2. Contents:
 Terminology
 Approaches
 Mechanism
 Injectable drug delivery system
 Long acting contraceptive formulations
 Implantable drug delivery
 Quality Control
 Case study
 References
2

3. Terminology
Parenteral is the introduction of nutrition, a medication, or
other substance into the body via a route other than the mouth,
especially via infusion, injection or implantation.
Controlled Release drug delivery systems aim to maintain
plasma concentration of drugs within the therapeutic window
for a longer period of time
3

4. Difference between IR-SR-CR in terms of plasma concentration
4

5. Approaches:
1) Use of viscous, water miscible vehicles, such as an aqueous
solution of gelatin or polyvinyl pyrrolidone.
Change in solubility characteristics of drug
Change in time of release once drug is administered
Change in state of drug post administration
2) Utilization of water immiscible vehicles, such as vegetable
oil, some water repelling agents, like aluminium monostearate.
3) Formation of thixotropic suspension
Structural break point
Change in flow properties
Change in dissolution characteristics
5

6. Approaches:
4) Preparation of water insoluble drug derivatives such as salts,
complexes and esters.
Chemical modification without affecting therapeutic activity
Kinetics are influenced
Stability is enhanced
5) Dispersion in polymeric microspheres, or microcapsules such as
lactides-glycolides homopolymers or copolymers
Use of Surface active agent
Polymerization insitu or through reaction
Microcapsules using various techniques
6) Co-administration of vasoconstrictors
6

7. Mechanism:
On the basis of different mechanism, depot formulation categories
into four types
1) Dissolution controlled depot formulation
2) Adsorption type depot formulation
3) Encapsulation type depot formulation
4) Esterification type depot formulation
7

8. Class Mechanism Rate limiting step Examples
Dissolution
controlled
depot
Drug absorption is
controlled by slow
dissolution of drug
particle.
Dissolution of drug
particles.
Formation of salt or
complexes with low
aqueous solubility,
Suspension of
Macrocrystals.
Adsorption
type depot
Binding of drug
molecules to
adsorbent [Al(OH)3]
Rate of
absorption.
Vaccine preparations
Encapsulation
type depot
Encapsulating drug
within permeation
barrier /dispersing
drug particles in a
diffusion matrix.
Permeation across
the permeation
barrier & the rate
of biodegradation.
Naltrexone pamoate-
releasing biodegradable
microcapsule, liposome, &
Norethindrone-releasing
biodegradable beads.
Esterification
type depot
Esterifying drug to
form bioconvertible
Prodrug-type ester
& then into
injection.
Number of
enzyme present,
Interfacial
partitioning of
drug esters.
Fluphenazine enanthate,
nandrolone decanoate in
oleaginous solution.
8

9. Injectable drug delivery system
In situ forming drug delivery systems (ISFD)
Classified into five categories according to their mechanism of depot
formation:
Thermoplastic pastes
In situ cross linked systems
In situ polymer precipitation
Thermally induced gelling system
In situ solidifying organogels.
Microspheres
Liposomes
Suspension
Solid lipid nanoparticles
9

10. Class Mechanism of depot formation Examples
Thermoplastic
pastes
Semisolid polymers which injected as a
melt and form a depot upon cooling to
body temperature.
D,L-lactide, glycolide,
E-caprolactone, dioxanone and
orthoesters
In situ cross
linked polymer
systems
Cross-linked polymer network can be
found in situ by free radical reactions
initiated by heat (thermosets) /absorption
of photon / ionic interactions between
small cation & polymer anions.
Benzoyl pero
PEG(polyethylene
glycol)-oligo-glycol-acrylate, using a
photo initiator, such
as eosinxide( banned)
In situ polymer
precipitation
Water-insoluble and biodegradable
polymer in biocompatible organic solvent.
Phase separation and precipitation of the
polymer forming the depot at the site of
injection
Atrigel
Thermally
induced gelling
system
Gelation at body temperature when highly
concentrated polymer solution
>15% w/w were injected
PEO-PPO-PEO
(pluronics or poloxamers)
In situ
solidifying
organogels
Water insoluble amphiphilic lipids, which
swell in water and forms various types of
lyotropic liquid crystals.
Glycerol monooleate/
monopalmitostearate/
monolinoleate, sorbitan
monostearate (SMS) & different
gelation modifiers (polysorbates 20
10

11. Generic name Trade name Dosage form
Penicillin & Procaine Duracillin Squibb Suspension injection
Medroxyprogesterone
acetate
Depo-Provera, Upjohn Suspension injection
Fluphenazine enanthate and
decanoate
Prolixin enanthate and
Prolixin decanoate; Squibb
oil solutions
Microcrystalline
deoxycorticosone pivalate
Percortan pivalate; Ciba oleaginous suspension
Nandrolone decanoate Decadurabolin, Organon injection
Insulin Zinc Utralente, Lente and
semilente, Novo
suspensions
Testosterone enanthate /
estradiol valerate in ethyl
oleate B
Ditate - DS, Savage repository vehicle
11

12. Long acting contraceptives formulations:
(A)Injectables:
Depo-Provera C-150 (Depot Medroxyprogesterone acetate injection)
Deladroxate
Norethindrone releasing biodegradable polymer based
suspension
Norethindrone enanthate in oleaginous solutions
Norgestrel 17 beta fatty acid esters
(B)IUD’s and subdermal implants:
Hormonal intrauterine device (Mirena - also known as IUC or IUS)
Nonhormonal intrauterine device with copper (US -Paragard)
Subdermal contraceptive implant (US - Nexplanon/ Implanon/
Implanon NXT); internationally– Norplant- Jadelle
12

13. Implants
13

14. Approaches:
A Controlled drug release by diffusion
1) Membrane permeation-controlled release system
Non porous membranes,
Porous membranes
Semiporous membranes
eg. - Norplant subdermal implants of levonorgestrel
2) Matrix diffusion-controlled release system
Lipophilic polymers
Hydrophilic polymers
Porous polymers
eg. - Compudose implant of estradiol
3) Micro-reservoir dissolution-controlled release system
Hydrophilic reservoir in lipophilic matrix
Lipophilic reservoir in hydrophilic matrix
eg. - Synchro-mate implant of norgestomet
4) Membrane matrix hybrid type-controlled release system
Lipophilic membrane with hydrophilic matrix
Hydrophilic membrane with lipophilic matrix
eg.- Norplant II subdermal implant of Levonorgesterl (4 years) 14

15. Approaches:
B Controlled drug release by activation
Osmotic pressure activated eg.- Alzet pump
Vapour pressure activated eg.- Infusaid pump
Magnetically activated
Phonophoresis
Hydrolysis activated eg.- for control release of levonorgestrel
(poly ortho esters used)
Hydration activated eg.- Hydron implant
C Controlled drug delivery by feedback regulated
mechanism
Bioerosion regulated drug delivery system
Bioresponse activated drug delivery system
15

16. Approach Mechanism example
Membrane permeation-
controlled release
Drug encapsulated in
capsule / spherical
compartment
Norplant subdermal
implant
Matrix diffusion-controlled
release
Homogenous dispersion of
drug in lipophilic/
hydrophilic polymer matrix
Compudose implant
Micro-reservoir dissolution-
controlled release
Drug in suspension in
aqueous solution of water
miscible polymer forms
dispersion of drug reservoir
in polymer matrix
Syncro mate implant
Membrane matrix hybrid
type-controlled release
Hybrid of polymer
membrane permeation
controlled DDS and
Polymer matrix diffusion
controlled DDS
Norplant II
A. Controlled drug release by diffusion
16

17. Approach Mechanism Examples
Osmotic pressure activated Drug reservoir solution or
semisolid placed within
semipermeable housing with
controlled water permeability
Alzet osmotic pump
Vapour pressure activated Drug reservoir is solution is
placed inside infusate chamber
Infusaid pump
Magnetically activated Magnetic wave triggering
mechanism is incorporated
into drug delivery device
Hydrolysis activated Solid drug is homogenously
dispersed throughout polymer
matrix of bioerodible or
biodegradable polymer
Levonorgestrel using Poly
ortho esters
biodegradable polymer
Hydration activated Solid drug is coated by
hydrophilic polymer
Hydron implant
B. Controlled drug release by activation
17

18. C. Controlled drug delivery by feedback regulated mechanism
Approach Mechanism
Bioerosion regulated Drug dispersed bioerodible matrix fabricated
with polymer coated with immobilised urease
Bioresponse activated Drug enclosed in bioresponsive polymer
whose permeability is controlled by
concentration of biochemical agent in tissue
18

19. Quality Control of Parenterals
1) Sterility Tests.
2) Pyrogen Tests.
3) Leaker Tests.
4) Particulate matter testing.
5) Weight variation or content uniformity
6) Bacterial endotoxin test
19

20. 20
Case study
Patel D. B. et al in Journal of Global Pharma Technology, 2010; 2(2):
85-90 has presented an article on Atrigel® system describing it as a
proven sustained-release drug delivery platform that delivers therapeutic
levels of a wide spectrum of drugs over a few days to several months with a
single injection. Atrigel system is used for both Parenterals and site-
specific drug delivery. The ease of manufacture of the Atrigel system and
its relatively pain-free subcutaneous injection into the body provide
significant advantages over both solid implants and micro particles. Most
of the standard biodegradable polymers can be used in the Atrigel
technology. The hydrophilic solvents employed in the Atrigel system to
dissolve the polymers. The low- molecular- weight polymers at low
polymer concentrations can be easily injected into the body using standard
needles. The high molecular- weight polymers at high polymer
concentrations may be used as gels or putties that can be placed into sites
in the body where they solidify and provide support. Atrigel technology
provides a more stable, ready-to-use formulation.

21. References:
Yie W. Chien, Marcel Dekker Inc.; Novel Drug Delivery Systems- New York, Volume
50, 381:517
J. R. Robinson, V. H. Lee; Controlled drug delivery- fundamentals and applications-
Marcel Dekker Inc., volume-20, 2nd edition, 5:58, 179:208, 484:515
K. E. Avis, H. A. Lieberman, L. Lachman; Pharmaceutical Dosage forms: Parenteral
medications- Marcel Dekker Inc., Volume 1, 2nd edition, 1:-55, 5:106
Xiaoling Li, Bhaskara Jasti; Design of Controlled Release Drug delivery systems-
McGraw-Hill Publications, 107:124, 139:168, 203:229
Vasant Ranade, Mannfred Hollinger; Drug delivery systems-CBS Publications, Second
Edition, 115:135
G. S. Banker, C. T. Rhodes; Modern Pharmaceutics- Marcel Dekker Inc., 4th edition,
381:414, 501:528
21

22. References:
N. K. Jain; Advances in Controlled and novel drug delivery-CBS Publications, 1st
edition 2010, 204:229
Vyas S. P., Khar R. K. In; Controlled Drug Delivery Concepts and Advances- CBS
Publication, 1st edition 2002, 452:457
Vyas S. P., Khar R. K. In; Targeted and Controlled Drug Delivery- CBS Publication,
4th edition, 2005, 213:215
Michael J. Akers, D. S. Larrimore, D. M. Guazzo; Parenteral Quality Control-CBS
Publications, 2008, 3:17, 124:183, 287:354
Hitesh Bari; A prolonged release Parenterals drug delivery system – an overview,
International Journal of Pharmaceutical Sciences Review and Research, Volume 3,
Issue 1, July – August 2010; Article 001
Patel D. B. et al., Journal of Global Pharma Technology. 2010; 2(2): 85-90
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