A reviewed note on the several types of injectable drug delivery approaches in NDDS.

1. Worked by: Mukesh (RE-edited by: Suraj C)
ADDS
1
Approaches for Injectable Controlled Release
Formulation
1. Introduction
2. Advantage &Disadvantage
3. Process
4. Approaches
By
Mukesh kumar Sah 1st m.pharm
Re-edited by
Suraj Choudhary
 INTRODUCTION
 It is defined as
“The delivery of drug at predetermined rate, and maintaining optimal and effective
drug level for prolonged duration.”
 Parenteral dosage form, are designed for the drugs having poor aqueous solubility which
undergoes first by pass metabolism poor aqueous solubility.
 The ingredient used for parenteral controlled release formulation should be sterile, pyrogen
free, non-irritating, bio-compatible and biodegradable into nontoxic compounds.
 ADVANTAGES
1. Improved patient convenience and compliance.
2. Prolonged steady state drug plasma concenter tion.
3. Maxium utilization of drug.
4. Less frequency of dosing.
5. Reduction in health care cost through improved therapy.
 DISADVANTAGES
1. Decreased systemic availability
2. Poor in vitro-in vivo correlation
3. Possibility of dose dumping.
4. Retrieval of drug is difficult in case of toxicity, poisoning or hypersensitivity
reactions.

2. Worked by: Mukesh (RE-edited by: Suraj C)
ADDS
2
5. Reduced potential for dosage adjustments.
6. Higher cost of formulations.
 PROCESS
1. Dissolution controlled
2. Adsorption type depot preparation
3. Encapsulation type preparation
4. Esterification type depot prepation
1. DISSOLUTION CONTROLLED
 The rate of dissolution is controlled by slow dissolution of drug particle in the formulation or tissue
fluid surrounding the formulation.
 The rate of dissolution can be determined mathematically as
Q/t = SDC/h
where Q/t = rate of dissolution,
S = surface area of drug particle
D = diffusion cofficient
C = saturation solubility,
H = thickness of hydrodynamic diffusion layer.
 The dissolution can be controlled by
A. Formation of Salt or complexes with low aqueous solubility
E.g.:preparation of penicillin G procaine (C=4 mg/ml) and penicillin G benzathaine
(C=0.2mg/ml) from highly water soluble alkali salt of penicillin G.
2. ADSORPTION TYPE DEPOT SYSTEM
 This depot preparation is formed by the binding of drug molecule to adsorbents.
 The unbound free species of drug is available for adsoption.
 To maintain the equilibrium as the unbound drug is absorbed, fraction of bound drug is released.
 The equilibrium concentration of free unbound drug species is determined by Langmuir
relationship i.e.,
(Cf/Cb)=1/a(C)b,m+(C)f/(C )b,m
where (C)b = amount of drug adsorbed by 1gm adsorbent,
( C)b,m = maximum amount of drug adsorbed by 1gm adsorbent
E.g.: vaccine preparation in which antigens are bound to highly disprsed aluminium hydroxide
gel to prolong their release and stimulate antibody formation.

3. Worked by: Mukesh (RE-edited by: Suraj C)
ADDS
3
3. ENCAPSULATION TYPE DEPOT SYSTEM
 The drug solid is encapsulated within a permeation barrier or dispersing drug particle in a diffusion
matrix.
 The both permeation barrier and diffusion matrix are fabricated from biodegradable or
bioabsorbable macromolecules such as gelatin, Dextran, polylacytate, phospholipid etc.
E.g.: Naltrexone pamoate releasing biodegradable –macrocapsules.
 The release is controlled by rate of permeation across permeation barrier and rate of biodegradation
of barrier macromolecule.
4. ESTERIFICATION TYPE DEPOT SYSTEM
 This is produced by esterifying a drug to form bioconvertible prodrug type ester and then
formulating into injectable preparation .
 The rate of absorption is controlled by intra-facial partitioning of drug esters from reservoir to the
tissue fluid and rate of bioconvertion of ester drug to regenerate active drug .
E.g: fuluphenazine enanthate in oleginous solution.
 APPROACHES
 Various approaches have been made in formulation of parenteral formulation which can be broadly
classified as
A. Injectable:-
1. Solution
2. Coarse dispersion:-Emulsion, Suspension
3. Colloidial /nanometric dispersion
a. Liposomes
b. Niosomes
c. polymeric mixed micelle.
d. Nanoparticle
4. Microparticle
a. Microsphere
b. Microcapsules
5. Resealed Erythrocytes
B. Implants:-
1. in-situ Forming Implants
2. Solid Implants
3. Vapour pressure powered pumps
4. Battery powered pumps

4. Worked by: Mukesh (RE-edited by: Suraj C)
ADDS
4
SOLUTIONS
 Both aqueous as well as oil solution can be used for parenteral controlled drug release formulation.
 By the use of aqueous solution (i.m.)the release of drug can be controlled in following ways.
4. By increasing the viscosity of vehicle
 Using methyl cellulose, carboxy-methyl cellulose and thus decreasing molecular diffusion and
4ocalizing the injected drug.
2. By forming complex (dissociation)
 Complex with macromolecules like MC, CMC or PVP from which drug dissociates at controlled
rate( only free drug will get absorbed)
3. By forming complex (solubility change)
 With macromolecules that control the release of drug by reducing the solubility of parent drug e.g.
protamine zinc insulin.
4. Oil suspension
 It control the release of drug by partitioning the drug out of oil in surrounding aqueous biofluids.
 Veg. oil like arachis oil, cottonseed oil are used.
COARSE DISPERSIONS
 Dispersed system like emulsion OR suspension can be administered by i.m., s.c. or i.v. routes.
1. Emulsion
 The o/w system have not been used successfully because absorption drug in the oil phase is
rapid due large interfacial area and rapid partitioning.
 Multiple emulsion like w/o/w and o/w/o are being used more conveniently because additional
reservoir is present for partitioning which can retard drug release.
2. Suspension
 Suspension control of drug release from suspension is easier and predictable.
 Drug dissolution and subsequent diffusion is main rate-controlling steps.
 Release of water soluble drug can retard by formulating it as oil suspension vice-versa for
oil soluble drugs.
 Factor consideration
 Solid content-0.5-5.0%.
 Particle size-larger the particle size slower is the dissolution.
 Greater particle size cause difficulties like irritation at site of injection, poor syringibility
and rapid sedimentation.
 Particle size should be below 10 μ for optimum activity.
 Generally crystalline and polymorphic forms of drugs are selected to delay release.

5. Worked by: Mukesh (RE-edited by: Suraj C)
ADDS
5
COLLOIDAL DISPERSION
 There are different types of colloidal dispersion
1. Liposomes
2. Niosomes
3. Polymeric/ mixed micelle
4. Nanoparticles
 Nanocrystals
 Nanoemulsion
 Nanocapsule
 Polymeric Nanoparticles
 Solid lipid nanoparticle
 Nanostructured lipid carrier
5. Microparticles
 Microsphere
 Microcapsule
6. Resealed erythrocytes
 LIPOSOMES:
 Water soluble drugs are trapped in aqueous compartment.
 Lipophilic ones are incorporated in the lipid phase of liposomes.
 Can be given by I.M., S.C., for controlled rate release.
E.g. progesterone, cisplatin.
 Can be given by I.V. for targeted delivery.
 Advantages
1. Type of drug: It can incorporate both hydrophilic and hydrophobic drugs.

6. Worked by: Mukesh (RE-edited by: Suraj C)
ADDS
6
2. Surface activity: The surface treatment is possible, so that the pharmacokinetic profile can be
altered.
3. Release at high temperatures: It enables the ability in some cases to deliver and release the
drug at higher temperatures.
4. Targetted treatment: It can be safely used for the targettting of cancer, etc. whose drugs are
higly toxic if given by conventional way.
5. Bypassing Macrophages: If treated with polymers like PEG, then such grafting can enable it
to reduced effects by macrophages.
 Disadvantages
1. Production cost is high
2. Leakage and fusion of encapsulated drug / molecules.
3. Sometimes phospholipid undergoes oxidation and hydrolysis like reaction
4. Short half-life
5. Low solubility
6. Fewer stables
 NIOSOMES:
 It is defined as ……
“the non-ionic surfactant vesicles ,bilayered structure which can entrap both hydrophilic and
lipophilic drug either in aqueous layer or vesicular layer, made up of lipids.”
 Advantages:
 Low cost
 Greater chemical stability
 Low toxicity due to its non- ionic nature.
 Biodegradable, bio-compatible and non-immunogenic.
 Can improve the performance of drug via better availability and controlled delivery at a
particular site.
 Disadvantages:
 Aqueous suspension of niosomes may exhibit fusion, aggregation, leaching or hydrolysis of
entrapped drug, thus limiting the shelf-life.
 Time consuming process
 Requires specialized equipments
 In-efficient drug loading
 POLYMERIC/MIXED MICELLE:
 These are nano-sized core/shell assemblies of amphiphillic block copolymer that are suitable for
delivery of hydrophilic and amphiphillic agent.

7. Worked by: Mukesh (RE-edited by: Suraj C)
ADDS
7
 Copolymer with PEO as shell –forming block and poly (l-amino acid)s are most popular in drug
development.
 Hydrophobic core of polymeric micelle provide an excellent host for incorporation and
stabilization of anticancer agent that are hydrophobic.
 NANOPARTICLES:
 Nanoparticles are called as nanospheres or nanocapsules depending upon the position of drugs.
 Polymer used are biodegradable ones.
Eg: Polyacrylic acid, Polyglycolic acid
 For selective targeting therapy.
 Advantages………
 Disadvantages ……
 MICROPARTICLES:
 Microparticles are defined as particulate dispersions or solid particles with a size in the range of
1-1000 μm. The drug is dissolved, entrapped, encapsulated or attached to a microparticle matrix.
Depending upon the method of preparation, microparticles, microspheres or microcapsules can
be obtained.
 TYPES:
1. Microsphere
 Each microsphere is basically a matrix of drug dispersed in a polymer from which release
occurs by first order process.
 Polymers used are biocompatible and biodegradable.
Eg: Polylactic acid, Polylactide co-glycolide, etc.
 Drug release is controlled by dissolution degradation of matrix.
 Small matrices release drug at a faster rate.
 Drug is centrally located within the polymeric shell.
 Release is controlled by dissolution, diffusion or both.
 For potent drugs such as steroids, peptides and antineoplastics.
2. Microcapsule
 Microcapsules contain an active agent and surrounded polymeric shell or dispersed in
polymeric matrix.
 Microcapsule size : 1 to 1000 micron
 Microcapsules can be of different structures.

8. Worked by: Mukesh (RE-edited by: Suraj C)
ADDS
8
 RESEALED ERYTHROCYTES
 Biodegradable, biocompatible, nonimmunogenic.
 Can circulate intravascularly for days and allow large amounts of drug to be carried.
 Drug loading in erythrocytes is easy.
 Damaged erythrocytes are removed by liver and spleen.
EXAMPLES OF INJECTABLE CR FORMULATIONS
1. Long-acting Penicillin Preparations
2. Long-acting Vitamin B12 preparations
3. Long-acting Adrenocorticotropic Hormone Preparations
4. Long-acting Steroid preparations
5. Long-acting Antipsychotic Preparations
6. Long-acting Antinarcotic Preparations
7. Long-acting Contraceptive Preparations
8. Long-acting Insulin Preparations
LONG-ACTING PENICILLIN PREPARATIONS
 Penicillin in the form of water-soluble Na+
or K+
salt is rapidly absorbed from subcutaneous &
intramuscular sites of parenteral administration.
 Intramuscular route of administration is preferred because of its rapid absorption & high peak
serum levels.
 The high serum penicillin concentrations then declines rapidly as a result of the rapid urinary
excretion, following its absorption from the site of injection.
 APPROACHES:
 Earliest approach was to reduce the aqueous solubility of penicillin by converting
water soluble Na+
or K+
salt into extremely low aqueous solubility, such as penicillin
G procaine.
 Intramuscular administration of penicillin G procaine in vegetable oil produces a
depot effect that sustain the therapeutic blood level of penicillin for 24-48 hours.
 Gelation of this oil suspension with 1% aluminium monostearate further sustain the
therapeutic blood level of penicillin to 96 hours.
 The therapeutic concentration of penicillin is prolonged approximately five times and
peak plasma level is suppressed sevenfold when suspension is gelled with 1%
aluminum monostearate.
Approach
1
Approach
2

9. Worked by: Mukesh (RE-edited by: Suraj C)
ADDS
9
 Serum concentration of penicillin is maintained over minimum effective
concentration longer than 168 hours when gelled with 2% aluminum monostearate.
 Depot effect is due to a reduction in aqueous solubility of penicillin G by formation
of procaine salt with low aqueous solubility and retardation in drug absorption by
formation of compact cohesive depot within muscular tissue following i.m. injection.
 Scientist at Abbott laboratories discovered that therapeutic concentration of
penicillin can also be prolonged by formulating the same in aqueous thixotropic
suspension by maintaining high solid –vehicle ratio(40-70% of e milled and
micronized penicillin Gprocaine particles).
NOTE: To form a spherical depot aqueous suspension of penicillin G procaine must
possess structural breakdown point of 1000000dyn-cm
LONG-ACTING INSULIN PREPARATIONS
 Due to its extensive 1st
pass metabolism, it is given by parenteral administration via sub cutaneous
route.
 Improper injection techniques have been found to be responsible for poor bioavailability of insulin.
 APPROACHES:
Approach
3
Approach
4
Effect of particle size of penicillin G procaine on the blood profile of penicillin following
i.m.50,000 units/kg in rabbits:
 ▲ 150-175µm,
 □ 45-60µm,
 ● <5µm in peanut oil gelled with 2% aluminium monostearate.

10. Worked by: Mukesh (RE-edited by: Suraj C)
ADDS
10
 Insulin molecule reacts with zinc ion & precipitates as a water insoluble Zn-insulin complex.
 Depending upon pH of solution, it may precipitate as an amorphous or a crystalline solid.
 7 - parts of crystalline insulin and three parts of amorphous insulin zinc insulin
complex preparation is called LENTE INSULIN.
 It provides intermediate acting form of insulin.
 It provides minimum effective concentrations within 1-1.5hrs.
 It reaches peak level within 8-12 hrs and has duration of action 24 hrs.
 Other modified types:
i. Ultra-Lente Insulin
 Insulin crystals can be precipitated from acetate buffer at pH 5-6.
 This crystalline insulin-zinc complex is absorbed very slowly & has a prolonged
normo-glycaemic activity.
 After s.c injection of these Zn-Insulin crystals as a suspension in buffer, the insulin
is slowly released, absorbed & retains its activity for more than 36 hrs.
ii. Semi-Lente Insulin
 Amorphous Zn-Insulin complex is precipitated at higher pH (6-8)
 This amorphous insulin has low Zn content & is absorbed more readily & achieves
duration of action shorter than that of ultre-lente.
 When administered subcutaneously, the Insulin in amorphous Zn-Insulin suspension
is quickly released, absorbed & has shorter duration of normo-glycaemic activity (12-
16hrs).
LONG-ACTING VITAMIN B12 PREPARATION
 By oral administration the systemic bioavailability of vitamin B12 is limited & variable.
 Vitamin B12 is rapidly & quantitatively absorbed from intramuscular & subcutaneous sites of
injection.
Approach
1
Approach
2
Approach
3
Comparative normoglycemic activity of ultralente, semilente,
regular insulin preparation in 26 rabbits by crossover tests.

11. Worked by: Mukesh (RE-edited by: Suraj C)
ADDS
11
 On administration of intramuscular or deep subcutaneous injection, the peak plasma level of
Vitamin B12 reaches its peak concentration within 1 hr, which is the choice of medication in case
of pernicious anemia & other vitamin B12 deficiency states.
 Unfortunately, much of the injected doses is lost in the urine. For these reasons, it becomes
necessary to develop a parenteral controlled-release formulation for Vit-B12.
 APPROACHES:
 The development of a parenteral controlled vitamin B12 release formulation was to
formulate the Vitamin B12 in a controlled partially hydrolyzed gelatin 32% solution.
 However, no sustained-release behavior was observed in human testing.
 Crystalline Vitamin B12 was suspended in sesame oil gelled with 2% aluminum
monostearate.
 This approach achieved a significant prolongation of the absorption of Vitamin B12
compared to an aqueous solution of Vitamin.
 Synthesize an insoluble derivative of Vitamin B12, the Vit-B12 zinc-tannate complex,
& then suspend it in sesame oil gelled with aluminum monostearate 2%.
 This preparation achieved a significant prolongation of the absorption of Vitamin B12
& urinary loss was significantly reduced.
LONG-ACTING ACTH PREPARATION
 ACTH is a polypeptide hormone that stimulates & regulates the secretion of adrenal steroids,
mainly the corticosteroids, from the adrenal cortex.
 The adrenocorticotropic activity of ACTH is easily destroyed by proteolytic enzymes in the
gastrointestinal tract, exogenous ACTH is therefore ineffective when given orally.
 On the other hand, ACTH is readily absorbed from parentral sites of administration & is usually
administered by intramuscular injection & occasionally by i.v infusion.
 APPROACHES: (Approach-1)
 Gelatin was found to inhibit the protein binding of ACTH.
 Addition of a partially hydrolyzed gelatin into the injectable ACTH solution was
found to enhance adrenal ascorbic acid responses in hypo-sectomized rats.
 The results of this investigation provided the foundation for the development of a
repository corticotropin injection, a long acting injectable formulation that contains
a highly purified preparation of ACTH in 16% gelatin solution.
 This preparartion is active for 24hr, over the regular corticotropin injection, which
has a duration of action of only 8 hr.
LONG-ACTING ANTI-PSYCOTICS PREPARATION
 The major problem in the management of psychotic disorder treatment is patient compliance.
Approach
1
Approach
2
Approach
3

12. Worked by: Mukesh (RE-edited by: Suraj C)
ADDS
12
 Development of long acting antipsychotic preparation certainly provide a practical solution to
minimize this non-compliance problem.
 Prolongation of antipsychotic activity of fluphenazine can be achieved by esterification,
E.g.: development of fluphenazine enanthate and fluphenazine deconate.
 Parenteral administration of either ester in sesame oil produces antipsychotic action for average
duration of 2 weeks and onset of action appears within 24-72 hrs following injection
 Esterification approach has been utilized to render longer duration of action for other neuroleptic
drugs.
LONG-ACTING ANTI-NARCOTICS
 Narcotic addicts become psychologically dependent upon the drug.
 Believe that the effects produced by self-administration of narcotics are necessary for maintaining
optimal state of well-being.
 At peak concentration, brain –serum ratio is only 0.1for morphine where as it is 15times greater
for naloxone.
 As serum level declines the ratio become greater for morphine (0.5), but remains within a narrow
range 1.5-2.0 for naloxone.
 APPROACHES:
 First approach : to form insoluble salt of naloxone and forming ionic complex.
 The formation of Zn –tannate naloxone complex prolonged the antinarcotics activity
up to 24hrs, whereas the formation of water soluble naloxone –HCl salt shows
antinarcotics activity up to only 4 hrs.
 The antinarcotic activity of naloxone tannate and pamoate was found only up to 8hrs
following i.m.
 Second approach: The incorporation of zinc reduce the dissociation of tannate from
53.3 to13.9 %.
 The naltrexone Zn –tannate complex showed three times more prolonged action than
the naltrexone HCl salt.
 Third approach: When pea nut oil suspension of naltrexone Zn –tannate complex
gelled with 2%aluminium monostearare was administered i.m., the antagonistic
analgesic effect of morphine was prolonged up to 19 days in 70% rats.
 Fourth approach: The use of polymeric drug delivery system such as microcapsule,
microsphere for antinarcotics preparation has been successfully used.
E.g long term bioavailability of naltrexone from lactide –glycolide copolymer
is constant for 53 days and 0.83% of drug was released daily.
LONG-ACTING STEROID PREPARATION

13. Worked by: Mukesh (RE-edited by: Suraj C)
ADDS
13
 Androgenic steroids:
 Testosterone is rapidly absorbed orally, but such administration is ineffective orally due to
pre-systemic metabolism by liver before reaching systemic circulation.
 Testosterone is also quickly metabolized and excreted after parenteral administration in an
oleaginous solution.
 APPROACHES:
 First Approach: for prolong androgenic activity was achieved by esterification of
testosterone.
 The effect was related to oil /water partition of these fatty acid ester.
 The androgenic activity was prolonged by acylation of 17-β hydroxy group in
testosterone molecule and was administered via i.m.
 This was due to the reduction in water/oil partition coefficient.
 Second Approach: The enanthate ester of testosterone prolong androgenic action up
to 4 weeks.
 Estrogenic steroids:
 APPROACHES:
 First Approach: prolong action was achieved by the benzoylation of the 3-hydroxy
group of estradiol which is oil soluble ester from which release of active beta
esteradiol is slow
 Second Approach: prolong estrogenic effect is also achieved by esterifying estadiol
at both 3and 17 position by treatment with valeryl chloride (in pyridine and removing
3-Valerate by treating with potassium carbonate (in aqueous methanol).
LONG-ACTING CONTRACEPTIVE PREPARATION
 Progesterone in high doses suppress the pituitary release of luetenizing hormone and
hypothalmic release of LH –releasing, hence prevent ovulation.
 The following APPROACHES have been made for long acting progesterone preparation:
o Medroxyprogesterone acetate in aqueous suspension (Depo-provera, Upjohn)
o Dihydroxy-progesterone acetophenide and estradiol enanthate in oleaginous solution
(Deladroxate, Squibb).
o Norethindrone in a biodegradable polymer beads.
NOTE: The long term contraceptive action of medroxy-progesterone acetate is due to:
1. Inhibition of secretion of luteinizing hormone and follicle stimulating hormone.
2. Reducing the penetration of spermatozoa into the uterus by increasing the viscosity
of cervical mucus.