APPROACHES FOR INJECTABLE CONTROLLED RELEASE

FORMULATIONS

Presented By:Chiranjibi Adhikari

1st year M. Pharm. (Pharmaceutics)MALLIGE COLLEGE OF PHARMACY

Para - Other

Enteral - Alimentary canal

Major Routes of Parentral Administration 1. Subcutaneous region: 0.5-1.5ml.limited to non-irritating, water-soluble drugs.eg.

Insulin2. Intramuscular region: < 2 ml.Solutions, Suspensions & implants. 3. Intravenous: 1-500ml. liposomes, nano-particles, erythrocytes, and

polypeptides.4. Intra-peritoneal: Macromolecules as carrier to target anti-neoplastic

agents.

Advantages of parenteral drug delivery systems:

Can be administered to unconscious patients. Drugs which cannot be delivered through oral

route. Administration of the drug to the targeted area. Fluid and electrolyte balance can be rapidly

corrected and maintained. Used in case of emergencies- rapid absorption. Bypass the GIT and liver, modification of the drug

by enzymes. The drug produces cent percent bioavailability. Dose required is small. In patient who are unable to retain anything in the

mouth.

DISADVANTAGES :o Invasive and Painful. o Self medication is not possible except insulin.o Proper care should be taken during its

manufacturing.o Withdrawal of drug is not possible in case of

toxicity. o Quite expensive.o Negligence during its administration can lead

to infection.

Conventional parenteral dosage forms: Offers rapid onset of action & rapid decline of

systemic drug level.Requires frequent injection, leads to patient

discomfort.Desires continuous IV infusion to maintain systemic

drug levels within the therapeutically effective concentration range.

Requires continuous hospitalization during treatment.

Sustained release of parenteral drug from depot formulation reduces the inherent disadvantage of conventional dosage forms.

Parenteral controlled release drug delivery systems

Designed to achieve a prolonged therapeutic effect by continuously releasing medications over an extended period of time after administration of single parenteral dose.

Will result in a prolonged drug blood level.Drug molecules will be released continuously

from the reservoir at a rate determined by the characteristics of each formulation.

The rate of absorption will be determined by the nature of the vehicle.

More concentrated on the subcutaneous & intramuscular routes.

Rationality behind the development of PCDDS

Drug carrier systems like microspheres, liposomes, monoclonal- antibodies and emulsions, etc.

Drugs are incorporated into these systems to increase the duration of action and to provide selective delivery of the drug to a specific target site or organ .

Infusion pumps provide a delivery system with uniform and continuous flow.

Specific dose of a drug such as insulin may be administered to a patient on a continual or intermittent basis.

ADVANTAGES OF PCDDS It can be used to maintain a sustained drug level within

a therapeutic concentration range as long as required. A reduced dose, decreased side effect and improved

drug utilization. Reduced frequency of administration. Versatility in the carrier can deliver a variety of

agents. Uniform distribution within the capillary vasculature. Restricting the drug activity at the target site over a

prolonged period. Protecting the drug from inactivation by plasma

enzymes. No surgical removal of the depleted system

DISADVANTAGES OF PCDDS Poor in vitro - in vivo correlation. Dose dumping is possible (in case of sudden burst of

polymer). Withdrawal of drug is not possible in case of toxicity. There is continuous hospitalization during treatment

and requires close medical supervision. Invasive and painful. Danger of device failure. Commercial disadvantage. Limited to potent drugs.

When a controlled drug formulation is administered parenterally into a tissue , a depot is formed. Before the drug can exert its therapeutic action, it must first be released from the formulation into the general circulation and then to the site of drug action. Drug particles Dissolution

Drug molecules in solution

Partitioning Drug molecules in tissue fluid

Biopharmaceutics of controlled release Biopharmaceutics of controlled release parenteral drug products.parenteral drug products.

General circulation Entero hepatic circulation

Target tissue Elimination Biliary Excretion The rate limiting step in parenteral drug

absorption are dissolution of drug particles in the formulation and partitioning of drug molecules from the vehicle to the surrounding tissue fluid.

Absorption

Blood flow through sites of injection : Since a drug must enter the systemic circulation before

reaching its target tissue, the onset and magnitude of drug response are affected by blood flow through the injection site.

Co-administration of agents that affect blood flow through the injection site have been found to influence the absorption rate.

Eg: Epinephrine causes constriction of the vascular bed and decreases blood flow, there by delaying S.C absorption of drugs.

Biocompatibility of Polymeric Materials : • Biocompatibility of polymeric material with tissues

is described in terms of acute and chronic local inflammatory responses. Mostly polymerized albumin was used for sustaining drug release.

• The biocompatibility of implants can be measured in terms of sensitivity reactions and infections. Majority of sensitivity reactions were caused by metal implants.

• One potential method of improving the compatibility of polymers in the blood is to impregnate these polymers with Heparin. Types:

1.Those that release heparin at a controlled manner at the blood/polymer interface.

2.Those that immobilize heparin at the surface.

Approaches for injectable controlled release formulations

Several pharmaceutical formulation approaches:1.Use of viscous, water-miscible vehicles, such as an aqueous

solution of gelatin or polyvinyl-pyrrolidone.2.Utilization of water-immiscible vehicles, such as vegetable oils,

plus water-repelling agent, such as aluminum monostearate.3.Formation of thixotropic suspension.4.Preparation of water insoluble drug derivatives, such as salts,

complexes, and esters.5.Dispersion in polymeric microspheres or microcapsules, such as

lactide-glycolide homopolymers or copolymers.6.Co-administration of vasoconstrictors.

Minor (depot type formulation) approaches: Long acting parenteral drug formulation is

designed, ideally to provide slow, constant and prolonged action.

They may be classified based on the process used for controlled drug release are as follows:

1. Dissolution - controlled Depot formulations

2. Adsorption type Depot preparations

3. Encapsulation-type Depot preparations

4. Esterification -type Depot preparations

1.Dissolution - controlled Depot formulations

The rate of drug absorption is controlled by slow dissolution of drug particle in the formulation or in the tissue fluid surrounding the formulation.

Rate of dissolution is given by : dQ/dt = DACs/h--------------»»(1) Where, dQ/dt = rate of dissolution D = diffusion co-efficient of the drug molecule in the medium A = surface area of the drug particle in contact with medium. Cs = saturation solubility of the drug in the medium h = thickness of the hydrodynamic diffusion layer surrounding

each particle .

Two approaches can be utilized to control the dissolution of drug particle to prolong the absorption.

a) Formation of salts or complexes with low aqueous solubility

Drug ___________Transformation____________» salt (water soluble) (low water soluble) E.g. 1. Aqueous suspensions of benzathine penicillin G from

water soluble alkali salts of acidic pencillin G. Penicillin G procaine ( Cs = 4mg/ml) Penicillin G benzathine (Cs = 0.2 mg/ml) 2. Naloxone and naltrexone hydrochloride 3. Oleaginous suspensions gelled with aluminum

monstearate will produce prolonged therapeutic activities.

b) Suspensions of macrocrystals: Large crystals are known to dissolve more slowly than

small crystals. This is called the macrocrystal principle. Ex:1.Aqueous suspension of testosterone isobutyrate for IM

administration. 2. stilbestrol monocrystals for subcutaneous injection.

DRAWBACK: Release of drug molecule is not zero order because: Surface area of drug particles diminishes with time because of

increased drug dissolution. Saturation solubility (Cs) of drug at the site of injection will

not be maintained because of rapid absorption.

2. Adsorption - type depot preparations Formed by the binding of drug molecules to adsorbents. E.g. vaccine preparations. Bound form ----------Equilibrium-------------

Free form-------- Absorbed (Drug adsorbed (Unbound drug (C)f ) onto adsorbent (C)b ) As soon as the unbound drug molecules are absorbed, a fraction of the

bound drug molecule is released to maintain the equilibrium. The Equilibrium concentration of free, unbound drug species is determined

by Langmuir relationship, (C)f /(C)b = 1/ a(C) b,m +(C)f /(C)b,m Where, (C)b = amount of drug (mg) adsorbed by 1 gm of adsorbent (C)b,m = is max. amount of drug (mg) adsorbed by 1 g of adsorbent a = is a constant and can be determined from the intercept and (C)b,m.

3. Encapsulation – type Depot preparationPrepared by encapsulating drug solids within a permeation

barrier or dispersing drug particles in a diffusion matrix.Both permeation barrier and diffusion matrix are fabricated

from biodegradable or bioabsorbable macromolecules like gelatin, dextran, polylactate, lactide-glycolide copolymers, glyceride and phospholipids.

E.g.- Naltrexone pamoate–releasing biodegradable microcapsules, liposomes and norethindrone-releasing biodegradable lactide –glycolide copolymer beads.

The release of drug molecules is controlled by : a) The rate of permeation across the barrier b) Rate of biodegradation of barrier molecules.

4.Esterification- type Depot preparations Produced by esterifying a drug to form a

bioconvertible pro-drug type ester and then formulating it in an injectable formulation .

Forms a drug reservoir at the site of injection. The rate of drug absorption is controlled by1. interfacial partitioning of drug esters from the reservoir

to the tissue fluid.2.rate of bioconversion of drug esters to generate active

drug molecule. E.g. fluphenazineenanthate, testosterone 17 β cypionate

in oleaginous solution, nandrolone decanoate, etc.

The commonly used major approaches are:

a. Aqueous solutions f. Biocompatible carriers b. Aqueous suspensions g. Liposomes c. Oil suspensions h. Nanoparticles d. Oil solutions i. implants e. Emulsions j. prodrugs

k. Infusion devices

A. Aqueous solutions: 1. High viscosity products - By increasing viscosity of the vehicle, the diffusion

coefficient of the drug will be reduced, there by delaying drug transfer.

Eg. Viscosity agents are methylcellulose, sodium carboxy methyl cellulose, and polyvinylpyrrolidone.

Delay in drug absorption also occurs if a water soluble drug undergoes complexation with these macromolecules.

The increased viscosity of the medium not only decreases molecular diffusion but also localizes the injected volume.

Thus ,the absorptive area is reduced and the rate of drug transfer is better controlled. In fact, this is one of the reasons for incorporating gelling agents like aluminum monostearate into oil solutions.

2.Complex formation: The role of plasma protein and tissue binding in

prolonging drug action is well known. In principle, the same result can be achieved by forming a dissociable complex of a drug with macromolecules like methylcellulose, sodium carboxymethylcellulose and P.V.P for I.M Administration.

Assuming that a constant fraction of drug is complexed and that only free drug is absorbed, the absorption rate (dc/dt) may be expressed as :

dc / dt = - kfc » 1 where, k- absorption rate constant f – fraction of free drug c-total concentration of drug at the

absorption site.

In terms of the apparent association constant (K) and the

equilibrium concentration of a macromolecule (M), it can be shown that:

f = 1/ [ 1+Ka (M)] » 2 which, if Ka is very much larger than 1, simplifies to : f = 1/ Ka (M) » 3 From eqn 3, the free drug conc. is inversely proportional

to the macromolecule conc. • In addition to complexes between drug molecules and

macromolecules, complexes can also be formed between drug molecules and other small molecules such as caffeine.

• In contrast to complexes with macromolecules, complexes with small molecules can be absorbed, but has certain disadvantages like-

i) Small association constant i.e. substantial portion of drug will exist in the non- complexed form.

ii) This approach doesn't appear to hold much potential for development of prolonged – action intramuscular products.

There is yet a third class of complexes which controls the release of drug , not by dissociation but decreasing solubility of the parent drug .

Ex. Acetaminophen formed 1:1 complexes with theophylline and caffeine, which had lower solubilities and hence lower dissolution rates than the parent compound.

Another example – protamine zinc insulin.

B. Aqueous suspensions : A suspension usually give longer duration of action

than an aqueous solution when given I.M or S.C In the case of suspensions, the drug is continuously

dissolving to replenish what is being lost. To appreciate how suspensions can be utilized to

control rate of a drug delivery can be described by a modified form of the Noyes- Whitney equation –

Mean dissolution rate = ADCs/ L

Where , A – mean surface area available for dissolution.

D – drug’s diffusion coefficient Cs – saturation solubility of the drug L – thickness of the diffusion layer. From a formulation standpoint, the parameters

that are accessible to change are A (i.e. particle size ), D and , to some extent Cs.

The main problem in stability of suspensions is “sedimentation”

The factors that determine the rate of sedimentation are initiated by stoke’s law as –ρ

µ= d2 (ρs – ρi) δ 18η

ρs – density of solid particles ρi- density of fluid phaseη – viscosity of the fluid phase.d – mean diameter of particles. Thus, increasing particle size as a means to decrease

dissolution rate causes an increase in the sedimentation rate resulting in an unstable suspension

This suggests that by appropriately varying viscosity and particle size, a stable suspension that offers controlled release can be produced.

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ViscosityParticle size

As a working rule, the content of solids in parenteral suspension should fall between 0.5 and 5%.To minimize pain and tissue irritation , it is recommended that the particle size should be below 10µm.

1.Use of viscosity builder:-to increase vehicle viscosity and reduce the diffusion coefficient of the drug molecules can also be applied to aqueous suspensions. The net result is that the dissolution rate is diminished in proportion to the reduction in diffusion coefficient.

2.Microspheres : Microspheres are solid, spherical particles containing dispersed drug molecules either in solution or crystalline form.

This delivery systems has been applied to narcotic antagonist and anti-neoplastic agents.

Dispersed drug molecules in solution or crystalline form

MicrospheresMicrospheresDrug solution of suspension in the center core

MicrocapsulesMicrocapsules

The method consists of suspending the drug in a

biodegradable/ bioerodible polymer, followed by reducing the mixture to particles of 600 µm, which are then injected as a suspension in carboxymethylcellulose solution.

Some examples of biodegradable / bioerodible polymers are :

1.Polyglactin 2.polylactic acid 3.polyisobutyl cyanoacrylate.

In principle, by using polymer particles with a characteristic distribution of sizes, one can achieve various degrees of controlled release.

3.Microcapsules : Microcapsules are spherical particles containing drug

concentrated in the center core. Microencapsulation can be used to encase particles of liquids , solids, or gases.

polymers – nylon, albumin and cross-linked starch. The amount of coating material used ranges from 3 to

30% of total weight, which corresponds to a dry film thickness of less than 1-200 µm, depending upon the surface area to be coated.

The possible mechanism of release can be divided

into:- Dissolution control, diffusion control and dissolution

and diffusion control.

A variety of drugs have been microencapsulated . These include antineoplastic drugs, potassium chloride, hemoglobin and proteins.

Even vaccine, living cells and tissues have been microencapsulated.

4.Magnetic Microspheres : Developed to minimize reticulo-endothelial

clearance and to increase target site specificity. Prepared from albumin and magnetite(Fe3O4). They are about 1 µm in size. These are relatively non-toxic and non-reactive

with blood components. They can be stabilized by heating or chemically

cross-linking albumin to achieve a wide spectrum of drug release kinetics.

• Typically, magnetic microspheres are infused into an artery supplying a given target site. A magnet of sufficient field strength is then placed externally over the target area to localize the microspheres at the capillary bed in this region.

• Mainly applied in the treatment of localized tumors in the regions of well-defined blood supply.

C. Oil solutions : Drug release is controlled by partitioning of drug out of the oil

into the surrounding aqueous medium.• This process is a dynamic equilibrium between drug in the oil

phase and that in the aqueous phase with a apparent coefficient K, given by

K= drug conc. in oil / drug in conc. in water = Do / Dw Where, drug conc. in water refers to both ionized and unionized

drug. In terms of the volume of the oil phase Vo and volume of the

aqueous phase Vw, total amount of the drug Dt in the system is given by:

Dt =Dw (KVo + V w) Vw- volume of aqueous phase Vo- volume of oil phase

If the equilibrium is established sufficiently fast to replenish what is absorbed, the fractional amount of drug, f, that is in the aqueous phase can be calculated according to: f=1/ Kα+ 1

where α is Vo/ Vw. Since absorption is driven by conc., not amount, an expression for fractional conc. of drug that is in the aqueous phase ‘f’ is more appropriate.

f1 = ( 1 + α ) / ( 1+ K α )

from this equation . It is clear that a)The fraction of drug that is available for absorption is controlled by the partition coefficient and the ratio of the volumes of the two phases, α ,and (b)b) That it remains constant as long as ‘α’ is constant. Thus the success of this approach depends on the magnitude of K which is a function of the drug involved and the oil selected.

The ‘oily solution’ approach is limited to those drugs which are appreciably oil soluble and optimum partition coefficient.

D. Oil Suspensions :

Drug release from oil suspension combines the principles involved in aqueous suspensions and oil solution.

With the suspended particles acting as a drug reservoir , the

process of drug availability consists of drug from the oil solution to the aqueous medium.

In contrast to the case of oil solutions where conc. is equal to or less than equilibrium solubility is possible, the drug conc. in the oil phase containing the suspended particles is close to equilibrium solubility.

Thus one would expect that the duration of action obtained from oil suspensions would be longer than that from oil solution.

E. Emulsions : Used as drug vehicles both orally and parenterally. Ex. Emulsions have been administered I.V in parenteral nutrition.

1.Oil in water and water in oil emulsions: In immunology, water in oil emulsions find popularity as adjuvants.Assuming that drug release proceeds via diffusion rather than by

breaking of the emulsion and that the body fluid acts as a perfect sink, the rate of disappearance of drug from the aqueous phase

( dc/dt) in the two dimensional diffusion model can be described by: Dc/ dt = - k ( co) (-kt) Where; co- initial conc. in aq. phase k- rate constant of disappearance of drug from the aq phase therefore; k= ADK/VL

Where; A – surface area of droplet, D – Diffusion coefficient of drug, V- volume of aq phase,. K- partition coefficent of drug between oil and water. L- effective thickness of oil phase. For a given drug , a fast rate of release is favored by a large

K, small droplets and a phase volume ratio favoring the oil phase.

2.Magnetic emulsion : The emulsion is a magnetically responsive oil in water

type emulsion with the capacity to localize the chemotherapeutic agent by magnetic means to a specified target site.

The magnetic emulsion consists of ethyl oleate – based

magnetic fluid as the dispersed phase and casein solution as the continuous phase.

The anticancer agent was trapped in the oily dispersed phase. Magnetic emulsions appear to have potential in conferring site specificity to certain chemotherapeutic agents.

F. Biocompatible Carriers : 1.Erythrocytes: When erythrocytes are lysed and then resealed,

exchange of intracellular and extracellular solutes will occur.

A drug present in the medium during the lysis procedure will therefore be encapsulated with in the membrane envelope of the erythrocyte upon resealing.

There are several advantages of resealed erythrocytes :a. These are biodegradable.b. These are non-immunogenic since the patients own erythrocytes are used.c. Degree of damage on the cell membrane of erythrocytes determines the drug release time.d. These protect the entrapped drug from immunological detection and enzymatic deactivation.e. The entrapment of drug within erythrocytes doesn't require that the drug be chemically modified.

• The major sites of removal of damaged erythrocytes are the phagocytic cells located in the liver and spleen. It is possible to target drugs to these specific cells by using erythrocytes.

• The release of drug from the erythrocytes carriers may occur following phagocytosis, via simple diffusion, or transport out of the cell by some specific transport system.

• Erythrocytes can be coupled with other drug carrier systems to achieve controlled and sustained drug release. These include DNA, albumin, polysaccharides, polymers or proteins.

Transport proteins have been inserted into membranes of released erythrocytes. The entrapped proteins are protected by erythrocytes from antibiotics or other plasma proteins.

2.Biological and synthetic macromolecules :• Serum albumin can be polymerized and cross-linked to form

micro beads to entrap steroid hormone, anticancer drugs, dyes and peptides.

• Similar beads containing insulin when implanted subcutaneously were found to sustain the release of this hormone in diabetic animals for longer than 2 months.

• Other examples of biological carriers are DNA, lipoproteins , antibodies and dextrans . They are directed to the lysosomes following entry into cells by endocytosis, pinocytosis or phagocytosis.

• Besides biological macromolecules, a number of synthetic polypeptides and polymers have been studied as carriers for drug delivery. These includes polymers of ethylene glycol , lysine and glutamic acid.

G. Liposomes :

• Liposomes are hydrated liquid crystals formed when phospholipids are allowed to swell in an aqueous media.

• When suitably dispersed , they consist of a series of concentric bilayers alternating with other compartments

• Depending on the phospholipids used and the composition of the medium ,liposomes of various sizes and shapes can be obtained.

Like, Unilamellar and multilamellar.

• These are several reasons why liposome's offer great potential in parenteral therapy:-

a. Versatility in terms of size and electrical charge. b. Ability to encapsulate both hydrophilic and lipophilic drugs. c. Relatively non- toxic. d. Ability to protect labile drugs from inactivation in the blood

by isolating them from the surrounding medium.

• The elimination and distribution of liposome's have been shown to be controlled by the size, surface charge ,and composition of the liposome.

• Because of their affinity for the phagocytic cells of the liver and spleen , liposome's have been investigated to target drugs to those phagocytic cells which have been infected with parasites.

H. Nanoparticles:

• These are transport carrier compartments for drugs or other active molecules of non-liposomal character in the nanometer size range (10nm- 1000  nm)

• The advantage of nanoparicles as drug delivery systems

are that- 1.They are biodegradable 2.non-toxic 3.Capable of being stored for a period up to 1 year Since they are mainly taken up by the reticuloendothelial

system following i.v administration, nanoparticles are useful in delivering drugs to the liver and to cells that are active phagocytically.

Furthermore, by modifying the surface characteristics of nanoparticles by coating them with substances such as surfactants , it is possible to enhance delivery of nanoparticles to spleen relative to the liver.

Methods of incorporating drugs into nanoparicles are as follows-

A. Colloidal co-acervation of macromolecules. B. Adsorption on the surface of the solid colloidal

macromolecular carriers. C. Coating of the particles by polymerization,

polycondensation or coacervation. D. Interfacial polymerization technique using electrocapillary

emulsification.

I) Implants Implants are typically placed subcutaneously to sustain the

drug release via the mechanism of drug diffusion, polymer dissolution, or a combination of both.

Non-biodegradable polymers such as polydimethylsiloxane, deliver drug by simple diffusion at a rate dependent on the drug solubility in the polymer and surface area of the implant.

Biodegradable polymers, such as polycaprolactone, polylactic acid, poly glycolic acid and poly ortho esters, deliver drug by diffusion and/ or polymer erosion.

Provided the bio-erosion rate is constant, drug release rate will be directly proportional to its physical dimension.

J) Prodrugs:

Naturally, a prodrug which is converted back to its parent compound in its target tissue or organ can be used to achieve site-specific drug delivery eg, L-dopa.

The main purpose for designing produgs is to improve some unfavorable physical, chemical or biological characteristics of the parent drug.

For a parent drug that is incompletely absorbed after i.m or s.c administration, the prodrug approach can be used to improve bioavailability.

If poor bioavailability is due to poor dissolution characteristics, it can be improved by forming a more water soluble prodrug.

On the other hand ,if poor bioavailability is due to unfavorable partitioning characteristics, it can be improved by forming a more lipophilic prodrug.

When the parent drug has poor therapeutic action due to degradation or metabolism of the parent drug , a prodrug can be formed by protecting the functional group that is susceptible to inactivation.

Finally, the prodrug approach can be used to provide sustained parenteral drug delivery by controlling its drug release rate from the formulation or by controlling its reconversion rate.

Examples of few Injectable controlled release formulations

1. Long-acting Penicillin Preparations2. Long-acting Vitamin B12 preparations3. Long-acting Adreno corticotropic Hormone

Preparations4. Long-acting Steroid preparations5. Long-acting Antipsychotic Preparations6. Long-acting Antinarcotics Preparations7. Long-acting Contraceptive Preparations8. Long-acting Insulin Preparations

References :-Novel Drug Delivery Systems by Yie.W. Chien, 2nd

edition, p. 381-385.Robinson J, Lee V H. “Controlled drug delivery-

fundamentals and applications”. 2nd edition.Vyas S P and Khar K R. “Controlled drug delivery

system-concept and advances”. 2nd edition. Jain N K. “Novel drug delivery system”. 2nd edition.Kalyani M. et al. International Journal of Research in

Pharmaceutical and Nano Sciences 2013; 2(5):572- 580.