Advanced Drug Delivery Systems

The term “drug delivery systems” refers to the technology utilized to present the drug to the desired body site for drug release and absorption. The first drug delivery system developed was the syringe, invented in 1855, used to deliver medicine by injection. The modern transdermal patch is an example of advanced drug delivery system.

The goal of any drug delivery system is to provide a therapeutic amount of drug to the proper site in the body to promptly achieve and then maintain the desired drug concentration.

This idealized objective points to the two aspects mostimportant to the drug delivery, namely:

*Spatial placement: relates to targeting of a drug to a specific organ or tissue.

*Temporal delivery of a drug: refers to controlling the rate of drug delivery to the target tissue.

Dosage FormsThere are numerous dosage form into which a drug substance can be incorporated for the convenient and efficacious treatment of a disease. Dosage forms can be designed for administration by all possible delivery routes to maximize therapeutic response.

Dosage Forms Available For Different Administration Routs:

Oral- Solutions, syrups, elixirs, suspensions, emulsions, gels, powders, granules, capsules, tablets.

Topical- Ointments, creams, pastes, lotions, gels, solutions, topical aerosols.

Parenteral- Injections (solutions, suspensions, emulsions forms), implants, irrigation and dialysis solutions.

Rectal- Suppositories, ointments, creams, solutions, powders. Lungs- Aerosols (solutions, suspensions, emulsions, powder

forms), inhalation, sprays, gases. Nasal- Solutions, inhalations. Eye- Solutions, ointments. Ear- Solutions, suspensions, ointments.

Conventional Dosage Form or Immediate – Release Dosage FormConventional / Immediate – release dosage form is a dosage form which is formulated / designed to give rapid and complete release of the drug contained therein immediately after administration.

Kinetic scheme for the extra vascular administration the conventional dosage form of a drug that follows one – compartment open model for disposition:

Dosage Form

Absorption Pool Body Compartment

Urine

Drug Release

Kr

Absorption ( INPUT )

Elimination( OUTPUT )

Ka

Ke

Kr, Ka and Ke : first order rate constants for drug release, absorption and overall elimination respectively.

Immediate release from a convenient dosage form implies that Kr >>> Ka. This means that absorption of a drug across a biological membrane (e.g. GI epithelium) is the rate–timing step in delivery of the drug to the body compartment.

For non–immediate–release dosage forms Kr <<< Ka. i.e. release of drug from the dosage form is the rate limiting step. Therefore the above scheme reduces to the following:

Dosage Form

Body Compartment Urine

Drug Release

Kr

Elimination

Ke

Essentially, the absorptive phase of the kinetic scheme becomes insignificant compared to the drug release. Thus the effort to develop a non–immediate–release dosage form must be primarily directed at altering the release rate by affecting the value of Kr.

Typical drug blood level vs. time curve / profile for extra vascular administration of a single dose of the conventional dosage form of a drug following one – compartment open model for disposition:

MTC /MSC

IV rout

Absorption phase

Ineffective range

MEC

Therapeuticrange

Rate of drug input= Rate of drug output

Toxic range

Time

Typical drug blood level – time profile for multiple dosage (non–immediate–release) regimen (equal doses of the drug at fixed intervals) of a conventional dosage form:

A) For time intervals allowing complete elimination of the previous dose: A series of isolated single dose profiles are obtained

MSC

MEC

Dose

Time

Dose Dose

B) For the dosing time intervals shorter than the time required for complete elimination of the previous dose:

MSC

MEC

TimeD DD D D D D D

At the start of the multiple dosage regimen, the blood levels of drug tends to increase in successive doses. But the rate of drug elimination will increase as the average blood level of drug rises (first order kinetics) and a situation is eventually reached when the overall rate of elimination of drug becomes equal to the overall rate of supply. This situation is called “Steady State”.

For a drug administered at equal time intervals, the time required for the average blood levels to reach the 95% of the steady state value is 4.3 times the biological half–life (t½) of the drug. The corresponding figure for 99% is 6.6 times.

Advantages of Conventional Dosage Form:

1. Per unit cost of conventional dosage form is less than non-immediate release dosage form.2. More flexibility for the physician for adjusting dosage form in conventional dosage form.3. Conventional dosage form can accommodate the

patient variation.4. No problems with drug having too small half life.5. Potent drugs can’t be formulated as sustained release dosage form.

Limitations of Conventional Drug Therapy:

1. Unable to maintain therapeutic blood level for a prolonged period of time.

2. Fluctuation of blood level over successive dosing intervals (giving peak and valley pattern).

3. Risk of over medication or under-medication because of drug blood level fluctuation. 4. Require frequent dosing Patient inconvenience + Poor

patient compliance Therapeutic failure / Inefficiency.

5. No therapeutic action during overnight no dose periodRisk of symptom break through in chronic disease.

6. Total amount of drug required is higher over the entire course of therapy. (compared to SRDF)7. Local/systemic side effect + overall health care cost is high.

Non-Immediate Release Dosage FormNon-immediate release dosage form is those which do not release whole amount of drugs contained, immediately after administration.

Why Non-Immediate Release Dosage Form?a) Delayed release of an immediate release unit. Ex: Enteric coated tablet or capsule. b) Repetitive intermittent release of two or more immediate release unit incorporated into a single dosage form. Ex: Repeat action tablet or capsule.

***Although a repeat action dosage form exhibits the same “peak and valley” pattern as associated with conventional dosage forms, but it improves patient compliance by reducing dosing frequency.

Types of Non-Immediate Release Dosage Form :

1. Delayed release dosage form2. Sustained release dosage form

a) Control release b) Prolonged release

3. Site specific release dosage form4. Receptor release dosage form

Site–Specific Release and Receptor–Release Dosage Forms

Site–specific and receptor release dosage forms offer targeted delivery of a drug directly to a certain biological location.

In case of site–specific release dosage forms, the target is the specific receptor for the drug within an organ or tissue.

Sustained Release Dosage Forms

Sustained release dosage forms are those dosage forms which are designed to release drug continuously at sufficiently slow or controlled rate over an extended period of time to provide prolonged therapeutic effect. In case of oral dosage forms, this period is usually measured in hours. But in case of injectable dosage forms, the period may range from days to months or even years.

Sustained release dosage forms can further be categorized as:a) Controlled release dosage forms: those sustained–release dosage forms which are designed to release drug at a sufficiently controlled rate to maintain a constant blood level over an extended period of time.

b) Prolonged release dosage forms: which cannot maintain a constant blood level, but the blood level declines at such a sufficiently slow rate that it remains within the therapeutic range for a satisfactory prolonged period of time.

Time (hrs)

MSC

MEC

AB

Fig: The blood level–time profile of (A) Controlled–release (B) Prolonged–release dosage form

Criteria of a Drug Required for Designing as Sustained Released Dosage Form:

• They exhibits neither very slow nor very fast rates (t½<2hrs) of absorption and excretion. [Drugs having biological half lives of between 4 & 6 hours make good candidates in sustained – release formulations.]

• They are uniformly absorbed from the GIT.

• They are administered in relatively low dose.

• They are used in the treatment of chronic rather than acute conditions.

• They possess a good margin of safety. [Accidental dose dumping from potent drugs may be strongly hazardous.]

Formulation Methods for Oral Sustained–Release Dosage Forms

The more common methods used in the design oforally administered sustained release dosage formsinclude:

– Reservoir systems or devices– Matrix Systems or Devices– Osmotic Pumps or Systems– Ion–Exchange Resin Complexes– Other Drug Complexes– Drug Adsorbates– Prodrugs

1. Reservoir Systems or DevicesThese systems or devices consists of a core of drug material is surrounded

by a coat of retardant barrier (polymeric membrane). The layer of retardant material separates the drug and the elution medium.

Mechanism of Drug Release from a Reservoir Device: The release of drug from a reservoir system can take place by four mechanisms:

A. Diffusion of drug present in the reservoir through the barrier. Here the barrier is impermeable to the elution medium.

B. Penetration of elution media through the barrier into the reservoir, dissolution of the drug followed by diffusion of the dissolved drug through the barrier.

C. Timed erosion of the barrier.D. Rupture of the barrier as a result of permeation of elution

medium.

DrugReservoir

C

B

D

A

Common Methods Employed to Develop Reservoir Systems/ Devices Include:A. Coating B. Microencapsulation

A. Coating: A number of reservoir devices can be prepared by applying the technology of coating which includes:

a. Mixed release coated granules/ pelletsb. Uniform release coated granules/ pelletsc. Microdialysis cellsd. Drug coat of retardant material over placebo pellets

a. Mixed Release Coated GranulesDrug pellets/ granules are divided into 3 to 4 groups. One group is left uncoated to provide the initial loading dose and the other groups of pellets/ granules are coated to different thicknesses. The various groups are mixed together and placed in capsules or compressed into tablets.

Mechanism of drug release: Moisture penetration through the barrier→ swelling of the core → rupture of the barrier

The retardant materials used for coating includes Combination of waxes, fatty acids, alcohols and esters, Enteric materials such as cellulose acetate phthalate and formalized gelatin, Mixture of solid hydroxylated lipids such as hydrogenated castor oil or glyceryl trihydroxy-stearate mixed with modified celluloses.

Examples of drugs designed as SRDF by this method include Erythromycin, Pancreatin etc.

b. Uniform Release Coated Granules / Pellets

In this method, drug granules / pellets are uniformly coated by a retardant material that slowly release drug over sufficiently prolonged period of time.

Retardant materials employed for this purpose include hydrolyzed styrene maleic acid copolymer, partially hydrogenated cotton seed oil etc.

Examples of drugs designed as SRDF by this technique include Crystals of ascorbic acid, Methylprednisolone etc.

c. Microdialysis CellsDrug pellets are coated with a mixture of ethyl cellulose (a water insoluble and pH insensitive polymer) and sodium chloride particles or some other water soluble materials (e.g. polyethylene glycol). Leaching of the sodium chloride molecules from the film results in dialytic membrane. This allows permeation of water, dissolution of drug and diffusion of drug through the essentially intact membrane.

Examples of drugs designed as SRDF by this technique are Nitroglycerin, Propoxyphene, Aspirin etc.

d. Drug Coat of Retardant Material over Placebo Pellets

The drug is suspended in the coating of retardant material applied onto placebo pellets. The prepared pellets are placed in capsules. The drug is released by erosion or rupture of the barrier.

Retardant materials employed include polyethylene glycol, modified ethyl cellulose, shellac or cellulose acetate phthalate.

Example of drugs designed as SRDF by this technique is theophylline

B. Microencapsulation: Microencapsulation means encapsulation of drug

material in microscopic size particles of a ‘wall forming’ material. The most common method of microencapsulation is coacervation. There are other techniques; like, spray drying.Drug designed as SRDF by microencapsulation is KCl. Coacervation: In this technique, the prospective wall–forming material e.g. gelatin, is dissolved in water. The drug material to be microencapsulated is added to the solution and the two–phase mixture is thoroughly stirred until the drug material is broken up to the desired particle size.

Then a solution of a second material (usually acacia) is added which concentrates gelatin into tiny liquid droplets called “coacervates” that encircle drug particles.

The particles are coated to different thicknesses, mixed together and compressed into tablets or placed in capsules. The drug is released by dissolution of coating materials.

2. Matrix System or DevicesIn these systems or devices, the drug is dispersed (embedded) in a matrix of retardant material, which may be encapsulated in particulate form or compressed into tablets.

Fig. Network model (Drug is insoluble in the retardant material)

Fig. Dispersion model (Drug is soluble in the

retardant material)

Mechanisms of Drug release from a matrix device takesplace by any one or a combination of the followings:

1. Penetration of water/ eluting media into the matrix, dissolution of the drug creating channels followed by diffusion of the drug through the channels (pore diffusion). This occurs when the matrix is insoluble in water, and the drug is insoluble in the matrix but soluble in water.

2. Primarily diffusion of drug through the matrix and secondarily partition between matrix and water. This occurs when the matrix is insoluble in water, but the drug is soluble in the matrix and has a high solubility in water / elution media.

3. Primarily partition between matrix and water / elution media and secondarily diffusion through the matrix. This occurs when the matrix is water insoluble, but the drug is soluble in the matrix and has low water solubility.

4. Erosion. This occurs when the matrix is insoluble in water but potentially erodable.

Retardant Materials Used in Matrix Devices Three classes of retardant materials are used to formulate matrix devices:1. Insoluble plastics / plastic materials / “Skeleton” matrixExamples: polyethylene, polyvinyl chloride, methyl acrylate – methacrylate copolymer and ethyl cellulose

2. Insoluble but potentially erodable materialsExamples: waxes, lipids and related materials. Specific examples include carnauba wax, castor wax (hydrogenated castor oil) and triglycerides.

3. Hydrophilic polymersExamples: These are insoluble inert polymers.

3. Osmotic Systems / PumpsThese systems employ osmotic pressure as the driving force to cause the release of drug. A constant release of drug can be achieved if a constant osmotic pressure is maintained and a few other features of the system are controlled.

A number of osmotic pumps / systems have been designed by pharmaceutical manufacturers including:

1. Oral Osmotic Systems 2. Push – Pull Osmotic System 3. Multi Directional Osmotic Drug Absorption System

Mechanism of Drug Release: Mechanism of Drug Release: GI fluid enter the GI fluid enter the tablet core across the semi-permeable membrane → tablet core across the semi-permeable membrane → dissolve drug→ creates an osmotic gradient across dissolve drug→ creates an osmotic gradient across the membrane →pumps the drug out through the the membrane →pumps the drug out through the delivery orifices. delivery orifices. The rate of drug solution release is approximately The rate of drug solution release is approximately one to two drops per hour.one to two drops per hour.

4. Ion – Exchange Resin ComplexesIon – exchange resins are water insoluble polymers containing salt forming groups on the polymer chain.

Resins used are special grades of styrene / divinyl benzene copolymers that contain substituted acidic groups (carboxylic and sulfonic for cation exchanges) or basic groups (quaternary ammonium for anion exchanges).

Drug is bound to the resin by repeated exposure of the resin to the drug in a chromatographic column or by prolonged contact of the resin with the drug solution.

For example, drug-resin salts may be prepared by percolation of the sodium salt of the resin with a concentrated solution of a drug hydrochloride salt. The following equation represents the drug release in-vivo:Resin – SO3Na + Drug HCl → NaCl + Resin-SO3. Drug H

Similarly drug-resinates are prepared by reaction of sodium salts of acidic drugs with resin chloride.Resin – NH4Cl + Drug Na → NaCl + Resin-NH4. Drug

Release in-vivo :Resin – NH4.Drug + NaCl → Drug Na + Resin-NH4Cl

The resin.drug complex is then washed with ion-free water and dried. The resulting product can be encapsulated, tabletted or suspended in ion-free vehicles.

5. Other Drug ComplexesCertain drug substances that are only slowly soluble in the body fluids are inherently long acting (Griseofulvin).

Thus drugs that are, high water soluble may be bound to suitable complexing agents to form complexes which are poorly water soluble and consequently give sustained action.The steps or mechanism involved in controlling the release of drug from drug complexes in GI fluid can be illustrated as follows:

Examples include:Tannic acid complexes of basic drugs like amphetamine and antihistamines.Other complexing agents to prepare complexes of basic drugs include polygalacturonic acid, algenic acid and arabogalactose sulfate.

Dissolution DissociationDC . solid DC . solution D

6. Drug AdsorbateDrug adsorbates represent a special case of complex formation in which the product is essentially insoluble.

Drug availability is determined only by the rate of dissociation (desorption) and, therefore access of the adsorbent surface to water as well as the effective surface area of the adsorbate.

The mechanism involved in controlling the release of drug from adsorbates can be illustrated as follows:

The adsorbate, can be formulated as liquid suspensions, tablets or capsules.

DesorptionAD. Solid D

7. ProdrugsProdrugs are therapeutically inactive drug derivatives

that regenerate the parent drug in-vivo by enzymatic or non-enzymatic hydrolysis. The steps or mechanisms involved in controlling release of drug from a prodrug can be depicted by the following scheme:

Desorption AbsorptionPD. Solid PD. Solution PD. Plasma

Metabolism

D

Elimination

Parenteral Sustained Release Dosage Forms

The most common types of dosage forms used for parenteral sustained-release drug therapy are:

1. Intramuscular Injections2. Implants for subcutaneous tissues and

various body cavities3. Transdermal systems/devices

Intramuscular InjectionsThe intramuscular injections used for sustained-release drug therapy may be a number of types including:

1. Drug complexes2. Aqueous suspensions3. Oil solution and oil suspension4. Emulsions

ImplantsImplants are drug-bearing polymeric device which are implanted subcutaneously or in various body cavities. This is one of the oldest and most highly developed forms of drug delivery. This method finds particular applicability to cases where chronic administration of drug over period ranging from days to years is required.

Examples include: Insulin for diabetes, Pilocarpine for glaucoma, Immune agents for various diseases and allergies, Contraceptive steroids, Narcotic antagonists, Antibiotics, Anticancer drugs, Anti-hypertensive drugs.

The polymer materials must be biocompatible and nontoxic. They are usually of the following types: Hydrogels, Silicones, Polyethylene, Ethylene vinyl acetate (EVA) copolymers, Biodegradable polymers.

There are four types of implantable devices based on the site of implantation. These include:

1. Subcutaneous devices2. Intravaginal devices3. Intrauterine devices4. Intraocular devices

USP Requirements and FDA Guidance for Sustained-Release Dosage Forms:

The USP contains general chapters and specific tests to determine the drug release capabilities of sustained release tablets & capsules. Release of Drug: The USP test for drug release for sustained release dosage forms is based on drug dissolution from the dosage unit against test time. According to USP the individual monographs contain specific criteria for compliance with the test and the apparatus and test procedures to be release tablets.

Uniformity of Dosage Units: Modified release tablets & capsules must meet the USP standard for uniformity for conventional dosage units. Uniformity of dosage units may be demonstrated by either of two methods, weight variation or content uniformity.

In vitro-In Vivo Correlations: In vitro-in vivo relationships (IVIVRs) or in vitro-in vivo correlations (IVIVCs) one critical to the development of oral sustained release products. Asserting (IVIVCs) is important through out product development, clinical evaluation, submission of an application for FDA approval for marketing and during post approval for any proposed formulation or manufacturing changes. In 1997, The FDA published a guidance document, sustained release Oral Dosage Forms: Development, Evaluation and Application of in-Vitro / in-Vivo Correlations.

It provides guidance to sponsors of new drug applications (NDAs) for sustained release oral products.

Labeling: The USP indicates labeling requirements for modified-release dosage form in addition to general labeling requirements. The requirements are specific to the monograph article.

For example, the label of Aspirin Delayed release tablets must state that, the tablets are enteric coated. The labeling for Theophylline extended release capsules must indicate whether the product is intended for every 12 or 24 hours and state with which in vitro drug release test are described in the monograph.

Conventional Drug Therapy

1. Rapid and complete release of drug immediately after administration.

2. Absorption is the rate-limiting step (kr >>> ka).

3. Blood level fluctuates (Peak and Valley).

4. There is risk of overmedication or under medication at periods of time.

5. Frequent dosing. 6. Patient non compliance.

Therapeutic inefficiency / failure.7. Inconvenience of patient.

Sustained-Release Drug Therapy

1. Slow/controlled release of drug over an extended period of time.

2. Drug release from the dosage form is the rate-limiting step (ka >>> kr ).3. Constant blood level is maintained over a prolonged period (Reduced fluctuation).4. Reliable therapy as the risk is minimized.

5. Reduced frequency of dosing.6. Improved patient compliance.

7. Enhanced patient convenience with day-time and night-time medication.

Comparison between conventional and sustained-release drugs

8. No therapeutic action during overnight no dose period.

9. Risk of symptom breakthrough.

10. Incidence and severity of untoward effects related to high -peak plasma concentration .

11. More total dose over the entire course of therapy.

12. More side effects.

13. Health care cost .14. Permits prompt testing of

therapy.15. Incidence of severity of GI side

effects due to dose dumping of irritant drugs .

16. More flexibility for physician in adjusting dosage required.

8. Maintains therapeutic action during overnight no dose period.9. Improved treatment of many chronic diseases (minimizing symptom breakthrough).10. Incidence and severity of untoward effects related to high – peak plasma concentration .11. Less total dose over the entire course of therapy.12. Minimize/eliminate incidence of local/systemic side effects. 13. Health care cost .14. Does not prompt.

15. Incidence of severity of GI side effects due to dose dumping of irritant drugs . 16. Less flexibility.

17. Can accommodate abnormal cases of disease safety offering drug disposition etc.

18. Chance of at any site of GIT (local irritation ).

19. No problems for drugs with too short half lives.

20. Per unit cost is less.

21.

17. Can not accommodate.

18. Chance of at any site of GIT (local irritation). 19. Not suitable for drugs with too short half lives, drugs needing specific requirements for absorption from GIT.20. Per unit cost is more.

21.

Time Time