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SUSTAINED RELEASE AND CONTROLLED DOSAGE FORMS
 


Syllabus:
Concept and principles in the formulation of SR dosage forms. Drug delivery rate from the dosage forms, formulation and manufacture of sustained action dosage forms. In vitro-in vivo drug availability from the formulations. Quality control tests.
 



INTRODUCTION

Most conventional drug products, such as tablets and capsules are formulated to release the active drug immediately after administration to obtain rapid and complete systemic drug absorption.
The goal of any drug delivery system is to provide a therapeutic amount of drug to the proper site in desired concentration.

Controlled drug delivery systems

These systems deliver the drug at the absorption site at a controlled rate.

 

Classification of controlled drug delivery systems (DDS)


1. Extended release dosage forms
A dosage form that allows at least a two-fold reduction in dosage frequency as compared to an immediate release (conventional) dosage form.
It contains       (a) Prolonged release DDS            and         (b) Sustained release dosage forms.
(a) Prolonged release DDS
After a single dose the drug is released slowly and rate of absorption is slow. Onset of action is delayed. Duration of action is greater than a conventional dosage form.
(b) Sustained release DDS
·        Contains loading dose + maintenance dose.
·        Loading dose is immediately released to produce quick onset of action.
·        Maintenance dose is released at a controlled rate so that the plasma concentration remains constant above Minimum Effective Concentration (MEC).
·        Plasma concentration comes down according to first order elimination kinetics.
2. Delayed release dosage forms
On delayed release dosage forms one or more immediate release units are incorporated into a single dosage form.
e.g. repeat action tablet, enteric coated tablet.
Advantages: These dosage forms produce better patient compliance.
Disadvantages: Drug level is not uniform within the therapeutic range.
3. Targeted release dosage forms
This is a dosage form that releases drug at or near the intended physiologic site of action.



Advantages of a controlled drug delivery system over a conventional dosage forms are:-

1.      Frequency of drug administration is reduced – patient compliance is improved.
2.      In multiple dosing of conventional dosage forms the blood level of drug shows oscillatory characteristic. In controlled release dosage form the blood level is evenly maintained.
3.      The safety margin of high potency drugs can be increased and thus side-effects or adverse effects can be minimized.
4.      Total amount of drug administered can be reduced because of maximum utilization.
5.      Reduction in health care costs through improved therapy, shorter treatment period, less frequency of dosing and reduction in personnel time to dispense, administer and monitor patients.

Disadvantages of controlled release dosage forms  :-
1.      Decrease systemic availability in comparison to immediate release conventional dosage forms, this may be due to incomplete release, increased first-pass metabolism, increased instability, insufficient residence time for complete release site specific absorption, pH dependent solubility etc.
2.      Poor in vitro-in vivo correlation.
3.      Possibility of dose dumping due to food, physiologic or formulation variables or chewing or oral formulations by the patient and thus increased risk of toxicity.
4.      Retrieval of drug is difficult in case of toxicity, poisoning or hypersensitivity reactions.
5.      Reduced potential for dosage adjustment of drugs normally administered in varying strength.
6.      Higher cost of formulation.

DESIGN OF CONTROLED DRUG DELIVERY SYSTEM (DDS)

The performance of a drug presented as a controlled release system depends upon its:
1.      Release of drug from the dosage form.
2.      Movement of the drug within the body.


The release depends on the fabrication of the dosage forms and the movement depends on the pharmacokinetics of the drug.

Desired characteristics of drug suitable for controlled DDS

 

A. Biopharmaceutical characteristics

1.      Molecular weight of the drug: Less than 600 daltons are suitable for passive diffusion. Larger molecules are not suitable e.g. peptides and proteins.
2.      Aqueous solubility of the drug:
·        Good aqueous solubility, with pH independent solubility serves as a good candidate for oral controled DDS. E.g. pentoxifylline.
·        Drug with pH dependent aqueous solubility (e.g. phenytoin) or drug soluble in nonaqueous solvents (e.g. steroids) is suitable candidates for parenteral controlled DDS (e.g. intramuscular depot).
·        Poorly water-soluble drugs are not suitable candidates because their dissolution is rate limited.
3.      Ionization and pKa of the drug
·        Drug that remains is unionized state at absorption site is  a good candidate.
·        Drug that remains in ionized state (e.f. hexamethonium) are poor candidates.
4.      Drug stability: Drugs unstable in gastro-intestinal environment are poor candidates for oral controlled DDS because bioavailability will be less.
5.      Mechanism of absorption: Drugs absorbed by carrier mediated transport and those absorbed through an “absorption window” are poor candidates e.g. several B-vitamins.


6.      Route of administration:
(a)    Oral route: Duration of action may be extended to 12 to 24 hours. Maximum 1000mg can be given.
(b)   Intramuscular / Subcutaneous route: Duration of action can be prolonged from 24hours to 12 months. Maximum 2ml or 2 gm can be administered through this route.
(c)    Transdermal route : 12 hours to several days. Very low dose drugs (e.g. nitroglycerine) can be administered. Drugs with extensive first pass metabolism is suitable.

 

Pharmacokinetic characteristics

1. Absorption rate: The rate of release( Kr) << Rate of absorption (Ka.)
2. Elimination half life:                       –  excellent candidate for controlled release DDS
                                                       – good candidate for controlled release DDS
                                             long  t1/2.                             – not suitable for controlled release DDS
3. Rate of metabolism:  Drug that is rapidly metabolized in the liver are not good candidate for oral controlled release DDS they are better given by parenteral controlled release formulation.

Pharmacodynamic characteristics

1.      Therapeutic range:   Therapeutics range of a drug is wide ® good candidate for controlled DDS
2.      Plasma concentration – Response relation ship: Drugs such as reserpine whose pharmacological activity is independent of its plasma concentration are poor candidate for controlled DDS.

Calculation of amount of drug required for designing a sustained release dosage form
The amount of drug required in a sustained release dosage form to provide a sustained drug level (CSS) in the body is determined by
·        the pharmacokinetic parameters of the drug (Vd, KE, CL),
·        the desired therapeutic concentration of the drug (CSS)and
·        the intended duration of action (T).

Total dose (Dtot ) required =  Initial dose or loading dose (Di)  +  Maintenance dose (Dm)
Dtot  =  Di  +  Dm
Calculation of initial dose
At the desired therapeutic concentration (CSS) the body contains( CSS  x  Vd ) amount of drug.
If Di amount of drug is administered as loading dose then (FxDi ) amount of drug will be absorbed in the body where F is the oral bioavailability of drug
Therefore,            F Di  =  CSS  x  Vd.              or,
Calculation of maintenance dose
The Di dose will raise the plasma concentration of the drug to CSS and will reach the peak. After CSS is reached the elimination rate from the body will be maximum and the elimination rate will be KE x Vd x CSS. An ideal maintenance dose will supply drug at a rate in which the drug is eliminated from the body.
Therefore, the rate of delivery from the maintenance dose = elimination rate (Routput)

i.e. Routput  = KE x Vd x CSS. =  CL x  CSS.  where the clearance value of the drug, CL = KE x Vd.

If the intended duration of action = T then the amount of drug required for maintenance dose Dm can be calculated from the equation:
FxDm =  Routput  x T            or,   
Therefore,     




Drug release pattern from various oral dosage forms



EVALUATION OF SUSTAINED RELEASE DOSAGE FORMS
In vitro tests
Objective of evaluation
1.      In-vitro tests are required to guide the researchers during the developmental stage, prior to clinical testing.
2.      In vitro testing is necessary to ensure batch to batch uniformity in the production of an already developed sustained release product.
Test using USP dissolution rate test apparatus
In vitro tests include release studies from the dosage forms in a dissolution medium. It may be either simulated gastric fluid (pH 1.2) or simulated intestinal fluid (pH 7.2) or may be pH in between gastric and intestinal. USP dissolution rate test apparatus 1 (rotating basket type) or apparatus 2 (paddle type) may be taken. Simulated gastric or intestinal fluid is taken in the round bottom beaker. Samples are taken at known intervals and is replaced with fresh medium, amount of drug released from the SR dosage form is potted against time.

Test using rotating bottle assembly
Samples are tested in 90ml bottles containing 60 ml dissolution medium, which are rotated at 40rpm in water bath of 370C. Time to time samples are withdrawn.

Test using Sartorius device
Sartorius device includes a semi-permeable membrane (dialysis membrane) separating the dissolution chamber and simulated plasma chamber. Samples are withdrawn from plasma chamber. Thus amount absorbed is plotted against time.

Stability tests
Most SR dosage forms are complex and the special ingredients used in them may produce stability problem. So the stability testing program includes storage of formulation under both normal (shelf) and exaggerated (accelerated) conditions of temperature, humidity, light etc.
Physical stability, chemical stability and release profile is checked after a time interval at each set of conditions.

In vivo tests
Objectives
1.      To determine the fraction of drug absorbed (should be ideally ³ 80% of conventional release dosage form).
2.      To check for the occurrence of dose dumping.
3.      To determine the influence of food on drug absorption.
4.      To determine the duration of action
5.      To determine the Cmax / Cmin ratios at steady state.
6.      To determine the percent fluctuation calculated from equation: 100(Cmax – Cmin) / Css.

A single dose is sufficient to assess the first three objectives but the subsequent ones can only be evaluate from a multiple dose study. The reference standard is a solution or suspension of the drug or currently marketed controlled dosage forms.




ORAL CONTROLLED RELEASE SYSTEMS
A. Continuous controlled release systems
               1. Dissolution controlled release systems
(a)    Matrix (or monolith) systems
(b)   Encapsulation / Coating systems
2. Diffusion controlled release systems
(a)    Matrix systems
(b)   Reservoir systems
3. Dissolution and diffusion controlled release systems
4. Ion-exchange resin – Drug complexes
5. Slow dissolving salts and complexes
6. pH independent formulation
7. Osmotic pressure controlled systems
8. Hydrodynamic pressure controlled system.
B. Delayed transit and then continuous release systems
1.      Altered density systems
2.      Mucoadhesive systems
3.      Size-based system
C. Delayed release systems
1.      Intestinal release systems
2.      Colonic release systems