SUSTAINED RELEASE FORMULATIONS

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SUSTAINED RELEASE FORMULATIONS
BY
Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph.
D Department of Pharmaceutics KLE Universitys
College of Pharmacy, Belgaum- 590010, Karnataka,
India Cell No 0091 9742431000 E-mail
bknanjwade_at_yahoo.co.in
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CONTENTS

• Introduction
• Concept
• Advantages and disadvantages
• Physicochemical properties
• Biological properties

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HISTORY

• The period between 1950 to 1970 is considered as
  period of Sustained drug release.
• The main AIM of preparing sustained release
  formulations was intended to modify and improve
  the drug performance by
• Increasing the duration of drug action.
• Decreasing the frequency of dosing.
• Decreasing the required dose employed.
• Providing uniform drug delivery.

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INTRODUCTION

• DEFINITIONS-
• SRFs describes the slow release of a drug
  substance from a dosage form to maintain
  therapeutic response for extended period
  (8-12hrs)of time. Time depends on the dosage
  form. In oral form it is in hours, and in
  parenterals it is in days and months. Ex
  Aspirin SR, Dextrim SR.
• Controlled release dosage form In this the rate
  or speed at which the drug is released is
  controlled.
• Ex Adalat CR (Nifidipine), Dynacirc CR
  (Isradipine.)

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CONCEPT

• The of SRDFs is to obtain Zero
  order release from the dosage form.
• Zero order release is a release which is
  independent of the amount of drug present in the
  dosage form.
• Usually SRDFs do not follow zero order release
  but they try to mimic zero order release by
  releasing the drug in a slow first order fashion.
• Pharmacological action is seen as long as the
  drug is in therapeutic range, problems occur when
  drug concentration is above/below therapeutic
  range.

GOALS
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SUSTAINED RELEASE DOSAGE FORMS
PARENTRALS
Capsules
Tablets
Slow release
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ADVANTAGES

• Improved patient compliance
• Less frequent dosing
• Allows whole day coverage.
• Decreased local and systemic side effects.
• Decreased GIT irritation.
• Decreased local inflammation.
• Better drug utilisation.
• Decreased total amount of drug used.
• Minimum drug accumulation on chronic dosing.
• Improved efficiency in treatment.
• Uniform blood and plasma concentration.
• Decreased fluctuation in drug level i.e uniform
  pharmacological response.
• Increased bioavailability of some drugs
• Special effects SR Aspirin gives symptomatic
  relief in Arthritis after waking
• Economy

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DISADVANTAGES

• DOSE DUMPING Increase quantity of drug release
  causes dumping of drug which in turn leads to
  toxicity.
• REDUCED POTENTIAL FOR ACCURATE DOSE ADJUSTMENT
  Administrating a fraction of drug is not
  possible.
• NEED FOR ADDITIONAL PATIENT EDUCATION
• Do not Crush or Chew the dosage unit.
• Tablet residue may appear in stools.
• STABILITY PROBLEMS The complexity of SRFs will
  lead to stability problem.
• REDUCTION IN SYSTEMIC AVAILABILITY Example
  Theophylline, Procainamide and vitamin
  combinations.

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DISADVANTAGES continued..

• Retrieval of the drug is difficult in case of
  toxicity / poisoning /
• hypersensitive reaction.
• Higher cost of the formulation.
• Half life Drugs having shorter half life (less
  than one hour) and
• drugs having longer half life (More than
  twelve hrs) cannot be
• formulated as SRDFs.
• If a dosage form contains more than 500mgs., of
  active ingredient formulation of SRDFs is
  difficult.
• If CRDF is required (With New polymers) cost of
  government
• approval is very high.

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FACTORS TO BE CONSIDERED WHILE FORMULATING A
SRDFs

• DRUG PROPERTIES Stability, solubility, partition
  coefficient
• and protein binding are to be considered.
• ROUTE OF DRUG DELIVERY Area of the body where
  drugs
• are applied or administered play a vital
  role.
• TARGET SITES To minimize side effects, its
  desired to maximize the fraction of dose
  applied.
• ACUTE OR CHRONIC DOSING Cure, Control and length
  of drug therapy must be considered.
• THE DISEASE Pathological conditions play a
  significant role.
• THE PATIENT Ambulatory/ bedridden, young or old,
  etc., must be considered.

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PHYSICOCHEMICAL PROPERTIES

• AQUEOUS SOLUBILITY pKa
• PARTITION COEFFICIENT
• DRUG STABILITY
• PROTEIN BINDING
• MOLECULAR SIZE DIFFUSIVITY
• DOSE SIZE

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• AQUEOUS SOLUBILITY
• For a drug to be absorbed, it must first
  dissolve in the aqueous phase surrounding the
  site of administration.
• AqS of a drug influences its dissolution rate
  which in turn establishes its concentration in
  solution.
• Dissolution rate is related to AqS solubility
  as shown by Noyes Whitney equation under sink
  condition( CGITC)
• dc/ dt KD ACS
• dc/ dt- dissolution rate
• KD - dissolution rate constant
• A- Total surface area of drug particles.
• CS- Aqueous saturation solubility.

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• Drugs with low aqueous solubility have low
  dissolution rate and have oral bioavailability
  problems. E.g. Tetracycline.
• Drugs with high aqueous solubility are
  undesirable to formulate SRDFs. E.g. Aspirin.

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• The aqueous solubility of weak acids weak
  bases is governed by the pKa of the compound and
  pH of the medium.
• FOR WEAK ACID
• St So(1Ka\H So(110pH-pKa)
• St Total solubility of the weak acid
• So Solubility of the
  un-ionized form
• Ka Acid dissociation
  constant
• H - Hydrogen ion
  concentration
• Weakly acidic drug exist as unionized form in
  the stomach
• absorption is favored by acidic medium

pKa
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• FOR WEAK BASES
• St So(1H \Ka) So(1pKa-pH)
• St Total solubility of both conjugate and
  free base form
• of weak base.
• So Solubility of the free base.
• Weakly basic drug exists as ionized form in the
  stomach hence absorption of this type is poor in
  this medium.

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• PARTITION COEFFICIENT
• Between the time of drug administration
  elimination it diffuse through several membranes
  ( Lipid barriers)
• Oil/Water partition coefficient plays a major
  role in evaluating the drug penetration.
• KCo/Cs
• Where..
• Co Equilibrium concentration in organic phase.
• Cs Equilibrium concentration in aqueous phase.
• Drugs with extremely high partition coefficient
  are very oil soluble and penetrates in to various
  membranes very easily.

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Contd..

• The relationship between tissue penetration and
  partition coefficient for the drug is known as
  Hansch Correlation.

• The activity of the drug is a function of its
  ability to cross membranes and interact with
  receptors. The more effectively the drug crosses
  the membrane the greater is the activity

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• Contd..
• There is an optimum partition coefficient for a
  drug in which it permeates membrane effectively
  and shows greater activity.
• Partition coefficient with higher or lower than
  the optimum are poorer candidates for the
  formulation
• Unionized water soluble are highly absorbed from
  the intestine and lipid soluble drugs are
  absorbed from the tissue.

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• Contd..
• Values of partition coefficient below optimum
  result in the
• decreased lipid solubility and remain
  localized in the first
• aqueous phase it contacts.
• Values larger than the optimum , result in poor
  aqueous
• solubility but enhanced lipid solubility and
  the drug will not
• partition out of the lipid membrane once it
  gets in.

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• Solid state undergoes degradation at much
  slower rate than
• in the suspension or solution etc..
• Drugs stable in stomach gets released in
  stomach and which
• are unstable gets released in intestine.
• Drugs with stability problems in any
  particular area of G.I.T
• are less suitable for the formulation.
• Drugs may be protected from enzymatic
  degradation by
• incorporation in to a polymeric matrix.

DRUG STABILITY
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• Drug binding to plasma proteins (albumins)
  resulting retention of the drug in the vascular
  space.
• Drug-protein complex can serve as a reservoir in
  vascular
• space.
• Main forces for binding are Vander Waal forces,
  hydrogen
• bonding , electrostatic forces.
• Charged compounds has greater tendency to bind
  proteins
• than uncharged ones.
• Extensive binding of plasma proteins results in
  longer half-life
• of elimination for the drug
• E.x..95 binding in Amitriptyline , diazepam ,
  diazepoxide.

PROTIEN BINDING
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• The ability of the drug to diffuse through a
  membrane is called diffusivity (Diffusion
  coefficient). It is the function of its molecular
  size (molecular weight).
• In most polymers it is possible to relate log D
  to some function of molecular size as,
• Log D -Svlog V Kv -Smlog M Km

MOLECULAR SIZE DIFFUSIVITY

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Contd...,

• V Molecular volume.
• M Molecular weight.
• Sv, Sm, Kv Km are constants
• The value of D is related to the size and shape
  of the cavities, as well as the drugs.
• The drugs with high molecular weight show very
  slow kinetics.

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• For those drugs requiring large conventional
  doses, the
• volume of sustained dose may be too large to
  be practical.
• The compounds that require large dose are given
  in
• multiple amounts or formulated into liquid
  systems.
• For oral route the volume of product is limited
  by patients.
• For IM,IV or SC routes its tolerated.

DOSE SIZE
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• ABSORPTION
• DISTRIBUTION
• METABOLISM
• ELIMINATION HALF LIFE
• SIDE EFFECTS MARGIN OF SAFETY
• ROLE OF DISEASED STATE
• ROLE OF CIRCADIAN RHYTHM

BIOLOGICAL PROPERTIES
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• The release of a drug from a dosage form is
  important than
• its absorption.
• The reason of poor absorption are poor water
  solubility, low
• partition coefficient, acid hydrolysis and
  metabolism.
• For SRDFs rate of release is much slower than
  the rate
• of absorption.
• Transit time of drug is between 9-12hrs.
• Maximum absorption half-life should be 3-4hr.

ABSORPTION
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• Continued..
• Low density pellets, capsules or tablets are
  formulated which
• float on top of gastric juice and delay their
  transfer out of
• stomach e.g. PABA
• GI retention for drugs with poor absorption can
  be increased
• by enhancers.
• Bioadhesive materials is made which has high
  affinity to the
• mucin coat.
• A drug that is slowly absorbed is poor candidate
  for SRDF
• eg.,Gentamycin, Hexamethonium

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• Distribution of drugs in to vascular extra
  vascular spaces is an important factor.
• Apparent volume of distribution drug
  concentration in tissue to that of plasma at
  steady state are important parameters for
  distribution. It is called T\P ratio.
• Calculation of this distribution is mainly based
  on one compartment pharmacokinetic models.
• It is given by..
• V Dose\Co
• CoInitial concentration immediately after i.v
  bolus injection

DISTRIBUTION
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• For two compartment models, the total volume
  of distribution is given by the apparent volume
  of the distribution at steady state
• Vss (1K12\K21)V1
• Where.
• V1 - Volume of the central compartment
• K12-Rate constant for distribution of
  the drug
• from central compartment to
  peripheral
• K21 - Peripheral to the central
  compartment
• blood or plasma to the total
  volume.

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• Metabolic conversion of drug to another chemical
  form.
• Factors associated with metabolism are
• Ability of drug to induce or inhibit enzyme
  synthesis. This results in fluctuating drug blood
  level with chronic dosing.
• Fluctuating drug blood level due to intestinal
  metabolism or through a hepatic first pass
  effect. Ex.., intestinal metabolism upon oral
  dosing are hydralazine , salicylamide ,
  nitroglycerine.

METABOLISM
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• Rate of elimination of the drug is described
  quantitatively by its biological half life i.e..
  T1/2.
• The half life of the drug is related to its
  apparent volume of distribution and its systemic
  clearance.
• t1/2 0.693V/CLs
  0.693 AUC/dose

ELIMINATION BIOLOGICAL HALF-LIFE
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• Contd...
• A drug with shorter half life requires frequent
  dosing.
• Drugs with half life 2hr should not be used
  ,since such system
• requires unexpectedly large release rate and
  large doses.
• E.x.., Ampicillin , Cephalosporin
• Drugs with half life greater than 8 hrs should
  not be used,
• formulation of such drugs is unnecessary.
• E.x.., Diazepam, Digitoxin , Digoxin

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• SRDF is useful in minimizing the side effects of
  the drug.
• Slow release potassium SR of potassium to
  prevent gastric irritation. Timed release of
  aspirin to prevent gastric irritation.
• Measure of margin of safety of the drug is
  THERAPEUTIC INDEX(TI).
• TI TD50\ED50
• TD50 median toxic dose
• ED50 median effective dose.
• For potent drugs TI value is small. Larger the
  value of TI safer the drug.
• Drugs with small value of TI are poor candidates
  for the formulation.
• A drug is considered to be relatively safe if TI
  exceeds 10.
• Some drugs of TI less than 10 are Digitoxin,
  Digoxin and Phenobarbitone.

SIDE EFFECTS
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• Different methods used are..
• BASED ON DRUG MODIFICATION.
• BASED ON DOSAGE FORM MODIFICATION.

TECHNIQUES FOR PREPARING SR FORMULATIONS
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• BASED ON DRUG MODIFICATION
• COMPLEX FORMATION
• DRUG-ADSORBATE PREPARATION .
• PRO DRUG SYNTHESIS.
• ION EXCHANGE RESINS.

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• Complex formation
• The rate of dissolution of solid complex in
  biological fluids and rate of dissociation of
  complex in the solution are considered and they
  depend upon pH and composition of gastric and
  intestinal fluids.
• Drug-adsorbate preparation
• In this product is insoluble. Drug availability
  is determined by rate of disabsorption.
• Pro drug synthesis
• They are inactive and need enzymatic hydrolysis
  for regeneration. Solubility, absorption rate of
  prodrug must be lower than parent drug.

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• Ion exchange resins
• They are water insoluble, cross linked polymers
  containing salt forming groups. The drug is bound
  to the resin by using chromatographic column or
  by prolonged contact.
• Drug release from this complex depends on pH
  property of resin. Drug that is attached to the
  resin is released by exchanging with the ions
  present in the GIT.
• Resin -Drug- X-
  Resin- X- Drug-
• Example Biphetamine.

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• BASED ON DOSAGE FORM MODIFICATION.
• Microencapsulation
• Its a process in which tiny particles are
  surrounded by uniform coating (microcapsule) or
  held in a matrix of polymer (microsphere.) Spray
  drying is used which involves rapid evaporation
  of the solvent from the drug surface.
• Barrier coating
• In this one quarter of the granules are in non
  sustained form for sudden drug release, remaining
  part are coated for sustained release. Both these
  granules are filled in hard gelatin capsule or
  compressed in a tablet, and the release mechanism
  is by diffusion. Coating material used are fats,
  waxes.

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• Matrix embedding Drug is dispersed in a matrix
  of retardant material which may be encapsulated
  or compressed in a tablet.

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MARKETED FORMULATIONS
Name Marketer Dosage form Indication
Carbotrol Glucotrol Xl Adderall XR Procardia Xl Ortho Evra Dura gesic Shri Us Pfizer Shri US Pfizer Ortho Mcneil Janssen Oral capsule Oral Tablet Oral Capsule Oral Tablet Trans Dermal Patch Trans Dermal Patch Epilepsy Hyperglycaemia ADHD Angina / Hypertension Contraceptive Chronic pain
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• Text book of Sustained release dosage form by
  Y.S.Robinson, Decker Series.
• Controlled release dosage form by Y.W.Chien.
• Ansels Pharmaceutical Dosage forms and Drug
  delivery Systems.
• Tutorial Pharmacy by Cooper and Gunns.
• Remingtons Pharmaceutical Sciences
• Text book of Pharmaceutics by Bentley and
  Drivers.
• www.google.co.in (CRDF design- google book
  result- cherng-jukin).
• Text book of Pharmaceutical Sciences by Aulton.

REFERENCES
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Queries
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