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SUSTAINED RELEASE FORMULATIONS

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SUSTAINED RELEASE FORMULATIONS Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D Department of Pharmaceutics KLE University s College of Pharmacy, Belgaum- 590010 ... – PowerPoint PPT presentation

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Title: SUSTAINED RELEASE FORMULATIONS


1
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
2
CONTENTS
  • Introduction
  • Concept
  • Advantages and disadvantages
  • Physicochemical properties
  • Biological properties

3
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.

4
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.)

5
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
6

SUSTAINED RELEASE DOSAGE FORMS
PARENTRALS
Capsules
Tablets
Slow release
7
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

8
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.

9
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.

10
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.

11
PHYSICOCHEMICAL PROPERTIES
  • AQUEOUS SOLUBILITY pKa
  • PARTITION COEFFICIENT
  • DRUG STABILITY
  • PROTEIN BINDING
  • MOLECULAR SIZE DIFFUSIVITY
  • DOSE SIZE

12
  • 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.

13
  • 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.

14
  • 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
15
  • 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.

16
  • 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.

17
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

18
  • 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.

19
  • 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.

20
  • 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
21
  • 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
22
  • 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

23

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.

24
  • 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
25
  • ABSORPTION
  • DISTRIBUTION
  • METABOLISM
  • ELIMINATION HALF LIFE
  • SIDE EFFECTS MARGIN OF SAFETY
  • ROLE OF DISEASED STATE
  • ROLE OF CIRCADIAN RHYTHM

BIOLOGICAL PROPERTIES
26
  • 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
27
  • 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

28
  • 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
29
  • 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.

30
  • 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
31
  • 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
32
  • 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

33
  • 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
34
  • Different methods used are..
  • BASED ON DRUG MODIFICATION.
  • BASED ON DOSAGE FORM MODIFICATION.

TECHNIQUES FOR PREPARING SR FORMULATIONS
35
  • BASED ON DRUG MODIFICATION
  • COMPLEX FORMATION
  • DRUG-ADSORBATE PREPARATION .
  • PRO DRUG SYNTHESIS.
  • ION EXCHANGE RESINS.

36
  • 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.

37
  • 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.

38
  • 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.

39
  • Matrix embedding Drug is dispersed in a matrix
    of retardant material which may be encapsulated
    or compressed in a tablet.

40
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
41
  • 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
42

Queries
43
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