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Sustained release dosage form
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SUSTAINED RELEASE DOSAGE FORMS
Presented by:
Sujit R. Patel,
1st M. pharm.
DEPARTMENT OF PHARMACEUTICS,Maratha Mandal’s College OF PHARMACY,
Belgaum - 590 010.
April 10, 2023 1M.M.C.P.
INTRODUCTIONDrug delivery systems refer to the technology utilized to present the drug to the desired body site for drug release and absorption.
Newer discoveries and advancements in technology has lead to various new techniques of delivering the drugs for maximum patient compliance at minimal dose and side effects.
April 10, 2023 2M.M.C.P.
IDEAL DRUG DELIVERY SYSTEM
First, it should deliver drug at a rate dictated by the needs of the body over the period of the treatment.
Second it should channel the active entity solely to the site of action.
This is achieved by development of new various modified drug release dosage forms, like-
Control release dosage forms Time release dosage forms Sustained release dosage forms Site specific or targeted drug delivery systems etc
April 10, 2023 3M.M.C.P.
SUSTAINED RELEASE DRUG DELIVERY: Any of the dosage form that maintains the therapeutic blood or tissue levels of drug by continuous release of medication for a prolonged period of time, after administration of a single dose. In case of injectable dosage forms it may vary from days to months.
SITE SPECIFIC AND RECEPTOR TARGETINGSITE SPECIFIC AND RECEPTOR TARGETING : : Targeting a drug directly to a certain biological location .For site specific release the target is the adjacent to or in the diseased organ or tissue, for receptor release the target is the particular drug receptor within an organ or tissue.
CONTROLLED RELEASE DRUG DELIVERY :Delivery of the drug at a predetermined rate and /or to a location according to the needs of the body and disease states for a definite period of time.
April 10, 2023 4M.M.C.P.
Contd..
REPEAT ACTION DOSAGE FORMREPEAT ACTION DOSAGE FORM: contain 2 or 3 full doses which are so designed that the doses are released sequentially one after the other.
OTHER NOVEL(NEW) DOSAGE FORMS:OTHER NOVEL(NEW) DOSAGE FORMS:
includes- Microspheres, Nanoparticles,, Trans-dermal delivery systems, Ocular drug delivery, Nasal drug delivery, Implants etc.
TIMED RELEASE OR DELAYED RELEASETIMED RELEASE OR DELAYED RELEASE: : These are the systems that use repetitive, intermittent dosing of a drug from one or more immediate release units incorporated into a single dosage form or an enteric delayed release systems e.g. Repeat action tablets and capsules and enteric coated tablets where time release is achieved by barrier coating, or wherein the release of the drug is intentionally delayed until it reaches the intestinal environment.
April 10, 2023 5M.M.C.P.
Sustained release dosage forms
(SRDF’S)
timeApril 10, 2023 6M.M.C.P.
INTRODUCTION
Sustained release describes the release of drug substance from a dosage form or delivery system over an extended period of time. Also referred to as prolonged-release (PR),
slow release (SR), sustained action (SA), prolonged action (PA) or extended-release (ER).
April 10, 2023 7M.M.C.P.
COMPARISION OF DRUG RELEASE PROFILES
April 10, 2023 8M.M.C.P.
Differences between sustained and controlled drug delivery system
Sustained release Sustained release dosage formdosage form
•Constitutes dosage form that Constitutes dosage form that provides medication over provides medication over extended period of timeextended period of time
•SRDF generally do not SRDF generally do not attain zero order release attain zero order release kinetics kinetics
•Usually do not contain Usually do not contain mechanisms to promote mechanisms to promote localization of the drug at localization of the drug at active site. active site.
Controlled release Controlled release dosage formdosage form
•Constitutes dosage form that Constitutes dosage form that maintains constant drug levels in maintains constant drug levels in blood or tissue blood or tissue
•Maintains constant drug levels in Maintains constant drug levels in the blood target tissue usually by the blood target tissue usually by releasing the drug in a zero order releasing the drug in a zero order pattern.pattern.
•Controlled dosage forms contain Controlled dosage forms contain methods to promote localization methods to promote localization of the drug at active site.of the drug at active site.
April 10, 2023 9M.M.C.P.
Merits of SRDF Reduction in blood level fluctuations of drug, thus
better management of the disease. Reduction in dosing frequency. Enhanced patient convenience and compliance. Reduction in adverse effects(both systemic and local),
esp. of potent drugs, in sensitive patients. Reduction in health care costs. Improved efficiency of treatment. Reduces nursing and hospitalizing time. Maximum bioavailability with a minimum dose.
April 10, 2023 10M.M.C.P.
Contd..
Minimize drug accumulation with chronic dosing.
Cure or control condition more promptly.
Make use of special effects, e.g. Treatment of Arthritis.
Constant blood levels achieve desired effect and this effect is maintained for an intended period of time.
Drug susceptible to enzymatic inactivation or by bacterial decomposition can be protected by encapsulation in polymer system suitable for SR.
April 10, 2023 11M.M.C.P.
Limits of SRDF
Administration of sustained release medication dose not permit prompt termination of therapy. Immediate changes in the drug if needed during therapy when significant adverse effects are noted cannot be accommodated.
The physician has less flexibility in adjusting dosage regimen, as it is fixed by dosage form design.
Sustained release dosage forms are designed for normal population i.e. on basis of average biologic half-life. Consequently, disease states that alter drug disposition, significant patient variation, and so forth are not accommodated.
More costly process and equipment are involved in manufacturing many sustained release dosage forms.
April 10, 2023 12M.M.C.P.
Contd..
Dose dumping
Unpredictable and poor in vitro and in vivo relationship.
Effective drug release time period is influenced and limited by GI
residence time. Need additional patient education.(such as not to chew or crush the
dosage form before swallowing) Drugs having very short half life or very long half life are poor
candidates for sustained release dosage forms. For Ex: diazepam. Delayed onset of action, hence sometimes not useful in acute
conditions
April 10, 2023 13M.M.C.P.
Characteristics of Drugs Unsuitable for Peroral SRDF
I. Those which are absorbed and excreted rapidly; short biological half life(<1 hr). Ex- Penicillin G , Furosemide.
II. Those with long biologic half life(>12 hrs). Ex- Diazepam, Phenytoin.
III. For those which require large doses(>1 gm) Ex- Sulfonamides.
IV. Extensive binding of drugs to plasma proteins will have long elimination half life and such drugs generally do not require to be formulated to SRDF.
April 10, 2023 14M.M.C.P.
Contd..
V. Those with cumulative action and undesirable side effects. Ex-Phenobarbital
VI. Those with low therapeutic indices. ex- Digitoxin.
VII. Those requiring precise dosage titration for every individual. Ex- Warfarin, Digitoxin.
VIII. In general a very highly soluble drug or a highly insoluble drug are undesirable for formulation into SRDF product.
April 10, 2023 15M.M.C.P.
Materials Used in Coating of Sustained Release Dosage Forms (Encapsulation)
Mixtures of waxes [bees wax, carnauba wax, etc] with glyceryl monostearate , stearic acid , glyceryl mono palmitate and cetyl alcohol.These provide coatings that are dissolved slowly or broken down in the GIT.
Shellac and zein – polymers that remain intact until the PH of the GI contents become less acidic
Ethyl cellulose , which provides a membrane around the dosage form and remains intact throughout the GIT. However, it does permit water to permeate the film, dissolve the drug , and diffuse out again.
Acrylic resins , which behave similarly to ethyl cellulose as a diffusion controlled drug release coating material.
Cellulose acetate [di acetate and tri acetate] Silicone elastomers.
April 10, 2023 16M.M.C.P.
Polymers for Micro-encapsulation
Water-soluble resins
Water-insoluble resins
Waxes and lipids
April 10, 2023 17M.M.C.P.
Water-soluble resins
Gelatin
Povidone (PVP)
CMC
HEC
MC
PVA
April 10, 2023 18M.M.C.P.
Water-insoluble resins
Ethyl cellulose
Polyamide (Nylon)
Polyethylene
Cellulose nitrate
April 10, 2023 19M.M.C.P.
Waxes and lipids
Paraffin
Carnauba
Beeswax
Stearic acid
Stearyl alcohol
April 10, 2023 20M.M.C.P.
Physicochemical Properties of Drug Candidate:–
DoseDose sizesize
DoseDose sizesize
Molecular size Molecular size and diffusivityand diffusivity
Molecular size Molecular size and diffusivityand diffusivity
Protein bindingProtein binding Protein bindingProtein binding
Drug Drug stabilitystabilityDrug Drug
stabilitystability
Partition Partition coefficientcoefficientPartition Partition
coefficientcoefficient
Aqueous Aqueous
solubility and pka solubility and pka
Aqueous Aqueous
solubility and pka solubility and pka
Physicochemical Physicochemical propertiesproperties
Physicochemical Physicochemical propertiesproperties
April 10, 2023 21M.M.C.P.
Physicochemical properties:–
1) Aqueous solubility & PKaː– Aqueous solubilityː–
A drug with good aqueous solubility, especially if pH independent, serves as a good candidates
Drug to be absorbed it first must dissolve in the aqueous phase surrounding the site of administration and then partition into absorbing membrane.
April 10, 2023 22M.M.C.P.
Contd..
Noyes Whitney Equation
dc = KDACs dt
where ,dc/dt= dissolution rate.
KD = Dissoltion rate constant. A = total surface area of drug.
Cs = aqueous saturation solubility.
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 SRDF’s.
E.g.: Paraacetamol
.
April 10, 2023 23M.M.C.P.
PKaː–
The aqueous solubility of weak acids & weak bases is governed by the pKa of the compound and pH of the medium.
FOR WEAK ACIDSt = So(1+Ka\[H ] =So(1+10pH-pKa)
where, 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.
April 10, 2023 24M.M.C.P.
FOR WEAK BASES
St = So(1+[H ] \Ka) =So(1+pKa-pH)
Where, 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 .
April 10, 2023 25M.M.C.P.
2) Partition coefficientː– Between the time a drug is administered and is eliminated from the body, it must diffuse through a variety of biological membranes.
• Oil/Water partition coefficient plays a major role in evaluating the drug penetration.
K=Co/Cs
where, Co= Equilibrium concentration in organic phase. Cs= Equilibrium concentration in aqueous phase.
April 10, 2023 26M.M.C.P.
According to ‘Hanch correlation’ a parabolic relationship between the log of its partition coefficient has with that of the log of its activity or ability to be absorbed.
Drugs with extremely high partition coefficient are very oil soluble and penetrates in to various membranes very easily.
Log K
Log
acti
vit
y
April 10, 2023 27M.M.C.P.
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
April 10, 2023 M.M.C.P 28
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.
April 10, 2023 M.M.C.P 29
3) Drug stabilityː– 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.
April 10, 2023 30M.M.C.P.
4) Protein bindingː– 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.
April 10, 2023 31M.M.C.P.
5) Molecular size & diffusivityː–
The ability of a drug to diffuse through membranes is called diffusivity which is a function of molecular weight.
In most polymers it is possible to relate log D to some function of molecular size as,
Log D = - Sv log v + Kv = - SM log M + Km where,V – Molecular volume. M – Molecular weight. Sv, Sm, Kv & Km are constants.
April 10, 2023 32M.M.C.P.
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.
April 10, 2023 33M.M.C.P.
6) Dose sizeː– 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.
The greater the dose size,greater the fluctuation.
So the dose should have proper size.
April 10, 2023 34M.M.C.P.
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 TabletOral Tablet
Oral Capsule Oral Capsule
Oral TabletOral Tablet
Trans Dermal PatchTrans Dermal Patch
Trans Dermal PatchTrans Dermal Patch
Epilepsy
Hyperglycaemia
ADHD
Angina / Hypertension
Contraceptive
Chronic pain
April 10, 2023 35M.M.C.P.
REFERENCEː–1) Remington’s pharmaceutical sciences.
2) Sustained and controlled release systems.
-James W Robinson.
3) Theory and Practice of Industrial Pharmacy.
-Lachmann and Liebermann.
4) Biopharmaceutics And Pharmacokinetics A Treatise. - D.M. Brahmankar.
5) www.google.com
April 10, 2023 36M.M.C.P.
April 10, 2023 37M.M.C.P.