liquid sustained release systems
TRANSCRIPT
LIQUID SUSTAINED RELEASE SYSTEMS
K.SRAVAN(256212886047)
M.PHARM Dept.of pharmaceutics
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CONTENTSINTRODUCTIONMERITS ANDDEMERITSAPPROACHES TO LIQUID SUSTAINED RELEASE SYSTEMMETHOD OF PREPARATIONEVALUATIONAPPLICATIONS
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WHAT IS DRUG DELIVERY SYSTEM?
The term “drug delivery systems’’ refer to the technology utilized to present the drug to the desired body site for drug release and absorption.
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Conventional Modified
Drug Delivery
Sustained
Extended
Site-specific
Pulsatile
Enteral
Parenteral
Other
In the conventional therapy aliquot quantities of drugs are introduced into the system at specified intervals of time with the result that there is considerable fluctuation in drug concentration level as indicated in the figure.
HIGH
LOW
HIGH
LOW
INTRODUCTION
What is Sustain Release Dosage Form? “Drug Delivery system that are designed to achieve prolonged therapeutic effect by continuously releasing medication over an extended period of time after administration of single dose.” The basic goal of therapy is to achieve steady state blood level that is therapeutically effective and non toxic for an extended period of time. The design of proper dosage regimen is an important element in accomplishing this goal.
The difference between controlled release and sustained release,
Controlled release is perfectly zero order release that is the drug release over time irrespective of concentration.
Controlled drug delivery- which delivers the drug at a pre determined rate for a specified period of time.
Sustain release dosage form- is defined as the type of dosage form in which a portion i.e. (initial dose) of the drug is released immediately, in order to achieve desired therapeutic response more promptly, and the remaining(maintanance dose) is then released slowly there by achieving a therapeutic level which is prolonged, but not maintained constant.
Sustained release implies slow release of the drug over a time period. It may or may not be controlled release.
Rationality in designing S.R.Dosage form.
The basic objective in dosage form design is to optimize the delivery of medication to achieve the control of therapeutic effect in the face of uncertain fluctuation in the vivo environment in which drug release take place.
This is usually concerned with maximum drug availability by attempting to attain a maximum rate and extent of drug absorption however, control of drug action through formulation also implies controlling bioavailability to reduce drug absorption rates.
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The history of controlled release technology is divided into three time periods
From 1950 to 1970 was the period of sustain drug release
From 1970 to 1990 was involved in the determination of the needs of the control drug delivery
Post 1990 modern era of controlled release technology
HISTORY
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The main AIM of preparing sustained release formulation’s was intended to modify and improve the drug performance by Increasing the duration of drug action. Decreasing the frequency of dosing. Providing uniform drug delivery.
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SRF’s 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.
Usually SRDF’s do not follow zero order release but they try to mimic zero order release by releasing the drug in a slow first order fashion.
HOW IS THE DRUG RELSEASED
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Improved patient compliance Decreased local and systemic side effects. Better drug utilization. Improved efficiency in treatment. Increased bioavailability of some drugs Special effects: SR Aspirin gives symptomatic relief
in Arthritis in the morning. Economic in preparation
MERITS
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Dose dumping
Reduced potential for accurate dose adjustment:
stability problems:
Retrieval of the drug is difficult in case of toxicity /
poisoning and hypersensitive reaction.
Higher cost of the formulation.
Drugs having shorter half life (less than one hour) and
drugs having longer half life (More than twelve
hrs) cannot be formulated as SRDF’s
DEMERITS
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The dosage forms which are liquid in nature and are
capable of delivering the drug in a sustained manner
are called as liquid sustain release systems.
They generally include suspensions , emulsions, gels
etc.
WHAT ARE LIQUID SUSTAINED RELEASE SYSTEMS
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Mainly used for ease of swallowing in paedeatric and
geriatric use
Ease of formulation
Economic in preparation
Better bioavailability
than solid dosage forms
Flexibility in dose adjustment
WHY LIQUID SUSTAINED RELEASE SYSTEMS?
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SuspensionsLiquid crystalline phasesDrug – resin complexesIn situ gel formationMicroencapsulationMesogenic moleculesEmulsions/ multiple emulsions
APPROACHES TO LIQUID SUSTAINED RELEASE SYSTEMS
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A method of preparing sustained-action liquid dosage forms
for various compounds is by microencapsulating the
biologically active ingredient and subsequently suspending
the microencapsulated form in a vehicle saturated with the
biologically active ingredient.
It is possible to formulate liquid product, having sustained
action, by suspending coated granules or particles in a
suitable liquid media which has no action on the coats of the
granules. These formulation are similar to suspensions.
GENERAL METHOD OF PREPARATION
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Polymers used--- carbopol 934p, ethylcellulose(suspensions), HPMC, eudragit RL30D
Resins used--- AMBERLITE(drug resin complexes), carboxylated styrene crosslinked by di vinyl benzene
Drugs used– theophylline, proponolol, timolol,etc
Other materials such as oil, peptides are also used.
Materials used
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Suspensions are biphasic dosage forms in which the solid phase is suspended in a liquid phase.
To produce a sustained release liquid dosage form the drug is encapsulated with in a suitable polymer and then it is formulated as suspension using tragacanth as suspending agent.
SUSPENSIONS
The techniques like spray drying includes 2 different methods for preparation of suspensions1st methodsolution of drug and polymer are used as feed solution (solvent used ethanol /water 80:20, acetone)2nd methoddispersion of drug in polymer solution was feed solution( solvent used methylene chloride)
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Among sustained-release drug delivery systems, microcapsules have received much attention because of uniform distribution in GI tract which leads to uniform absorption and decreasing risk of local effects on GI tract.
Another advantage of microparticulate systems is their feasibility to be Incorporated into liquid dosage forms such as suspensions.
SUSPENSIONS
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Polymer– hydroxy propyl methyl cellulose phthalate 1.5%PEG6000 - plasticizer Formulation- sustained release suspension of
theophylline microcapsules
suspensions
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Heating of polymer
below its Tg
pressurized at 28mpa for 30sec-
5min
temperature maintained above
tg
Liquid crystalline phases
method of preparation
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liquid crystal system
thermo tropic
lyotropic
nematic
smectic
cholesteric
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Lyotropic crystals in invitro condition provide sustained release.
Provides thermodynamically , kinetically stable matrix
Investigations done using polar lipid-water-peptide Released peptide was found out using
immunoreactivity of peptide in plasma Peptide is absorbed in pseudo zero order Lyotropic LC acts as parenteral depot Peptide protected against degradation
Liquid crystalline phases
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Ion exchange resins are solid and suitably insoluble high
molecular weight polyelectrolytes that can exchange their
mobile ions of equal charge with the surrounding medium. size of the ion-exchange resins -about 20 to about 200 µm
particle sizes. Drug – resinate complexes are prepared by batch and column
method Influence of formulation on rate and equilibrium was
done using ion exchange resin. Diffusion of drug from resin particles controlled by particle
diffusion process.
Drug resin complexes
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Coated with SURELEASE(aqueous ethyl cellulose dispersion)
pH has no effect on drug release. Increase in ionic concentration, increase in rotation
speed will increase the release The drug release follows first order kinetics Strong acidic cationic exchange resin AMBERLITT
IRP69 ( SR, taste masking, drug stabilizing agent) is used.
Drug resin complexes
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The size and state of the particle in the internal phase play an important role in the final status of the microparticles.
The choice of the internal and the external phase of the emulsion, type of emulsifier and method of homogenizing two phases will effectively determine the characteristics of the final microparticles.
EC is a non-biodegradable and biocompatible and gastro-resistant polymer which has been extensively used as drug release retardant which easily forms microcapsules with a one-step encapsulation method
Micro encapsulation
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Preparation of sustained release microcapsules using emulsion- solvent evaporation method using EC.
Preparation has two strategies. The first being preparation of o/w emulsion containing
EC dissolved in dichloromethane+ drug as oily phase. 1.5%SLS in water as aqueous phase. Where oily phase is
added to aqueous phase. 45 min stirring to remove DCM. And then the microcapsules are obtained.
Micro encapsulation
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The second strategy containing drug and EC as oily phase in acetone.
Added to external phase 1.3% tween 80 in 100ml liq.paraffin.
Stirred for 5 hrs Microcapsules are then obtained These are then formulated as suspensions
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In situ gel formation
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Elderly patients with swallowing dysfunction may benefit from the oral administration of liquid dosage forms with in situ gelling properties.
Gels are made by using METHYL CELLULOSE a thermo reversible gelation properties containing polymer and sodium alginate having ion responsive gelation properties
This is mainly done for ease of administration and provides suitable integrity for the drug in stomach to produce sustained release.
Generally used gelling agents are chitosan, pectin(0.1-2%), sodium alginate(0.25-1%), methylcellulose(2%),
In situ gel formation
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Mixtures of 2.0% methylcellulose and 0.5% alginate containing 20% d-sorbitol were of suitable viscosity for ease of swallowing by dysphagic patients and formed gels at temperatures between ambient and body temperature allowing administration in liquid form and in situ gelation in the stomach
A 2.0% methylcellulose/0.5% alginate formulation showed improved sustained release compared to that from 2.0% methylcellulose and 0.5% alginate solutions and from an aqueous solution of paracetamol
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Mesogen is the fundamental unit of a liquid crystal that induces structural order in the crystals.
Typically, a liquid-crystalline molecule consists of a rigid moiety and one or more flexible parts.
The rigid part aligns molecules in one direction, whereas the flexible parts induce fluidity in the liquid crystal.
This rigid part is referred to as mesogen, and it plays a crucial role in the molecule. The optimum balance of these two parts is essential to form liquid-crystalline materials.
Mesogenic molecules
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MULTIPLE EMULSIONS
Multiple emulsion (w/o/w or o/w/o), Prepared by two step procedure
First step (o/w)Primary emulsion
Second step (o/w/o)Secondary emulsification phase
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Oil + Aqueous phase Low HLB surfactant + Oil
Blend and heat up to 70-80º C
Formation of very fine droplets
Heat and blend with low shear
Oil
Multiple emulsion
Blend with low shear
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Viscosity
surface tension
conductivity
Syringability
pH
Globule size
Test for sterility
Microscopic method
Particle size distribution
Entrapment efficiency 39
Evaluation of Multiple Emulsions
Syringability
All the formulation were tested by different size of needle under the
guidance by the experters (Physicians) and the data obtained was put
in tabulated form.
The O/W/O multiple emulsion with a minimum concentration of
surfactants showed excellent syringability. The multiple emulsion
prepared with maximum concentration of surfactants and for given
time period entrapped 83.14 % of Hydroxyprogesterone.
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Globule/droplet size determination
Droplet size was determined by the microscopy, the compound
microscope was used to determine the droplet size of the formulation.
It was found that the droplets decrease in size with increase in the
concentration of surfactants. The average diameters of the dispersed
water droplets in o/w/o emulsions
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Multiple Emulsion
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Entrapment efficiency
The entrapment efficiency is the capacity of the multiple emulsions
that how much quantity of drug is entrapped in the internal phase. It
was calculated in %.
All the formulations were centrifuged at high speed and the
separated phase was evaluated for drug content.
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Sterility Test
All the formulations were subjected for the sterility test by direct
inoculation method (I.P.).
The sterility test was carried out for aerobic and anaerobic
microorganism, fluid thioglycollate media and soybean casein
digest media was used for sterility test. 44
Stability study
The stability study was carried out of optimized formulation Fa.
Formulation was stored in amber colored ampoule at 40o C for three
months. It was evaluated for physical characteristics.
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In -vitro diffusion study
•The drug release profile of all formulations was studied in buffer
media (pH 7.4 and Alcohol 20%) by using K-Cell.
•The cellulose membrane used as a barrier.
•The drug release profile was studied for 24 hrs.
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• The amount of the drug diffused out was relatively small,
indicating that the water layer of the multiple emulsion shows a
stable diffusion barrier, thus the drug was released mainly by
permeation through this membrane.
• The comparative drug diffusion studies were carried out,
comparison with the marketed formulation and shown the
percentage drug release of marketed formulation more than the
multiple emulsions.
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Microscopic method Dissolution studies Entrapment efficiency pH Viscosity surface tension Sedimentation volume Degree of flocculation Ease of dispersibility
EVALUATION
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Liquid crystalline phases are applied for cosmetics In treatment of paradontitis the drug is dispersed in gel
such that it adheres to the gum pockets. LC of DNCG is applied as mast cell stabilizer used as
prophylactic agent in asthma & hay fever Used in treatment of bronchial asthma
APPLICATIONS
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Drug form
Hydroxy progesterone Multiple emulsion
Timolol Liquid eye drops
Theophylline Suspension
Propranolol Hydrochloride Drug resin complex
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Kenneth J. Fredrick. Performance and problems of pharmaceutical suspensions, Journal of Pharm. Sciences. 50,531-35,1961
George M., Grass IV, Robinson J. "Sustained and controlled release drug delivery systems" ,"Modern Pharmaceutics" edited by Banker G.S., Rhodes C.T., 2nd edition, Marcel Dekker, 1990: 639-658pp.
Longer M.A., Robinson J.R. "Sustained release drug delivery system" ,"Remington's pharmaceutical sciences" 18th edition, Mack Publishing Company, 1990: 1675-1684pp.
References
Brahmnkar DM, Jaiswal SB: Biopharmaceutics and Pharmacokinetics – A Treatise. 1sted. Delhi: Vallabh Prakashan; 1995. p. 62, 282.
Liberman HA, Martin A, Gilbert R,. Banker S: Pharmaceutical Dosage Forms: Disperse system: Marcel Dekkar. Volume III; 1994; p. 423-471.
Liberman HA, Martin R, Gilbert R, Banker S: Pharmaceutical Dosage Forms: Disperse system: Marcel Dekkar. Volume II,;1994; p. 47- 97, 261 – 310, 183- 239.
Liberman HA, Martin R, Gilbert R, Banker S: Pharmaceutical Dosage Forms: Disperse system: Marcel Dekkar. Volume III; 1994; p. 423-471.
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