FORMULATION ASPECTS BY APPROACHING DIFFERENT …

www.wjpr.net Vol 8, Issue 8, 2019.

Kailas et al. World Journal of Pharmaceutical Research

336

FORMULATION ASPECTS BY APPROACHING DIFFERENT

POLYMERS OVER MATRIX TABLETS

Kailas Tarkase1*, Sandesh Bole

2*, Snehal Khatke

2, Sonal Shinde

2 and Sagar Yenare

2

1Asst. Prof. Department of Pharmaceutical Quality Assurance, Dr. Vitthalrao Vikhe Patil

Foundation’s Collage of Pharmacy, Vilad Ghat, Ahmednagar, (MS), India, 414111.

2Department of Pharmaceutical Quality Assurance, Dr. Vitthalrao Vikhe Patil Foundation’s

Collage of Pharmacy, Vilad Ghat, Ahmednagar, (MS), India, 414111.

ABSTRACT

An ideal drug delivery system should aid in the optimization I the drug

therapy by delivering an appropriate amount to the intended site at a

desired rate. An oral drug delivery system providing a uniform drug

delivery can only partly satisfy therapeutic and biopharmaceutical

needs, as it doesn’t take in to account the site specific absorption rates

within the Gastrointestinal Tract (GIT). Therefore there is a need of

developing drug delivery system that release the drug at the right time,

at a specific site and desired rate. A matrix system consists of active

and inactive ingredients that are homogeneously dispersed and mixed

together into dosage form. In this, we discuss about oral controlled

release dosage form and its various polymers used to formulate in

sustained release matrix tablet. The use of polymer in the matrix tablet

is to controlling the drug release and play important role in

formulation.

KEYWORDS: Polymer, Matrices, Drug Release, Dissolution, Diffusion, Biological factors,

Physiological factor etc.

INTRODUCTION

Tablets are offered to safe end with drug administration with appropriate method of active

pharmaceutical administration with excellent biological and physiochemical stability and

accurate dosing of a drug.

World Journal of Pharmaceutical Research SJIF Impact Factor 8.074

Volume 8, Issue 8, 336-353. Review Article ISSN 2277– 7105

Article Received on

02 May 2019,

Revised on 22 May 2019,

Accepted on 12 June 2019,

DOI: 10.20959/wjpr20198-15271

*Corresponding Author

Kailas Tarkase

Asst. Prof. Department of

Pharmaceutical Quality

Assurance, Dr. Vitthalrao

Vikhe Patil Foundation’s

Collage of Pharmacy, Vilad

Ghat, Ahmednagar, (MS),

India, 414111.



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Modified release dosage forms whose drug release kinetics of time course or location are

chosen to accomplish therapeutic or convenience objective not provided by conventional or

immediate release forms.

Extended release dosage form whose drug release slowly, so that plasma concentration is

maintained at a therapeutic level for period of time.

Delayed release dosage form whose drug is now being released immediately following

administration but at a later time, E.g. Enteric coated tablet.

Prolonged release dosage form this type of dosage form indicates that the drug is provided for

absorption over a longer period of time than the from a conventional dosage form.

Sustained release dosage form this dosage form which indicated an initial release of drug

sufficient to provide a therapeutic amount dose soon after administration, and then a gradual

release over an extended period of time.

Extended Release Tablet V/S Conventional Release Tablet

Extended release tablet and capsules = Administered once or twice a day,

While conventional release tablet and capsule = Administered 3 to 4 times a day to

achieve same therapeutic effects.

For non oral rate-controlled drug delivery system = 24 hours for most Transdermal

patches from months to years.

Drawbacks Associated With Conventional Dosage Forms

1. A drug with short biological half life which needs a close succession administration is

required, so it may increase the missing of dosage forms leads to poor patient compliance.

2. The uncontrolled fluctuation of drug level may leads to either below effective range or

over the effective range.

3. Plasma concentration verses time profile of dosage form and it’s difficult to achieve the

steady state active drug level.

4. The rise and fall of drug level it may give to accumulation of adverse effects especially

for a drug having less therapeutic index.



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Figure no. 1: Plasma drug concentration profiles for conventional tablet formulation, a

sustained release formulation and a zero order controlled release formulation.

Advantages of sustained release drug delivery system

1. Reduction in dosing frequency.

2. Reduced fluctuation in circulating drug levels.

3. Increased patient convenience and compliance.

4. Avoidance of night time dosing.

5. More uniform effect.

6. Maximum utilization of drug.

7. Reduction in GIT irritation and other side effects.

8. Reduction in health care cost through improved therapy.

9. Improve bioavailability of some drugs.

Disadvantages of sustained release drug delivery system

1. Decreased systemic availability in comparison to immediate release conventional dosage

form, this may be due to

Incomplete release

Increased first-pass metabolism, increased instability

Site specific absorption, pH dependent solubility, etc.

2. Poor in vitro-in vivo correlation.

3. Possibility of drug dumping.

4. Retrival of drug is difficult in case of toxicity, poisoning, or hypersensitivity reactions.

5. Higher cost of formulation.



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Techniques employed in the design and fabrication of Oral Drug Delivery System

1. Dissolution controlled release

Encapsulation dissolution control

Matrix dissolution control

2. Diffusion controlled release

Reservoir devices

Matrix devices

3. Diffusion and dissolution controlled system

4. Ion-exchange resins

5. pH-independent formulations

6. Osmotically controlled release

7. Altered density formulations

Classification of Matrix Tablets

(A) Hydrophobic matrix system

In this type of matrix system the use of polymer is not essential to provide controlled drug

release, and in it the insoluble polymers are used. These ingredients include waxes, fatty

acids, and polymeric materials such as ethyl cellulose, methyl cellulose and acrylate

copolymer. The presence of insoluble ingredients in the formulations helps to maintain the

physical dimensions of hydrophobic matrix during drug release.

(B) Hydrophilic matrix system

When the release medium (i.e. water) is thermodynamically compatible with a polymer, the

solvent penetrate into the free spaces between macromolecular chains. The polymer may

undergo a relaxation process, due to the stress of the penetrate solvent, so that the polymer

chain become more flexible and the matrix swells. This allows the encapsulated drug to

diffuse more rapidly out of the matrix.

(C) Lipid matrix system

These materials manufactured by the lipoid waxes and related ingredients. Active from of

drug from the dosage form release the content such matrices followed by either diffusion or

erosion. A drug release properties are mainly depends on the absorption medium fluid

component than hydrophobic-polymers. Either Stearyl alcohol or stearic acid mixed with



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carnauba wax it has been mainly applicable for release retarding polymer in sustained release

formulation of tablet.

(D) Biodegradable matrix system

These types of polymer are biodegraded either by enzymatic or non enzymatic process. It

contains the polymeric substance which is composed of monomeric linking to the other

functional group and gives unstable linkage in the backbone. Consist of the polymer which

comprised of monomers linked to one another functional groups and have unstable linkage in

the backbone. Finally the biodegradable material is excreted in the enzymatic process.

Advantages of matrix tablet

1) Maintains therapeutic concentrations over prolonged periods.

2) Reduction in toxicity by slowing drug absorption.

3) Minimize the local and systemic side effects.

4) Improvement in treatment efficacy.

5) Minimize drug accumulation.

6) Increase the stability by protecting the drug from hydrolysis or other derivative changes in

GIT.

7) Reduction in health care cost.

8) Usage of less total drug.

9) Improved patient compliance.

Disadvantages of matrix tablet

1) The remaining matrix must be removed after the drug has been released.

2) Greater dependence on GI residence time of dosage form.

3) Increased potential for first-pass metabolism.

4) Delay in onset of drug action.

5) Release rate continuously diminishes due to increased diffusion resistance and decrease in

effective areas at the diffusion front.

Drug release system of matrix tablet

Drug in the outer layer exposed to the bathing solution is dissolved first and after that diffuses

out of the matrix. This process continues interact with bathing solution and the solid drug

moving toward the interior. It allows that for this system to be diffusion controlled, the rate of

the dissolution of drug particles within the matrix must be faster than the diffusion rate of



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dissolved drug leaving the matrix. Derivation of the mathematical model to describe this

system involves the following assumptions:

A pseudo-steady state is maintained during drug release.

1. The diameter of the drug particle is less than the average distance of drug diffusion

through the matrix.

2. The bathing solution provides sink condition at all times.

The majority of oral CR systems are depending on dissolution, diffusion or a combination of

both mechanisms, to generate slow release of drug into the gastrointestinal milieu.

1. Dissolution controlled systems

Drug with slow dissolution rate will demonstrate sustaining properties, since the release of

the drug will be limited by rate of dissolution. This being the case, SR preparations of drugs

could be made by decreasing their dissolution rate. This includes preparing appropriate salts

or derivatives, coating the drug with a slowly dissolving carrier.

The dissolution process at steady process state, is described by Noyes-Whitney equation,

dc/dt = KDA(Cs-C) = D/h A (Cs-C)

Where,

dc/dt = Dissolution rate

KD = Diffusion co-efficient

A = Surface area of the dissolving solid

Cs = Saturation solubility of the solid

C = Concentration of solute in bulk solution

H = Thickness of diffusion layer

Figure no. 2: Dissolution controlled matrix system.



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2. Diffusion controlled systems

Basically diffusion process shows the movement of drug molecules from a region of higher

concentration to one of lower concentration. Diffusion systems are characterized by the

release rate being dependent on its diffusion through an inert membrane barrier. Usually this

barrier is an insoluble polymer.

Figure no. 3: Schematic representation of reservoir diffusion controlled drug release

reservoir.

3. Dissolution and diffusion-controlled release systems

Normally, therapeutic system will never be dependent on dissolution only or diffusion only.

In practice, the dominant mechanism for release will over shadow other process enough to

allow classification as either dissolution rate limited or diffusion controlled.

4. Ion exchange systems

These are salts of cationic or anionic exchange resins or insoluble complexes in which drug

releases results from exchange of bound drug ions that are normally present in GI fluids.

The use of ion exchange resins to prolong the effect of drugs is based on the principle that

positivity or negativity charged therapeutic molecules combined with appropriate resins yield

insoluble poly salt resonate.

5. Osmotically controlled systems

This device is fabricated as tablet that contains water soluble osmotically active drug, of that

was blended with osmotically active diluents by coating the tablet with a cellulose triacetate



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barrier which functions as a semi permeable membrane. A laser is used to form a precision

orifice in the barrier, through which the drug is released due to development of osmotic

pressure difference across the membrane, when it is kept in water.

Figure no. 4: Osmotically controlled system.

6. pH independent formulations

A Buffered controlled release formulation is prepared by mixing a basic or acidic drug with

or more buffering agents, granulating with appropriate pharmaceutical excipients and coating

with GI fluid permeable film forming polymer.

Figure no. 5: Drug delivery from environmentally pH sensitive release system.



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7. Altered density formulations

Several approaches have been elaborated to extend the residence time of drug delivery

system in the gastrointestinal tract.

High-density approach

Low-density approach

Release limiting parameters

1) Drug Solubility

Hydrophilic or hydrophobic and molecular weights of drug molecule are important

determinants in the release of drug from swelling and erosion controlled polymeric matrices.

2) Polymer hydration

The most important step in polymer dissolution include absorption of water in more

accessible places, rupture of polymer – polymer linkages with the simultaneous forming of

water polymer linkages, separation of polymeric chains, swelling and finally dispersion of

polymeric chain in dissolution medium.

3) Polymer viscosity

While increasing the molecular weight or viscosity of the polymer and excipients in the

matrix formulation increases the gel layer viscosity and thus slows drug dissolution. The

greater the viscosity of the gel, the more resistant the gel is to dilution and erosion, thus

controlling drug dissolution.

4) Polymer concentration

An increase in polymer concentration causes an increase in the viscosity of gel as well as

formation of gel layer with a longer diffusion path.

5) Surface area and Volume

Both the in-vivo and in-vitro rate of drug release is observed to be dependent on Surface area

of the dosage form.

6) Diluents effect

The effect of diluents or fillers depends on the nature of diluents. Water soluble diluents like

lactose increases in drug release rate and release mechanism is also shifted towards Fickian

diffusion; also the insoluble diluents like dicalcium phosphate reduce the Fickian diffusion

and increases the relaxation (erosion) rate of matrix. Because water soluble fillers in matrices



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stimulate the water penetration in to inner part of matrix, due to increase in hydrophilicity of

the system, causing rapid diffusion of drug, leads to increased drug release rate.

7) Additive

The effect of adding non polymeric excipients to a polymeric matrix has been increases in the

release rate of hydro soluble active principles. These increases in release rate would be

marked if the excipients are soluble like lactose and less important if the excipients are

insoluble like dicalcium phosphate.

Drug properties relevant to sustained release formulation

The formulation of sustained release drug delivery systems, consider the some criteria such as

the route of administration, type of drug delivery system, what disease to be treated, the

patient, the duration of treatment and the characteristics of the drug those above mentioned

factor should be considered. The pharmaceutical interest to research scientist for designing of

the delivery system the following properties could be considered in the development of

dosage form. These properties can be classified by –

A. Biological properties

By definition, biological properties will be those that result from Pharmacokinetic studies

such as absorption, distribution, metabolism and excretion of drug and those resulting from

pharmacological experimental study.

B. Physicochemical properties

By definition, physicochemical properties of the drug like can be determined from in vitro

study.

Biological and Physiochemical properties having the greater importance in the design of the

drug in the delivery system and in the body. But there is no distinction between these two

categories because the biological properties of a drug as like a function of its

physicochemical properties.

Biological factors influencing oral sustained-release dosage form design

A) Absorption

Since the purpose of forming a SR product is to place control on the delivery system, it is

necessary that the rate of release is much slower than the rate of absorption. If we presume

that the transit time of most drugs in the absorptive areas of the GI tract is about 8-12 hours,



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the maximum half-life for absorption should be approximately 3-4 hours; otherwise, the

device will pass out of the potential absorptive region before drug release is complete. One

method to provide sustaining mechanism of delivery for compounds tries to maintain them

within the stomach. These methods have been developed as a consequence of the observation

that co-administration results in sustaining effect.

B) Distribution

The distribution of active ingredient into the body tissue and extra vascular spaces in the

body is an important parameter for drug elimination kinetics model. Some parameters are

using to give idea about distribution of drug. Apparent volume of active component is high it

will influence the elimination of dosage form and not suitable for making sustained release

tablet. The term apparent volume of distribution of a drug is mostly used to explain the

distribution, including bound to the body system. The total apartment volume of distribution

of a drug at steady state will be calculated by given equation.

Vdss = [(K12 + K21) / K21] Vp

Where,

Vdss = Apparent volume of distribution at steady state level

K12 = Drug from central to peripheral compartment

K21 = Drug from peripheral to central compartment

Vp = Volume of central compartment

C) Metabolism

Drugs those are significantly metabolized before absorption, either in the lumen or the tissue

of the intestine, can show reduced bioavailability from slower-releasing dosage form.

Hence criteria for the drug to be used for formulating SR dosage form is,

Drug should have low half-life (<5 hrs)

Drug should be freely soluble in water

Drug should have larger therapeutic window

Drug should be absorbed throughout the GIT.

D) Biological half life

The usual goal of an oral SR product is to maintain therapeutic blood levels over an extended

period of time. To achieve this, drug must enter the circulation at approximately the same rate



347

at which it is eliminated. The elimination rate is quantitavely described by the half life (t1/2).

Each drug has its own characteristics elimination rate, which is the sum of all elimination

processes, including metabolism, urinary excretion and all over processes that permanently

remove drug from the blood stream. Therapeutic compounds with short half-life are generally

are excellent candidate for SR formulations, as this can dosing frequency.

E) Protein binding

The Pharmacological response of drug depends on unbound drug concentration drug rather

than total concentration and all drug bound to some extent to plasma and or tissue proteins.

Proteins binding of drug play a significant role in its therapeutic effect regardless the type of

dosage form as extensive binding to plasma increase biological half-life and thus sometimes

SR drug delivery system is not required for this type of drug.

F) Side effects

The incidence of side effect of a drug is depends on its therapeutic concentration level in

blood. It can remedy by the drug concentration level is controlled at which timing that drug

exists in blood after administration. Toxic effect of a drug is expected above the maximum

effective range level and fall in the therapeutic effect if a drug below the level of minimum

effective range. So the above problem we can solve by making sustained release preparation.

G) Margin of safety

Therapeutic index of a drug is very important for either sustained or controlled release

delivery system. Its value only desired the margin of safety. Therapeutic index value it has

been longer means excellent for preparation of sustained release tablet. Narrow therapeutic

index of some drug precise to release the active content in therapeutic safe and effective

range.

Therapeutic index = TD50/ED50

Where,

TD50 = Median toxic dose ED50 = Median effective dose



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Physicochemical factors influencing oral sustained-release dosage form design

A) Dose Size

In general, a single dose of 0.5-1.0 gm is considered maximal for a conventional dosage

form. This also holds for sustained release dosage form. Compounds that require dosing size

can sometimes be given in multiple amounts or formulated into liquid systems.

B) Ionization, pka and aqueous solubility

Most drugs are weak acids or bases. Since the unchanged form of a drug preferential

permeates across lipid membranes, it is important to note the relationship between the pka of

the compound and the absorptive environment. Unfortunately, the situation is made more

complex by the fact that the drug’s aqueous solubility will generally be decreased by

conversion to unchanged to unchanged form. These dosage forms must function in an

environment of changing pH, the stomach being acidic and the small intestine more neutral,

the effect of pH on the release process must be defined.

C) Partition Coefficient

When a drug is administered to the GI tract, it must cross a variety of biological membranes

to produce a therapeutic effect in another area of the body. It is common to consider that

these membranes are lipidic; therefore the partition coefficient of oil-soluble drugs becomes

important in determining the effectiveness of membrane barrier penetration. Compounds

which are lipophilic in nature having high partition coefficient are poorly aqueous soluble

and it retain in the lipophilic tissue for the longer time. In case of compounds with very low

partition coefficient, it is very difficult for them to penetrate the membrane, resulting in poor

bioavailability.

D) Drug stability

Orally administered drugs can be subject to the both acid-base hydrolysis and enzymatic

degradation. Degradation will proceed at a reduced rate for drugs in solid state; therefore, this

is the preferred composition of delivery for problem cases. For the dosage forms that are

unstable in stomach, systems that prolong delivery over entire course of transit in the GI tract

are beneficial; this is also true for systems that delay release until the dosage form reaches the

small intestine. Compounds that are unstable in small intestine may demonstrate decreased

bioavailability when administered from a sustaining dosage form. This is because more drugs

is delivered in small intestine and hence, is subject to degradation. Propentheline and

Probanthine are representative example of such drugs.



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Evaluation of tablets

1) Characterization of Tablets

a) Tablet dimensions

The diameter, thickness of five randomly selected tablets per batch was determined using

Vernier Calliper.

b) Hardness

Tablet hardness has been defined as the required force for breaking a tablet in a diametric

compression test. A tablet was placed between two anvils of hardness tester, force was

applied to the anvils, and the crushing strength that causes the tablet to break was recorded in

kg/cm2, while hardness tested using Monsanto hardness tester.

c) Organoleptic Characters of tablet

In which Taste, Odour, Color, Shape of tablet is noted. It is the preliminary test for IPQC of

tablet.

d) Friability

Tablets require certain amount of capacity or hardness and resistance to adhere mechanical

shock of handling in manufacturing, packaging, and shipping. The friability should be not

more than 1%. A pre-weighed sample (20 tablets) were placed in the friabilator, and operated

for 100 revolutions, then again weighed the tablets and % friability was calculated using the

formula,

F = (1- ) x 100

Where,

Wo = Weight of tablet before test

W = Weight of tablet after test

e) Weight Variation Test

Twenty tablets were selected randomly and then weighed these tablets individually. The

average weight of 20 tablets was calculated. Individual weights of the tablets were compared

with the average weights of the tablets.



350

f) Drug Content

To evaluate tablets ability for efficacy, the amount of drug per tablet needs to be monitored

from tablet to tablet, and batch to batch. To perform the test, 10 tablets were crushed using

mortar pestle. Quantity equivalent to 10 mg of drug was dissolved in 100 ml phosphate buffer

pH 6.8, filtered and diluted up to 50μg/ml, and analyzed spectrophotometrically at 225.0 nm.

The concentration of drug was determined by using of standard calibration curve.

2) Swelling Index

a) In this weighed matrix tablet (n=3) was kept in a Petri plate containing phosphate buffer of

pH 6.8.

b) Phosphate Buffer pH 6.8

Dissolve 28.80 gm of Disodium Hydrogen Phosphate & 11.45 gm of Potassium Dihydrogen

Phosphate in sufficient amount of water & finally adjust the pH by using sufficient amount of

0.1N NaOH solutions.

c) Final the weight of each tablet is calculated at an interval of 15, 30, 45 & 60 min of

interval, and % weight increased in the tablet was calculated.

Swelling Index

3) In vitro Drug Release Study

The in vitro dissolution study of formulated Venlafaxine matrix tablets were carried out using

USP apparatus Type-II (Paddle) in 900 ml of phosphate buffer solution (pH 6.8) at 37°C ±

0.5°C at a rotational speed 50 rpm. After each hr starting the test, 2 ml sample of dissolution

medium were withdrawn and analyzed spectrophotometrically at 225.0 nm by using

Shimadzu-1700 UV/visible spectrophotometer. An equal volume of freshly prepared

dissolution medium, maintained at the same temperature, was added after withdrawing each

sample to maintain the volume. The absorbance values were transformed to concentration by

reference calibration curve to a standard calibration curve obtained experimentally.

Drug selection criteria for oral sustained release drug delivery systems

The biopharmaceutical evaluation of a drug for potential used in controlled release drug

delivery system requires knowledge as follows,



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Table no. 1: Pharmacokinetic parameters for drug selection.

Parameter Comment

Elimination half life Preferably between 0.5 and 8 hr

Total clearance Should not be dose dependent

Elimination rate constant Required for design

Apparent volume of distribution Vd The larger Vd and MEC, the larger will be

the required dose size.

Absolute bioavailability Should be 75% or more

Intrinsic absorption rate Must be greater than release rate

Toxic concentration

Apart the values of MTC and MEC, safer

the dosage form. Also suitable for drugs

with very short half-life.

Table no. 2: Physical parameters for drug selection.

Parameter Preferred value

Molecular weight/ size < 1000

Solubility > 0.1 mg/ml for pH 1 to pH 7.8

Apparent partition coefficient High

Absorption mechanism Diffusion

General absorbability From all GI segments

Release Should not be influenced by pH and enzymes

Key attributes for a successful SR hydrophilic matrix include

1) Fast hydration of surface polymer and gel formation (To prevent burst release of soluble

to highly soluble drugs)

2) Uniform distribution of polymer in the drug matrix. (To give consistent swelling /erosion

intra and inter tablet batch)

3) Sufficient polymer concentration on the tablet surface as well as inside the tablet to

prevent pre mature tablet disintegration (Extremely crucial to prevent dose dumping)

4) Smaller particle size of polymer (In order to have uniform distribution within the tablet

and also to hydrate faster due to high surface area)

Drugs formulated under matrix tablet

Propranolol (Anti-hypertensive)

Saxagliptin (Anti-diabetic)

Minocycline (Anti-biotic)

Ibuprofen (Anti-inflammatory)

Metformin (Anti-diabetic)

Aceclofenac (Anti -inflammatory)

Aspirin (Anti- inflammatory)



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Enalprilmaleate (ACE inhibitor)

Indomethacin (Anti-inflammatory)

Metoprolol (Anti-hypertensive)

Losartan Potassium (Anti-hypertensive)

Metaprolol (Anti-hypertensive)

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