CHAPTER 3. LITERATURE REVIEW 3.1 Current status and...

Parejiya P. B. Literature Review

K.B.I.P.E.R. Kadi Sarva Vishwavidyalaya 11

CHAPTER 3. LITERATURE REVIEW

3.1 Current status and advantages of modified release formulations

It is well known that the blood levels of drugs need to be maintained above a

minimum effective level and below its minimum toxic level in order to obtain the desired

therapeutic effects and to minimize side effects. Drugs that are administered in the form

of conventional tablets or capsules become available to body fluids at a rate that is

initially very high, followed by a rapid decline. For many drugs, this delivery pattern

results in a transient overdose, followed by a long period of under dosing. This is a

pattern of limited clinical usefulness. The delivery pattern was improved in the 1970's

with the introduction of a variety of modified delivery systems [8].

Since recent years, there is an increasing interest in the modified release (MR)

formulations. This interest is largely based on the fact that MR drug products have

established and retained a place in the market, based on their uniqueness and their

clinical effectiveness as well as advantages in the practice of medicine.

Thus the absorption rate of drug into the body can be decreased by reduction of

the rate of drug release from the dosage form. Such products are referred to as sustain

release, prolonged release, controlled release, extended release, timed-release, depot

and repository forms.

The compendia describe all such dosage forms under one category as Modified

Release (MR) dosage forms. Modified Release dosage forms are the dosage forms for

which the drug release characteristics (as a function of time and/or conditions at the site

of dissolution) are chosen to accomplish therapeutic or convenience objectives not

offered by conventional dosage forms such solutions, ointment or tablets and capsules [9-

10].

The concept of Modified Release dosage forms developed with the "Spansules",

the first controlled drug delivery system of dexedrine produced by Smith Kline and French



Laboratories in 1952 [11]. After that, it expanded into different drug delivery systems

with different drug release mechanisms.

The key advantages offered by modified release formulations are as follows [12]:

Reduction in frequency of drug administration

Better patient compliance

Reduced medication errors

Reduce total dose

Reduce GI side effects

Reduction in fluctuation in plasma concentration of drug.

Reduction in toxicity

Total drug usage when compared with conventional therapy.

Opportunities for product differentiation, product life-cycle management,

market expansion and patent extension.

Improve efficiency of treatment (optimized therapy)

Less fluctuation in plasma drug levels allows better disease state management.

Sometimes the method by which a controlled release is acehived can improve

the drug bioavailability.

3.2 Scientific fundamental for release retardation of water soluble drugs

The release modulation of water soluble drugs can be governed by following scientifically

fundamentals:

1. By controlling process of diffusion of surrounding media into dosage form.

• Decreasing diffusion (matrix and reservoir system)

• Reducing effective surface area (avoiding use of disintegration)

2. By controlling diffusion of solubilized drug molecules from dosage form to bulk.

• Decreasing the release of drug from complex using competitive

environment (Ion exchange resin)



• Increasing thickness of stagnant layers surrounding to tablet (Swelling

system)

• Decreasing concentration of drug in stagnant layers

• Governing the exit of solution from dosage form by changing natural law

(Osmosis)

• By reducing solubility of drug in dosage (common- ion effect, modification

of chemical form)

3. By decreasing solubility of drug molecules

• Co processing of drug with polymer

• Chemical modification drug

• Providing lipophilicity to the drug molecules (Solid dispersion of wax, Hot

melt extrudates)

• Conversion of salt into free acid or base

• Conversion of free acid or base into sustained release salt

3.3 Approaches for modified release systems of water soluble drugs

Various approaches to formulate oral modified drug delivery systems for water

soluble drugs can be possible, which are discussed as under [8].

3.3.1 Matrix tablets

The matrix type of sustained drug delivery system is common due to its

effectiveness, low cost and ease of manufacturing. Especially hydrophilic polymer-based

(e.g. cellulose derivates) sustained release dosage forms are very popular. However, drug

release from a hydrophilic matrix is generally characterized by a time-dependent profile.

Initially, the drug present at the surface of the matrix is released quickly; yielding a burst

effect, then with time, as the diffusion path length increases the release rate is

progressively reduced.

There are basically two types of matrix system.

Diffusion systems

In diffusion systems, the release rate of drug is determined by its diffusion through a

water-insoluble polymer. There are two types of diffusion devices:



• Reservoir devices.

• Matrix devices.

In reservoir devices a core of drug is surrounded by polymeric membrane and release

of drug is governed by Fick’s first law of diffusion.

J = -D dCm/dx

Where, J is the flux of drug across a membrane in the direction of decreasing

concentration, D is the diffusion coefficient of the drug in the membrane, and dCm/dx is

the change in the concentration of the drug in the membrane over a distance x.

Reservoir type devices include microencuplation and press coating the whole

tablet. In matrix devices, the drug is dispersed or dissolved uniformly throughout an inert

polymeric matrix. The rate of release of drug is described by Higuchi; the change in

amount of drug released per unit area dm, with a change in the depleted zone thickness,

dh is expressed by following equation.

dm = Co*dh – (Cs/ 2)*dh

Where, Co is total amount of drug present per unit volume in the matrix, and Cs is the

saturation solubility of the drug per unit volume in the matrix.

Dissolution System

It is possible to prepare sustained release product by decreasing the dissolution

rate of drug which are highly water soluble. This can be done by preparing appropriate

salt or derivatives, by coating the drug with slowly dissolving materials, or by

incorporating it into tablet with a slowly dissolving carrier. Most of the formulations

relying on dissolution to release the drug, fall into three categories:

• Encapsulated dissolution systems.

• Matrix dissolution systems.

• Multi-layer matrix tablet.

Encapsulated dissolution systems can be prepared either by coating particles or granules

of drug with varying thickness of slowly soluble polymers, or by microencapsulation.

These coated particles can be compressed into tablets called as SPACETABS or placed in

capsules as in SPANSULES.



3.3.2 Osmotic drug delivery systems

Osmotically controlled drug delivery system, deliver the drug in a large extent and

the delivery nature is independent of the physiological factors of the gastrointestinal tract

and these systems can be utilized for systemic as well as targeted delivery of drugs.

Osmotically controlled oral drug delivery systems utilize osmotic pressure for controlled

delivery of active agents. Among the controlled release devices, osmotically controlled

hold a stable place because of its reliability to deliver the API at predetermined zero order

rate for prolonged period of time so these are used as the standard dosage forms for the

constant delivery of contents. Osmotic Pump Controlled Release Preparation is a novel

drug delivery system with eternally drug delivery rate as characteristic and controlled

with the osmotic pressure difference between inside and outside of the semipermeable

membrane as drug delivery power [13].

Majorly following two designs are successfully employed to achieve zero order release

which work on principle of osmosis.

OROS technology

Osmotic controlled release oral delivery system (OROS) is a unique oral drug

delivery system that releases the drug at a “zero order” rate. It is a complex system,

which consists of a tablet core containing a water soluble drug and osmotic agents such

as NaCl, mannitol, sugars, PEGs, Carbopol, Polyox, etc. The tablet core is coated with a

semi-permeable polymer such as cellulose acetate. This semi-permeable coating is

permeable to water but not to the drug. A laser-drilled hole, 100-250 µm in size, is

created as a drug delivery orifice. The osmotic pressure of the body fluid is 7.5 atm,

whereas, the osmotic pressure in an OROS tablet is around 130-140 atm. As a result,

aqueous fluid present in the GI-tract enters into the OROS tablet through the

semipermeable membrane and pushes the drug out through a delivery orifice. Glucotrol

XL® and Procardia XL® are classical examples of OROS tablets. Glucotrol XL® is a once a

day tablet formulation of glipizide, a blood-glucose lowering drug for diabetic patients,

whereas Procardia XL® is a controlled release formulation of nifedipine, a calcium-channel



blocker, for the treatment of hypertension. Pfizer launched Glucotrol XL® in 1984 and

Procardia XL®

Porosity Controlled Osmotic Pump (PCOP)

in 1989 [14].

The controlled-porosity osmotic pump tablet concept was developed as an oral

drug delivery system by Zentner et al, Appel and Zentner and Mc Celland et al. The

controlled-porosity osmotic pump tablet (CPOP) is a spray-coated or coated tablet with a

semipermeable membrane (SPM) containing leachable pore forming agents. They do not

have any aperture to release the drugs; drug release is achieved through the pores, which

are formed in the semipermeable wall in situ during the operation. In this system, the

drug, after dissolution inside the core, is released from the osmotic pump tablet by

hydrostatic pressure and diffusion through pores created by the dissolution of pore

formers incorporated in the membrane. The hydrostatic pressure is created either by an

osmotic agent or by the drug itself or by a tablet component, after water is imbibed

across the semipermeable membrane. This membrane after formation of pores becomes

permeable for both water and solutes. A controlled-porosity osmotic wall can be

described as having a sponge like appearance. The pores can be continuous that have

micro porous lamina, interconnected through tortuous paths of regular and irregular

shapes. Generally, materials (in a concentration range of 5% to 95%) producing pores

with a pore size from 10 Å -100 µm can be used.

3.3.3 Tablet in Tablet system

Compression coating is recently renewed as a novel technology due to advances in

tablet-press technologies. This technique requires specific tablet press with compression

coating capabilities. Compression coated tablets have two layers, an inner core and an

outer shell. First, the inner core is compressed as a small tablet, and then the inner core is

dry coated with rate controlling materials such as controlled release polymers and fillers

[15]. The drug release rate is dependent on various factors such as thickness and porosity

of the outer shell, types of material used to compress inner core and outer shell, particle



size of the excipients, compression force used to compress both the layers and position of

the inner core in the tablet.

Penwest's SyncroDose™ technology is a classical example of compression coated

tablets. These tablets contain an immediate release inner core and compression coating

outer layer of xanthan gum and locust bean gum. The lag time and rate of drug release is

controlled by the modulating the concentrations of the two polysaccharides [16].

3.3.4 Solid dispersion

The term solid dispersion refers to the dispersion of one or more active ingredient

in an inert carrier or matrix at solid state prepared by melting (fusion), solvent

evaporation or melting-solvent evaporation method. For poorly soluble drugs, when the

solid dispersion is exposed to aqueous media, the carrier dissolves and the drug releases

as fine colloidal particles. In case of solid dispersion, the nature of carriers determine

solubility enhancement or retardation. This concept creates an interest in controlled

release formulation of water soluble drugs. A wide array of polymers has been employed

as drug-retarding agents, each of which presents a different approach to the matrix

concept. Polymers that primarily form insoluble or skeleton matrices are considered as

the first category of retarding materials. The second class represents hydrophobic and

water-insoluble materials, which are potentially erodible, and the third group exhibits

hydrophilic properties [17-19].

3.3.5 Ion exchange resins as drug delivery systems

Formulators have used ion exchange resins as drug delivery systems. Ion exchange

resins are basically insoluble polymers such as polystyrene or polymethacrylate polymers

that contain non-ionizable groups. In the 1950s, Saunders and Srivatsava suggested that

ion exchange resins may be used for sustained/controlled release formulations [20]. The

drug release rate from resinate (drug-resin complex) is dependent on the ionic strength

and pH of the drug delivery site which explains why the resinate releases the drug in a

controlled manner. There are less chances of drug dumping from ion exchange resin drug

delivery systems. Resinates can be filled into capsules, coated with controlled release



polymers, compressed into tablets, and dispersed in liquids. Delsym®, dextromethorphan

cough syrup, and Phentuss®, codeine and chlorpheniramine syrup are marketed

formulations of ion exchange resin sustained release drug delivery systems [21]. In these

formulations, polyethylene glycol treated resinates are coated with hydrophobic

polymers to control the release of drugs. This particular technology is known as

Pennkinetic TM system, which was originally patented by Pennwalt Corporation [22].

3.3.6 Oral in situ forming system

Oral liquid in-situ gelling systems present a novel and interesting approach to

obtain sustained or prolonged release of drugs. In these systems an aqueous solution of

the polymer containing drug in dispersed or dissolved form, forms a gel owing to sol-gel

transition on coming in contact with the gastric fluid either due to change in pH or ionic

interaction. These are liquid aqueous solutions before administration, but gel under

physiological conditions. There are several possible mechanisms that lead to in situ gel

formation: ionic cross-linkage, pH change, and temperature modulation. Polymer

solutions of sodium alginate, gellan, pectin etc. contain divalent ions complexed with

sodium citrate that are designed to break down in the acidic environment of the stomach

to release free divalent ions (mostly Ca++

3.3.7 Multiparticulate system

). The divalent ion causes the in situ gelation of

the orally administered solution. The mechanism of gelation involves the formation of

double helical junction zones followed by aggregation of the double helical segments to

form a three-dimensional network by complexation with cations and hydrogen bonding

with water [23].

Multiparticulates as dosage forms have been known since the 1950s when the

first product was introduced to the market. Since then, these dosage forms have gained

considerable popularity because of their distinct advantages such as, ease of capsule

filling, better flow properties of the spherical beads, ease of coating, sustained, controlled

or site-specific delivery of the drug from coated beads, uniform packing, even distribution

in the GI tract, and less GI irritation. In addition, beads are less susceptible to dose

dumping, which results in reduced peak plasma fluctuations, thus minimizing the



potential side effects without appreciably lowering drug bioavailability [24].

Multiparticulate dosage forms can be prepared by a number of techniques such as, drug

layering on non-pareil sugar or microcrystalline cellulose beads, spray-drying, spray

congealing, roto granulation, hot-melt extrusion and spheronization of low melting

materials or extrusion-spheronization of a wet mass. Beads can also be either coated with

rate-limiting polymers or compressed into tablets to obtain slow-release, target-release

or controlled-release profiles. Multiparticulate dosage forms with different dose

strengths can also be prepared from the same batch of drug-loaded pellets without any

formulation or process changes [24]. Moreover, beads with two incompatible bioactive

agents and/or with different release profiles that need to be delivered to the same or

different sites in the body can also be prepared [25-26].

3.3.8 Melt-extrusion technology

In the melt-extrusion technology, the active pharmaceutical ingredient is mixed

with low melting point excipients such as waxes or polymers, and the resulting mixture is

extruded as beads or granules. The resulting granules are compressed into tablets.

Kaletra®

, an anti-HIV drug formulation was developed by Abbott laboratories to decrease

the number tablets to ingest and to increase the patient compliance uses the melt

extrusion technique.



3.4 Platform technologies (PTs) for release modulation of water soluble drugs

There are many platform technologies are existed in the pharmaceutical market

which are developed by various pharmaceutical industries for betterment of therapeutics

and human health. Table 2 overviews regarding various PTs for water soluble drugs [16,

22, 27-34].

Table 2. Details of PTs for release modulation of water soluble drugs

No Name of

PT

Dosage

form Characteristic features

Name of

company

1 Macro

Cap

Pellet It is based on the coating of pellets containing

pharmaceutical compounds with specialized

polymers and plasticizers to control the rate

and location of drug release in the

gastrointestinal tract. It uses the features of

pH-activated or pH- independent diffusion,

osmotic diffusion, or a combination of these

mechanisms.

Biovail

Corp.

Canada

2 Micro

pump

Micro

particles

It is suitable for drugs that require an extended

absorption time in the small intestine. Each

Micro pump dosage form is composed of

thousands of microparticles ranging in size

between 200 and 400 mm and having a

bioadhesive surface. Each microparticle

contains a drug crystal orgranule enclosed in a

polymer coating that acts as a shell through

which the drug can be released under the

effect of osmotic pressure.

Flamel

Tech.,

France

3 MODAS Multi

porous

It is surrounded by a non-disintegrating, timed-

release coating, which after coming in contact

Elan Corp.



tablet with gastrointestinal fluid is transformed into a

semipermeable membrane through which the

drug diffuses in a rate-limiting manner. The

tablet consists of a core of active drug plus

excipients. This is then coated with a solution

of insoluble polymers and soluble excipients.

After ingestion, the fluid of the gastrointestinal

tract dissolves the soluble excipients in the

outer coating leaving just the insoluble

polymer, thereby forming a network of tiny,

narrow channels connecting fluid from the GI

tract to the inner drug core of water-soluble

drug. Examples: Bron-12 (a 12-hour

multicomponent over-the-counter [OTC] cough

and cold product) and once-daily potassium

chloride.

4 SCOT Osmotic

Tablet

It is based on osmotic principles and utilizes

various osmotic modulating agents as well as

polymer coatings to provide a zero-order

release of a drug.

Andrx

Pharm.

USA

5 CEFORM Micro

sphere

These microspheres are almost perfectly

spherical, having a diameter that is typically

150 to 180 mm, and allow for high drug

content. The microspheres can be used in a

wide variety of dosage forms, including tablets,

capsules, suspensions, effervescent tablets,

and sachets. The microspheres can be

formulated for enhanced absorption (Ceform

EA) or taste isolation (Ceform TI) and may be

Fuisz

Tech. Ltd.,

USA



coated for controlled release (Ceform CR),

provided with an enteric coating (Ceform EC),

or combined into a fast/slow release

combination (Ceform EA/CR).

6 CONSURF Matrix

tablet

A constant surface area is presented during the

drug’s transit through the GI tract. It releases

drug by the concurrent swelling and dissolution

of a matrix tablet. Constant surface area is

presented during the drug’s transit through the

GI tract.

Biovail

Corp.

7 CONTRAM-

ID

Tablet It utilizes excipients (mainly starch) for the

controlled delivery of drugs. The chemical

cross-linking of a starch consisting mainly of

amylose leads to Contramid. Varying the

quantity of cross-linking reagent used in the

manufacturing process can control the degree

of the cross-linking. Once the Contramid

dosage form is in the stomach, gastric fluids

turn Contramid’s surface to gel and the

resulting semipermeable membrane stabilizes

rapidly.

Labophar

m Inc.,

Canada

8 DIMATRIX Matrix

System

It consists of either beads made by extrusion-

spheronization or by powder/ solution layering

on nonpareil beads or in the form of a tablet

matrix. The mechanism of release is by

diffusion of dissolved drug molecules.

Biovail

Corp.

9 MULTIPA-

RT

Tablet It consists of a tablet that carries controlled

release beads or pellets through the GI tract

while maintaining their integrity and release

Biovail

Corp.



properties. Release and distribution of the

beads is triggered by superdisintegration of the

tablet.

10 DPHS Pulsatile

system

It is designed for use with hydrogel matrix

products that are characterized by an initial

zero-order release of drug followed by rapid

release. This release profile is achieved by the

blending of selected hydrogel polymers to

achieve a delayed pulse.

Andrx

Pharma.

11 DUREDAS Bilayer

tablet

It utilizes bilayer-tableting technology, which

has been specifically developed to provide two

different release rates or dual release of a drug

from a single dosage form. The tablets are

prepared by two separate direct-compression

steps that combine an immediate-release

granulate (for rapid onset of action) and a

controlled-release hydrophilic matrix complex

within one tablet.

Elan Corp.

12 Gastric

retention

system

Polymeric

units

It consists of a drug containing polymeric units

that, if taken with a meal, remain in the

stomach for an extended period of time to

provide continuous, controlled delivery of an

incorporated drug.

DepoMed

Inc., USA

13 Geomatrix Multi

layer

tablet

It is a multilayer tablet with a matrix core

containing the active ingredient and one or

more modulating layers (barriers) applied to

the core during the tableting process. The

function of these barriers is to delay the

interaction of the core with the dissolution

Skye

Pharma

Plc., USA



medium. Eight Geomatrix technologies are

designed to meet a wide range of release

modulation.

14 GMHS Hydro

gel

It incorporates hydrogel and binding polymers

with the drug, which is formed into granules

and then pressed into tablet form

Andrx

Pharma.

15 IPDAS Multi

Parti

culate

tablet

IPDAS is composed of numerous high-density

controlled release beads. Each bead is

manufactured by a two-step process that

involves the initial production of a micromatrix

of drug embedded in polymer and the

subsequent coating of this micromatrix with

time release coatings that are transformed into

a rate-limiting semipermeable membrane in

vivo. Example: Naprelan®

Elan Corp.

(Naproxen sodium)

16 Multipor

technology

Coated

tablet

It consists of a tablet core of an active drug,

which is surrounded by a water insoluble

polymer membrane. The membrane consists of

minute water-soluble particles that, after

coming in contact with water, dissolve and

form pores from which the drug is released.

Ethical

Holdings

Plc., UK

17 Pharma-

zome

Micro

particles

It consists of combinations of polymers and

drugs in the size range of 5 to 125 µm. Each

microparticle is a micromatrix of drug

embedded uniformly throughout an insoluble

polymer and is produced by either a spray

drying or emulsion technique. By varying the

amount and nature of the polymer used to

form the micro particle, this technology allows

Elan Corp.



controlled and/ or delayed-release of drug

from the formulation.

18 PRODAS Mini

tablets

The PRODAS technology consists of mini-

tablets, which are filled into capsules to get

benefits of both tablets and multiparticulate

dosage forms. It is based on the encapsulation

of controlled-release minitablets in the size

range of 1.5 to 4 mm in diameter. This

technology represents a combination of

multiparticulate and hydrophilic matrix tablet

technologies and thus provides the benefits of

both these drug delivery systems in one dosage

form.

Elan Corp.

19 CODAS Pulsatile

tablet

It is tailored to give drug release according to

circadian pattern of the disease.

Example: Verelan®

UCB Inc.

PM (Verapamil HCl)

20 RingCap Matrix

tablets

It utilizes bands of insoluble polymer on a

matrix tablet. The manufacturing process

involves compressing the drug into cylindrical

matrix tablets that are subsequently film

coated. Then, existing capsule- banding

technology is used to apply two or more

polymeric rings around the circumference of

the matrix tablet. These bands lower the initial

release of the drug by reducing the surface

area exposed.

Alkermes

Inc., USA

21 SODAS Multi

Parti

culate

Each bead begins as an inert core onto which

the drug is applied, followed by a number of

layers of soluble and insoluble polymers

Elan Corp.



beads combined with other excipients to produce the

rate-controlling layer.

Examples: Verelan® , Ritalin LA®, Focalin XR®

22 SMHS Hydro

gel

It provides sustained release without the need

to use special coatings or structures, both of

which add to the cost of manufacturing. This

technology avoids the initial burst effect

commonly observed with other sustained-

release hydrogel formulations.

Example: Diltia XT (Deltiazem HCl)

Andrx

Pharma.

23 SQZGel Hydro

gels

It is an oral delivery system based on patented

pH-sensitive hydrogels comprised of

combinations of FDA-approved generally

recognized as safe (GRAS) polymers. In

response to internal or external pH levels, and

by design, this system evenly releases a drug

over an 8-20 hrs period based on the delivery

needs of the therapy.

Macrome

d,Inc.,

USA

24 TIMERx Matrix

tablet

This technology is based on an agglomerated

hydrophilic matrix. The matrix consists of

polysaccharides, locust bean gum and xanthan

gum. Interactions between these components

in an aqueous environment form a tight gel

with a slowly eroding core from which the drug

is released at a controlled rate for an extended

period of time.

Examples: Slofedipine XL (nifedipine), Cystrin

CR (oxybutynin)

Penwest

Pharma.

and Mylan

Lab., Inc.

25 Meter Multi It is a twice-a-day dosing, polymer based drug KV



Release Parti

culate

delivery system that offers different release

characteristics and used for products that

require a drug release rate of 8 to 12 hours.

Pharma.

(USA)

26 Gel-CapTM Gelatine

Capsule

It is based on highly viscous material called

SAIB (sucrose acetate isobutyrate), which is

insoluble in water, but soluble in alcohol. After

oral administration of the Gel-CapTM

formulation, the gelatin capsule and solvents

dissolve, and the drug is released in a

controlled manner from the adhesive SAIB

matrix. Dosage forms prepared with this

technology are still under clinical trials.

King

Pharm.

Inc.

27 DepoFoam Micro

particles

It is composed of hundreds to thousands of

nonconcentric chambers (depots)

encapsulating the drug to be delivered. The

individual chambers are separated by a bilayer

lipid membrane made up of synthetic

duplicates of lipids found naturally in the body,

resulting in a material that is both

biodegradable and biocompatible.

Examples:DepoCyt (cytarabine),

DepoMorphine (morphine sulfate),

DepoAmikacin (amikacin)

Depo

Tech

Corp., USA

28 Egalet Molded

tablet

It has the advantage of delivering zero-order or

delayed release with minimal impact from the

gastrointestinal conditions. Drug is dispersed in

the matrix and the release is controlled by the

rate of erosion in the two ends of tablets. The

surface area for erosion is constant. Egalet

Egalet



erodible molded multilayered tablets are

prepared by injection molding (IM).

29 Diffucaps Multi

Parti

culate

It is a flexible multiparticulate system providing

optimal release profiles for single drugs and

drug combinations.

Eurand

30 Eurand

Minitabs

Matrix

tablets

It acts as multiparticulates and can be utilized

for combination products with multiple release

profiles.

Eurand

31 Diffutab Matrix

tablets

It provides sustained release via a combination

of water-soluble particles with active drug,

well-suited for delivery of high-dose product.

Eurand

32 ORADUR Capsule It is unique for its dual performance attributes

of providing controlled drug delivery for both

water soluble and water insoluble drugs and

abuse resistance for those drugs that are

abusable. It has a number of built in

mechanisms to resist abuse by crushing and

drug extraction, which are usually the first

steps that lead to drug abuse via snorting,

ingestion and/or injection.

Durect

Corp.

33 Wrap

Matrix

System

Layered

tablet

It is designed to offer drug release at a

constant rate. This system can also be

formulated to give minimum "food effect" so

that medicine can be taken irrespective of the

meal pattern.

Example: Metaprolol XL

Sun

Pharma

Pvt Ltd.

34 Versatrol Matrix

tablet

TM It is based on emulsion-based matrix intended

to achieve a target extended release profile. It

has solidifying agents in the oil phase as well as

Banner

Pharmaca

ps



the controlled-release excipients (CRE) in the

aqueous phase.

35 NRobe™ Tablets It is a novel oral dosage form technology based

on a process consisting of light compression of

a drug loaded fill which is enrobed between

two dry, pre-formed films and sealed to

provide a non-friable, coated dosage form.

Bio

Progress

plc

and FMC

Corp.



3.5 Work done on modified release systems of various water soluble drugs

There are many delivery systems developed by F & D scientists to deliver water

soluble drugs in controlled manner. Table 3 focuses on various designs developed for

particular drug along with polymer composition and core conclusion derived from study.

Table 3. Work done on release modulation of water soluble drugs

No

Drug Polymers

used

Parameter

assessed Inference Ref Dosage

from

I. Matrix Tablets

1. Propranolol

HCl

• HPMC K 15M

• Phytowax

Olive 14L 48

• Physical

properties

• In vitro drug

release

• SEM study

Layering with polymeric matrix

comprising HPMC and phytowax

can prolong the release of HSDs

and shift the release pattern

approach to zero order.

[35]

Three-layer

tablet

2. Tramadol

HCl

• HPMC 6 cps

• Lubritab

• Methocel K

100M

• Ethocel

• Surelease

• Weight

variation

• Hardness

• In vitro drug

release

Solely hydrophilic matrix of

HPMC can’t control the release

of HSD effectively for more than

12 hours. Incorporation of HCO

into matrix is a better system

for controlled delivery of a HSD.

[36]

Matrix

System

3. Trimeta

zidine

Dihydro

chloride

• Guar gum

(3725 cps)

• HPMC

(15 cps)

• Drug content

• In vitro drug

release

• First-order

release rate

constant

• Kinetics of

drug release

Guar gum in the form of a

three-layer matrix system is a

potential hydrophilic carrier in

the design of oral controlled

drug delivery systems for water

soluble drugs.

[37]

Three-layer

matrix

tablet

4. Tramadol • Glyceryl • Drug - Glyceryl palmitostearate



HCl palmito

Stearate

glyceride

interaction

• In vitro drug

release

• Drug release

kinetics

• Statistical

analysis

(Precirol ATO 5) is an

appropriate waxy matrix former

for sustained release of water-

soluble drugs. Melt granulation

technique is far superior to

direct compression of the

physical mixture. Higuchi and

zero order release kinetics can

be achieved from this type of

system.

[38]

Matrix

tablet

5 Metoprolol

tartrate

• Guar gum • In vitro drug

release

• Clinical study

• Pharmacokin

etic analysis

The guar gum three-layer matrix

tablets may be useful for long-

term constant drug delivery of

HSD with minimum fluctuations.

[39]

Three-layer

matrix

tablets

6 Ranitidine

HCl

• Sodium

alginate

• Xanthan gum

• Zinc acetate

matrix

• In vitro drug

release study

• Effect of

polymer

blend

The helical structure and high

viscosity of xanthan gum might

prevent diffusion of zinc ions

from matrix. These zinc ions

react with sodium alginate to

form zinc alginate precipitate

with a cross-linking structure.

The cross-linking structure

might control HSDs to release

for 24 hours.

[40]

Caplet

7 Diltiazem

HCl

• Dextran

sulfate

• [2-diethyl

amino)ethyl]

• Drug micelle

forming

property

• Effect of

PIC-tablet is a promising device

for oral controlled release

delivery of water-soluble drugs

with good micelle-forming

[41]

Polyion

complex



(PIC-tablet) dextran Cl inonic

stetngth

-1

• Effect of

drug loading

ability. The release profiles of

the micelle-forming drugs can

be suppressed with different

solubility or opposite ionic

charges.

8 Venlafaxine • Xanthan gum

• Avicel PH 101

• In vitro

dissolution

Studies

• Optimization

by Radar

Graphs

The drug-release rate from

triple layer matrix tablet is

dependent on the percentage of

xanthan gum, pore forming

agent like pharmatose DCL 11,

and surface area of the

formulation exposed to the

dissolution medium. The drug

release kinetics follows Weibull

model.

[42]

Triple-

Layer

Matrix

Tablets

9 Diltiazem

HCl

•

•

Carnauba

wax

•

Beeswax

•

Cetyl alcohol

•

Glyceryl

mono

stearate

•

Kollidon SR

•

Effect of

waxy

materials on

drug release

Carnauba wax, Bees wax and

Kollidon SR show greater rate

retarding property in

comparison with cetyl alcohol

and glyceryl monosterate.

Combination of waxy materials

and Kollidon SR can be

successfully employed for SR

formulation of HSD.

Effect of

Ludipress on

drug release

[43]

Matrix

Tablets

10 Salbutamol

sulphate

• Compritol®

888 ATO

• Precirol®

ATO5

• Beeswax

• QC tests

• Influence of

Filler type

Type and

concentration

A hydrophobic matrix system in

which a drug is embedded into a

slowly eroding waxy material is

a viable technique to produce

sustained release tablets, and

[44]

Hydrophobi

c matrices



• Carnauba

wax

• Stearyl

alcohol

of Polymer

• Method of

preparation

especially those containing

freely water-soluble drugs

II. Osmotic Drug Delivery Systems

11 Diltiazem

HCl

• Cellulose

acetate (320

S)

• Na-CMC

• HPMC

• Effect of

HPMC and

Na CMC

• Drug release

study

• Kinetics

CPOPs showed minimum 65% of

consistent Diltiazem release at

16 h. Minimum 65 % of

consistent Diltiazem release at 6

h can be achieved by this

system. Drug release from the

systems follows Hixson-Crowell

cube root model and

mechanism of release follow

non-Fickian diffusion.

[45]

Controlled

Porosity

Osmotic

Pumps

12 Phenyl

Propanal

amine

hydro

chloride

• Cellulose

acetate

• NaCl

• Pharma

copoeial

specification

• Assay

• In vitro drug

release

studies

• Kinetic of

drug release

• Pharmacokin

etic study

Desired release can be achieved

with 100% osmogen to drug

ratio. Good IVIVC between

cumulative percent drug

released from EOP and AUC

values can be derived.

[46]

Elementary

osmotic

pump

13 Tramadol

HCl

• Cellulose

acetate

• PVP K-30

• Drug content

uniformity

• In vitro drug

Drug release is independent of

pH and agitation intensity of the

release media, assuring the

[47]

Elementary



Osmotic

Pump

• MCC pH 101 release study

• Swelling

index

• Burst

strength

release to be fairly independent

of pH and hydrodynamic

conditions of the absorption

site. Drug release from EOP is

directly related to the level of

plasticizer but inversely

proportional to the level of

swellable polymer and coat

thickness of SPM.

14 Diltiazem

HCl

• Guar. gum

• Carbopol 71G

Effect of

• Viscolysing

polymer and

Nacl

• Membrane

thickness

• Osmotic

pressure

• Surface

porosity

• Plasticizers

Glycerin at 20 % shows good

pore forming capacity. The drug

release rate is increased with

increasing PEG-400 amount and

reverse with DBT and TEC.

[48]

CPOP

15 Tramadol

HCl

• Eudragit

RLPO-RSPO

• Cellulose

acetate

• EC

• PEG- 4000

• Physical

characterizat

ion

• In-vitro drug

release

• SEM study

• Effect of of

film former

The ethyl cellulose films

suppress the initial burst effect

in drug release more than

cellulose acetate and

polymethacrylates films. PEG

4000 containing films exhibit

promising controlled and extend

drug release characteristics than

Tween 80 and Dextran.

[49]

Microporou

s

Membrane

Coated

Matrix

Tablet



16 Oxybutynin •

• CA-398-10NF

• Pearlitol

• Effect of pH,

agitation,

osmotic

pressure

• Drug content

and physical

evaluation

• Drug-

excipient

interaction

studies

The rate of drug release can be

controlled through osmotic

pressure of the core, level of

pore former, and membrane

weight with release to be fairly

independent of pH and

hydrodynamic conditions of the

body. Oxybutynin release from

the developed formulations is

inversely proportional to the

osmotic pressure of the release

media, confirming osmotic

pumping to be the major

mechanism of drug release

[50]

Porous

Osmotic

Pump

17 Theophy

lline

• Poly

caprolactone

• Polyethylene

glycol

• Type of

solvent

• Amount of

PEG

• Thickness of

films

The release rate of coated

tablets can be increased by

increasing the amount of pore-

forming agent, and the

corresponding values from

tablets coated in

dichloromethane is less than in

acetone. Much denser structure

and smaller pore size of films

can be formed from

dichloromethane.

[51]

Porous

Osmotic

Pump

III. Micro Particulate

18 Diltiazem

HCl

• L-HPC

• EC

• MCC

• Drug–

excipient

compatibility

The drug release from the

tablets takes place by

concentration-dependent

[52]

Pellets



• Eudragit

• NE 30 D

• Characterizat

ion of pellets

• In vivo study

diffusion process through

channels or capillaries in a pellet

matrix and those in between

closely packed pellets.

19 Etanidazole • Poly(L-lactic

acid)

• PLGA

• PVA

• Identification

of shell and

core polymer

• Encapsulatio

n efficiency

• SEM

The double-walled polymeric

drug delivery system is able to

circumvent most of the

limitations of traditional

monolithic polymer systems.

[53]

Double-

walled

microspher

es

20 Diltiazem

HCl

• Indion 254

• Polystyrene-

McG-100

• MC

• Diameter of

Microcapsule

• Drug

Entrapment

Efficiency

• SEM

Uniformly coated resinate-

loaded PS microcapsules can be

prepared by an oil-in-water ESE

method through proper

adjustment of the formulation

parameters.

[54]

Micro

capsules

21 Pravastatin • Cross linked

β CD

• Melting

point

• Solubility

studies

• Cross linking

• Swelling

index

• SEM, FTIR &

DSC

Cross linked polymer structure

is controlling determinant for

the sustained release

modulation of HSD. Loading

facilitators can help in drug

loading.

[55]

Micro

particulate

22 Guaifenesin • Ceresin wax • Assay

• In-vitro

release rate

• Particle size

The entrapment of a highly

water-soluble drug, guaifenesin,

into a hydrophobic wax matrix

can be increased significantly

[56]

Micro

spheres



distribution

• Entrapment

efficiency

using a salting-out procedure.

The maximum delay in the

release of guaifenesin can be

obtained from the microspheres

with 1:4 drug/wax ratio.

23 Metoprolol

Tartrate

• HPMC

K 100 M

• EC

• HPMC E 5

• Eudragit®

• Coating of

sustained

release

granules

RS

,and RL

• Surface

Topography

• In Vitro Drug

Release

study

• Biopharma

ceutical

analysis

Coating of matrix granules is

found to be an effective

technique for a highly water-

soluble drug—metoprolol

tartrate. Investigated sustained

release matrix granules in

capsule are capable of

maintaining constant plasma

level of HSD up to 10–12 h with

high value of IVIVC. Dosed

dumping can be avoided.

[57]

Coated

matrix

granules

24 Ketorolac

Tromethami

ne

• Eudragit RS

100 powder

• Eudragit

RL/RS 12.5%

solution

• Talc powder

• Evaluation of

KT pellets

• Determinatio

n of KT for

stability

study

• In vitro

release

• Release

kinetic study

The developed formulation can

extend release for 12 hrs and

exhibits good physical and

chemical stability. The pellets

are recommended to be stored

at conditions not exceeding 25

°C and 60% RH to maintain a

proper extended-release profile.

[58]

Pellets

IV. Compression Coated Tablets

25 Lornoxicam • Compritol • Morphologic® The press coated technology [59]



Compressio

ncoated

tablets

al

examination

• In vitro drug

release

studies

• XRD, FTIR

can be of great potential as an

effective approach to tailor the

release patterns of drugs to

accomplish the desired drug

release profile, according to

their pharmacokinetics and

therapeutic needs.

26 Metoprolol

succinate

• HPMC K15 M

• HCO

• Avicel PH 102

• Physical

evaluation

• In Vitro

Dissolution

Studies

The core-in-cup technology is a

potential technology, which can

control the release of highly

water soluble drugs for once-a-

day administration with the use

of a combination of hydrophilic

and hydrophobic polymers.

[60]

Core-in-Cup

Tablet

27 Theophyllin • PEO

• Avicel PH200

• Fabrication

of punches

(tooling)

The compression-coated tablet

process provides a means of

compression coating by simple

modifications to a three layer

press. There are many

advantages of this process over

traditional compression coating.

[61]

Compressio

n coated

tablet

28 Acetamino

phen

• HPMC 6 cps

• Lactose-

crystal

cellulose

spray dry

granules

• Radial tensile

strength

• Effect of

compression

pressure on

lag-time

Comparing with the controlled

release tablet using membrane

by the film coating tablets,

OSDRCs are useful in the simple

manufacturing method with low

manufacturing cost and easy

process management.

[62]

One-step

dry-coated

tablets

29 Nifedipine • PEO • In vitro drug Swelling and morphological [63]



Three

layers

compressio

n coated

tablet

• CP 971P-NF

and 934P-NF

• PEG 4000

study

• DSC

• XRD

• Effect of PEO

molecular

weight

change of CP layer on both side

of the tablet can minimize the

erosional release for rapidly

swelling PEO and thus changes

the drug release to a diffusion-

controlled process.

V. Gastro Retentive Drug Delivery Systems (GRDDS)

30 Nicardipine

HCl

• Hydrocolloids

of high

viscosity

grade

• Buoyancy

• Comparison

with market

product

• In vivo study

Drug duration after the

administration of sustained

release capsules significantly

exceeds that of the market

product MICARD. The

optimized design can exhibits

controlled drug release up to 16

hrs.

[64]

Floating

capsules

31 Diltiazem

HCl

• Gelucire

43/01

• Glyceryl

monosterate

• Methocel

K4M

• Ethocel 20 FP

• Floating

ability

• γ

Scintigraphy

• Drug content

• Hot stage

polarizing

microscopy

• Aging effect

Gelucire 43/01, can be

considered as an effective

carrier for the design of a multi-

unit floating drug delivery

system of highly water-soluble

drugs like diltiazem HCl.

[65]

Floating

Granules

32 Metoprolol

tartrate

• Methocel

K4M

• Na-CMC

• NaHCO

• Floating

capability

3

• Curve fitting

• Effect of

formulation

Drug-to-polymer ratio is the

major factor affecting the

floating time and the release

properties of FDDS. High

polymer load can control the

[66]

Floating

tablet



variables on

floating time

release of a Metoprolol tartrate

with good in vitro floating time

in the presence of a gas

generating agent.

33 Ranitidine

hydro

chloride

• HPMC-K4M

• Na-CMC

• HPMC-K100

• Evaluation of

core and

coated

tablets

• Floating

properties

• Performance

evaluation

Drug release is directly

influenced by concentration of

hydrophilic polymers in core

and thickness of SPM but

remain unaffected by pH,

hydrodynamic condition of

release medium and amount of

gas generating agent in

compression coat.

[67]

Floating

Osmotic

Drug

Delivery

System

34 Metformin • Eudragit NE

30 D

• Compactrol

• sodium

• alginate

(HVCR

grade)

• Magnesium

aluminomet

asilicate

(Neusilin)

• In Vitro durg

release study

• Buoyancy

Studies

• Percentage

Swelling and

Erosion

Study

• Kinetics of

drug release

It is a promising approach to

achieve in vitro buoyancy and

controlled release pattern for

HSDs. The combination of fast

hydrating, rate controlling

polymer and gel forming

polymer (NaCMC) with gel

strength modifier and gas-

generating agent is essential to

achieve in vitro buoyancy and

desired release profile.

[68]

Floating

tablet

35 Diltiazem

Hydro

chloride

• Methocel

K100M CR

• Compritol

888 ATO

• Sodium

• Buoyancy

Studies

• Comparison

with market

product

It is a promising approach to

achieve in vitro buoyancy by

using gel-forming polymer

Methocel K100M CR and gas-

generating agent. Combination

[69]

Oral

Floating



Matrix

Tablet

bicarbonate

• Succinic acid

• Drug release

Kinetics

• SEM

of Methocel and Compritol

results in minimal variation in

drug release.

VI. Oral In Situ Drug Delivery Systems

36 Ambroxol • Pectin (LM-

104AS)

• Rheological

properties

• In vitro drug

release

• Animal study

When the calcium ions are

released in the acidic

environment of the stomach,

resulting gel functioned as

depots for the release of

ambroxol.

[70]

In

situ

gelation

37 Theophyllin

e

• Deacetylated

Gellan gum

(KelcogelE)

• Gel strength

• In vitro drug

release

• Animal study

Sustained release of

theophylline, is achievable from

the gel vehicles over a period of

at least 6 h.

[71]

In situ gel

38 Lidocaine

HCl

• Chitosan

• Glyceryl

monooleate

• Drug load

• Cross-linker

concentratio

n on

• Reaction

time

• Mucoa

dhesive

properties

• Peel strength

In-vitro release of both

hydrophilic and hydrophobic

drugs from gel is very quick.

Incorporation of 0.2% (v/v)

glutaraldehyde as a cross-linker

can retard drug release. The

drug release can be sustained

by incorporation of drug-loaded

microspheres into the delivery

system which followed a

diffusion-controlled mechanism.

[72]

In situ gel

39 Cimetidine • Xyloglucan

• Sodium

alginate

• Duck Algin™

• Iscosity

• Drug release

rate

• Animal study

The gelation of Xyloglucan does

not require the presence of H+

ions and its use is not restricted

by the nature of the drug as is

[73]

Insitu gel



• Comparison

with market

product

the case with gellan

formulations where

incorporation of certain drug

salts may cause gelation before

administration.

40 Para

cetamol

• Xyloglucan

with a

percentage

of galactose

removal

• Pectin

• Flow

behavior of

sols

• Rheological

properties

• In vitro drug

release

The gel strength of xyloglucan

and sustained release

properties may be improved by

the inclusion of pectin.

Improvement of the gelation

characteristics of the

xyloglucan/pectin mixture is a

result of a combination of both

thermal and ion responsiveness

and synergistic interaction

between these two polymers

[74]

In

Situ gel

VII. Solid Dispersion

41 Metoprolol • Eudragit

RLPO- RSPO

• Different

methods of

preparation

• DSC

• XRD, FTIR

The 5:5 ratio of Eudragit RLPO:

RSPO by solvent method or 3:7

ratio with fusion method seems

more suitable to control release

of metoprolol.

[75]

Solid

Dispersion

42 Verapamil

HCl

• EC

• Eudragit-

RSPO

• Comparative

evaluation

• DSC

• Tabletting of

SD

Solid dispersion exhibits

polymer concentration

dependent drug release.

[76]

Solid

dispersions

43 Propranolol

HCl

• Eudragit

RSPO

• Drug release

study

The SD system can be more

efficient than physical mixing in

[77]



SD tablet • Evaluation of

matrices

• FTIR

the preparation of SR, inert and

insoluble matrices of

propranolol HCl and Eudragit

RS.

44 Nifedipine • EC

• Eudragit

RL100®

• Microscopic

characterizat

ion

• XRD

• DSC

• FTIR

There is a significant effect of

Nifedipine loading on release

kinetics or mechanism from

microparticles of EC and RL

binary mixture and non-

significant effect on the

microparticle size, morphology,

and size distribution.

[78]

Solid

dispersion

45 Phenacetin • PEO

• Carbopol

• Powder XRD

• Thermal

analysis

• FTIR

• Release

studies

It is feasible to control

Phenacetin release from the

PEO–CP solid dispersion by

varying the amount of PEO–CP

complex formation depending

on the CP grade with various

cross-linking degrees.

[79]

Solid

dispersion

46 Metformin

HCl

• Methocel

K100M

• Drug content

• % Yield

• SEM

• Dissolution

efficiency

• XRD

• DSC

• FTIR

The proposed strategy of

simultaneously exploiting the

combination of the drug with a

hydrophilic polymer such as

methocel K100M and its SD is

effective in adequately

modulating the drug-release

rate.

[80]

Solid

dispersion

VIII. Miscellaneous

47 Pseudoephe • HPMC • Influence of Novel EMT systems can be [81]



drine (TC-5R®)

• L-HPC

• Ethocel

L-HPC on

release of

drug

• Influence of

coating load

on release

designed to yield particular

stable drug release profiles by

combining different types or

quantities of PSEMT into one

dosage form: the IRMT provide

rapid-acting Pseudoephedrine,

and the SRMT ensure prolonged

release.

Mini

tablets

in

HPMC

capsules

48 Metoprolol

tartrate

• Polyethylene

oxide

• Textural

profiling

• Electrolyte

conductivity

and textural

measuremen

ts

• Comparative

study with

market

product

Through matrix textural

profiling the process of matrix

stiffening via electrolyte

interaction is accomplished with

pronounced stiffening and

densification in the case of

sodium carbonate–pentasodium

tripolyphosphate combination.

[4]

Electrolyte-

induced

matrix

stiffening

49 Niacinamid

e

• Chitosan (CS,

50 K Da)

• Methocel®

• Carbopol

974P-NF

K4M,

• Swelling

studies

®

• In vitro tissue

permeability

studies

Comparing with HPMC K4M

and Carbopol 974P-NF®, the

modified chitosan shows better

swelling properties, in vitro drug

release and transport of drug

across the intestine.

[82]

Lyophilized

chitosan

hydrogel

complex

50 Dexame

thasone

phosphate

• Poly (glycerol

adipate) and

the various

acylated

• Separation of

unincorporat

ed drug

• Particle size

Drug incorporation and release

retardation are linked to

potential interactions between

the drug and polymers.

[83]

Nano



particles derivatives • Zeta

potential

• TEM

51 Diminazene

diaceturate

• Stearic acid

(SA) DAB 7

• Tween 80

• Particle Size

• Two-

dimensional

PAGE

Analysis and

N-terminal

• Microsequen

cing

The approach of creating

nanoparticles with a high load

of hydrophilic drug, consisting

of physiological compounds via

lipid–drug conjugate formation

seems to be a promising

addition to the existing

nanoparticulate carrier systems.

[84]

Lipid–Drug–

Conjugate

(LDC) Nano

particles

52 Metoproiol

tatirate

• Poly

Caprolactone

(PCL)

• Sodium azide

• Effect of

drug loading

on solute

release

kinetics

• Effect of

diameter

• Release

kinetics

The core should be hard to

minimize porosity preventing

any infiltration of dissolution

medium which may cause dose

dumping. The coat should be

impermeable and rigid to

withstand any penetration and

deformity thereby restricting

drug release to the central hole.

[85]

Bioconcave

tablets

53 Mogui

steine

• Cellulose

acetate

phthalate

• Diphenyl

phthalate

• Glyceryl

monosterate

• White bees

wax

• Physical

characterizat

ion of

suspension

• In vitro drug

release

• Bioavailabilit

y

Coating of three successive

layers on drug particles can

protect Moguisteine form

dissolution in oral cavity after

reconstitution.

[86]

SR

Suspension



3.6 Patents on modified release systems of various water soluble drugs

Table 4 discusses various patents filed for release modulation of water soluble drug by

different investigators.

Table 4. Patents on release modulation of water soluble drugs

No Investigator Drug Description Ref

1 Peter

Timmins

Metformin

HCl

The delivery system includes (1) an inner solid

particulate phase comprising granules of drug,

blend of hydrophilic and hydrophobic

polymers and/or waxes, fatty alcohols and/or

fatty acid esters, and (2) an outer solid

continuous phase in which the above granules

of inner solid particulate phase are embedded

and dispersed throughout, the outer solid

continuous phase including one or more

hydrophilic polymers, one or more

hydrophobic polymers and/or one or more

hydrophobic materials such as one or more

waxes, fatty alcohols and/or fatty acid esters,

which may be compressed into tablets or filled

into capsules.

[87]

2 Thai Minh

Nguyen et

al.

Pimecrolimus The system includes an inner portion of a

water soluble drug in a drug matrix material

which stabilizes the drug. An outer portion of

the drug delivery system separates the inner

portion from a surrounding environment. The

outer portion retards the release of the water

soluble drug from the inner portion. The outer

portion includes a hydrophobic nonpolymer

[88]



compound and a binder. The hydrophobic

compound can be another drug which can be

delivered at an entirely different release

kinetic from the water soluble drug and for

treatment of the same or a different

condition.

3 Reza

Fassihi, Libo

Yang

Theophylline The present invention pertains to a controlled

release pharmaceutical tablet having at least

three layers (two barrier layers and one drug

layer). The two barrier layers erode more

quickly than the drug layer. All layers are

formed from swellable, erodible polymers. The

drug layer can have a different composition

from the two barrier layers. The three layers

can also differ in thickness. The

pharmaceutical agent is contained in the drug

layer and is released as the tablet layer swells

to allow diffusion through the tablet layers.

[89]

4 Anand R.

Baichwal et

al.

Diltiazem HCl This invention relates sustained release oral

solid dosage forms comprising a

therapeutically effective amount of a

medicament having a solubility of more than

about 10 g/ L; a pH modifying agent; and a

sustained release matrix comprising a gelling

agent. The gelling agent comprising a

heteropolysaccharide gum and a

homopolysaccharide gum capable of cross-

linking said heteropolysaccharide gum when

exposed to an environmental fluid, said

[90]



dosage form providing a sustained release of

said medicament after oral administration to

human patients.

5 Jean-Marc

Ruiz

Steroids A sustained release drug formulation

including: a drug; a biodegradable polymer

which is insoluble in water; and an oil vehicle

in which both the drug and the polymer are

dissolved. The oil vehicle contains 10-100% by

volume pharmaceutically acceptable oil and 0-

90% by volume a pharmaceutically acceptable

liquid carrier for the drug or the polymer.

[91]

6 Hyunjo Kim,

et al.

Diltiazem HCl A matrix based controlled release formulation

for a highly soluble drug over long periods of

time is developed. The release controlling

agent is a swellable gum which encapsulates

or make granules of drug, which is then

disposed in more swellable erodible polymers

follows such as HPMC or poly (ethyleneoxide).

[92]

7 Navin vaya

et al.

Metformin The dosage form comprises of a) Micro matrix

particles containing, high solubility active

ingredient and one or more hydrophobic

release controlling agent b) Coating of Micro

matrix particles with one or more hydrophobic

release controlling agents.

[8]

8 Hollenbeck,

Garry R.

Propranolol

HCl

The invention encompasses a liquid form

controlled release drug composition

comprising a dispersed phase comprising an

ion-exchange matrix drug complex comprising

a pharmaceutically acceptable ion-exchange

[93]



matrix and a water- soluble electrolytic drug

associated with the ion-exchange matrix.

9 Hiroaki

Okada et al.

Antitumor

drugs

A microcapsule produced by preparing a

water-in-oil emulsion comprising an inner

aqueous layer containing water-soluble drug, a

drug retaining substance and an oil layer

containing a polymer substance. An aqueous

layer is thickened to a viscosity of not lower

than about 5000 cps and finally subjecting the

resulting emulsion to in water drying gives

prolonged release of water-soluble drug.

[94]

10 Toshio

Yoshioka et

al.

5-fluorouracil Sustained release microcapsules including a

water soluble drug and an organic basic

substance as a drug retaining substance of this

invention not only have a high rate of

incorporation, but also show little initial

release so that they can be administered

safely and bring about persistent, stable

sustained release.

[95]

11 Eric H.

Kuhrts

Caffeine The composition consists of a gel-forming

dietary fiber, a biologically-absorbable drug or

other active therapeutic agent, and a

disintegrant (mineral salt) which releases a

physiologically- acceptable gas upon ingestion,

preferably carbon dioxide (a mineral

carbonate or bicarbonate) and advantageously

dextrose or like soluble sugar. The dietary

fiber-containing composition, when

compressed into a tablet together with the

[96]



drug and the specific disintegrants, provides a

unique and efficient prolonged-action drug-

delivery system.

12 Haibang Lee

5-fluorouracil A process for the microencapsulation of oil

droplets containing a medical drug for oral

administration, comprises the steps of mixing

the drug with liquid oil by sonication for 5-30

seconds to disperse the drug homogeneously

in the oil, and adding the drug-dispersed oil to

an aqueous solution mixture to form a two

phase system. The aqueous solution mixture

will form a capsule material, and comprises a

polysaccharide which has metal chelating

capacity, a biocompatible and water-soluble

polymer for improving the physical properties

of the capsule material, and emulsifying

agents. Further on sonication and subsequent

addition to multivalent cation containing

solution and lyophilization yield a final product

in a powdery state

[97]

13. Kenneth J.

Himmelstei

n

Sodium

Indomethacin

trihydrate

An osmotic drug delivery system comprises a

compartment with one or more chambers in

series formed by an external shell and

chamber-dividing walls of a microporous

material and successive over layers of

semipermeable membranes completely

covering the outer shell.

[98]

14 Mayumi

Naito et al.

Ibuprofen A suspension of a sparingly water-soluble

acidic drug which is stable for a prolonged

[99]



period of time and is highly dissolvable, and a

process for simply and easily producing the

suspension by specially designed pulverizer.

This suspension has a pH value of 2 to 5 and

and average particle size ranges from 1 to 15

μm.

15 Makoto

Suzuki et al.

Hyaluronic

acid

This invention relates to a drug composition

with a controlled drug release rate. The drug

composition comprises a matrix formed of the

biodegradable, biocompatible high-molecular

substance or polyvalent metal ions or

polyvalent metal ion source and hyaluronic

acid or its salt and a drug incorporated as an

ingredient.

[100]

16 Stephen

Brocchini et

al.

Platelet

aggregation

inhibiting

(PAI)

Peptides

Polymeric drug formulations containing a non-

releasing single-phase dispersion of a water-

soluble drug in a water insoluble tissue-

compatible polymer matrix. Polymeric drug

formulations are also disclosed containing a

single-phase dispersion of a water-soluble

drug and a water-insoluble tissue-compatible

polymer matrix, and a second, phase

disrupting polymer that is non-miscible with

the tissue compatible polymer and is present

in an amount sufficient to form phase-

separated micro domains of the second

polymer in the tissue-compatible polymer

matrix.

[101]

17 Bret Berner Metformin Drugs are formulated as oral dosage forms for [102]



controlled release in which the release rate

limiting portion is a shell surrounding the drug-

containing core. The shell releases drug from

the core by permitting diffusion of the drug

from the core. The shell also promotes gastric

retention of the dosage form by swelling upon

imbibition of gastric fluid to a size that is

retained in the stomach during the

postprandial or fed mode.

18 Andrew

Xian Chen

vinca

alkaloids

This invention relates to an emulsion

composition for delivering highly water-

soluble drugs such as vinca alkaloids.

[103]

19 Rafael Jorda

et al.

Metformin

HCl

A multi(micro)particulate tablet is provided

compriding microparticles which comprise a

mechanically non-deformable core of drug.

The tablet is formed from reservoir

microcapsules with prolonged release of the

drug, which are each made up of a non-

deformable core comprising drug and covered

with at least one film coating. The

microcapsules have a particle size of between

50 and 1000 microns and are coated with

envelope which allows release extension.

[104]

20 Pavan Bhat

et al.

Propranolol

HCl

This invention comprise sustained release

particles each having an inner core bead

comprising an active pharmaceutical

ingredient, an intermediate coating

substantially surrounding the inner core bead,

and an outer coating substantially surrounding

[105]



the intermediate coating comprising a pH

independent polymer. Two bead populations

have a different drug release profile and are

mixed proportionally to tailor desired drug

release.

21 Christine

Andersen et

al.

Hydrocodone The formulation describes pharmaceutical

compositions, such as controlled release

dosage forms, adjusted to a specific

administration scheme.

[106]

22 Andrew

Xian Chen,

David L.

Bledsoe

Tramadol HCl The present invention provides

pharmaceutical compositions for controlled

release of pharmaceutically active agents,

especially those with a high water solubility,

high dose, and/or short half-life. In addition, it

provides methods for preparing and using

such pharmaceutical compositions.

[107]

23 Duncan H.

Haynes

Biomolecules It deals with the novel uses of the

phospholipid-coated microcrystal in the

delivery of water-soluble biomolecules such as

polypeptides and proteins. The proteins are

rendered insoluble by complexation and the

resulting material forms the solid core of the

phospholipid-coated particle.

[108]



3.7 Work done on modified release systems of Milnacipran HCl

Exhaustive referencing revealed that not a single article related to release modulation of

MH (controlled release, sustained release, pulsatile release, etc.) is published in any

national and international journals. Only few patients are filed for related work of MH

which are mentioned as under.

Table 5. Work done on release modulation of MH

No Authors Title Description Ref.

1 Jane C.

Hirsh et

al.

Modified release

compositions of

Milnacipran.

The formulation comprises an extended

release dosage unit (Optionally containing the

immediate release portion) coated with

delayed release coating. The Milnacipran

composition, when administered orally, first

passes through the stomach releasing from

zero to less than 10% of the total Milnacipran

dose and then enters the intestines where

drug is released slowly over an extended

period of time 24 hrs.

[109]

2 Jane C.

Hirsh et

al.

Pulsatile release

compositions of

Milnacipran.

A once-a -day oral Milnacipran pulsatile

release composition has been developed that

releases the drug in spaced apart "pulses".

The dosage forms are comprised of first,

second and optional third dosage units, with

each dosage unit having a different drug

release profile.

[110]

3 Paillard

Bruno et

al.

Pharmaceutical

composition

with extended

release of

Multi-particulate system containing a plurality

of microgranules each comprising an active

microsphere containing a saccharose and/or

starch nucleus of a size between 200 and 2000

[111]



Milnacipran

μm and containing 150 to 1000 μm of

Milnacipran and a binding agent, each

microgranule being coated with a film having

a base of at least one polymer insoluble in

water but permeable to physiological liquids,

of a thickness between 20 and 100 μm.

4 Jane C.

Hirsh

Alison B.

Fleming

Roman V.

Rari

Multiparticulate

compositions of

Milnacipran for

oral

administration

The formulation is made by complexing

Milnacipran with an ion-exchange resin in the

form of small particles, typically less than 150

microns. Various types of coating are provided

onto drug particles (e.g. enteric coating,

coating to release in stomach but not in saliva,

extended release coating) and coated

particles are further formulated in various

dosage forms based on desired release profile.

[112]

5 Madan

Sumit et

al.

Extended release

composition of

Milnacipran.

A matrix tablet is prepared by compressing

the powder blend of (i) Milnacipran HCl,

Lactose, PVP, HPMC, Colloidal silica, talc and

magnesium silicate (ii) Milnacipran HCl, MCC,

Sodium carboxymethyl cellulose, HPMC. In

addition to this, Opadry® White/ethyl

cellulose aqueous dispersion/ coating was

applied to aforementioned core tablet to

manipulate the desired drug release profile.

[113]

6. Shirish

Kumar et

al.

Controlled

release

Pharmaceutical

compositions of

Milnacipran.

A process of preparing a controlled release

pharmaceutical composition comprises:

a) preparing a first layer comprising i) melting

hydrophobic release controlling agent and

Milnacipran in it ii) cooling followed by sieving

[114]



the melted mass to obtain granules and iii)

lubricating the granules; and

b) Preparing a second layer comprising

granules which comprises hydrophobic

release controlling agent and optionally

Milnacipran.

7 Mahendra

G.

Dedhiya

et al.

Milnacipran

Formulations

The present invention provides formulations

comprising MH including immediate release

formulations and modified formulations, such

as delayed release and extended release

formulations. The present invention provides

formulations with improved stability and high

bioavailability.

[115]

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