SUPERPOROUS HYDROGELS Mod

SUPERPOROUS HYDROGELS -VERSATILE DRUG RELEASE

RETARDANTS

D. HARIKA*, R. SUNITHA, P.SRIVALLI KUMARI, AND

D.VARUN.

Corresponding email id: [email protected]

[email protected]

ABSTRACT:

Superporous hydrogels (SPHs) are porous

hydrophilic crosslinked structures with the facility of

absorbing aqueous fluids. Initially hydrogels were developed

as a novel drug delivery system for gastric retention devices.

But they have the disadvantage that, they swells into aqueous

fluids at slow rate (it takes several hours to attain

equilibrium swelling), but many of the pharmaceutical

applications need fast swelling property. Therefore

Superporous hydrogels(SPHs) were developed, these systems have

to immediately swell in the stomach and retain their

consistency in the insensible stomach environment, while

releasing the pharmaceutical active constituent. For many

years, the synthetic characteristics and properties of these

SPH materials take account to meet the needs for gastric

retention applications. Moreover, an instant swelling of

hydrogel has too revealed potential application for peroral

intestinal peptide and protein absorption. This review

discusses the generations of SPHs, formulation, preparation,

characterization and applications of these SPH polymers.

INTRODUCTION:

A hydrogel is a three-dimentional cross linked

polymer network which are bonded physically or chemically and

they are insoluble in water but swells in the existence of

overload water. Hydrogels with effective pore sizes in the

range of 10 to100nm are termed as Microporous hydrogels and

pore sizes in the range of 100nm to 10µm are termed as

macroporous hydrogels. For the dried hydrogels to swell, water

has to be absorbed into the glassy matrix of the dried

hydrogels. The swelling kinetics of the dried hydrogels thus

depends on the absorption of water occurring by a diffusion

process and the relaxation of the polymer chains in the

rubbery region. Here the rate limiting factor with these

hydrogels has been to some extent slow swelling property of

dried hydrogels(i.e it takes atleast several hours to attain

equilibrium swelling). This slow swelling property is

advantageous in controlled drug delivery systems, but many of

the pharmaceutical applications need fast swelling property(1).

To overcome this slow swelling property of

dried hydrogels, the current inventors have synthesized a

super porous hydrogel that can swell within minutes despite

the consequences of the size of the matrix. SPHs swell very

fast regardless of their size, and this is due to the

interconnected porous structure. The interconnected structural

pores provide water absorption into the centre of the SPHs by

capillary force. Even though these super porous hydrogels

provided drastically fast swelling kinetics and high swelling

degree, the mechanical strength of the fully swollen super

porous hydrogels was besides poor to be useful. In some cases,

the abundant swollen super porous hydrogels could not be

picked up and broke easily due to their very poor mechanical

properties. Usually, mechanically strong super porous

hydrogels can be made by increasing the cross linking density,

but this would result in a very small extent of swelling with

a loss of the superabsorbent

property. Therefore, it is preferred

to make super porous hydrogels

having fast swelling and high

absorbency uniqueness as well as

high mechanical strength(2,3,4).

Figure1: Swollen

beads of SPHs

Superporous Hydrogels possess three unique properties that

conventional hydrogels do not have.

First, the swelling rate is extremely fast. Regardless of

the size of the dried superporous hydrogels, the full

swelling is complete in a matter of a minute.

Second, superporous hydrogels swell to very large sizes,

and the weights of the fully swollen superporous

hydrogels are orders of magnitude higher than the weights

of dried superporous hydrogels.

Third, the swelling superporous hydrogels can exert

significant expansion force during swelling, despite the

fact that the solid content is only a percentage of the

total weight.

Generations of super porous hydrogels:Superporous hydrogels are porous hydrophilic crosslinked

structures with the capability of absorbing aqueous fluids up

to a few hundred times their own weight. Highest swelling is

generally reached in a fraction of a minute with SPHs having

average pores of 200 mm in size.

There are three generations of super porous hydrogels were

developed:

First generation SPHs- Conventional SPHs.

Second generation SPHs- SPHs composite.

Third generation of SPHs- SPH hybrid.

First generation SPHs(CSPHs):

These first generation SPHs are prepared by Chen et

al, in the year 1999. First time he prepared SPHs with fast

swelling kineticks and superabsorbent properties. These are

polymerized and cross linked with different vinyl monomers and

they require a foaming agent, foam stabilizer and a foaming

aid, along with these different wetting agents are also added

to increase the water absorption rate to less than a minute.

Highly hydrophilic acrylamide, salts of acrylic acid, and

sulfopropyl acrylate are mostly used for preparation of CSPHs.

Generally dried SPHs are brittle and hard in nature, but when

they are dissolved in aqueous fluids, the moisture-induced

plasticization of these polymers results into soft and

flexible structures. When these polymers are in dry state,

handling is very difficult, because during drying process the

porous structure becomes collapsed due to the surface tension

of water, which pulls the polymer chains together. This

problem can be overcome by replacing the water with alcohol,

since it has low surface tension, which prevents the porous

structure from collapsing during drying(1,3,5,6).

The second-generation SPHs: (SPH composites)

In the year 2001 Park et al was first time

introduced these SPH composites. In second generation SPHs are

developed to overcome the lack of desirable mechanical

properties in CSPHs, by modifying the conventional SPHs with

the addition of superdisintegrants into the formulation. In

SPH composites, composite is a matrix, which contains both

dispersed phase and continuous phase. The preparation of SPH

composites also includes the same monomer, cross linker, and

initiating system in CSPHs, but along with these we also use

swellable filler, i.e composite agent (which is cross-linked

water-absorbent hydrophilic polymer). While this filler

dispersed into the reacting mixture, it would swells and

absorbs a mixed solution of monomer, cross linker, initiator

and the water-soluble foaming additives. Upon polymerization,

the polymer chains are formed, since the filler serves as the

local point of physical cross-linking. Each composite agent or

swollen filler serves as an isolated individual reactor,

throughout the polymerization process, in which cross-linking

polymerization occurs. As the cross-linking polymerization

precedes entire the solution, individual composite agent

particles are connected together by connecting the polymer

chains (3,7,8).

Third-generation SPHs: SPH hybrids

The third generation of SPHs are improved versions

of the second generation, and developed based on SPH hybrids

for synthesizing SPHs which are having high mechanical and

elastic properties. In second generation SPHs, pre-cross-

linked matrix-swelling additive is added, where as SPH hybrids

are prepared by adding a hybrid agent that can be cross-linked

after SPH is formed. The hybrid agent is a water-soluble or

water-dispersible polymer that can form crosslinked structure

(in a manner similar to forming interpenetrating network)

through chemical or physical cross-linking. Examples of hybrid

agents are polysaccharides including sodium alginate, pectin,

chitosan or synthetic water-soluble hydrophilic polymers such

as poly(vinyl alcohol). Once the second network is formed, the

whole system becomes similar to interpenetrating polymer

networks(9,10,11).

Figure 2: Complete swelling of super hydrogel(left) to a larger size

of same shape(right) in water in less than 30secs

Formulation csph, sphc, sphh (12):

Monomer: acrylic acid (AAc), salts and esters, SPAK,

HEMA, NIPAM acrylamide(AAm) etc

Crosslinker: Diacrylate, bisAAm Diacrylate, N,N’-

methylenebisacrylamide (Bis) is used most widely in

blowing technique. Glutarldehyde (chemical crosslinker),

metal ions like calcium, iron and phosphorus are used in

ionotropic crosslinking of hydrocolloids, bisAAm Higher

MW acrylates.

Solvent: water.

Foaming agent: bicarbonates.

Foaming aid: organic and inorganic acids AAc; acetic

acid; hydrochloric acid AAc; acetic acid AAc; acetic

acid; citric acid.

Foam stabilizer: PEO-PPO block copolymers Pluronic F127,

Pluronic P105, Silwet L7605, Span, Tween etc. .

Property modifier: a material used to enhance mechanical

properties; these include crosslinked and non-crosslinked

hydrophilic natural and synthetic polymers.

Hybrid agent: Natural polymers like sodium alginate, sodium

carboxymethylcellulose,

chitosan based on ionotropic gelation, none

Superdisintegrants including crosslinked CMC; Water-

soluble CMC,alginate, chitosan polyvinyl alcohol,

polyvinyl pyrrolidone andstarch glycolate.

Initiator: Persulfate/diamine; water soluble azo

Persulfate/diamine.

Polymerization initiator pair: APS/TEMED (Ammonium

persulfate/N,N,N,N-tetramethylethylenediamine, KPS/Sodium

metabisufite, APS/Sodium metabisulfite, Azo-initiator

(V545) etc.

Figure 3:

Swelling of dried hydrogels to a larger size

Preparation of superporous hydrogels:

For synthesis of SPHs, gas blowing technique was

used. In technique foaming and polymerization have to occur

simultaneously step by step. By using foaming technique, pore

size of SPHs was prepared larger than 100μm, and also it

reaches to mm range. SPHs are prepared by cross-linking

polymerization of monomers in the presence of gas bubbles.

Hence, for preparation of SPHs along with usual components

like monomers, cross-linker and chemical initiator, etc..

also add surfactants and blowing agents. Blowing agents are

required for producing gas bubbles and surfactants are

required for stabilizing the produced gas bubbles by lowering

the film-air interfacial tension and increasing the

viscosity13-15.

Fast gelling can be achieved by careful choice

of monomers (type and concentration), initiators (type and

concentration), solvent and temperature. In addition, high

monomer concentration, proper type of initiator, high

initiator concentration, high temperature, and good solvent

can all increase the polymerization rate.

Gas bubbles can be formed by any gas blowing

method, either chemical or mechanical. Mostly NaHCO3 is s

elected as a blowing agent because of its unique advantages

that may not be provided by other techniques, such as thermal

decomposition of chemical agent, mechanical whipping,

volatilization of low-boiling liquid, chemical reaction,

expansion of dissolved gas upon pressure release,

incorporation of microspheres into a polymer mass, and

expansion of gas-filled beads by heating. The amount of

blowing agent used controls the pore size and the porosity of

superporous hydrogels.

For large-scale production of superporous hydrogels,

mechanical blowing through one or more atomizers may be a

better choice than the chemical blowing method. This is

because it may not be desirable to complete a polymerization

in a few minutes since the heat generated during

polymerization may not be dissipated quickly. Thus, a smaller

amount of initiator may be used to delay the gelling time

(e.g., more than 10 minutes). Since mechanical blowing can

start at any time for any duration, the foaming process may

begin at the desired time and foam height can be maintained as

necessary. Accurate timing control is possible by mechanical

blowing in the large-scale production of superporous

hydrogels.

Characterization of sphs:

Gemeinhart et al in the year of 2000, uses SEM to assess

the surface morphology of conventional SPHs, and they

also measured the porosity of the hydrogel structure

using a mercury porositometer.

Dorkoosh et al in the year 2000, uses NMR for the

structural characterization of SPH and SPH composites.

Thangamatesvaran et al in the year 2004, by using 13C

nuclear magnetic resonance(NMR) and differential scanning

calorimetry(DSC), the structure and thermal properties of

the SPH hybrids can be studied.

X-ray scattering and molecular probes techniques are used

for further SPH characterization16,17.

Figure 4: Swollen crosslinkers of SPH under microscope.

Evaluation of superporous hydrogels18,19,20:

Swelling studies:

Initially the weight of a completely dried super

porous hydrogel was taken and then immersed in excess of

swelling medium. The weight of super porous hydrogel at

various time intervals after blotting excess of water on the

surface was determined. The swelling ratio is given by

Q = (Ms –Md)/ Md

Where, Q is the swelling ratio, Ms the mass in the swollen

state and Md the mass in the dried state.

Water retention:

The water retention capacity (WRt) as a function

of time was determined by using the following equation

WRt = (Wp - Wd) / (Ws - Wd)

Where Wd is the weight of the dried hydrogel, Ws is the weight

of the fully swollen hydrogel, and Wp is the weight of the

hydrogel at various exposure times.

Mechanical Properties:

Bench comparator was used to determine the

compressive strengths of various super porous hydrogel

formulations. The fully swollen hydrogel was put

longitudinally under the lower touch of a bench comparator,

different scale loads were successively applied on the upper

touch and the point at which the super porous hydrogels

completely fractured was determined. The pressure at this

point called penetration pressure (PP) was calculated by the

following equation:

PP = Fu/S

Where Fu is the ultimate compressive force at complete

breakage of polymer and S is the contact area of the lower

touch.

Rheological Characterization:

Rheological characterization of in

situ crosslinkable hydrogels formulated from oxidized dextran

and N-Carboxy ethyl Chitosan were established by performing

the study of gelation kinetics.

Determination of void fraction:

The void fraction was calculated by the following

equation:

Void Fraction = Dimensional volume of the hydrogel / Total

volume of pores

The void fraction inside super porous hydrogels was determined

by immersing the hydrogels in HCl solution (pH 1.2) up to

equilibrium swelling. By using these data, the dimensions of

the swollen hydrogels, sample volumes were determined.The

difference between the weight of the swollen hydrogel and the

weight of dried hydrogel gives the amount of buffer absorbed

into the hydrogels and it indicates the total volume of pores

in the hydrogels.

Porosity measurement:

The solvent replacement method was used for porosity

measurement. Dried hydrogels were immersed overnight in

absolute ethanol and weighed after excess ethanol on the

surface was blotted. The porosity was calculated from the

following equation:

Porosity = (M2 – M1) /ρV

Where M1 and M2 are the mass of the hydrogel before and after

immersion in absolute ethanol, respectively; ρ is the density

of absolute ethanol and V is the volume of the hydrogel.

Determination of drug content:

A weight of super porous hydrogel containing 4 mg

of drug mixed with 10 ml hydrochloric acid solution of pH 1.2

made upto 100 ml in volumetric flask. The mixture was filtered

and the filtered solution was analysed for drug content using

UV-Vis spectrophotometer.

In vitro drug release studies:

In vitro drug release from the super porous hydrogel was

performed by dissolution studies. Instruments used are UV-Vis

spectrophotometer/HPLC. The obtained data were fitted into

various release models for determination of n and k values in

case of Korsmeyer-Peppas equation was used to determine

release mechanism. Other tests like scanning electron

microscopy for surface topographic analysis, FTIR, DSC studies

for drug polymer compatibility studies etc will be

recommended.

Figure 5: Scanning electron micrographs of a nonporous SAP (A) and a

corresponding SPH (B and C).

PHARMACEUTICAL APPLICATIONS OF SPHS:

I. Development of Gastric Retention Devices

Gastric retention devices are mostly useful in

delivery of many drugs. From the last 2 decades there have

been a large number of approaches using well-established

principles to prevent the dosage form from exiting the pylorus

during gastric emptying. The main aim to develop gastric

retention devices is to make an oral formulation, which

doesn’t pass through the pylorus by fast swelling to a large

size. They are most beneficial in the delivery of drugs, which

acts locally in stomach (e.g., antacids and antibiotics for

bacteria-based ulcers etc), or primarily absorbed in the

stomach. These gastric retention devices are also useful for

drugs which are or degraded in the colon (eg: Metaprolol) and

which are poorly soluble in alkaline pH medium21.

However prolonged gastric retention devices are not

necessary in cases like, the drugs which are primarily

absorbed in the colon (since it sustain the blood levels up to

24hours), and also for drugs which are unstable in the

presence of acidic pH. This gastric retention is also not

desirable for drugs like asprin, and non-steroidal anti

inflammatory drugs.

II. Development of peroral peptide delivery systems

Superporous hydrogels are also used in the

development of peptide delivery systems via oral

administration. Peptide drugs have been administered mostly by

the parenteral route, and no peroral formulation has been

developed to year. Superporous hydrogels and their composites

can increase their volume by about 200-fold. Such volume

increase allowed the gels to mechanically stick to the

intestinal gut wall and deliver the incorporated drug directly

to the gut wall. The proper selection of functional groups of

the superporous hydrogels, e.g., carboxyl groups, induced the

extraction of calcium ions to induce opening of the tight

junctions of the gut wall and deactivate the deleterious gut

enzymes. After the peptide drugs have been delivered and

absorbed across the gut wall, the superporous hydrogels become

over hydrated, their structure is broken down by the

peristaltic forces of the gut, and the bits and pieces of the

delivery systems are easily excreted together with the feces

as miniparticulate systems.

Figure 6 shows prototype delivery systems. Cores

can be either inside or outside of the delivery system (or

shuttle), and the additional penetration enhancer, such as

trimethylchitosan, can be used. Recent in vivo pig experiments

showed that the absolute bioavailability of octreotide was

between 8% and 16%. Human scintigraphic studies also showed

the mechanical fixation of the SPHC-based delivery system in

the human duodenum and its subsequent breakdown (paper in

press)22.

III. Development of Fast-Dissolving Tablets

The major benefit of the fast-dissolving tablet

technologies is that the dosage forms can be administered

easily in the absence of water and without the need of

swallowing. This feature is especially useful to children and

the elderly. There are basically three different technologies

were developed from the initial success of first fast-

dissolving tablets: They are freeze-drying, sublimation or

heat molding, and direct compression. By using freeze-drying

technology the tablets which are dissolved within 5 seconds

can be prepared, whereas by using sublimation or molding

technology, tablets which are dissolved within 15 seconds can

be prepared. But these two methods are having the disadvantage

that they are expensive and the produced tablets are

mechanically weak. Therefore direct compression technology was

developed, which is less expensive and prepared tablets are

having good physical resistance. By this method the prepared

tablets are disintegrate within 10 seconds due to the fast

uptake of water into the core of tablet. This direct

compression method involves the addition of fine particles of

superporous hydrogels to the drug and other expients23.

IV. Development of Diet Aid

The main aim of this approach is to control the

body weight by reducing the food intake with the

administration of superporous hydrogel tablets. When these

tablets are taken they occupy a major portion of the stomach

space, leaving less space for food and they suppress the

appetite. For diet control, the superporous hydrogels can be

prepared which are taken orally are modified to delay the

swelling. Superporous hydrogels can be loaded inside hard

gelatin capsules for delaying the swelling. This will reduce

any disquiet on the early swelling of superporous hydrogels

for clinical applications24.

V. Development of Occlusion Devices for Treatment of

Chemoembolization:

Chemoembolization is a combined method of

embolization and chemotherapy. Embolization has been used for

cancer treatment by restricting the oxygen supply to the

growing tumours. This method could be combined with

chemotherapeutic agents to achieve local delivery and low

systemic toxicity. A chemotherapeutic agent and an anti-

angiogenic agent could be loaded into SPHs for

chemoembolization therapy. The property of fast swelling to a

large size of superporous hydrogels has been useful in the

development of a new biomedical device for treating aneurysms.

When the size and shape of an aneurysm site is predetermined

by a non-invasive imaging method, a superporous hydrogel of

the same shape (but smaller size) can be made. When a

superporous hydrogel is deployed at the aneurysm site, it

swells quickly to occupy the space and make the blood clot.

Deposition of superporous hydrogels resulted in up to 95%

aneurysm occlusion without any evidence of parent artery

compromise and inflammatory response. A new occlusion device

made of a combination of superporous hydrogel and platinum

coils, known as Hydrocoil, is currently under development. A

bioactive can be released from the superporous hydrogels

either to enhance or to delay blood clotting25.

VI. Biomedical applications:

In the biomedical area, SPHs

and SPH composites can be used to make various biomedical

devices, such as artificial pancreas, artificial cornea, and

artificial skin, articular cartilage, soft tissue substitutes,

cell growth substrates in tissue engineering, burn dressings,

surgical augmentation of the female breast, or hemoperfusion

in blood detoxification and in the treatment of uremia.

Vascular ingrowth into superporous hydrogels are useful for

cell transplantation, tissue engineering and in combination

with cell therapies. Hydroxyapatite containing super porous

hydrogel composites 35 and novel scaffolds of poly(2-

hydroxyethyl methacrylate) super porous hydrogels are useful

for bone tissue engineering20.

VII. Biotechnology area:

Biotechnologically, SPHs are used in the

separation of macromolecules and cells from the medium. SPHs

and SPH composites are ideal materials for chromatographic

supports due to their extremely larger pores.

VIII. Structural applications:

The low density of SPHs and SPH

composites allows applications as a high-strength, light-

weight structural material as well as a packaging material.

They will be also good as insulators and fillers in structures

with energy sensitive applications.

CONCLUSION:

From the past few decades, the pharmaceutical

industry has knowledgeable impressive growth year after year.

Constant introduction of life-saving drugs has propelled this

growth. Controlled-release technologies allow for effective

use of existing drugs and successful development of new drug

candidates. Developing new drug delivery technologies and

utilizing them in product development is critical for

pharmaceutical companies to survive. Superporous hydrogels are

a new class of hydrogel materials that, regardless of their

original size, rapidly swell to a large size. Different

generations of SPHs evolved to address the needs for certain

pharmaceutical applications, including gastric retention.

Studies have shown that some SPH formulations are potentially

exploitable for heavy duty applications in which superb

swelling and mechanical properties are required in harsh

swelling media. The feasibility of using these SPHs in oral

solid and semi-solid dose formulations have also been studied.

Preliminary safety and efficacy of certain SPH formulations

have been evaluated in-vivo, paving the way for further

development of these materials for pharmaceutical, food and

biomedical applications. Superporous hydrogels can be made

elastic, and this property can minimize their rupture. Various

harmaceutical and biomedical applications of superporous

hydrogels have been made, and several products are under

development. The unique properties of superporous hydrogels

can also be used for non-pharmaceutical and non-biomedical

applications.

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