in-situ gel drug delivery systems for the treatment …

www.wjpps.com Vol 9, Issue 4, 2020.

354

Sravani et al. World Journal of Pharmacy and Pharmaceutical Sciences

IN-SITU GEL DRUG DELIVERY SYSTEMS FOR THE TREATMENT

OF PERIODONTITIS

Sravani B.*, Sravani E., Keerthi K., Taruni T., Sandhya Rani B., Priyanka P. and

Padmalatha K.

Department of Pharmaceutics, Vijaya Institute of Pharmaceutical Sciences for Women,

Enikepadu-521108. A.P, India.

ABSTRACT

Periodontitis is an inflammatory disease characterized by progressive

destruction of periodontal soft and hard plaque tissues leading to

permanent tooth loss. The incidence of these diseases can be reduced

by mechanical plaque removal or scaling and root planning (SRP)

along with systemic and locally delivered antimicrobial agents or

statins. In-situ gels are the drug delivery systems that are in solution

form before administration in the body, but once administered in to the

body undergoes gelation in-situ to form gel. Mechanisms involved in

in-situ gel formation are solvent exchange, UV-irradiation, ionic cross-

linkage, pH change, and temperature modulation. Polymers exhibit sol-

gel phase transition and thus trigger drug release in response to

external stimuli. The polymers used must be biocompatible, adhere

properly to mucus, and exhibit pseudo plastic behavior. The main advantages of this route of

drug administration is that it can deliver the active agents directly to the site of action at

bactericidal concentration and it can facilitate prolong drug delivery.

KEYWORDS: In situ gel, Periodontitis, Thermo-sensitive modulation, pH change and

Statins.

INTRODUCTION

Periodontitis (PD) is an immuno-inflammatory disease of tooth supporting tissues (the

gingiva, bone and periodontal ligament), which results in progressive destruction of

surrounding soft and hard tissues with eventual tooth mobility and exfoliation. PD starts as an

*Corresponding Author

Prof. Sravani B.

Department of

Pharmaceutics, Vijaya

Institute of Pharmaceutical

Sciences for Women,

Enikepadu-521108. A.P,

India.

Article Received on

31 Jan. 2020,

Revised on 20 Feb. 2020,

Accepted on 11 March 2020

DOI: 10.20959/wjpps20204-15860

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 7.632

Volume 9, Issue 4, 354-368 Review Article ISSN 2278 – 4357


355


inflammatory reaction confined to the gingival tissue (gingivitis), but when left untreated it

spreads to periodontal ligament, cementum and supporting alveolar bone, resulting in pocket

formation which provides a favourable environment for the growth of pathogenic anaerobic

microorganisms. Chronic periodontitis primarily affects adults, but aggressive periodontitis

may intermittently occur in children. Perioceutics, involves the delivery of a right therapeutic

agent via systemic and local means as an adjunct to mechanical therapy.[1,2]

(a) (b)

Fig.1: a) Signs of Gum Disease/Periodontitis b) Stages of Periodontitis.

Classification of Perioceutics

Based on the application

1) Personally applied (in patient home self-care)

a. Subgingival non-sustained drug delivery: Home oral irrigation jet tips, Traditional jet tips,

Oral irrigation (water pick), Soft cone rubber tips (pick pocket).

b. Sustained subgingival drug delivery

2) Professionally applied (in dental office)

a. Nonsustained subgingival drug delivery - Professional pocket irrigation

b. Sustained subgingival drug delivery.[1,2]

Drugs used for the treatment of PD

1. Antimicrobial agents or Antibiotics: Tetracycline, Minocycline, Doxycycline,

Chlorhexidine, Clarithromycin, Clindamycin, Ciprofloxacin, Ampicillin,

Fluoroquinolones (Ciprofloxacin), Erythromycin, Azithromycin, Metronidazole.[12,15]

2. The pleiotropic effects of statins have been evaluated to assess their potential benefit in

the treatment of various inflammatory and immune-mediated diseases including

periodontitis.[4,7,25]

https://newteethforme.com/the-signs-of-gum-disease-periodontitis/


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Local drug delivery systems used for the treatment of PD

Local drug delivery systems (LDDS) exhibit several advantages over systemic agents, which

include minimally invasive and direct application at the site of infection, avoidance of gastro-

intestinal issues and presystemic metabolism, reduction in the dosage regimen, improved

patient compliance and serves as ideal means to incorporate agents, which are not suitable for

systemic administration eg. Chlorhexidine.[1]

Limitations of LDDS into periodontal pocket include, local irritants cannot be administered

and potent drugs are used because of relatively small area, enzymes like peptidase and

esterase may cause presystemic metabolism, peptide administration is not practicable due to

peptidase.

An ideal LDDS must be easy to administer, release the drug in a controlled manner, sustain

the drug release for prolonged period, should be biodegradable, biocompatible and donot

cause any sensitization and irritation to the tissues. Various LDDS aims to deliver therapeutic

agents to sub-gingival diseased sites are fibres, films, injectable systems, gels, strips,

compacts, vesicular system, microparticles and nanoparticles.[3,4]

Fig. 2: Local drug delivery systems used for the treatment of PD.[3]


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Gels

Gels are transitional state of matter containing both solid and liquid dosage forms. The solid

phase comprises a three dimensional network of interconnected molecules or aggregates

(polymer) which immobilizes the liquid continuous phase.[6]

Based on the nature of the bonds

involved in the three-dimensional solid network, gels can be classified into.

1. Physical gels: They arise when weak bonds like hydrogen bonds, electrostatic bonds and

vanderwaal bonds constitute together to maintain the gel network.

2. Chemical gels: They arise when strong covalent bonds constitute to maintain the gel

network. The network indicates the presence of cross-links which helps to avoid the

dissolution of the hydrophilic polymer in an aqueous medium.

3. Hydrogels: These are three dimensional polymeric networks that can absorb and retain

large amounts of water and biological fluids and swell, still maintaining their integrity.

These polymeric networks contain hydrophilic domains that are hydrated in an aqueous

environment, thereby creating the hydrogel structure.[1,2]

Advantages of hydrogels over other drug delivery systems

1. They exhibit good mechanical and optical properties and biocompatibility.

2. The degradation products of hydrogels are usually non-toxic or have lower toxicity.

3. Lower interfacial tension between the surface of the hydrogel and the physiological fluid

helps to minimize protein adsorption and cell adhesion on the hydrogel's surface.

4. The soft rubbery nature of hydrogels also can minimize mechanical irritation when used

as in-vivo implants.[11]

Hydrocolloids are polymers having the ability to swell in water or aqueous solvent and

induce transition of a liquid to gel. Gels are viscous preparations, which are formed when

high molecular weight polymers or high polymer concentrations are incorporated in the drug

formulations.[12,13]

In addition, the ability of hydrogels to release an entrapped drug in an

aqueous medium and to regulate the release of such drug by control of swelling and by cross

linking makes them particularly suitable for controlled release applications. Hydrogels can be

designed for the controlled release of hydrophilic and hydrophobic drugs and charged solutes.

Classification of hydrogels

Hydrogels are of two types. They are

1. Preformed hydrogels are defined as simple viscous solutions which do not undergo any

modification after administration.


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2. In-situ gels are the solutions or suspensions that undergo gelation after reaching the

particular site due to physico-chemical changes.[1,2]

In-situ gelling systems

„In-situ‟ is a Latin word which means „in position‟. In-situ gels are the formulations that are

in solution form before administration in the body, but once administration undergo gelation

to form gel. There are triggeed by different mechanisms such as pH change, temperature

modification, UV radiation, presence of specific molecules or ions and solvent exchange to

form in-situ gel.[21]

They provide sensor properties and can undergo reversible sol-gel phase

transitions upon changes in the environmental condition. Intelligent or smart polymers play a

vital role in drug delivery by dictating not only site of drug delivery, but also rate of drug

release.[5]

Routes administration of in-situ gelling systems

Oral, nasal, ophthalmic, vaginal, injectable, intraperitoneal and rectal route.

Advantages

1. It provides ease of administration and good patient compliance.

2. It shows increased gastric retention with slow drug release.

3. It reduces dosing frequency.

4. It shows local action and site specificity by acting directly onto the targeted site.

5. It shows less adverse effects compared to other pharmacological dosage forms.

6. It improves local bioavailability of drugs.

Disadvantages

1. It is more susceptible to stability problems due to chemical degradation.

2. It requires high level of fluids.

3. It leads to degradation due to storage problems.[6]

Suitable drug candidates for in-situ gel formulations

1. Narrow absorption window in GI tract, e.g., Ofloxacin

2. Primarily absorbed from stomach and upper part of GItract, e.g., Amoxicillin.

3. Drugs that act locally in the GItract, e.g., Chlorhexidine HCl.

4. Drugs that degrade in the colon, e.g. Metronidazole.

5. Drugs that disturb normal colonic bacteria, e.g., Amoxicillin trihydrate.


359


Ideal characteristics of In-situ gelling polymers

1. Biocompatible.

2. Capable of adherence to mucus.

3. Exhibit pseudo plastic behavior.

4. Exhibit good tolerance and optical activity.[26]

5. Capable of decrease the viscosity with increasing shear rate offering lowered viscosity

during blinking and stability of tear film during fixation.

Eg.: Natural: Gellan gum, Xyloglucan, Guar gum, Xanthan gum, Carrageenan, Lambda

carrageenan Chitosan, Thiolated chitosan, Pectin, Carbopol 934P, Gellan gum.

Synthetic: Poloxamers or pluronics, poly (lactic acid), poly (glycolic acid), poly (lactide-

coglycolide), poly (decalactone), poly ε-caprolactone.[6,7]

Mechanism involved in formation of in-situ gels

The in-situ gelling systems utilises various polymers that converts from solution and gel due

to change in physicochemical properties. In this system when low viscosity solution comes in

contact with body fluids undergo changes in confirmation of polymers and a viscous gel.

There are three mechanisms used for triggering the in-situ gel formation of biomaterials.

1. Physiological stimuli (e.g., temperature and pH)

2. Physicalchanges in biomaterials (e.g., solvent exchange and swelling)

3. Chemical reactions (e.g. enzymatic, chemical and photo-initiated polymerization)

I. Based on physiological stimuli

Thermoresponsive gels: The use of biomaterial whose transitions from sol-gel is triggered

by increase in temperature is an attractive way to approach in-situ formation. The ideal

critical temperature range is ambient and physiologic temperature for these systems, therefore

no external source of heat other than that of body temperature is required for trigger gelation.

1. Negatively thermo sensitive gels: They have lower critical solution temperature (LCST)

and contract upon heating above the LCST and transition between ambient and physiologic

temperature.

Eg: poly(N-isopropylacrylamide), Pluronics are poly (ethylene oxide)-poly (propylene

oxide)-poly (ethylene oxide) (PEO-PPOPEO).[26,28]


360


2. Positively thermo sensitive gels: They have an upper critical solution temperature

(UCST), such hydrogel contracts upon cooling below the UCST.

Eg: Polyacrylic acid and poly(acrylamide-co-butyl methacrylate).[26,28]

3. Thermoreversible gels: When injected as a solution into the body, the material forms a

firm, stable gel within minutes and remains at the site of injection providing absorption and

its action from less than one week to many months. These systems are very convenient and

easy to administer into desired body cavity.

Eg: Poloxamer, Pluronics, Tetronics.[12,13]

Fig. 3: Schematic of temperature triggered in situ gelling system.

pH triggered systems

In this approach, pH responsive or pH sensitive polymers are used to change pH liquid

formulation to gel. Polyelectrolyte pH sensitive polymers have acidic or alkaline ionisable

functional groups, used to increase external pH that leads to the swelling of hydrogel and then

in-situ gel. Swelling of hydrogel increases as the external pH increases in the case of weakly

acidic (anionic) groups, but decreases if polymer contains weakly basic (cationic)

groups.[12,13]

Eg,: Cellulose acetate phthalate (CAP), Carbomer and its derivatives, Polyethylene glycol

(PEG), Pseudo latexes and poly methacrilic acid (PMC) etc.[26,28]


361


Fig. 4: Mechanism of pH sensitive in-situ gelling system.

II. In-situ formation based on physical mechanism

1. Swelling: In this approach, the polymers that are surrounding the polymer imbibe the

fluids that are present in the external environment and swell from inside to outside and slowly

release the drug.

Eg: Myverol18-99 (glycerol mono-oleate), which is polar lipid that swells in water to form

lyotropic liquid crystalline phase structures.[29]

2. Diffusion: This method involves the diffusion of solvent from polymer solution into

surrounding tissue and results in precipitation or solidification of polymer matrix.[14]

Eg: N-methyl pyrrolidone (NMP)[27]

III. In-situ formation based on chemical reactions: It involves precipitation of inorganic

solids from supersaturated ionic solutions or enzymatic processes or photo-polymerization.

Ionic cross-linking: Polysaccharide polymers may undergo phase transition in presence of

ions. Eg.: k-carrageenan forms rigid, brittle gels in presence of small amount of K+ whereas i-

carrageenan forms elastic gels in the presence of Ca2+

. Gellan gum (Gelrite) is an anionic

polysaccharide form in-situ gel in the presence of mono-and divalent cations, including Ca2+

,

Mg2+

, K+

and Na+.[26]


362


Fig. 5: Schematic of mechanism of ion triggered in situ gelling systems.

Enzymatic cross linking: In this approach, gel is formed by cross linking with the enzymes

that are present in the body fluids.

Photo polymerisation: In this method, polymerisable functional groups in polymers undergo

dissociation in the presence of photo initiators like acrylates or other polymers contain long

wavelength ultraviolet and visible wavelengths are used.

Eg.: 2,2-dimethoxy-2-phenyl acetophenone is used as the initiator for ultraviolet photo

polymerization.

Characterization of in-situ gel formulations

In-situ gelling systems can be evaluated for various characterization parameters such as

clarity, pH measurement, gelling capacity, drug content, rheological study, in vitro diffusion

study, isotonicity and accelerated stability studies.

1. Physical Appearance

The formulations should be observed for general appearance i.e. color, odor and presence of

suspended particulate matter. Preferably the gels should be transparent in appearance.

2. Gelling capacity

The gelling capacity of formulations can be observed by time taken for gel formation in a vial

containing 2.0 ml of freshly prepared simulated salivary fluid.


363


3. Determination of pH

The pH of formulations must be evaluated by using pH meter and they should preferably be

near to salivary pH to avoid irritation and enhance patient compatibility and tolerance.

4. Viscosity and rheological properties

These parameters may be assessed by using Brookfield viscometer and Cone and Plate

viscometer. Viscosity of these formulations should be such that no difficulties are arise

during their administration to the patient. It should be 5-1000 m Pas, before gelling and after

formation of gel viscosity should have about 50-50,000 m Pas.[29]

5. Sol-gel transition temperature and gelling time

For in-situ gel forming systems incorporating thermoreversible polymers, the sol-gel

transition temperature may be defined as that temperature at which the phase transition of sol

meniscus is first noted when kept in a sample tube at a specific temperature and then heated

at a specified rate. Gel formation is indicated by a lack of movement of meniscus on tilting

the tube. Gelling time is the time for first detection of gelation as defined above.[22]

6. Texture analysis

The gel strength, firmness, consistency and adhesiveness of in situ gel is measured by texture

profile analyzer, which mainly indicates the syringeability of sol so the formulation can be

easily administered in-vivo. Higher values of adhesiveness of gels are required to maintain an

intimate contact with surfaces like tissues.

7. Drug polymer interaction studies

Interaction between drug and polymer must be observed to check the compatibility between

various ingredients of the formulation by suitable method such as Fourier Transform

InfraRed (FTIR) spectroscopy analysis of their physical mixture or Differential Scanning

Calorimetry (DSC) method.

8. In-vitro drug release studies

In-vitro release study of in situ gelling system can be carried out using Franz diffusion cell to

check the duration of drug release from the formulation.[14,15]

9. Drug content

It is an important parameter to be measured as the formulation should contain the accurate

amount of the drug as directed by the physician.


364


10. Accelerated stability studies

These studies are used to check the shelf-life the formulation and performed as per

International Conference on Harmonization (ICH) Guidelines.

Recent advancements in in-situ gelling systems[27,28,29]

Various novel drug delivery systems are used for sustained drug delivery by in-situ gelling

system such as in-situ gel implants, mucoadhesive polymers, polymer coated nanoparticles

and liposomal formulations are used.

1. Liposome incorporated in-situ gel

Active ingredients encapsulated in lipid vesicles like liposome allow not only improved

solubility but also transport of drug through dental cone and provide controlled delivery of

drug. The bioadhesive polymer such as poly (vinyl alcohol) and polymethacrylic acid

derivatives were used for gel preparation and lecithin and α-L-dipalmithoyl-phosphatidyl

choline provided the encapsulating agent for drug into liposome. Encapsulation of the drug

into liposomes prolonged the in-vitro release of the antibacterial agent from liposomal

vesicles and by use of liposomal formulation, higher drug concentration can be achieved at

the site of action along with prolonged contact time, thus bioavailability can be improved.

2. Micelles incorporated in-situ gel

Micelles incorporated in reverse thermal gel (RTG) as an injectable drug delivery system for

sustained release of drug for upto one year. The RTG chemistry exhibits a novel [poly

(nisopropylacrylamide), PNIPAAm] polymer coupled to a [poly (serinol hexamethylene

urea), PSHU] backbone, for complete physiological clearance of system during degradation.

PEGylated polyurethane triblock copolymer based micelle system was fabricated through a

filter extrusion method with favorable drug encapsulation capacity. Then micelles were

incorporated in RTG.

3. Nanoparticles incorporated in-situ gel

Nanoparticles have been employed to address issues related to topical formulations. They

provide prolonged release of active ingredient by particle degradation or erosion, drug

diffusion or a combination of both, depending on the biodegradable or inert nature of the

polymer.


365


4. Nanoemulsified in-situ gels

Nanoemulsions (NE) have been widely used as controlled drug delivery systems due to its

intrinsic advantages such as sustained release of drug, higher penetration into the deeper

layers of the tissue. They showed better biological performance, faster onset of action, and

prolonged effect as compared to drug solution.

5. In-situ gel implants

These are novel biodegradable, injectable polymeric liquid formulations that form semi-solid

or solid depots after injection at the site of injection due to phase separation and provide a

sustained release over weeks to few months duration. It consists of blend of drug and

biodegradable polymers dissolved or suspended in pharmaceutically acceptable water-

miscible organic solvents. After administration at the injection site, depot (gel) is formed

when water penetrates in; organic solvent dissipates into the surrounding tissue and leads to

phase separation and precipitation of the polymer. The drug entrapped in the gel is released

into the surrounding body fluid by degradation of the polymers and reaches the systemic

circulation, which ensures patient compliance. Three triggers are used to stimulate this sol to

gel transformation: (1) in-situ cross-linking, (2) in-situ solidifying organogels, and (3) in-situ

phase separation.

ATRIGEL Technology

Two new products, ATRIDOX periodontal treatment and ATRISORB guided tissue

regeneration (GTR) barrier designed based on the unique ATRIGEL technology used for

treatment of periodontal diseases. It consists of a solution of a resorbable polymer in a

biocompatible carrier and upon administration; the polymer undergoes a phase transition

from a liquid to gel formed implant. Being in liquid form, it initially provides the advantage

of in vivo placement by simple means, such as syringes to form implants at the site of use.

The system is biocompatible and has the capability of serving as a biomaterial and a drug

delivery system. Drug Release periods ranging from one week to four months have been

achieved with one month being the most often desired. For these reasons the ATRIGELÒ

system is being applied to a number of medical applications ranging from site and systemic

oncology to post-operative pain control and bone regeneration using growth factors.[30]


366


Fig. 6: Atrigel technology based product design.

Marketed products based on Atrigel technology[30]

Marketed

Product Active ingredient Use

Atridox 8.5% Doxycycline Sub gingival delivery used for the treatment of

periodontitis

Atrisorb ------------ GTR barrier product without any drug for guided

tissue regeneration of periodontal tissue

Atrisorb D 4%Doxycycline Periodontal tissue regeneration

CONCLUSION

The present review concludes that „in-situ gel‟ drug delivery system has emerged as one of

the best novel drug delivery systems for the treatment of periodontitis, by providing sustained

and controlled release of the drugs, improved patient compliance and comfort. Use of

biodegradable and water soluble polymers for the in situ gel formulations can make them

more acceptable and excellent drug delivery systems. There is high extent for research work

on in-situ gel system in order to provide advanced techniques in drug delivery systems.

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