Development of Controlled Release in Situ Gelfor the Treatment of Periodontal Diseases

DEVELOPMENT OF CONTROLLED RELEASE IN SITU GELFOR THE TREATMENT OF PERIODONTAL DISEASES

M.Pharm dissertation protocol submitted to

Rajiv Gandhi University of Health Sciences, Karnataka

Bangalore – 560041

Mr.MALAPAKA ANIL KARTHIK

Under the Guidance of

Mr. SATEESHA .S.B

Asst.Professor

Department of Industrial Pharmacy

Acharya & B.M.Reddy College of Pharmacy

Soldevanahalli,Chikkabanavara (Post)

Hesarghatta main road, Bangalore – 560 090

2010– 2011

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

KARNATAKA, BANGALORE.

ANNNEXURE II

PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION

1 / Name and address of candidate / Mr. MALAPAKA ANIL KARTHIK
D.no: 29-7-10,
Lakshmivarapeta,
Near surya palace theatre,
Rajahmundry -533104
East Godavari Dt.,
ANDHRA PRADESH.
2 / Name of institution / ACHARYA & B.M. REDDY COLLEGE OF
PHARMACY.
Soldevanahalli, Hesarghatta Main Road,
Chikkabanavara Post.
Bangalore-560090
3 / Course of study and subject / M. Pharm
(Industrial Pharmacy)
4 / Date of admission /

25-05-2010

5 / Title of the project / “DEVELOPMENT OF CONTROLLED RELEASE IN SITU GELFOR THE TREATMENT OF PERIODONTAL DISEASES”
6
6.1 / BRIEF RESUME OF INTENDED WORK
NEED FOR THE STUDY:
Periodontitis is an inflammatory condition that leads to destruction of periodontum, resorption of the alveolar bone and frequently tooth loss. It is one of the most prevalent oral diseases in humans and generally affects humans above 35 years of age.
Periodontal diseases include chronic periodontitis, aggressive periodontitis and systemic disease periodontitis. The clinical sign of periodontitis are changes in morphology of gingival tissue, bleeding upon probing as well as periodontal pocket formation. The etiology of periodontal diseases is gm (-) ve bacteria, mainly anaerobes like Porphyromonas gingivalis, Tanerella forsynthesis, Trepenoma denticola, etc.
Periodontal disease is considered to be one of the possible risk factor in other systemic diseases such as Cardiovascular disease including coronary heart disease, stroke and preterm low birth weight infants.
Currently, most commonly used procedure for the treatment of severe periodontitis is the use of mechanical disruption of the bacterial flora by a procedure called scaling and root planning. However studies have shown that this mechanical disrupment is insufficient in altering the makeup of the flora. As periodontal disease is associated with bacteria, an adjunctive anti microbial therapy appears to be appropriate.
But systemic route of antibiotic may not be ideal because of the concern over the development of bacterial resistance that may be induced over a prolonged period of time, and also the rise in number of undesirable side effects such as nausea, vomiting, diarrhoea, abdominal pain, pseudomembranous enterocollitis etc.
Hence local delivery of antimicrobial therapy to periodontal pockets has the benefit of putting more drugs at target site while minimizing exposure of the total body to the drug .This local delivery helps in maintaining effective levels of drug in gingival cervicular fluid (GCF) to produce desirable clinical effects. Localized therapy is given in the form of solid devices like chips, strips, microspheres, wafers, injectable gels , gels etc
With respect to solid devices, the injectable gels posses a higher biocompatibility and bioadhesivity by allowing adhesion to mucosa in dental pocket. Finally, they can be eliminated through normal catabolic pathways, decreasing risk of irritation or allergic host reaction at the application site.
Controlled release delivery of drugs in the periodontal pocket has received greater interest and appears to hold some promise in periodontal therapy. Controlled release can be attained through localized application of antimicrobial agent in the periodontal pocket. They are designed to release drug slowly with more prolonged drug availability and sustained drug action.
Controlled release systems offer an advantage of decrease in frequency of administration,
thereby improving patient compliance. The dose of the drug can also be decreased and hence, the toxicity when compared to conventional therapy. In controlled drug delivery, the anti microbial agent is released over an extended period of time by zero order kinetics and hence constant plasma drug concentration can be achieved.
6.2 / REVIEW OF LITERATURE:-
1) R.A Seymour and P.A. Heasman reviewed the importance of antimicrobials in the control of periodontal diseases. Antimicrobial agents are of value in the management of periodontal diseases, notably early onset, juvenile and refractory periodontitis. Routine systemic use of these drugs in chronic periodontitis is contraindicated. Tetracyclines and metronidazole are the agents most frequently used in the management of periodontal diseases. Both drugs can be given systemically or topically in the periodontal pocket. The tetracyclines have the additional advantage of inhibiting collagenases. The combination of metronidazole 250 mg and amoxicillin 375 mg has shown to be effective in the treatment of refractory periodontitis. Clindamycin is also effective in the treatment of refractory periodontitis. Doxycycline has been used as an adjunct to periodontal surgery in the management of juvenile periodontitis1.
2) M. Madan et al., reviewed the importance of in situ forming polymeric drug delivery systems. In situ forming polymeric formulations are drug delivery formulations that are in sol form before administration in the body, but once administered, undergo gelation in situ to form a gel. The formulation of gels depends on factors like temperature modulation, pH change, presence of ions and ultra violet irradiation, from which the drug gets released in a sustained and controlled manner. Various polymers that are used for the formulation of in situ gels include gellan gum, alginic acid, xyloglucan, pectin, chitosan and poly-caprolactone. Mainly in situ gels are administered by oral, ocular, rectal vaginal, injectable and intraperitoneal routes. The in situ gels forming polymeric formulations offer several advantages like sustained and prolonged action in comparison to conventional drug delivery systems2.
3) David S. Jones et al., designed novel mucoadhesive formulations of metronidazole (5%w/w) using hydroxyl ethyl cellulose (HEC) and carbopol as single and in combination with polycarbophil in different concentrations. Each formulation was characterized in terms of hardness, compressibility, adhesiveness, drug release and syringeability. It was found that formulations described offered a wide range of mechanical and drug release characteristics. Formulations containing HEC exhibited superior physical characteristics for improved drug delivery to the periodontal pocket and were subjected to further clinical investigations3.
4) C. Nastruzzi et al., formulated two different semisolid preparations using poloxomer and
monoglyceride containing tetracycline. Formulations were subjected to various evaluation parameters
like sol-gel transition time, temperature tests and rheological studies and drug release analysis etc. The
studies indicated that both the gels posses ideal properties as intrapocket delivery systemsi.e. they are
administrable by a syringe and when applied in the periodontal pocket becomessemisolid ,allowing
drug to be released in a controlled manner, thereby producing a significant outcome in moderate to
deep periodontal pockets4.
5) S. Senel et al., studied the effect of chitosan on the periodontitis causing pathogen Porphyromonas gingivalis (P.gingivalis) both in gel form and in film form, in the presence or in absence of chlorhexidine gluconate were prepared. The formulations were evaluated for viscosity, bioadhesive properties and degree of deacetylation. It was found that gels have a suitable flow property for the topical application on the oral mucosa and to syringe in the periodontal pocket. Both gels and chips have shown good bioadhesive properties. Chitosan exhibited antimicrobial properties against P.gingivalis, but, the combination of chlorhexidine and chitosan showed a higher activity than chitosan alone5.
6) H. Gupta et al., formulated a pH mediated in situ gelling system using prilocaine hydrochloride for periodontal anesthesia using combination of chitosan and HPMC. The gel was evaluated for many parameters like gelation, pH, viscosity, in vitro release, stability etc. It was observed that gel with chitosan and HPMC combination was found to have good gelation near pH 7.4 and showed 96.27% drug release after 24h6.
7) T. Govender et al., formulated tetracycline microspheres and employed Box-Bhenken design to optimize the formulation parameters for maximum bioadhesivity and controlled drug release. Formulation comprising of 3% (w/w) chitosan, 10% w/w tetracycline HCL and 9% (w/v) tripolyphosphate was identified for maximizing bioadhesivity and obtaining controlled drug release. The optimized microspheres were characterized for surface pH, hydration dynamics, release kinetics, antimicrobial activity and thermal properties. It was observed that the drug followed Fickiandiffusion. Thermal analyses showed a possible interaction between drug and the polymer. Scanning electron microscopy confirmed the integrity of the microspheres. Bioadhesion studies, drug release and physic chemical characterisation data obtained in this study confirmed the potential of this system7.
8) Alekha K. Dash and Sudipta Ganguly formulated a novel chitosan-glyceryl monooleate (GMO) in situ gel system for sustained and targeted drug delivery. The delivery system consists of 3% (w/v) chitosan and 3% (w/v) GMO in 0.33M citric acid. In situ gel was formed at biological pH. Characterisation of the gel included the effect of cross linker, determination of diffusion coefficient and water uptake study by thermogravimetric analysis. It was observed that cross-linker retarded the rate and extent of drug release. Inclusion of GMO enhanced the mucoadhesive property of chitosan by three to sevenfold. The in vitro release is further sustained by replacing the free drug with drug encapsulated microspheres. This novel in situ gel system can be useful for sustained delivery of drugs via oral as well as parenteral routes8.
9)U.S patent No 4,780,320 described the invention of a controlled release drug delivery system for placement in the periodontal pocket. The system described, consists of drug containing micro particles or microcapsules, between 10 to 500 microns in size, suspended in apharmaceutically accepted medium and is capable of maintaining an effective level of the drug in the periodontal pocket for a period of 10 to 30 days9.
10)U.S patent no 2006/0118583 described an invention of a system for the long term controlled release of a drug or therapeutic agent. According to the invention, one or more drug or therapeutic agents contained in microspheres are mixed with a temperature sensitive hydrogel which is then introduced into the body at the desired site. The temperature sensitive hydrogel is liquid at the room temperature and become gelatinous. It was explained that the system is suitable for treatment of localized diseases or disorder10.
11) Weisan Pan et al., formulated gatifloxacin based ion active in situ gel for ophthalmic delivery system using alginate as gelling agent and HPMC as the viscosity inducing agent. Formulations were evaluated for rheological properties and in vitro drug release. It was found that
alginate/HPMC solution retained drug better than HPMC or alginate solutions. This demonstrated that alginate and HPMC can be used as in situ gelling vehicles11.
12) Renata Fonseca Vianna Lopez et al., formulated an in situ gel comprising combination of thermosetting polymer, poloxomer and a mucoadhesive agent, chitosan combinations are prepared for ophthalmic use. Different polymer ratios are evaluated for rheology, texture, mucoadhesive profiles. It was observed that chitosan improves mechanical strength and texture properties of poloxomer and confers mucoadhesive properties in a concentration dependent manner. The developed formulations represented adequate mechanical and sensorial properties. The combination of poloxomer and chitosan found to be a good in situ gelling agents12.
13) B.Mishra etal., formulated gellan gum based amoxicillin floating in situ gelling (AFIG) systems by varying the concentrations of gellan gum in deionised water containing sodium citrate. Calcium carbonate was added as gas forming agent. The formulation variables like gellan and calcium carbonate affected the drug release rate. AFIG showed a significant invivo effect in gerbil model. It was concluded that AFIG has feasibility of gelling in the gastric environment and eradicated H. pylori more effectively than the amoxicillin suspension because of the prolonged residence time13.
14) Xin-guo Jiang et al., developed an ion activated in situ gel using gellan gum and xanthum gum as carrier for nasal administration of mometasone furoate in the treatment of allergic rhinitis. The system was stable when kept at 40±2⁰C for 6 months and micrographic results showed that thein situ gel can be given safely without any mucosal irritation. Mometasone furoate in gellan gum showed superior efficacy than the nasal suspension14.
15) Wei-yu Liu et al., studied the effects of carragenan on sustained release properties of poloxomer-407 based in situ gel using acyclovir as the model drug. Formulations were subjected for in vitro release and in vivo release studies in mice. It appeared that carragenan and poloxomer could form composite gel systems with good thermosensitivity when compared to that of poloxomer-407 alone. Carragenan was able to sustain the release of the drug by retarding the dissolution and erosion of the poloxomer-407 in a concentration dependent manner. This indicated that combination of carragenan and poloxomer-407 can be used in the development of vaginal in situ gel15.
16) Maria I. la Rotonda et al., studied the influence of hyaluronic acid (HA) on the gelation properties of poloxamer. The gelation temperature (Tgel), viscoelastic properties and mucoadhesive forces of the system were investigated and optimized with rheological analysis. It was observed that by formulating HA/poloxomer at specific concentrations it was possible to get Tgel close to body temperature. The presence of HA improved rheological properties of poloxamer. Mucoadhesion experiments showed a rheological synergism between poloxamer/HA formulations. In vitro release experiments showed that optimized formula was able to bring prolonged and controlled drug release16.
6.3 / OBJECTIVE OF THE STUDY:
The objectives of the present study are following:-
Selection of drug and other excipients.
Characterisation of drug and excipients for intended formulations.
Compatibility studies for selected drugs and polymers by FTIR, XRPDetc.
Development of controlled release in situ gel formulation.
Characterisation of controlled releasein situ gel for various parameters.
Statistical assessment of all the results andanalysis of the drug release data by pharmacokinetic models such as Higuchi, Peppas, 1st order and zero order kinetics, etc.
To carry out stability studies on the optimized formulation as per ICH guidelines.
7.0
7.1
7.2 / MATERIALS AND METHODS:
SOURCE OF DATA
1)Review of literature from:
a. Journals – such as

Indian Journal of Pharmaceutical Sciences

European Journal of Pharmaceutical Sciences
International Journal of Pharmaceutics
European journal of pharmaceutics and biopharmaceutics.
Journal of controlled release.etc b .Reference books- such as

Essentials of medical pharmacology, 6th edition- K D Thripathi
Novel drug delivery systems, volume 50- Yie W. Chien etc

World Wide Web
J-Gate@Helinet, etc

MATERIALS
DRUG: Anti microbial agent.
POLYMERS: Biodegradable/non biodegradable polymers.
EXCIPIENTS: excipients as required.etc
METHOD OF COLLECTION OF DATA:
Formulation of in situ gel and its evaluation for the following parameters such aspH using pH meter, characterisation of rheological parameters using Brookfield viscometer, drug content estimation using UV- Visible spectrophotometer, In vitro diffusion studies using Franz diffusion cell and any other study as required.
Formulation of microspheres using suitable methodology and their evaluation for the following parameters such as; micromeritic properties, entrapment efficacy, drug content estimation,drug release studies and any other study as required.
Formulation and characterisation of microsphere incorporated in situ gels
Analysis of in vitrodrug release data by pharmacokinetic models such as Higuchi, Peppas, 1st order, zero order etc
 Stability studies on the optimized formulation as per ICH guidelines.
7.3

7.4 / DOES THE STUDY REQUIRE ANY INVESTIGATION TO BE CONDUCTED ON PATIENT OR OTHER HUMANS OR ANIMALS?
“ NO”
Has ethical clearance been obtained from your institution in case of 7.3?
“ not APPLIcable”
8 / LIST OF REFERENCES:-
1) Seymour RA, Heasman PA. Pharmacological control of periodontal diseases.II. Anti microbial agents. J Dent. 1995;23(1):5-14.
2) Madan M, Bajaj A, Lewis S, Udupa N, Baig JA. In situ forming polymeric drug delivery systems. Indian J Pharm sci. 2009;71(3):242-51.
3) David SJ, Woolfson AD, Andrew FB. Mucoadhesive, syringeable drug delivery systems for controlled application of metronidazole to the periodontal pocket: In vitro release kinetics, syringeability, mechanical and mucoadhesive properties. J control Rel. 1997;49:71-9.
4) Esposito E, Carotta V, Scabbia A, Trombelli L, Antona PD, Nastruzzi C. Comparative analysis of tetracycline-containing dental gels:poloxamer and monoglyceride based formulations. Int J Pharm. 1996;142:9-23.
5) Ikinci G, Senel S, Akincibay H, kas S, Erics S, Hincal AA. Effect of chitosan on periodontal pathogen Porphyromonas gingivalis. Int J Pharm. 2002;235:121-7.
6) Gupta H, Singh RM, Singh GN, kaushik D, Sharma A. pH-induced in situ gel for periodontal anesthesia. Indian J Pharm Sci. 2008;70(6):776-8.
7) Govender S, Pillay V, Chetty DJ, Essack SK, Dangor CM, Govender T. Optimisation and characterisation of bioadhesive controlled release tetracycline microspheres. Int J Pharm. 2005;306:24-40.
8) Ganguly S, Dash AK. A novel in situ gel for sustained drug delivery and targeting. Int J Pharm. 2004;276:83-92.
9) US patent: 4780320: Baker RW.Controlled release drug delivery system for the periodontal pocket. Oct 25.1988.
10) US patent:2006/0188583:Lim TH, Park.JB, Lee W.Insitu controlled release drug delivery system. Aug 24.2005
11) Liu Z, Li J,Nie S, Pan W. Study of alginate/HPMC-based insitu gelling ophthalmic delivery system for gatifloxacin. Int J Pharm.2006;315:12-7
12) Grateri T,Gelfuso GM,Sermento V,Lopez RFV. A poloxamer/chitosan in situ forming gel with prolonged retention time for ocular delivery. Eur J Pharm Biopharm. 2010;75:186-93.
13) Rajinikanth PS, Balasubramaniam J, Mishra B.Development and evaluation of a novel floating in situ gelling system of amoxicillin for eradication of Helicobacter pylori. Int J Pharm 2007;335:114-22.
14) Cao S, Ren X, Zhang Q,Chen E, Xu F, Jiang X et al. In situ gel based on gellan gum for nasal administration of mometasone furoate. Int J Pharm. 2009;365:109-15.
15) Liu Y, Zhu Y,Wei G, Liu W.Effect of carragenan on poloxamer based in situ gel for vaginal use:improved invitro invivo sustained release. Eur J Pharm. 2009;37:306-12.
16) Mayol L, Quaglia F, Ambrosio L, Rotonda M.A novel poloxamers/hyaluronic acid insituforming hydrogel for drug delivery:Rheological mucoadhesive and invitro release properties. Eur J PharmBiopharm. 2008;70:199-06.
9 / Signature of the candidate:
10 / Remarks of the Guide:
11 / Name and Designation of:

11.1 Institutional Guide: / Mr.Sateesha S.B
Asst.Professor
11.2 Signature:
11.3 Co-Guide:
11.4 Signature:
11.5 Head of the Department: /

Mr. Anup Kumar Roy

Asst. Professor & HOD
Dept. of Industrial Pharmacy
11.6 Signature
12 / 12.1 Remarks of the Principal
12.2 Signature /

Dr. Goli Divakar

Principal

ACHARYA & B.M.REDDY COLLEGE OF PHARMACY,
SOLDEVANAHALLI,
HESARAGHATTA MAIN ROAD,
BANGALORE-90.