The Use of Topical Subgingival Application of Simvastatin Gel in the Treatment of Peri-Implant Mucositis: A Pilot Study
Phase: PHASE2
Conditions: Peri-implant Mucositis
Sponsor: Ahmed Mohamed Mahrous

 
Study Protocol 
Simvastatin 1.2% Topical Dental Gel 
August 30, 2014 
 
 
Study Title: The use of topical subgingival application of simvastatin gel in the treatment of 
peri- implant mucositis: a pilot study 
 
Principal Investigator: 
Ahmed Mohamed Mahrous, DDS 
 
S257 Dental Science Building 
 
Iowa City, Iowa 52242 
 
e-mail: ahmedmohamed-mahrous@uiowa.edu 
 
Phone: (319) 333-6517 
 
 
 
Table of Contents 
 
I. 
Introduction 
 
II. Physical, Chemical and Pharmaceutical Properties and Formulation 
 
III. Nonclinical Studies 
 
IV. Effects in Humans 
 
a. Nonclinical Pharmacology 
b. Pharmacokinetics and Product Metabolism in Humans 
c. Safety and Efficacy 
 
V. Summary of Data 
 
 

2 
Simvastatin 1.2% Topical Dental Gel 
 
I. Introduction 
 
 
Peri-implant mucositis is the precursor to peri-implant diseases 1 , which are responsible 
for many of the failures that affect dental implants2. Bacteria are regarded as the main 
cause of peri-implant diseases, however the host mediated inflammatory response is 
what causes the associated tissue destruction via inflammation.3-7 
 
Simvastatin (SMV), is a specific competitive inhibitor of 3- hydroxyl- 2- methyl-glutaryl 
coenzyme A ( HMG-CoA) reductase.8 Research has shown that simvastatin use also 
reduces periodontal inflammation 9 and it has been shown that simvastatin reduces 
interleukin IL-6 and IL-8 ,10  both of which have been associated with diseased implants.11-
12  The use of simvastatin as a subgingivally delivered gel in human subjects has shown 
reduction of modified bleeding index (mSBI) probing depth (PD), mean clinical attachment 
loss (CAL) as well as a decreased intrabony defect in patients with periodontitis.13 Animal 
studies on the use of topically applied statins resulted in greater bone densities around 
implants 14-15  
 
References 
1. Schwarz F, Becker J. Peri-Implant Infection : Etiology, Diagnosis and Treatment 
Quintessence publishing; 2010. 
2. Berglundh T, Persson L, Klinge B. A systematic review of the incidence of biological and 
technical complications in implant dentistry reported in prospective longitudinal studies of 
at least 5 years. Journal of clinical periodontology. 2002;29:197-212. 
3. Medzhitov R. Recognition of microorganisms and activation of the immune response. 
Nature. 2007;449(7164):819-26. 
4. Offenbacher S, Heasman PA, Collins JG. Modulation of host PGE2 secretion as a 
determinant of periodontal disease expression. Journal of periodontology. 1993;64(5 
Suppl):432-44. 
5. Giannobile WV. Host-response therapeutics for periodontal diseases. Journal of 
periodontology. 2008;79(8 Suppl):1592-600. 
6. Graves D. Cytokines that promote periodontal tissue destruction. Journal of 
periodontology. 2008;79(8 Suppl):1585-91. 
7. Kornman KS. Mapping the pathogenesis of periodontitis: a new look. Journal of 
periodontology. 2008;79(8 Suppl):1560-8. 
8. Todd PA, Goa KL. Simvastatin. A review of its pharmacological properties and 
therapeutic potential in hypercholesterolaemia. Drugs. 1990;40(4):583-607. 
9. Lindy O, Suomalainen K, Makela M, Lindy S. Statin use is associated with fewer 
periodontal lesions: A retrospective study. BMC oral health. 2008;8:16. 
10. Sakoda K, Yamamoto M, Negishi Y, Liao JK, Node K, Izumi Y. Simvastatin decreases IL-6 
and IL-8 production in epithelial cells. Journal of dental research. 2006;85(6):520-3. 

3 
Simvastatin 1.2% Topical Dental Gel 
11. Liskmann S, Vihalemm T, Salum O, Zilmer K, Fischer K, Zilmer M. Correlations between 
clinical parameters and interleukin-6 and interleukin-10 levels in saliva from totally 
edentulous patients with peri-implant disease. The International journal of oral & 
maxillofacial implants. 2006;21(4):543-50. 
12. Mengel R, Stelzel M, Hasse C, Flores-de-Jacoby L. Osseointegrated implants in patients 
treated for generalized severe adult periodontitis. An interim report. Journal of 
periodontology. 1996;67(8):782-7. 
13. Pradeep AR, Thorat MS. Clinical effect of subgingivally delivered simvastatin in the 
treatment of patients with chronic periodontitis: a randomized clinical trial. Journal of 
periodontology. 2010;81(2):214-22. 
14. Moriyama Y, Ayukawa Y, Ogino Y, Atsuta I, Koyano K. Topical application of statin affects 
bone healing around implants. Clinical oral implants research. 2008;19(6):600-5. 
15. Moriyama Y, Ayukawa Y, Ogino Y, Atsuta I, Todo M, Takao Y, et al. Local application of 
fluvastatin improves peri-implant bone quantity and mechanical properties: a rodent study. 
Acta biomaterialia. 2010;6(4):1610-8. 
 
 
 
II. Physical, Chemical and Pharmaceutical Properties and Formulation 
 
Simvastatin is a synthetic derivative of a fermentation product of Aspergillus terreus and 
is a methylated form of lovastatin.  Like lovastatin, simvastatin is a prodrug which requires 
hydrolysis for activation as an HMG CoA reductase inhibitor.1,2,3 Our gel will be used 
topically for local anti-inflammatory effect. 
 
Lecithin/isopropyl palmitate solution (Lipoil®) , Poloxamer 407 gel (Polox Gel 20%®) will be the gelling agent 
used.  Cellulose derivatives are considered virtually unabsorbed by the human digestive tract 
and are non-allergenic.3 
 
The gel is a yellow, viscous gel. 
 
(Formulations of the study gel and placebo gel are on the following page) 
 
References 
1. Simvastatin. In: Lexi-Drugs. Hudson, OH : Lexi-Comp, Inc. [Updated October 15, 2014; 
Accessed August 
28,2014]. http://online.lexi.com.proxy.lib.uiowa.edu/lco/action/doc/retrieve/docid/patch_f
/7671?hl=Antilipemic Agent, HMG-CoA Reductase Inhibitor 
2. Simvastatin. In: American Hospital Formulary Service (AHFS) Drug Information. Hudson, OH : 
Lexi-Comp; Inc.; [Updated October 15, 2014; Accessed August 28,2014]. 
3. Select Committee on Gras Substances (SCGOS) Opinion: Methylcellulose. US Food and Drug 
Administration {Online Database] [Updated 04/18/2013, Accessed 09/02/2014] at 
http://www.fda.gov/food/ingredientspackaginglabeling/gras/scogs/ucm260473.htm 

4 
Simvastatin 1.2% Topical Dental Gel 
 
 
 

5 
Simvastatin 1.2% Topical Dental Gel 
 
MASTER FORMULA SHEET 
Dental Pharmacy Compounding Procedure Form 
 
FORMULA NUMBER:                                                                         Date compounded:____________ 
FORMULA NAME: Simvastatin 1.2% W/V Dental Gel 
LOT NUMBER:  _________________ 
 
 
Ingredient 
 
Source 
Lot  
Number 
Lot 
Exp. 
 
Quantity 
 
Simvastatin Powder, U.S.P.  
 
 
 
 
 
0.024 g 
Ethyl Alcohol 200 proof, 
U.S.P 
NDC: 51552-0897-05 
 
 
Fagron 
 
 
 
 
0.06 ml 
Methylcellulose 4000 CPS 
powder, U.S.P.  
 
Fagron 
 
 
0.2 g 
Methylcellulose Gel 3% 
NDC: 51552-0827-05 
 
Fagron 
 
 
QS 20.0 
ml 
Total Qty: 
20 ml 
 
Method of Preparation: 
1. 
Weigh 0.2 g methylcellulose 4000 CPS powder 
2. 
Measure 18 ml methylcellulose 3% gel 
3. 
Combine powder and gel in 100 ml beaker and heat to 70 - 90 °C with stirring until 
 
powder dissolves.  Remove from heat and allow to cool to room temperature. Transfer 
 
to 30 ml sterile Luer Lok syringe. 
4. 
Weigh 0.024 grams simvastatin powder on analytical balance, place in capped sterile  
 
30 ml Luer Lok syringe. 
5. 
Draw up 0.06 ml of ethyl alcohol in 0.3 ml volume syringe.  Add alcohol to simvastatin  
 
powder.  Immediately cap syringe.  
6. 
Swirl contents of syringe until powder dissolves. 
7. 
Draw up 5 ml of prepared methylcellulose gel into 30 ml sterile Luer Lok syringe and  
 
cap.  
8. 
Connect syringes with Luer Lok connector and transfer between syringes to mix well 
9. 
Add additional prepared methylcellulose gel QS to 20 ml and mix well (syringe to  
 
syringe) 
10. 
Transfer prepared gel into one of the 30 ml syringes, add plunger and remove all air. 
11. 
Cap syringe with sterile Luer Lok cap. 
12. 
Label: Product, date, lot.  Refrigerate. Use within 48 hours. 
 
 
 
Prepared by: ____________________ 
  
Checked by: ___________________ 

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Simvastatin 1.2% Topical Dental Gel 
MASTER FORMULA SHEET 
Dental Pharmacy Compounding Procedure Form 
 
FORMULA NUMBER:                                                                         Date compounded:____________ 
FORMULA NAME:  Placebo  Gel:  4% Methylcellulose W/V Dental Gel 
LOT NUMBER:  _________________ 
 
 
Ingredient 
 
Source 
Lot  
Number 
Lot 
Exp. 
 
Quantity 
Methylcellulose 4000 CPS 
powder, U.S.P.  
 
Fagron 
 
 
 
0.2g 
Ethyl Alcohol 200 proof, 
U.S.P 
NDC: 51552-0897-05 
 
 
Fagron 
 
 
 
 
0.06 ml 
Methylcellulose Gel 3% 
NDC: 51552-0827-05 
 
Fagron 
 
 
 
QS 20.0 ml 
Total Qty: 
20 ml 
 
 
Method of Preparation: 
1. 
Weigh 0.2 g methylcellulose 4000 CPS powder. 
2. 
Measure 18 ml methylcellulose 3% gel. 
3. 
Combine powder and gel in 100 ml beaker and heat to 70- 90 °C with stirring until 
 
powder dissolves.  Remove from heat and allow to cool to room temperature. Transfer 
 
to 30 ml sterile Luer Lok syringe. 
4. 
Draw up 0.06 ml of ethyl alcohol in 0.3 ml volume syringe. Transfer to 30 ml sterile Luer  
 
Lok syringe. Immediately cap syringe.  
7. 
Draw up 5 ml of prepared methylcellulose gel into 30 ml sterile Luer Lok syringe and cap  
8. 
Connect syringes with Luer Lok connector and transfer between syringes to mix well. 
9. 
Add additional prepared methylcellulose gel QS to 20 ml and mix well (syringe to  
 
syringe). 
10. 
Transfer prepared gel into one of the 30 ml syringes, add plunger and remove all air. 
11. 
Cap syringe with sterile Luer Lok cap. 
12. 
Label: Product, date, lot.  
13. 
Place in light resistant ziplock bag. Label. Refrigerate. Use within 48 hours. 
 
 
 
Prepared by: ____________________ 
  
Checked by: ___________________ 
 
 

7 
Simvastatin 1.2% Topical Dental Gel 
 
III. Nonclinical Studies 
 
Sakoda et al. studied the anti-inflammatory effect of simvastatin in oral tissues, 
specifically the effect of simvastatin on a human epithelial cell line KB which has been 
extensively used as a model for the study of gingivalepithelial cells stimulated by IL-1. 
Simvastatin was found to reduce IL-1_-induced production of inflammatory cytokines IL-
6 and IL-8 by human oral epithelial cells 1  
 
References 
1- Sakoda K, Yamamoto M, Negishi Y, Liao JK, Node K, Izumi Y. Simvastatin decreases IL-6 and 
IL-8 production in epithelial cells. Journal of Dental Research. 2006;85(6):520-3. 
 
 
 
IV. Effects in Humans 
 
 
a. Pharmacokinetics and Product Metabolism in Humans 
 
Simvastatin is FDA approved in therapeutic doses of 5-80 mg/day per os as a 
hypolipidemic agent. Simvastatin is a methylated derivative of lovastatin, both of 
which are prodrugs that must be activated in the liver. After oral ingestion, 
simvastatin, which is an inactive lactone, is hydrolyzed to the corresponding beta-
hydroxyacid form.1 This is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A 
(HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to 
mevalonate, which is an early and rate-limiting step in the biosynthesis of 
cholesterol.1 
 
Orally administered simvastatin is metabolized in the liver via CYP3A4 with an 
extensive first-pass effect. Bioavailibility is <5%. Simvastatin and its active 
metabolite are 95% bound to plasma proteins. Approximately 60% of an orally 
absorbed dose is excreted in the feces and 13% in the urine.  The half-life is 1.9 
hours.2,3 
 
Simvastatin is a substrate of CYP3A4 and CYP2D6 hepatic metabolism. Other drugs 
that inhibit CYP3A4 can result in increased HMG-CoA reductase inhibition and 
toxicity.  This is a dose-related phenomenon which usually occurs with repeated 
dosing of both interacting drugs and in the higher dosage range (maximum of 80 
mg/day) of simvastatin. Simvastatin does not affect the metabolism of other 
CYP3A4 substrates.2,3 Simvastatin is also a substrate and inhibitor of the P-gp 
transport system.2,3 

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Simvastatin 1.2% Topical Dental Gel 
 
Strong inhibitors of CYP3A4 can cause at least a 5-fold increase in plasma AUC 
values or more than an 80% decrease in clearance. These include protease 
inhibitors (ritonavir, indinavir, nelfinavir, saquinavir), some macrolide antibiotics 
(clarithromycin, 
telithromycin), 
some 
azole 
antifungals 
(ketoconazole, 
itraconazole), an antidepressant (nefazodone).4 
 
Moderate inhibitors of CYP3A4 may cause at least a 2 fold increase in the plasma 
AUC values or a 20-50% decrease in clearance. Moderate inhibitors include some 
calcium channel blockers (verapamil, diltiazem), a macrolide antibiotic 
(erythromycin), an azole antifungal (fluconazole), an antiemetic (aprepitant), 
valerian and bergamottin (found in grapefruit juice).4 
 
 
b. Safety and Efficacy 
Simvastatin was first approved by the FDA in July 1998 and initially marketed under 
the trade name Zocor® by Merck and Company, Inc.1 The first generic versions were 
approved in December 2006. Simvastatin is listed as a core medication on the 
current World Health Organization’s List of Essential Medicines for the global 
patient population.6 
 
Allergic reactions to HMG-CoA reductase inhibitors are rare, estimated to be 0.1% 
and the incidence of cross-reactivity is unknown.2,3.7 Allergic reactions to this drug 
when taken orally can include face and mouth swelling or severe skin rash. Other 
adverse reactions of simvastatin when taken in the normal oral dosage range 
include eczema, headache, edema, myalgia, nausea, gastritis and vertigo. These are 
most likely dose-related reactions and not anticipated in this study.2.3 
 
It is anticipated that the topical application of 1.2 mg of simvastatin (0.15% of the 
maximum recommended daily dose) will not produce an allergic reaction. In case 
of an immediate allergic reaction, the subjects will be escorted to the University of 
Iowa Hospitals and Clinics emergency room, which is in close proximity to the 
College of Dentistry. In addition, all UI Dental Clinics are equipped with standard 
emergency supplies/devices should they become necessary, and ACLS trained 
practitioners will be on site. 
 
Simvastatin is considered a pregnancy category X drug and should not be used in 
women of childbearing age unless conception is highly unlikely.  It is unknown if 
simvastatin is excreted in breast milk and the drug’s use in women who are breast-
feeding is contraindicated by the manufacturer.1-3 
 

9 
Simvastatin 1.2% Topical Dental Gel 
This study will administer a single topical dose of 1.2 mg simvastatin (0.15% of the 
maximum recommended daily dose) to healthy adult subjects, so we do not 
anticipate any toxicity issues. Limited information is available on the acute toxicity 
of statins.8 If any reaction does occur, supportive and symptomatic treatment will 
be initiated and the patient will be closely observed and sent to the UIHC 
emergency room for evaluation and management. 
 
Simvastatin has toxic potential similar to other statins. Increases in serum 
aminotransferase concentrations (AST [SGOT], ALT [SGPT] more than 3 times upper 
limits of normal have been reported with statins. These increases are dose related 
and often transient, resolving in the majority of patients without a change in drug 
or dose. 2,3,8 
 
Myopathy occurs in less than 0.7% of patients receiving statins and the risk is dose 
related and also higher in patients with renal or hepatic disease, uncontrolled 
hypothyroidism and geriatric patients.2,3 
 
A study by Pradeep et al. used subgingival 1.2% simvastatin gel along with scaling 
and root planning on 60 patients with periodontitis (inflammation of both bone 
and gums around natural teeth). The study showed that on 1, 2, 4 and 6 month 
recalls, a statistically significant reduction in bleeding on probing, probing depths, 
clinical attachment loss, as well as increased bone regeneration.9 
 
References 
 
1. Zocor/simvastatin tablets drug approval package. Food and Drug Administration 
[Updated July 2005, Accessed August 30, 2014]. 
2. Simvastatin. In: Lexi-Drugs. Hudson, OH : Lexi-Comp, Inc. [Updated October 15, 2014; 
Accessed August 28,2014]. 
http://online.lexi.com.proxy.lib.uiowa.edu/lco/action/doc/retrieve/docid/patch_f/76
71?hl=Antilipemic Agent, HMG-CoA Reductase Inhibitor 
3. Simvastatin. In: American Hospital Formulary Service (AHFS) Drug Information. 
Hudson, OH : Lexi-Comp; Inc.;  [Updated October 15, 2014; Accessed August 
28,2014].At: 
http://online.lexi.com.proxy.lib.uiowa.edu/lco/action/doc/retrieve/docid/complete_
ashp/414032#ubnlist 
4. Drug development and drug interactions: Table of substrates, inhibitors and 
inducers. U.S. Food and Drug Administration, Silver Spring MD :[Updated September 
16, 2011, Accessed August 26, 2014]. At:  
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/D
rugInteractionsLabeling/ucm093664.htm#4 
5. Select Committee on Gras Substances (SCGOS) Opinion: Methylcellulose. US Food 
and Drug Administration {Online Database] [Updated 04/18/2013, Accessed 
09/02/2014] 
at http://www.fda.gov/food/ingredientspackaginglabeling/gras/scogs/ucm260473.ht
m 

10 
Simvastatin 1.2% Topical Dental Gel 
6. WHO model list of essential medicines, 18th ed. World Health Organization.  [Updated 
October 2013, Accessed August 30, 2014 ] 
http://www.who.int/medicines/publications/essentialmedicines/en/ 
7. Liebhaber MI, Wright RS, Gelberg HJ, et al, "Polymyalgia, Hypersensitivity Pneumonitis 
and Other Reactions in Patients Receiving HMG-CoA Reductase Inhibitors: A Report of 
Ten Cases," Chest, 1999, 115(3):886-9.[PubMed 10084510] 
8. Merck & Co., Inc. Zocor® (simvastatin) tablets prescribing information. Whitehouse 
Station, NJ; 2012 Jun. 
9. Pradeep AR, Thorat MS. Clinical effect of subgingivally delivered simvastatin in the 
treatment of patients with chronic periodontitis: a randomized clinical trial. Journal of 
Periodontology. 2010;81(2):214-22. 
 
 
V. Summary of Data  
Recent research has shown that simvastatin (SMV); a specific competitive inhibitor of 
3- hydroxyl- 2- methyl-glutaryl coenzyme A (HMG-CoA) reductase  FDA approved 
for lowering cholesterol, also reduces periodontal inflammation(1,2,3, 4) . Simvastatin 
is has rare allergic reactions ( 5,6), and other complications are mainly dose dependent 
(6) .  The use of Simvastatin results in  reduction of the clinical parameters of gingival 
inflammation, like modified Bleeding index (mSBI) probing depth (PD) and mean 
clinical attachment loss (CAL) in patients with periodontitis (7).  Moreover, 
Simvastatin reduces the crevicular  levels of interleukin IL-6 and IL-8 (8) both of 
which have been associated with  implants with peri implant disease (9, 10 ).  
The anti- inflammatory effect of simvastatin on implants with peri-implant mucositis 
has not yet been tested, thus the purpose of the present study is to assess the anti- 
inflammatory action of locally delivered simvastatin in subjects with implants affected 
by peri-implant mucositis (defined as BOP and/or purulence but not signs of 
mesial/distal bone loss greater than 1mm from the accepted reference point on the 
implant system).the gel used will be used at 0.15% of the maximal recommended dose 
thus any adverse effects are not expected.   
 
 
 
 
 
References 
 
 
 
1. Simvastatin. In: Lexi-Drugs. Hudson, OH : Lexi-Comp, Inc. [Updated October 15, 2014; 
Accessed August 28,2014]. 
http://online.lexi.com.proxy.lib.uiowa.edu/lco/action/doc/retrieve/docid/patch_f/76
71?hl=Antilipemic Agent, HMG-CoA Reductase Inhibitor 
2. Simvastatin. In: American Hospital Formulary Service (AHFS) Drug Information. 
Hudson, OH : Lexi-Comp; Inc.; [Updated October 15, 2014; Accessed August 
28,2014]. 

11 
Simvastatin 1.2% Topical Dental Gel 
3. Select Committee on Gras Substances (SCGOS) Opinion: Methylcellulose. US Food 
and Drug Administration {Online Database] [Updated 04/18/2013, Accessed 
09/02/2014] at 
http://www.fda.gov/food/ingredientspackaginglabeling/gras/scogs/ucm260473.htm 
4. . Lindy O, Suomalainen K, Makela M, Lindy S. Statin use is associated with fewer 
periodontal lesions: A retrospective study. BMC oral health. 2008;8:16. 
5. Simvastatin. In: Lexi-Drugs. Hudson, OH : Lexi-Comp, Inc. [Updated October 15, 2014; 
Accessed August 28,2014]. 
http://online.lexi.com.proxy.lib.uiowa.edu/lco/action/doc/retrieve/docid/patch_f/76
71?hl=Antilipemic Agent, HMG-CoA Reductase Inhibitor 
6. Simvastatin. In: American Hospital Formulary Service (AHFS) Drug Information. 
Hudson, OH : Lexi-Comp; Inc.;  [Updated October 15, 2014; Accessed August 
28,2014].At: 
http://online.lexi.com.proxy.lib.uiowa.edu/lco/action/doc/retrieve/docid/complete_
ashp/414032#ubnlist 
7.  
8. Sakoda K, Yamamoto M, Negishi Y, Liao JK, Node K, Izumi Y. Simvastatin decreases IL-
6 and IL-8 production in epithelial cells. Journal of dental research. 2006;85(6):520-3. 
9. Liskmann S, Vihalemm T, Salum O, Zilmer K, Fischer K, Zilmer M. Correlations 
between clinical parameters and interleukin-6 and interleukin-10 levels in saliva from 
totally edentulous patients with peri-implant disease. The International journal of 
oral & maxillofacial implants. 2006;21(4):543-50. 
10. Mengel R, Stelzel M, Hasse C, Flores-de-Jacoby L. Osseointegrated implants in 
patients treated for generalized severe adult periodontitis. An interim report. Journal 
of periodontology. 1996;67(8):782-7.