You are on page 1of 4

International Journal of Pharmacy and Pharmaceutical Sciences

ISSN- 0975-1491

Vol 3 Suppl 3, 2011

ResearchArticle

ATRANSDERMALGLUCOSAMINEFORMULATIONIMPROVESOSTEOARTHRITICSYMPTOMS
INANOPENCLINICALSURVEY

NGGUATHUA1,MBBS;LEEYUMING2,MBBS;ANDJONATHANOBAJE3*,PHD
1

SheffieldClinic,BLK69#01361,TaoPayohLor4,Singapore310069,2ComwellMedicalClinic,BLK6#0180HougangAve,Singapore
5300063EunosTechpark,60KakiBukitPlace#0408,Singapore415979Email:ugane07@yahoo.com
Received:13Feb2011,RevisedandAccepted:12March2011

ABSTRACT
Objective:Toevaluatetheefficacyandsafetyofanewtransdermalformulationofglucosamineinthetreatmentofosteoarthritis(OA).
Method:Fortyfour(44)patientswithmildtomoderateOAattending16differentoutpatientclinicsinSingaporewererecruitedinto the4week
study.Threecriteriawereusedtoquantifytheseverityofdiseaseactivityevaluatedbeforeandaftertreatmentwithonegram(3timesdaily)of
Urahtransdermalglucosamine(UTG)creamformulationviz:Ritchiearticularindex(RAI),functionaldisabilityassessment[DoctorsEvaluationof
Healthstatus(DEH)]andarthritisselfefficacyscale[PatientsAssessmentQuestionnaire(PAQ)].
Results:Afterfourweeks,UTGtreatmentwasobservedtoimprovedRAIpainscorefromthebaseline(day0)inalldemographicgroupandfurther
enhancedfunctionalabilities.Overall,59%ofthepatientshadagoodopinionratingforthistransdermalformulationandshowedbeneficialeffects.
Efficacyappeared tobe relatedto thesite ofarthritiswith 100% of patients havingarthritis of theshoulders reporting beneficial effectsofUTG
therapyasopposedto75%ofpatientswithankle,wristandelbowOAand58%ofkneeOArespectively.Additionally,compliancetotreatmentwas
observedtobeover95%andtherewerenoreportsofadversereactionsandnoskinirritationswereobservedatanytimepoint.Conclusion:Urah
Transdermal Glucosamine Creamsignificantlyalleviatedpainin arthritic jointswhen appliedoverfourweekssuggestinganimprovementinthe
qualityoflife.Thisresultssupportfurtherclinicaltrialintotheuseoftransdermalrouteofadministrationofglucosamine.
Keywords:Osteoarthritis,Transdermal,Glucosamine,RouteEfficacy

INTRODUCTION
Despiterecentadvancesinthemedicalsciences,arthritis,achronic
degenerativedisorderofmultifactorialaetiology,continuestobethe
most common musculoskeletal disorder in clinical practice and a
leading cause of pain and handicap in many countries.
Approximately43millionAmericans(ie16.6%oftheUSpopulation)
areknown to be afflicted by one form of arthritisorthe other 1.In
Japan,Yoshimuraetalreportedprevalenceofosteoarthritis(OA)of
thekneein25millionJapaneserepresenting30%ofthepopulation
2. Zhang et al examined 1,787 Chinese residents of Beijing and
reported prevalence of radiographic knee OA as 42.8% in women
and21.5%inmen3.Thehighprevalenceofthispotentiallydisabling
diseaseoftentranslatesintosignificanteconomicandsociocultural
implicationstopatientsandthesocietyatlarge,accountingfor25%
ofvisitstoprimarycarephysiciansandhalfofallnonsteroidalanti
inflammatoryprescriptionsintheUnitedStatesofAmerica4.
Current treatment of OA is limited to palliation through the use of
analgesicssuchasnonsteroidalantiinflammatory drugs(NSAIDs),
andthecyclooxygenase2(COX2)inhibitors 4.Thefailureofthese
conventional medications to satisfactorily treat OA has resulted in
increasingsearchforsuperiortreatmentoptions.ManyOApatients
resort to the use of unconventional treatment methods such as
herbal or selfmedication 5, spa treatments 6, and painful intra
articularinjections7.
In recent years, glucosamine has been increasingly endorsed
putatively as an overthecounter remedy for OA, with estimated
annual sales exceeding $700 million in the United States alone 8.
Although several laboratory studies have shown glucosamine to be
good chondroprotective agent 9, many reported human clinical
studies on orally administered glucosamine formulations have not
shown results complementing these laboratory findings 10. A
multicenteroralglucosamineclinicaltrialpublishedin2006bythe
American National Institute of Health concludes that glucosamine
andchondroitinsulphatealoneorincombinationdidnoteffectively
reducepainintheoverallgroupofpatientswithosteoarthritisofthe
knee 11. This contrasting report between laboratory and clinical
findings has done little to assuage skepticism on the therapeutic
efficacyofglucosaminetherapyamongpatientsanddoctors.

Although oral ingestion continues to be the popular route of


administrationofglucosamine,studieshavesuggestedthateffective
intraarticular concentrations may not always be achieved by oral
route 12. A number of recent studies in horses and humans have
quantifiedtheserumlevelsoffreeglucosamineafteradministration
of clinically relevant dosages 13, 14. These studies observed low
bioavailability. They concluded that insignificant trace amounts of
glucosamine enter human serum after oral ingestion and that this
amount is far below any amount that could make significant
therapeutic contribution. In addition to low bioavailability, oral
ingestionofglucosaminecompoundsislimitedbyothersideeffects
such as gastric irritation, nausea and gastric ulceration. A research
reporthassuggestedthatthoughglucosaminemayindeedhaveanti
arthritic properties but theroute of administration may be thekey
to attaining the necessary physiological concentration of
glucosamine to take full advantage of its potential effects 15. This
notion of a routeefficacy relationship in glucosamine therapy is
furthersupportedbytheresults ofaclinicalevaluation ofa topical
preparation containing glucosamine (30mg/g), chondroitin
(50mg/g), shark cartilage 140mg/g), camphor (32mg/g) and
peppermintoil(9mg/g) 16.However,thecurrentclinicalskepticism
on glucosamine seems to hamper wider clinical research on the
effectsoftheroutesofadministrationonglucosaminetreatments.
Recently, a Transdermal Glucosamine Cream (TGC) formulation
containing80100mg/gofglucosaminecompoundwasintroduced
as an alternative to oral glucosamine. However, no independent
clinical evaluation on theefficacy andsafety ofthe formulation has
beenreported.Thissurveywasthereforedesignedasapreliminary
evaluation of efficacy and safety of this new formulation of
glucosamine.
MATERIALSANDMETHODS
StudyDesignandPatients
Atotalof44patientswererecruitedat16outpatientclinicsspread
acrossSingapore.ThesepatientshadbeendiagnosedwithOAprior
tothesurveybythephysiciansintherespectiveoutpatientclinics.
The exclusion criteria used are: known hypersensitivity to
glucosamine; severe organ or systemic diseases; and open wound
aroundthearthriticjoint;pregnancyorlactating.Demographicand

Obajeetal.
IntJPharmPharmSci,Vol3,Suppl3,2011,8083
glucosamine sulphate 2KCl. Patients were instructed to apply
approximately 1 g of the cream three times daily to each of the
affected joints. If both knees were affected, both were treated and
evaluated. Treatment compliance was estimated by collecting
finished tubes before issuing new tubes. Patients were not given
specific additional instructions with regard to exercise or any
restrictionofactivities.

baseline data collected were age, sex, occupation, history and


location of pain, Ritchie articular index baseline score, information
regardingotherillnesses,anduseofotherdrugs.Patientswereseen
weeklybythephysicianfor48weeks.
UrahTransdermalGlucosamine(UTG)creamusedinthisstudywas
manufactured under GMP conditions and contains 8% w/w
[[

Table1:showsamodificationofRitchiearticularindex(mRAI)usedtoevaluatethestatusofarthriticsymptominpatients
a)ModifiedRitchieArticularIndex(mRAI)
Pain
Nopain
Slightpain
Moderatepain
Severepain

b)PatientsAssessmentQuestionnaire(PAQ)

Score
0
1
2
3

Pain
Norelief
Slightrelief
Moderaterelief
Completerelief

Score
1
2
3
4

Outcomescorewasmeasuredasthedifferencebetweentherecruitment/baselineandtheendpointscoreonthemRAIscale.Theoutcomescores
areratedasExcellent(>2.5);Good(1.5to2.4);Fair(0.5to1.4);Useless(0to0.4)andWorsethanuseless(<0).

representing 95.5% compliance. Over 63% (28/44) of the patients


were below the age of sixty. Over 56% (25/44) had a history of
arthritis lasting less than one year duration or early stage arthritis
(Table 2). The severity of arthritic symptoms before and at each
followupvisitswasdocumentedandgradedadoptingamodification
of the Ritchies Articular index and according to the Patients
AssessmentQuestionnaire(Table1aandb).

Ritchiespainscoreandfunctionaldisabilityevaluation
At baseline and on each followup (weekly) visit, the investigators
assessed the severity of disease activity using the modified Ritchie
articular index (mRAI) 17, functional disability score [Doctors
Evaluation of Health status (DEH)] and Patients Assessment
Questionnaire(PAQ)18,asgiveninTable1a&b.
RESULTSANDDISCUSSION

Over the minimum four weeks treatment period, all demographic


groups of patients indicated a relative improvement of symptoms
from baselineandexpressedfavourable opinionto theuse ofUTG
(Table2and3).

The sex distribution among the 44 OA patients recruited for this


survey was even (1:1 male:female ratio). Forty two (42) patients
completed the minimum 4week requirement of the clinical survey

Table2:Showsgeneralopinionratingofthetreatmentoutcome
Goodopinion

Pooropinion

Total
number

Excellent

Good

Fair

Good
opinion

Useless

Worsethan
useless

Poor
opinion

Safety

Male

22

68.2%

31.8%

Female

22

50%

10

50%

<65yrold

28

13

57.14%

12

42.86%

>65yrold

16

62.5%

37.5%

<1yrpain
duration

25

44%

13

56%

13yrpain
duration

10

80%

20%

>3yrpain
duration

77.8%

22.2%

22
(100%)
22
(100%)
28
(100%)
16
(100%)
25
(100%)
10
(100%)
9
(100%)

TotalGoodOpinion

26

59%

Totalpoor
opinion

18

41%

Overall, 59% of the patients had a good opinion rating for the
transdermal formulation (Table 2). The most favourable opinion
(80%) was expressed by patients with arthritic pain duration
ranging from 13 years closely followed by patients with over 3
yearsarthriticsymptoms.Fewerearlystagepatients(44%)whohad
arthritis lasting less than 1 year expressed favorable opinion when
compared with later stage (13 years and greater than 3 years
duration)patients.Thisfindingwasinterestingandunexpected.
Theexactreasonunderliningthisfindingisnotimmediatelyknown.
However,itcouldberelatedtothephysicalactivitylevelsofpatients
aslongerhistoryofarthritisisexpectedtobeassociatedwithlower
activity levels, being a progressing and disabling disease. Lower
activity level or resting of the affected joints while applying

medications couldenhancerecoveryandregenerativeabilityof the


joint.Thisdeductioncallsforfurtherinvestigation.
Although UTG cream was found to be beneficial and relieved arthritic
symptomsirrespectiveoftheaffectedjoint,Table4showsthatpatients
with shoulder, neck or back pain expressed the highest level of
satisfaction withUTG cream (100%) while those with knee symptoms
wereleastrelieved(58%).Thisfurtherhighlightstheimportanceofjoint
activity levels and the potential regenerative ability of glucosamine.
Besidestheshoulderjointwhichconnectstheappendiculartotheaxial
skeleton,theneck,backandkneeareallintheaxialskeleton.Expectedly,
thekneecarrieslargerpassiveweightthantheshoulder,neckandback.
Thiscould,atleastinspart,explainthisobservationofhigherrelievefor
shoulder,neck,andbackjointswhencomparedtoknee.
81

Obajeetal.
IntJPharmPharmSci,Vol3,Suppl3,2011,8083

Table3:Showspatientsdemographic,treatmentandoutcomedata
Sex

Agerange

Patient
S/N

Male

Female

65yrs

Above
65yrs

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
TOTAL

x
x
x

x
x

x
x
x

x
x
x
x
x
x

x
x

x
x

22

x
x

x
x

x
x
x

x
x

x
x
x
x
x
x
x
x
22

x
x
x
x
x

x
1
1
1
1
x
x
x
x
x
x
x

x
x
x
x
x

x
x
x
28

x
x
x
x
x
x
x

x
x
x

x
x

16

DurationofpainbeforeUTG
treatment
Lessthan
13yrs
More
1yr
than
3yrs
x
x

x
x
x

x
x

x
x
x

x
x
x

x
x

x
x
x

x
x
x

x
x
x

x
x
x

x
x
x

x
x

x
x

25
10
9

Outcome
Durationof
treatment

Outcome
score

Rating

6weeks
4weeks
8weeks
6weeks
8weeks
8weeks
8weeks
8weeks
4weeks
8weeks
8weeks
8weeks
6weeks
4weeks
4weeks
6weeks
8weeks
8weeks
8weeks
8weeks
8weeks
8weeks
8weeks
8weeks
8weeks
6weeks
4weeks
8weeks
8weeks
1week
1week
4weeks
6weeks
6weeks
6weeks
8weeks
8weeks
8weeks
8weeks
8weeks
8weeks
8weeks
8weeks
8weeks

3
2
1.5
2
2.5
2
2
2
1
1
0
1
0.5
0.5
0.5
0
0
0.5
0
0.5
0
0.5
0.5
0.5
0
0
0
0
0
0
0
0
0.5
0
0
2
0
0
1
1
1
1
1.5
1

Excellent
Good
Good
Good
Excellent
Good
Good
Good
Fair
Fair
Useless
Fair
Fair
Fair
Fair
Useless
Useless
Fair
Useless
Fair
Useless
Fair
Fair
Fair
Useless
Useless
Useless
Useless
Useless
Withdrawn
Withdrawn
Useless
Fair
Useless
Useless
Good
Useless
Useless
Worse
Fair
Fair
Fair
Good
Fair

Table4showsopinionratingofthetreatmentoutcomebasedonsiteofpain
LocationofPain
Knee
Ankle
Shoulder/Neck/back
Wrist/Elbow

Total(n)
33
8
4
4

Goodopinion(%)
58
75
100
75

Pooropinion(%)
42
25
0

25

Ofparticularinterestisthesafetyreport.Therewerenoreports of
adversereactionsandnoskinirritationswereobservedatanytime
point. This further underlines the advantages of transdermal over
oral route of administration.Similarly,the highlevel of compliance
observed in this survey could be due to the absence of
gastrointestinalsideeffectsoftenreportedforacidicformulations.
Theuseofmicelleand nanotechnology in enhancingbioavailability
of poorly soluble drugs is gaining popularity in research and the
pharmaceutical industry 1921. This has provided therapeutic agents
that could be administered to patients via routes other than the
traditionaloralorparenteralroutes.Onesuchalternativeroutethat

couldbeverybeneficialfortherapeuticagentswithtraditionallylow
bioavailabilityisthetransdermalrouteofadministration.Observed
advantagesofthetransdermalrouteofadministrationovertheoral
route and hypodermic injections includes: 1) improved control of
the rate of direct delivery into the bloodstream as it bypasses the
gastrointestinalenzymesandsignificantfirstpasseffect,2) smaller
peaktovalley fluctuation in plasma concentration especially when
patchesareadoptedand3)improvedpatientcomplianceastheyare
generally painless and causes little or no discomfort 22, 23. These
factors could account for the discrepancies in the therapeutic
efficacy of glucosamine between laboratory and clinical studies
reported previously. AghazadehHabashi et al studied the
82

Obajeetal.
IntJPharmPharmSci,Vol3,Suppl3,2011,8083
pharmacokineticsandbioavailabilityofglucosamineandconcluded
that orally administered glucosamine has rapid but low absorption
andiswidelydistributedandefficientlycleared.Theyfurtherstated
thatthegutratherthanliveristheorganmainlyresponsibleforthe
lowbioavailabilityofglucosamineandthatthelimitedabsorptionof
glucosaminesuggestsatransportdependentabsorption.Theywent
further to state that food does not significantly affect the
bioavailability of glucosamine 24. This suggest a high first pass
metabolismaswillbeexpectedformanysupplements,beingnormal
part of the human metabolic chain, with well established
degradationpathways.
In the present clinical survey, we found a new transdermal
glucosamine formulation, Urah TGC, to be effective in relieving
symptoms of arthritis. If this clinical observation is further
establishedinadouble blind studies,thiscouldopenthe way fora
new era of glucosamine research and therapy. Being a clinical
survey,directcomparisonoftheseresultswithpreviousstudiesare
difficult due to differences in methodology. However, the results
presented here are consistent with earlier reports by Cohen et al
[16] which concludes that topical application of glucosamine and
ChondroitinsulphatewaseffectiveinrelievingthepainofOAofthe
kneeandimprovementwasevidentin4weeks.Takentogether,our
surveyandthatstudyleancredencetoarouteefficacyrelationship
intheuseofglucosamineforthetreatmentofOA.
Thecurrentclinicalsurveyisnotwithoutlimitations.Beingasurvey,
there is a need to conduct a double blind study on this product as
well as enlarge the cohort and protocol. However, being the first
study to evaluate patient response to this new transdermal
formulation in this community, the survey achieved its main
objectivesandthuspavesthewayformoredetailedstudies.
ACKNOWLEDGEMENT
We are indebted to Pharmaforte Singapore Pte Ltd for organizing
thissurveyasanindependentpartywithnovestedinterest.
REFERENCES
1.

2.

3.

4.
5.
6.

7.
8.

9.

Centers for Disease Control and Prevention A, GA: Targeting


arthritis: reducing disability for 43 million Americans at a
glance. US Department of Health and Human Services, CDC;
Atlanta,GA2006;Availableatwww.cdc.gov/nccdphp/aag/aag_
arthritis.htm.
YoshimuraN,MurakiS,OkaH,MabuchiA,EnYoY,YoshidaM,
Saika A,Yoshida H,SuzukiT, Yamamoto Setal: Prevalence of
knee osteoarthritis, lumbar spondylosis, and osteoporosis in
Japanese men and women: the research on
osteoarthritis/osteoporosis against disability study. J Bone
MinerMetab2009;27:620628.
ZhangY,XuL,NevittMC,AliabadiP,YuW,QinM,LuiLY,Felson
DT: Comparison of the prevalence of knee osteoarthritis
between the elderly Chinese population in Beijing and whites
intheUnitedStates:TheBeijingOsteoarthritisStudy.Arthritis
Rheum2001;44:20652071.
JohnsonJE:Patienteducationandselfadvocacy.Managingpain
in osteoarthritis. J Pain Palliat Care Pharmacother 2009;
23:171173.
May S: Selfmanagement of chronic low back pain and
osteoarthritis.NatRevRheumatol2010;6:199209.
ForestierR,DesfourH,TessierJM,FranconA,FooteAM,Genty
C, Rolland C, Roques CF, Bosson JL: Spa therapy in the
treatment of knee osteoarthritis: a large randomised
multicentretrial.AnnRheumDis2010;69:660665.
Hochberg MC: Role of intraarticular hyaluronic acid
preparations in medical management of osteoarthritis of the
knee.SeminArthritisRheum2000;30:210.
TikuML,NarlaH,JainM,YalamanchiliP:Glucosamineprevents
in vitro collagen degradation in chondrocytes by inhibiting
advanced lipoxidation reactions and protein oxidation.
ArthritisResTher2007;9:R76.
Shikhman AR, Amiel D, D'Lima D, Hwang SB, Hu C, Xu A,
Hashimoto S, Kobayashi K, Sasho T, Lotz MK:

10.
11.

12.

13.

14.

15.

16.

17.
18.

19.

20.
21.
22.
23.
24.

Chondroprotective activity of Nacetylglucosamine in rabbits


withexperimentalosteoarthritis.AnnRheumDis2005;64:89
94.
Kirkham SG, Samarasinghe RK: Review article: Glucosamine. J
OrthopSurg(HongKong)2009;17:7276.
CleggDO,RedaDJ,HarrisCL,KleinMA,O'DellJR,HooperMM,
Bradley JD, Bingham CO, 3rd, Weisman MH, Jackson CG et al:
Glucosamine, chondroitin sulfate, and the two in combination
for painful knee osteoarthritis. N Engl J Med 2006; 354:795
808.
Laverty S, Sandy JD, Celeste C, Vachon P, Marier JF, Plaas AH:
Synovial fluid levels and serum pharmacokinetics in a large
animal model following treatment with oral glucosamine at
clinicallyrelevantdoses.ArthritisRheum2005;52:181191
PersianiS,RodaE,RovatiLC,LocatelliM,GiacovelliG,RodaA:
Glucosamineoralbioavailabilityandplasmapharmacokinetics
after increasing doses of crystalline glucosamine sulfate in
man.OsteoarthritisCartilage2005;13:10411049.
Biggee BA, Blinn CM, McAlindon TE, Nuite M, Silbert JE: Low
levels of human serum glucosamine after ingestion of
glucosamine sulphate relative to capability for peripheral
effectiveness.AnnRheumDis2006;65:222226.
Gouze JN, Gouze E, Popp MP, Bush ML, Dacanay EA, Kay JD,
Levings PP, Patel KR, Saran JP, Watson RS et al: Exogenous
glucosamine globally protects chondrocytes from the
arthritogenic effects of IL1beta. Arthritis Res Ther 2006;
8:R173.
CohenM,WolfeR,MaiT,LewisD:Arandomized,doubleblind,
placebo controlled trial of a topical cream containing
glucosamine sulfate, chondroitin sulfate, and camphor for
osteoarthritisoftheknee.JRheumatol2003;30:523528.
Huskisson EC: Measurement of pain. Lancet 1974; 2:1127
1131.
van Haselen RA, Fisher PA: A randomized controlled trial
comparing topical piroxicam gel with a homeopathic gel in
osteoarthritis of the knee. Rheumatology (Oxford) 2000;
39:714719.
Ghosh PK, Majithiya RJ, Umrethia ML, Murthy RS: Design and
development of microemulsion drug delivery system of
acyclovirforimprovementoforalbioavailability.AAPSPharm.
SciTech2006;7:77.
Muller CE: Prodrug approaches for enhancing the
bioavailability of drugs with low solubility. Chem Biodivers
2009;6:20712083.
Yang W, Wiederhold NP, Williams RO, 3rd: Drug delivery
strategies for improved azole antifungal action. Expert Opin
DrugDeliv2008;5:11991216.
Burkman RT: Transdermal hormonal contraception: benefits
andrisks.AmJObstetGynecol2007;197:134e131136.
Prausnitz MR, Langer R: Transdermal drug delivery. Nat
Biotechnol2008;26:12611268.
AghazadehHabashi A, Ibrahim A, Carran J, Anastassiades T,
Jamali F: Single dose pharmacokinetics and bioavailability of
butyrylglucosamineintherat.JPharmPharmSci2006;9:359
364.

APPENDIX
Inadditiontotheauthors,thefollowinginvestigatorsparticipatedin
this Survey: Dr. Richard Tan Tiong Heng, Elim Family Clinic &
Surgery, East Coast Road; Dr. M. Tahir, Crescent Clinic, Eunos
Crescent; Dr. Chow Shen Jung, Chow Surgery, Tanglin Road; Dr.
Kelvin Phua Cheng Pua, Clarke Medical Pte Ltd, Geylang; Dr. Yong
Chee Fah, Yong Clinic & Surgery, Yishun; Dr. Neo Eng Kiong, Neo
Clinic & Surgery, Bankit Road; Dr. Doris Heng, The Medical House
Clinic&Surgery,HollandClose;Dr.LeeEngSeng,HealthcareFamily
Clinic & Surgery, Sin Ming Avenue; Dr. Fong Seng Yew, Fong Clinic
MLST,MeiLingStreet;Dr.WongWeeNam,WongClinic&Surgery,
ClementiAve2;DrHuKuoMing,HuClinic,ClementiAve3;Dr.Koo
XianYeang,LimClinic&Surgery,ChaiCheeRoad;Dr.Rohaili,Usrah
MedicalClinic,BedokNorthSt.3;andDr.ThamHoeMeng,Everwell
Clinic&Surgery,OwenRoad.

83