医薬品相互作用研究

Vol.42, No. 2（2018）

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医薬品相互作用研究
一般論
文42（2） 9-14 （2018）

Changes in the viscosity of metronidazole gel mixed with other agents totreat malodorous ulcerated skin cancers
Iori HIROSAWA 1）, Kaname HASHIZAKI 2）, Kentaro MATSUMURA 1）,
Makiko FUJII 2）, Kazuhiro WATANABE 1, *）1）

Laboratory of Pharmacy Practice, Center for Education and Research on Clinical Pharmacy, Showa Pharmaceutical University
2）
Laboratory of Physical Chemistry, School of Pharmacy, Nihon University（Received December 26, 2017; Revised January 31, 2018; Accepted February 2, 2018）Ulcerated skin cancers cause severe pain, bleeding, and the formation of exudate. When treating these symptoms
with topical mixtures of metronidazole (MTZ) gel and other drugs in clinical settings, it has been observed that thegel does not always adhere well to the affected areas. In this study, the viscosity of MTZ gels mixed with othersubstances were measured with a viscometer, and the cause of the reduced viscosity was analyzed. Lidocaine jellyand sodium alginate, common additives for suppressing pain and bleeding, were added to the MTZ gel, and changes
in the viscosity and pH of the different MTZ gel mixtures were measured. Viscosities were also measured after somesodium solutions were added to the MTZ gel. The results showed that the viscosities of MTZ gels mixed withlidocaine jelly and sodium alginate were decreased to one-tenth or less of MTZ gel without additives. There was nochange in pH after addition of lidocaine jelly and sodium alginate to the MTZ gel. Addition of aqueous solutions ofsodium chloride also reduced the viscosity of the MTZ gel. These data show that the viscosity of the MTZ gel
decreased with the addition of other agents, presumably due to the effects of a cationic component.
Key Words: Topical metronidazole, Malodorous fungating tumors, Viscosity, Carboxyvinyl polymer

Backgroundthis make it difficult for patients to maintain

Malodor associated with ulcerating tumors is

personal relat ionships, but it also lowers theircaused by invasion into the skin or metastases.

self-esteem and reduces their quality of life. TheC a n c e r s t h a t a r e l i k e l y t o d e ve l o p s k i n u l c e r s

quality of medical care can also be adversely

include breast cancer, head and neck cancer, andaffected. Thus, ulcerating tumors place a heavysquamous cell carcinoma of the skin. In

burden on all concerned, making it important toparticular, the rate of ulcers in breast cancer issimultaneously reduce both the pain andhigh, with an incidence of approximately 4%.

malodor 4）.

Such skin ulcers are accompanied by severe pain,

Metronidazole (MTZ) is a well-known andbleeding, and formation of large amounts ofeffective antibiotic that can reduce the malodor

exudate. The discharged fluid is infected withof ulcerat ing skin cancers 5 , 6 ）. Thus, the Worldanaerobic bacteria such as Trichomonas species,

Health Organization and American Society offungi, and decomposition compounds such as

Clinical Oncology have recommended its topicalputrescine and cadaverine, which are produced

application 4,7）. However, until recently it was notfrom bacteria and cause a strong o dor 1 ‒ 3 ）. The

approved in Japan, and formulations weremalodor causes distress in patients and alsoi n d i v i d u a l l y p r e p a r e d b y e a c h h o s p i t a l 6 , 8 , 9 ）. I naffects those around them, such as family

2015, a topical medicine containing MTZ, 0.75%

members and healthcare workers. Not only does

MTZ (Rozex®) gel, was approved for use in Japan

Laboratory of Pharmacy Practice, Center for Education and Research on Clinical Pharmacy, Showa Pharmaceutical University, 3-3165
Higashi-Tamagawagakuen, Machida-shi, Tokyo 194-8543, Japan2）
Laboratory of Physical Chemistry, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan* Corresponding author: Kazuhiro Watanabe
Tel: +81-42-721-1440; Fax: +81-42-721-1440; E-mail: kazunabe@ac.shoyaku.ac.jp1）

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医薬品相互作用研究

as a bactericide and for the reduction of odor at

Vol.42, No. 2（2018）

Viscosity measurementsskin ulcer sites in cancer. MTZ gel acts against

Viscosity measurements were performed using

Gram-positive and Gram-negative anaerobic

a stress-controlled rheometer (HAAKE RS600;

bacteria, which produce malodorous substances

Thermo Fisher Scientiﬁc, Waltham, MA, USA)such as putrescine and cadaverine at the sites ofequipped with a Peltier-based temperatureulcerating skin tumors in patients with advanced

control device. All measurements werecancer. A clinical trial showed that MTZ gel

performed at 25 °C. The viscosities of individual

reduced the intensity of malodors in 95.2% of

substances were measured by cone-plate

breast cancer patients 10）.

geometry (35 mm diameter, 1 °cone angle), andPatients with ulcerated skin cancer who

the viscosities of the mixed gels were measured

develop either severe pain or bleeding arewith an evaporation assist plate (50 mm

typically administered topical MTZ gel mixed

d i a m e t e r, 0 . 5 m m g a p ) . T h e v i s c o s i t y o f e a c hwith 2% lidocaine jelly or sodium alginate,sample was measured three times, and ther e s p e c t i v e l y. H o w e v e r, t h e v i s c o s i t y o f t h e s eresults are presented as the mean ± standard

mixed MTZ gels decreases and they do notdeviation (SD). The viscosities of the MTZ gel

adhere well to the affected areas. Moreover,and lidocaine jelly were measured at a shear rate

pat ients w ith ulcerated skin may find a topicalof 10 s-1; subsequently, the viscosities of

agent painful to apply if the base material is too

lidocaine jelly or sodium alginate mixed withthick; however, the medicine w ill not adhere if

MTZ gel were measured. MTZ gel (0.22 g) was

the material lacks sufficient viscosity. Hence, theset in the apparatus and the viscosity

correct viscosity, expansibility of the base, andmeasurement was started at a shear rate of 10usability are essential for topical application.

s -1 . After 2 min, lidocaine jelly, sodium alginate,C a r b o x y v i ny l p o l ym e r ( C V P ) , w h i c h i s u s e d i nor an aqueous solution of sodium chloride (0.9%,MTZ gels, has moderate viscosity and good

0.09%, 0.009%; 0.05 mL) was added, and therelease characteristics, and as such, is used as aviscosity was measured for 4 min. MTZ gel andmatrix for various pharmaceutical products. Its

lido caine jelly were mixed at a weight rat io ofviscosity changes depending upon the pH and4:1, and MTZ gel and sodium alginate powderc a t i o n i c c o m p o n e n t s o f t h e p r o d u c t . H o w e ve r,

were mixed at a weight ratio of 20:1; those are

there have been no reports of its incompatibility

the rat ios used in actual clinical pract ice at St.

with MTZ gel.

Lukeʼs International Hospital in Tokyo. Sodium

In this study, we examined the changes inalginate aqueous solution was prepared with theviscosity and pH of MTZ gel mixed with othersame amount of sodium alginate powder used inagents and analyzed the mechanisms leading to

the previous test experiment in 0.05 mL water.

the observed changes, with the goal of
elucidating the factors that affect its viscosity.

pH measurements
The pH values of the samples were measured

Methods
Materials

using a pH meter (pHTestr 10 BNC, Oakton,
Vernon Hills, IL, USA). The temperature of eachRozex® gel 0.75% (containing 0.75% MTZ; MTZ

sample was adjusted to 25 °C, and after mixinggel), Xylocaine® Jelly 2% (containing 2%for 3 min, the pH meter was directly placed intolido caine) and Alto® (so dium alg inate powder)

the prepared sample and the pH was measured.

were purchased from Galderma Co., Ltd. ( Tokyo,The pH of each sample was measured 3 times,Japan), Aspen Japan Co., Ltd. ( Tokyo, Japan), andand the measurement results were presented as

Kaigen Pharma Co., Ltd. (Osaka, Japan),the mean and standard deviat ion. The samples

respectively. Water was purchased from Otsuka

were prepared at the same ratios as those used

Pharmaceutical Factory, Inc. ( Tokushima, Japan).

in the viscosity tests.

Sodium chloride was purchased from Kanto
Chemical Co., Inc. (Tokyo, Japan).

医薬品相互作用研究

Vol.42, No. 2（2018）11（91）

fluctuated, possibly due to the powder; thus

Resultsso dium alg inate dissolved in aqueous solut ion

Viscosity measurements
The viscosity of the MTZ gel was 10.2±0.3-1

was added to the MTZ gel. After 4 min, thePa·s at 25 °C, and the shear rate was 10 s (Fig.

viscosity abruptly decreased to 0.83±0.09Pa·s1A). The viscosity of the lidocaine jelly was 2.6

that after addition of the powder (Fig. 1D). Thus,

Pa · s . T h e v i s c o s i t i e s o f t h e M T Z g e l s a b r u p t l y

the sodium alginate lowered the viscosity of thedecreased upon addition of lidocaine jelly to

MTZ gel, and it was thought that the influence on

1.08±0.11 Pa·s (Fig. 1B). After sodium alginate

viscosity after water was added was negligible.

powder was added, the viscosity decreased butFigure 1. Changes in viscosity of the MTZ gel after the addition of other agents.
Lidocaine jelly, sodium alginate power, or sodium alginate solution was added 2 min after viscosity measurement of the original MTZ gel
at 25°
C. A, MTZ gel; B, MTZ gel + lidocaine jelly; C, MTZ gel + sodium alginate powder; D, MTZ gel + sodium alginate solution.

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医薬品相互作用研究

Vol.42, No. 2（2018）alginate aqueous solution were added to the MTZ

pH measurements
The MTZ gel had a pH of 4.87±0.02 and was aw e a k a c i d . T h e p H l e ve l s w e r e 4 . 8 4 ± 0 . 0 3 a n dgel, respectively, which were similar to the pH of
the original gel (Table 1).

4.79±0.03 after lidocaine jelly and sodium

Table 1. The pH of MTZ gel, lidocaine jelly, and MTZ gel mixtures (n=3)

Changes in viscosity of MTZ gel after addition

For low concentrations of sodium chloride,of sodium chloride

gradual restitution of the viscosity occurred, but

The viscosities of MTZ gels upon addition offor high concentrat ions (0.9%), it decreased tosodium chloride aqueous solutions (threeless than 1 Pa·s and remained in a state of lowconcentrations) were measured. All of theviscosity.

samples showed decreases in viscosity (Fig. 2).

Figure 2. Changes in viscosity of the MTZ gel after addition of sodium chloride aqueous solutions.
Sodium chloride aqueous solutions at 0.009, 0.09, and 0.9 w/v% were added 2 min after viscosity measurement of the original
MTZ gel at 25°
C.

Discussion

ulcer and the treated area is covered with aIn this study, the viscosity of the MTZ geld r e s s i n g . I n t h e o t h e r, t h e g e l i s s p r e a d o n t o arapidly decreased when mixed with other agents.

dressing that is then placed over the ulcer. Thus,In clinical practice, MTZ gel is applied in two

it is essential that the MTZ gel has adequateways. In one, the gel is directly applied to theviscosity. The viscosity of the MTZ gel w ithout医薬品相互作用研究

Vol.42, No. 2（2018）13（93）

addit ional agents was approximately 10 Pa·s inthe water of dissolved sodium alginate. Because

this study. In contrast, the viscosity of the MTZ

CVP is anionic, neutralization of the charge

gel mixed with lidocaine jelly or sodium alginate

occurs due to incorporation of the cationicdecreased to 1 Pa·s, which was one-tenth that ofcomponents, resulting in the abrupt reduction of

the original gel. These findings showed that theviscosity, aggregation, and turbidity. The addition

decreases in viscosity in this study resulted inof sodium chloride caused a sharp decrease inviscosities that were even lower than the typicalviscosity.

viscosity of glycerin (1.5 Pa·s).

Sodium alginate powder contains 0.116 g Na/g.

MTZ gel contains the gelling agent, CVP. CVP

I n t h i s v i s c o s i t y s t u d y, a p p r o x i m a t e l y 1 0 m gforms a transparent gel with good rheologicalsodium alginate powder was added to 0.22 g MTZ

characteristics, so it is widely used in bothgel, so a greater amount of sodium was added topharmaceutical products and cosmetics. MTZ gel

the MTZ gel with addition of the powder thanalso contains sodium edetate hydrate, propylene

with addition of 0.05 mL of the 0.9% sodium

glycol, methyl p-hydroxybenzoate, propyl

chloride solution. Thus, sodium ions likely

p-hydroxybenzoate, and sodium hydroxide as

explain the effects of sodium alginate on MTZ

additives, and adequate viscosity is maintained ingel.

the presence of these ingredients. This lower

Lidocaine jelly contains additives such as

viscosity of the MTZ gel was thought to result

methyl paraben, propyl paraben, carmellose

from changes in the components of the gelling

sodium, and a pH regulator. Carmellose sodiuma g e n t , n a m e l y C V P. C V P g e l i s p r e p a r e d b yc o n t a i n s 6 . 5 ‒ 8 . 5 N a / g ; h o w e ve r, t h e c a u s a t i ve

dispersing CVP in water at a concentration of 1%

substance in lidocaine jelly is unknown. Because

or less, and then neutralizing it with a basic

it produced a sharp decrease in MTZ gel viscosity

solution to a pH of 6‒8. When dispersed in water,

similar to that of sodium alginate and sodium

CVP has a pH of approximately 4, and thechloride aqueous solution, a cationic component

viscosity gradually increases with as the pHof the additive may be the cause. Realdon

increases towards alkaline levels. The viscosity isshowed that the viscosities of hydrogels werehighest at pH 6‒8 and decreases as thereduced by procaine hydrochloride in a12）

. 13）

. The pH ofconcentration-dependent manner. Because

MTZ gel is approximately 5, which is relat ively

lidocaine has a similar cationic structure tolow, and there were no significant changes in pH

procaine, cations may play a role in reducing theafter it was mixed with other agents, showing

viscosity of the hydrogel.

preparation becomes more alkalinethat the changes in viscosity of MTZ gel mixed
with multiple agents were not due to changes inpH.

Conclusions
The results of this study showed that theThe viscosities of CVP gels are also affected by

viscosity of MTZ gel was reduced by mixing it withsalt and buffers 1 1 ）; thus, we suspected that theother drugs such as lido caine jelly and so diumchange in viscosity of the MTZ gel was due to thealginate, possibly due to the effects of theirpresence of salt. To this end, we added aqueous

cationic components.

solutions of sodium chloride to the MTZ gel,which resulted in a sharp decrease in viscosity,Declarations

similar to that observed upon addition oflidocaine jelly or sodium alginate aqueous

Not applicable

solution. Because the amount of sodium chloride
solution was fixed at 0.05 mL, the decrease in

Not applicableviscosity was dependent on the concentration ofsodium chloride and not on the addition of water.

All data generated or analysed during this study

This was also supported by the fact that theare included in this published article.

change in viscosity was not strongly affected by14（94）

医薬品相互作用研究

The authors declare that they have no competinginterests.

Vol.42, No. 2（2018）９）Watanabe K, Tsuchiya M, Shinano H, Nakamura
S, Kizu J, Inoue T: A survey about manufacturesof ointment preparation in-house for cancerous

Not applicablemalodor in this country, J Jpn Soc Hosp Pharm.,
43, 371-373, 2007.

IH collected the data and wrote the manuscript. KH10）Watanabe K, Shimo A, Tsugawa K, Tokuda Y,

designed the study and collected the data. KM

Yamauchi H, Miyai E, Takemura K, Ikoma A,collected the data. MF and KW designed andNakamura S: Safe and effective deodorization ofsupervised the study. All authors read andmalodorous fungating tumors using topicalapproved the final manuscript.

metronidazole 0.75 % gel (GK567): amulticenter, open-label, phase III study

Not applicable(RDT.07.SRE.27013), Supportive Care inCancer, 24, 2583-2590, 2016.

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