医薬品相互作用研究

Vol.43, No. 1（2019）25（25）

医薬品相互作用研究
一
般論
文
43（1） 25-31 （2019）

Difference in physical properties between brand-name andgeneric topical 0.3% heparinoid lotions
Takayoshi ONODERA1, 2）, Munetaka MARU 2）, Tomoya SAKURADA1）,
Eriko KOBAYASHI1）, Nobunori SATOH1）
Department of Social Pharmacy, Graduate School of Pharmaceutical Sciences, Chiba University
2）
Maru Corporation, Ltd.

1）

（Received August 24, 2018; Revised October 17, 2018; Accepted December 08, 2018）
Physical properties of a topical 0.3% heparinoid lotion brand-name drug and two generic drugs were evaluated by
the spread-meter test for slope, intercept, and yield values and by the fluidity test for the time to flow 100 mm. The
effect of application-surface temperature was compared for the specification value of 25 ± 0.5℃ with 31 ± 0.5℃
and 33 ± 0.5℃, which approximated skin temperatures. In the spread-meter test, the generic drugs flowed out
within 14 s, which was too short to measure their characteristics properties. The expansion diameters at 5 s of thegeneric drugs were approximately 1.5 times that of the brand-name drug, confirming their high fluidity. The slopesof the brand-name drug measured at simulated skin temperatures were significantly higher than that at 25 ± 0.5℃
and the yield values were significantly lower, respectively indicating that the product spread more easily and became
softer at skin temperatures. The fluidity results indicated that the generic drugs were significantly more fluid thanthe brand-name drug. These test results revealed that the physical properties differed between the brand-name andgeneric drugs, indicating that they are more suitable for different topical applications.
Key Words: topical heparinoid lotions, physical properties, generic drugs, skin temperature, spread meter

Introduction

also reported that generic patches for topical

The Japanese government is currently

application usually differ in physical properties

promoting the use of generic drugs as a policy tofrom those of the brand-name drug 5 , 6 ）, and that

control increasing medical costs . The Ministerpatients placed special emphasis not only on theof Health, Labour and Welfare approves generice f f i c a c y b u t a l s o o n f u n c t i o n a l u s a b i l i t y 7 ）.

drugs based on evidence that they are confirmed

Furthermore, in application of an ointment or gelt o b e eq u iva le nt to th e respect ive brand-namepreparation, the functional usability of different

drug in a bioequivalence study. It is, however,physical properties affects the drug compliancenot necessary for generic drugs to be completely

and it was therefore recommended that the“identical” to the brand-name drug, and soformulat ion of a topical preparat ion should be2）

generic drugs can contain different additives .

s e l e c t e d b y t h e p a t i e n t s w h o u s e i t 8 ）. P h y s i c a l

Although the physical properties of drugs haveproperties are key information for medical

been reported to differ depending on additives ofprofessionals to select a suitable pharmaceutical, thepreparation or conduct pharmaceutical1）different pharmaceutical formulations

3,4）

bioequivalence study on generic drugs does not
validate these properties. Some studies havereported that topical preparations with different

counselling.
In the Japanese Pharmacopoeia (JP XVII),
lotions are as defined as "physical properties may cause differences infunctional usability or even in efficacy 3,4）. It was
Department of Social Pharmacy, Graduate School of Pharmaceutical Sciences, Chiba University
Chiba, 260-8675 Japan
2）
Maru Corporation, Ltd. 17-7 Shin-machi, Chuo-ku, Chiba-Shi, Chiba, 260-0028 Japan
Corresponding author: Takayoshi Onodera
Tel/Fax: +81-43-226-2884; e-mail: ahua4413@chiba-u.jp
1）

1-8-1 Inohana, Chuo-ku, Chiba-shi,

26（26）

医薬品相互作用研究

Vol.43, No. 1（2019）" and is classified into "emulsion lotion",

onto the meter to measure the spread diameter"solution lotion" and "suspending lotion".

(mm) at selected times (5, 10, 50, 100, 150, orEspecially "emulsion lotion" is a formulation

200 s). When the drug flowed beyond at least

form prepared by emulsifying the base composed

one of the four sides of the fixing plate of theof the oily components and the aqueous

spread meter, the time to scale-over wascomponents with the surfactants. Since previous

measured (scale-over time). The test wass t u d y, t h e s p r e a d - m e t e r t e s t w a s u s e d f o r t h e

conducted six times for each application-surface

physical property comparison of the lotions 5）, wet e m p e r a t u r e . M e a n v a l u e s o f s l o p e ( ) 1 1 ）,used the spread-meter test to explore theintercept (difference in the physical properties ofscale-over time were calculated as follows:) 1 1 , 1 3 ）, y i e l d v a l u e () 1 1 ）, a n dbrand-name drug A, generic drugs B and C in thisConcerning topical heparinoid ointments or
creams, some physical properties have beenreported

2 −＝(experiment.

, but only a few studies have

9,10）

compared the brand-name and generic topical
0.3% heparinoid lotions. In addition, whereas

where1 )/log10 (

1 and

2/

at measuring times (s)1, 5 ≤

2 >

where

1 ),

(1)

2 are the spread diameters (mm)

and

2,

r e s p e c t i ve l y,

2 ≤ 100, and Δ

1,1 ) > 40. In this test,

1

= (

2 −

1 was set to 10 s and2 to

100 s.

studies on physical properties are usuallyconducted at room temperature, no study has(mm) =

2 − 2(

2 −1) = 2)/(π 2

∞ ),

1 −

2.

(2)

been done under conditions that approximate(Pa) = (4.8

skin temperature.
In this study, the physical properties affecting

where

5

(3)

is the mass of the loading glass-plateis sample volume (m 3 ),functional usability were compared between the(kg),

brand-name and two generic topical 0.3%

free-fall velocity (m/s ), andheparinoid lotions at temperatures close to

spread diameter (m) at 200 s.

2is the standard∞ is the maximum

actual skin temperature, to provide information
to enable selection of the most appropriate drug

2-2. Fluidity test
The test followed the measurement method offor a specific patient application.

by Horisawa et al 14）. Using a syringe, 0.5

Methods

mL of the test drug preparation was dropped

1. Materials

onto an acrylic resin plate, the elevation angle ofBrand-name topical 0.3% heparinoid lot ion A

which was set to 45°, and the time (s) taken to

and generic lotions B and C were used. Before

move a distance of 100 mm was measured in a

the tests, the drugs were held for 1 h in a waterroom held at 25 ± 2℃. Each test was conductedbath ( Thermominder SDminiN, No. 3062017,

six times and the mean values calculated. When

TAITEC, Japan) that was set to 25°C.

the distance moved by the cut-off t ime (300 s)
w a s l e s s t h a n 1 0 0 m m , t h e d i s t a n c e m o ve d a t

2. Test methods

that time point was measured and the mean

2-1. Spread-meter test

values calculated.

The test followed the, as specified by JIS K5701-1:2000,

3. Statistical analysis. The

The spread diameter at 5 s was comparedtemperature of the laboratory was held at 25 ±between the brand-name and generic drugs, and

2℃. In addition to the value of 25 ± 0.5℃

the slope, intercept, and yield values measured at

specified by the standard, the application-surface

the application-surface temperature at 25 ±temperatures of the spread meter were also set

0.5℃ were compared w ith those at 31 ± 0.5℃

to 31 ± 0.5℃ or 33 ± 0.5℃ to simulate actualand 33 ± 0.5℃ using the mult iple comparison

mean skin temperature 12）. Each drug was applied

Dunnettʼs T3 test. The statistical significanceL i t h o g r a p h i c i n k s - Pa r t 1 : Te s t m e t h o d s

11）医薬品相互作用研究

level was set at a

-value below 0.05. All analyses

were conducted using

software (version

20.0, IBM, Japan).

Vol.43, No. 1（2019）27（27）

49.67 ± 0.75 mm and 65.92 ± 1.07 mm at 31± 0.5℃ and 49.67 ± 0.61 and 64.83 ± 1.51mm at 33 ± 0.5℃ after 5 and 200 s,
respectively. In contrast, the spread diameters ofResults
2-1. Spread-meter tests

generic drugs B and C were measurable only at 5s. The mean scale-over times of generic drugs B

Figure 1 shows the spread-meter test results.

and C were 10.5 ± 2.26 s and 8.2 ± 1.17 at 25

Brand-name drug A slowly spread until 200 s at

± 0.5℃, respectively, 8.8 ± 0.41 s (B) and 8.2

all application-surface temperatures. The mean

± 0.98 s (C) at 31 ± 0.5℃, and 9.8 ± 0.75 s (B)values of spread diameters on theand 7.8 ± 0.75 s (C) at 33 ± 0.5℃. All drugs

applicat ion-surface temperature at 25 ± 0.5℃

spread out from within 14 s at all

were 48.92 ± 0.49 mm (mean ± standard

application-surface temperatures. In

deviation, S.D.) and 61.00 ± 2.43 mm at 5 andconsequence, it was not possible to calculate the

200 s, respectively. Similarly, these values werecharacteristic values of

,

, and

Fig. 1. Mean values of spread diameter of 0.3% topical heparinoid lotions measured by spreadmeter at different application-surface temperatures. ( = 6, mean ± standard deviation)of the28（28）

医薬品相互作用研究

generic drugs.

Vol.43, No. 1（2019）

drugs B and C were significantly larger at 78.08

Figure 2 shows the mean values of the 5 s± 1.86 mm (< 0.001) and 82.83 ± 1.21 mm (spread diameters of the three drugs at each

< 0.001), respect ively. Even at 31 ± 0.5℃ andapplication-surface temperature. In comparison

33 ± 0.5℃, the mean spread diameters of thew ith brand-name drug A (48.92 ± 0.49 mm at

generic drugs at 5 s were significantly larger

25 ± 0.5℃), the spread diameters of genericthan that of brand-name drug A (< 0.001 for all

Fig. 2. Spread diameter at 5 s of brand-name and generic 0.3% heparinoid lotions measured by spread meter at different
application-surface temperatures. ( = 6, mean ± standard deviation)cases).

2-2. Fluidity tests
indices for

Table 2 shows the fluidity test results.

brand-name drug A at each applicat ion-surface

Table 1 shows the

,

, and

Brand-name drug A did not reach 100 mm withintemperature. When looking at changes withthe cut-off time of 300 s: the mean distanceapplication-surface temperature, thevalue ofmoved was 75.17 ± 1.72 mm. In contrast, the10.42 ± 0.20 at 31 ± 0.5℃ was significantly

mean times for movement of 100 mm of generichigher than that of 7.42 ± 1.59 at 25 ± 0.5℃ (drugs B and C were 0.69 ± 0.07 s and 0.51 ±< 0.05). There was no significant difference

0.04 s, respectively.

between the value of 9.58 ± 0.38 at 33 ± 0.5℃
and that at 25 ± 0.5℃.

showed no significant

Discussion

difference in comparison of values of 43.42 ±The purpose of this study is to compare the1.46 mm at 25 ± 0.5℃ with 41.67 ± 0.98 mm

differences in physical properties of brand-nameat 31 ± 0.5℃ and 42.50 ± 1.14 mm at 33 ±and generic drugs. Generally, variations in quality

0.5℃.

was 0.22 ± 0.02 Pa at 31 ± 0.5℃ andinclude variations among lots of the same

0.24 ± 0.03 Pa at 33 ± 0.5℃, both values being

product and variations in brand-name drug andsignificantly lower than that of 0.33 ± 0.07 Pa

other generic drug of the same pharmaceut ical

at 25 ± 0.5℃ (compound. However, with regard to the former,< 0.05 in all cases).

o n l y p h a r m a c e u t i c a l s c o n f o r m i n g t o a p p r o ve d

医薬品相互作用研究
Table 1. Slope ( ), intercept ( ), and yield value (( = 6, mean ± standard deviation)

Vol.43, No. 1（2019）29（29）) of 0.3% heparinoid lotions measured by spread meter.

Table 2. Time taken by 0.3% heparinoid lotions to move 100 mm on acrylic resin plate.
( = 6, mean ± standard deviation)

standards are in the market and it is consideredspread diameters of generic drugs B and C at 5 s

that there is no variation in quality among lots ofwere more than 1.5 times larger than that of

the same product in the market. Therefore, in thisbrand-name drug A at the three application-

study, we do not consider the physical properties

surface temperatures tested.

due to differences between lots and fo cused on

Brand-name drug A is categorized for lotion

physical differences between products of

preparation, having excellent spreadability whenbrand-name and generic drugs.

compared with ointments and creams containing

The spread meter is used to calculate the slope,intercept, and yield values of ointment
preparations. In these tests, brand-name drug

9,15）

t h e s a m e a c t i ve i n g r e d i e n t ( H i r u d o i d
0.3%, Hirudoid
Hiludoid

CreamSoft Ointment 0.3%, andLotion 0.3%. Pharmaceutical Interview

A slowly spread until 200 s after the start of theF o r m s , r e v i s e d i n F e b. 2 0 1 6 ( Ve r. 9 ) ) ; h o w e ve r,

test, making it possible to measure the spread

generic drugs B and C were more spreadable thandiameter; however, generic drugs B and C flowed

brand-name drug A. Generic drugs B and C are

out of the fixing plate within 14 s, making it

accordingly presumed to spread too far at narrow

impossible to calculate their values. The physicalapplication sites, such as fingers and arms, whenproperties of generic drugs B and C suggested acompared with drug A: the generic drugs willdefinite greater spread in comparison withremain for a shorter period at the affected site,brand-name drug A. Furthermore, the mean

but may be more easily applied onto broad sites,30（30）

医薬品相互作用研究

such as the back and chest, within a short time.
Of the property characterist ics calculated forbrand-name drug A,

Vol.43, No. 1（2019）b r a n d - n a m e d r u g A . H o w e ve r, t h e a d d i t i ve s o fgeneric drugs B and C do not contain the oily

was 10.42 ± 0.20 at 31 ±components. It was inferred that difference of

0.5℃, which was larger than the value of 7.42 ±addit ives influences physical propert ies in this1.59 measured at 25 ± 0.5℃. This allowed better

study.

spreading at higher temperature.

was 0.22 ±In this pilot study based on the use of an

0.02 Pa at 31 ± 0.5℃ and 0.24 ± 0.03 Pa at 33

appropriate applicat ion-surface temperature to± 0.5℃, compared with 0.33 ± 0.07 Pa at 25 ±compare the physical properties of brand-name0.5℃, indicating that it became softer withand generic drugs, the results revealed that theirhigher applicat ion temperature. In these tests,

physical properties did differ: it was not possible

theto calculate the indices ,value showed no significant difference at, orof the generic

the different temperatures. It is therefore

drugs. Pharmacists should therefore select drugs

considered necessary to evaluate these physicalappropriate for the patient application based on

properties of topical preparations, which aretheir physical properties.

likely to significantly affect the method ofConflicts of Interest

applicat ion and funct ional usability, at an
applicat ion-surface temperature approximat ing

The authors declare no conflicts of interest.

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