Note
Evaluation of the Film-Forming Ability for Heparinoid Cream Formulations
2025 年 73 巻 9 号 p. 852-856
詳細
2025 年 73 巻 9 号 p. 852-856
We compared the film-forming ability of a heparinoid cream (HP-C) formulation, an oil-in-water-type emulsion used as a moisturizer, and found that the original HP-C (HP-CO) formulation formed a thick and robust film that floated easily on an acrylic plate. It is suggested that the thickness and robustness of HP-CO contributed to the retention of its high keratin water content, while its floatability helped prevent adhesion to clothing after application. Among the generic HP-C formulations tested, only one (HP-CG1) formed a film with properties similar to those of HP-CO. When the HP-C formulations were mixed with white petrolatum, the floatability of the resulting film was eliminated, and the film easily disintegrated upon physical stimulation with a spatula. These results suggest that mixing the HP-C formulations with other ointment bases, such as white petrolatum, is not appropriate from the standpoint of film formation. Because peaks corresponding to glycerin (GL) were clearly observed in the near-IR spectra of both HP-CO and HP-CG1 after 24 h at room temperature, we explored the addition of water-soluble polyhydric alcohols, such as GL and propylene glycol (PG), to generic HP-C formulations that did not initially demonstrate good film-forming properties. The state of the film and its floatability tended to improve when these generic HP-C formulations were mixed with GL or PG. Thus, these results indicate that the film-forming ability differed depending on the HP-C formulation. Furthermore, the results suggest that GL played a key role in the successful film formation observed in both HP-CO and HP-CG1.
Heparinoid cream (HP-C), which is mainly used as a moisturizer, is a type of oil-in-water (o/w) formulation. It is available in original and generic formulations. Heparinoid is a mucopolysaccharide used as an active pharmaceutical ingredient (API). In recent years, it has become evident that, beyond its physical water retention action on the skin surface, various pharmacological effects have also been observed.1,2)
In contrast, a comparative study of keratinocyte water content in human skin revealed that treatment with the original HP-C formulation resulted in significantly higher hydration levels than treatment with the generic formulation.3) One possible reason for the difference in clinical efficacy between the original and generic HP-C formulations is the formation of a film at the site of application of the original formulation.4) This film is believed to be derived from non-APIs, such as stearic acid and cetostearyl alcohol.4) It has also been found that the original HP-C formulation is less likely to adhere to clothing than the experimental o/w-type cream formulation containing 0.3% heparinoid and having no film-forming ability,4) suggesting that this film plays a role in that effect. However, no scientific studies have yet been published on the characteristics of this film. Thus, we focused on the film-forming ability of HP-C formulations and compared the original formulation with that of several generic alternatives, and investigated factors contributing to the formation of high-quality films.
The HP-C formulations, Hildoid® cream 0.3% (Lot. EA0S7, Maruho Co., Ltd., Osaka, Japan; HP-CO), heparinoid cream 0.3% [Amel] (Lot. 2301, KYOWA Pharmaceutical Industry Co., Ltd., Osaka, Japan; HP-CG1) (Manufacturing and marketing approval succeeded to KENEI Pharmaceutical Co., Ltd., Osaka, Japan, in September 2024.), heparinoid cream 0.3% [YD] (Lot. Y24003, Yoshindo Inc., Osaka, Japan; HP-CG2), heparinoid cream 0.3% [Rakool] (Lot. 99255D, Rakool Pharmaceutical Marketing Co., Ltd., Tokyo, Japan; HP-CG3), and heparinoid cream 0.3% [Nichi-Iko] (Lot. BP060, Nichi-Iko Pharmaceutical Co., Ltd., Toyama, Japan; HP-CG4), were analyzed. The non-API values for each HP-C formulation are listed in Table 1.5–9)
| HP-C formulations | Non-APIs |
|---|---|
| HP-CO | glycerin, stearic acid, potassium hydroxide, white petrolatum, lanolin alcohol, cetostearyl alcohol, mixture of cetostearyl alcohol and sodium cetostearyl sulfate, myristyl alcohol, methyl paraoxibenzoate, propyl paraoxibenzoate, isopropanol |
| HP-CG1 | glycerin, white petrolatum (contains dibutylhydroxytoluene as antioxidant), stearic acid, cetostearyl alcohol, myristyl alcohol, 2, 2′, 2″-nitrilotriethanol, thymol, methyl paraoxibenzoate, propyl paraoxibenzoate |
| HP-CG2 | cetomacrogol, glycerin stearate, triglycerides of medium-chain fatty acids, cetostearyl alcohol, petrolatum (contains BHT as antioxidant), propylene glycol, glycerin, methylparaben, propylparaben, sodium edetate hydrate, diisopropanolamine, pH adjustment regulators |
| HP-CG3 | cetostearyl alcohol, sodium edetate hydrate, thymol, diethanolamine, stearic acid, 1,3-butylene glycol, synthetic squalane, polyoxyl stearate, glycerin stearate |
| HP-CG4 | cetanol, petrolatum, liquid paraffin, isopropyl myristate, macrogol stearate, butyl paraoxybenzoate, methyl paraoxybenzoate, propylene glycol, d-sorbitol |
White petrolatum (WP) was purchased from Maruishi Pharmaceutical Co., Ltd. (Osaka, Japan, Lot. 664007). Glycerin (Lot. SKF4281: GL) and propylene glycol (Lot. ACR6851: PG) were purchased from FUJIFILM Wako Pure Chemical Corporation (Osaka, Japan).
Preparation of MixturesMixtures of HP-C formulations and WP (mass mixing ratio 1 : 1), and mixtures of HP-C formulations and GL or PG (GL concentration: 5 and 10%; PG concentration: 10%) were prepared using a dual-action ointment mixer that combines spinning and revolving motions (NRJ-250, THINKY Corporation, Tokyo, Japan) under the following conditions: 1500 rpm for 30 s.
Film Formation TestThe HP-C formulation, alone or in mixtures, were each uniformly applied to a black acrylic plate with an area of 2.5 × 2.5 cm (6.25 cm2) using a finger covered by a laboratory glove. The weight after application was confirmed to be 10.0 mg (1.6 mg/cm2: equivalent to 1 FTU [1 fingertip unit]) or 30.0 mg (6.4 mg/cm2: equivalent to 3 FTU). The samples were then allowed to stand for 3 h at room temperature. Next, the acrylic plate coated with the sample was immersed in a hot water bath (40°C) for 15 min to visualize the film, and the state of the film formation was visually evaluated according to the criteria listed in Table 2. In addition, the presence or absence of floating films in the hot water bath was evaluated. When floating of the film was observed, damage“ + ” was determined when the film was physically stimulated with a spatula and destruction of the film was observed. When no floating film was observed, damage“ + ” was determined when the film was lightly rubbed with a spatula and destruction of the membrane was observed. Films with a state of “++” or higher (Table 2), film floating of “+,” and damage caused by physical stimulation of “−” were evaluated to be high quality.
| State | Condition equivalent to the state |
|---|---|
| − | No film forming |
| ± | A film-like substance was observed (which was destroyed and disappeared in the hot water bath) |
| + | Only a part of the film is formed (cutting of the film is observed) |
| ++ | A very weak film is formed (although the film is thin overall, some cutting of the film may be observed) |
| +++ | A strong film is formed (the film becomes thick overall and there is no cutting of the film) |
| ++++ | A very strong film is formed (significantly stronger than +++) |
| +++++ | A very thick and strong film is formed (significantly stronger than ++++) |
The HP-C formulations were removed from the tube and thinly spread onto a quartz plate for the NIR measurements. The NIR spectra were recorded immediately after removal from the tube, as well as 3 and 24 h after the formulations were spread on the quartz plate, using a transmission method (optical path length: 0.2 mm). The measurements were performed with an NIR spectrometer (Spectrum One NTS, PerkinElmer Inc., Waltham, MA, U.S.A.) at a resolution of 8 cm−1, with 32 scans across the wavelength range of 4000–12000 cm−1 (background: air).
Figure 1 shows the results of the film formation test for the HP-C formulation alone. In each formulation, film formation was more pronounced with the application of 3 FTU) compared to the application of 1 FTU. The films of HP-CO and HP-CG1 formed by the application of 1 FTU floated in a hot water bath and were not damaged by physical stimulation with a spatula. Relatively thick and robust films were formed with the 3-FTU application of HP-CO and HP-CG1, and these films floated in a hot water bath. The film flotation occurred earlier in HP-CO than in HP-CG1.
State: The film conditions were evaluated according to the criteria listed in Table 2. Floating: +, the film floats completely in the bath; ±, part of the coating floats; −, the film did not float. Damage: +, after the film formed, it was easily broken by light poking with a spatula; −, the film was not damaged, even when lightly poked with a spatula. Blue painted areas indicate conformance to high-quality film requirements.
The thin film was formed following the application of the 1 FTU of HP-CG2, and the film did not float. Although floatability was observed with the 3-FTU application, both the 1- and 3-FTU films were easily disrupted by physical stimulation with a spatula. For HP-CG3, a film similar in appearance to that of HP-CG2 was observed. Both the 1- and 3-FTU applications of HP-CG3 showed a tendency to float; however, some damage was observed during flotation. In contrast, HP-CG4 produced the thinnest film among the HP-C formulations, and no floatation was observed. This is likely due to the absence of non-APIs essential for film formation in the HP-CG4 formulation4) (Table 1).
The WP exerts its moisturizing effect by coating the skin, but has the disadvantage of easily adhering to clothing. HP-CO has been shown to be less likely to adhere to clothing than certain generic formulations.4) Because of this property, it is expected to remain on the skin without adhering to clothing after application and exert an excellent moisturizing effect. In this study, although the materials of the clothing and the acrylic plate are not necessarily identical, the property of the film that easily separates from the acrylic plate (i.e., tends to float) in a hot water bath is thought to be partially responsible for its difficulty in adhering to clothing. This behavior may be related to the low adherence of the formulation to clothing, even though the materials involved are different. In contrast, it has been suggested that formulations that form a nonfloating film adhere easily to clothing, similar to WP. The movies of film forming test of HP-CO and HP-CG4 were shown in Supplementary Materials (left: HP-CO, right: HP-CG4, respectively).
Film-Forming Ability in Mixtures of HP-C Formulations and WPAs mixed prescriptions of HP-C formulations and other ointment formulations are often observed in clinical practice. WP is the main base used in the majority of ointments that are likely to be mixed with HP-C formulations in clinical practice. Therefore, a film formation test was performed on a mixture of the HP-C formulation and WP (Fig. 2). Although film formation was observed for both application amounts (1 FTU and 3 FTU) in all the mixtures of HP-C formulations and WP, no floating film was observed in the hot water bath. These results suggest that mixing WP with HP-C formulations impairs the properties of the film, likely due to an increased proportion of oleaginous components in the film. In general, mixing o/w-type HP-C formulations with steroid ointments that contain fatty bases is considered undesirable from the standpoint of base stability. This study further indicates that such mixing is also inappropriate in terms of film formation.
State: The film conditions were evaluated according to the criteria listed in Table 2. Floating: +, the film floats completely in the bath; ±, part of the coating floats; −, the film did not float. Damage: +, after the film formed, it was easily broken by light poking with a spatula; −, the film was not damaged, even when lightly poked with a spatula.
The NIR spectra of the HP-C formulations showed peaks at 4300 and 5700 cm−1 reflecting the combination band and 1st overtone band of hydrocarbons, and peaks at 5200 and 6900 cm−1 reflecting the combination band and 1st overtone band (or combination band of symmetric and asymmetric stretching vibrations) of hydroxyl groups from water10) (Supplementary Fig. S1). After application to the quartz plate for the NIR measurement, the peak reflecting the water content gradually decreased over time (Supplementary Fig. S1). Three hours after application, a peak at 5200 cm−1 was observed in HP-CO and HP-CG1, accompanied by a shoulder near 4800 cm−1 (Fig. 3a). These formulations produced thick films with a high degree of floatation. At 24 h after application, the 5200 cm−1 peak in HP-CO and HP-CG1 had further diminished, while a distinct peak near 4800 cm−1 became evident in both formulations (Fig. 3b).
The formulations that have been left for (a) 3 h or (b) 24 h after being spread on a quartz plate. NIR: near-IR.
In the NIR spectra of water-soluble polyhydric alcohols, such as GL and PG, a peak originating from the alcoholic hydroxyl group typically appears around 4800 cm−1. Furthermore, in a previous study, we reported that the NIR spectrum of a cream formulation with high PG content,11) showed a gradual decrease in the water-related peak at 5200 cm−1 over time, accompanied by the emergence of a clear peak near 4800 cm−1.12) Most HP-C formulations contain polyhydric alcohols such as GL and PG (Table 1), suggesting that these non-APIs play a significant role in the appearance of the peak at approximately 4800 cm−1. This peak was more prominent in HP-CO and HP-CG1 than in the other formulations (Fig. 3b), suggesting that these products may contain higher levels of GL, which could contribute to improved film quality.
Effect of Water-Soluble Polyhydric Alcohols on the Film-Forming Ability of HP-C FormulationsAs the results of the NIR measurements strongly suggested that GL contributes to film quality, we mixed GL (5 and 10%) and PG (10%) with HP-CG2, HP-CG3, and HP-CG4 to evaluate whether the film properties differed compared to those of the original formulations (Fig. 4). Although HP-CG2 showed a smoother film and significant improvement in floatability when mixed with GL (5 and 10%), the sample mixed with GL (5%) was easily disrupted by physical stimulation with a spatula. No damage was observed in the mixture of HP-CG2 and GL (10%) after physical stimulation. In HP-CG3, mixing with GL (5 and 10%) produced a smoother film similar to that of HP-CG2, and a marked improvement in floatability was observed; however, the film was easily damaged by physical stimulation. Similar film formation was also observed in the mixtures of HP-CG2 and PG, or HP-CG3 and PG; however, physical stimulation caused damage only in the mixture of HP-CG2 and PG. Mixing HP-CG4 with GL or PG showed a tendency to float in some cases but did not improve floatability, as in HP-CG2 and HP-CG3. The effects of polyhydric alcohols on film formation were not completely consistent across the HP-C formulations; however, this may be due to differences in the composition of the non-APIs in the HP-C formulations. Nevertheless, these results suggest that polyhydric alcohols play a significant role in forming high-quality films, particularly in improving the film’s floatability.
The application amount of the mixtures was 3 FTU. State: The film conditions were evaluated according to the criteria listed in Table 2. Floating: +, the film floats completely in the bath; ±, part of the coating floats; −, the film did not float. Damage: +, after the film formed, it was easily broken by light poking with a spatula; −, the film was not damaged, even when lightly poked with a spatula. Blue painted areas indicate conformance to high-quality film requirements.
This study showed that although the HP-C formulation formed a film upon application, its robustness and floatability in a hot water bath varied depending on the specific formulation. However, many aspects of HP-C film formation remain unclear. Future research should focus on evaluating the physical properties of the films and their contribution to moisture retention of the film.
This study was funded by a research grant from Teikyo Heisei University. Y. Yamamoto received a lecture fee for academic seminars for pharmacists from Maruho Co., Ltd.
This article contains supplementary materials.
