Topical Formulations of Propranolol for Infantile Hemangiomas: Characteristics of Formulations and Three Cases of Infants Administered Topical Propranolol Cream

Abstract

Propranolol is used as the first-line treatment for infantile hemangiomas (IHs). As oral formulations can cause systemic adverse drug reactions (ADRs), we prepared topical propranolol formulations and evaluated their pharmaceutical profiles. We also present three cases of pediatric patients with IHs who were treated with the propranolol formulations. Propranolol cream (hydrophilic cream, 1, 3, and 5%) and gels (carboxyvinyl polymer, hydroxypropyl methylcellulose, gellan gum, 1%) were prepared. The in vitro skin permeability of these formulations was assessed using Franz-type diffusion cells. The pharmaceutical profiles, including propranolol content, pH, and ductility, of the propranolol creams were evaluated. For the stability test, similar pharmaceutical evaluations were performed after the creams were stored at 25 °C and 56% relative humidity for 3 months. We examined three patients treated with propranolol cream to investigate the clinical course of IH and adverse events after the propranolol cream was applied for 5–12 months. In the in vitro skin permeability assay, topical propranolol formulations made of hydrophilic cream and gellan gum permeated the most. The amount of propranolol that permeated increased with propranolol concentration. After storage for 3 months, no substantial changes were observed in any pharmaceutical profile. The IHs were discolored in all patients. Tumor size also decreased in some patients. Furthermore, no adverse events caused by propranolol cream were observed during application. In conclusion, propranolol cream can be prepared as a hospital formulation with adequate quality. Topical propranolol therapy is effective in reducing the incidence of systemic ADRs.

Introduction

Infantile hemangiomas (IHs) are one of the most common tumors of infancy and are benign and more common in girls and premature infants.¹⁾ IHs develop within 1 week after birth and rapidly grow at approximately 3–6 months of age (proliferation phase). Many IHs spontaneously involute by approximately 1 and 5 years of age (involution phase) and then resolve at or after 5 years of age (resolution phase). Thus, IH is often managed by observation.¹⁾ Meanwhile, IH may adversely affect the appearance and mentality of infants because approximately 60% of IHs occur in the head and neck region. Furthermore, approximately 24% of IH cases cause complications. The major complications include ulceration, visual disturbance, and airway obstruction.²⁾ Patients with such complications require treatment, including systemic therapy.^3,4) Therapeutic interventions typically performed include surgical interventions, laser therapy, oral administration, or local injection of steroids. However, surgical intervention and laser therapy are highly invasive. In addition, oral administration and local injection of steroids are associated with a high incidence of adverse drug reactions (ADRs). The administration of steroid therapy requires caution.

Oral administration of propranolol, a β-adrenergic antagonist, was reported to be useful in France in 2008, when children with hypertrophic obstructive cardiomyopathy complicated by IH were treated with propranolol and showed improvement in IHs.⁵⁾ At present, oral propranolol formulations are approved as pharmaceutical agents in Japan, the United States, and other countries worldwide and are used as the first-line treatment for IHs that are associated with a risk of dysfunction and esthetic problems.⁵⁾ Propranolol has several mechanisms of action on IHs, such as vasoconstriction,⁶⁾ cell growth inhibition,^7,8) antiangiogenesis,⁹⁾ and apoptosis induction.^10,11) Although oral propranolol therapy is highly effective, it causes systemic ADRs, such as bronchospasm, bradycardia, hypotension, hypoglycemia, and sleep disturbances.¹²⁾ This therapy is not necessarily applicable to all patients.

Topical skin application can help maintain high drug concentrations at local or focal sites and is also a characteristically easy method of administration. In drug therapy for IHs, topical propranolol formulations can selectively increase concentrations of propranolol at the focal sites of IHs, which develop on or under the skin surface. Thus, topical skin application may ensure the efficacy of propranolol and simultaneously reduce the incidence of systemic ADRs compared to oral administration. In addition, topical formulations are easier to administer to infants than oral formulations. There have been several studies on topical propranolol formulations used for the treatment of IH.^13–17) However, few have evaluated the skin permeability and pharmaceutical profiles of topical propranolol formulations.

Thus, in the present study, we prepared four types of topical propranolol formulations (cream and gel) and aimed to elucidate their pharmaceutical profiles. Here, we also present a case series in which propranolol creams were selected from these topical propranolol formulations and applied to three pediatric patients with IHs. Because no topical propranolol formulations are commercially available, such formulations may be prepared at hospitals and pharmacies and applied to patients to meet various medical needs in clinical settings. Therefore, we identified a simple method for preparing topical propranolol formulations with excipients readily available at hospitals and pharmacies.

Experimental

Materials

Propranolol hydrochloride was purchased from the Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan). Hydrophilic cream was purchased from Mylan Seiyaku Ltd. (Tokyo, Japan). Polyethylene glycol 400 (PEG400) was purchased from Sanyo Chemical Industries, Ltd. (Kyoto, Japan). Propylene glycol was purchased from Kanto Chemical Co., Inc. (Tokyo, Japan). Carboxyvinyl polymer (Carbopol 940 NF polymer) was purchased from Lubrizol Advanced Materials (OH, U.S.A.). Hydroxypropyl methylcellulose (HPMC, METOLOSE 60SH-4000) was purchased from the Shin-Etsu Chemical Co., Ltd. (Tokyo, Japan). Gellan gum (Kelcogel HM) was purchased from the DSP Gokyo Food & Chemical Co., Ltd. (Osaka, Japan). Ammonia solution was purchased from the Tokyo Chemical Industry Co., Ltd. All other chemicals used were of reagent grade.

Methods

Preparation of Topical Propranolol Formulations

Table 1 shows the composition of the four types of topical propranolol formulations. Propranolol hydrophilic cream (PHC) was prepared according to the following procedure: Propranolol hydrochloride was added to a 10% PEG400 solution and sonicated for 15 min to prepare propranolol dispersion solutions at three concentrations (5, 15, and 25%). Each propranolol dispersion solution (4 g) was added to a hydrophilic cream (16 g) and mixed with a planetary centrifugal mixer (Awatori-Rentaro™ AR-500, Thinky, Tokyo, Japan) at a centrifugal acceleration of 100 × g for a mixing time of 1 min to prepare 1, 3, and 5% PHCs.

Table 1. Composition of Cream and Gel Formulations Containing Propranolol Hydrochloride

Ingredients (%)	Cream and gel formulation (content of propranolol hydrochloride)
	PHC			PCVPG	PHPMCG	PGGG
	1%	3%	5%	1%	1%	1%
Propranolol hydrochloride	1.0	3.0	5.0	1.0	1.0	1.0
Polyethylene glycol 400	1.9	1.7	1.5	—	—	—
Propylene glycol	—	—	—	24.5	—	—
Ethyl alcohol	—	—	—	24.5	—	—
Hydrophilic cream	80	80	80	—	—	—
Hydroxypropyl methylcellulose (METOLOSE 60SH-4000)	—	—	—	—	5.0	—
Carboxyvinyl polymer (Carbopol 940 NF polymer)	—	—	—	2.0	—	—
Gellan Gum (Kelcogel HM)	—	—	—	—	—	0.3
Ammonia Solution	—	—	—	1.6	—	—
Purified water	17.1	15.3	13.5	46.4	94.0	98.7
Total	100	100	100	100	100	100

PHC, propranolol-hydrophilic cream; PCVPG, propranolol-carboxyvinyl polymer gel; PHPMCG, propranolol-hydroxypropyl methylcellulose gel; PGGG, propranolol-gellan gum gel.

Propranolol carboxyvinyl polymer gel (PCVPG) was prepared by mixing propylene glycol and ethanol at a 1 : 1 ratio, and propranolol hydrochloride (300 mg) was dissolved in this solution (14.7 g). Purified water (14.2 g) and carboxyvinyl polymer (0.6 g) were added to this solution. Finally, a 28% ammonia solution (0.2 g) was added to prepare 1% PCVPG.

Propranolol HPMC gel (PHPMCG) was prepared according to the following procedure: Propranolol hydrochloride (250 mg) was added to the purified water (23.5 g) and dispersed. To this product, HPMC (1.25 g) was added and stirred to prepare 1% PHPMCG.

To prepare the propranolol gellan gum gel (PGGG), gellan gum (0.3 g) was added to purified water (95 g) and stirred for 5 min while being heated to 90 °C. Propranolol hydrochloride (1 g) was added to the solution and mixed. Purified water was added to obtain a total volume of 100 g, which was then stirred and cooled to less than 10 °C in an ice bath. The resultant solution was used as a 1% PGGG.

In Vitro Skin Permeability Assay of the Propranolol Creams and Gels

An in vitro skin permeability assay of propranolol creams and gels was performed as previously reported.¹⁷⁾ Pig ear skin was placed in a vertical Frantz-type diffusion cell (effective diffusional area: 3.14 cm²; receptor volume: 16 mL) with the stratum corneum side facing the donor chamber and the dermal side facing the receptor chamber. PHCs (1, 3, and 5%), PCVPG, PHPMCG, and PGGG were applied to the stratum corneum side at a dose of 200 mg/3.14 cm², and the solution in the receptor chamber was collected 24 h later. The receptor chamber was filled with phosphate-buffered saline at a pH of 7.4, which was maintained at 37 °C. The propranolol concentration in the solution collected from the receptor chamber was measured by HPLC to calculate the amount of skin permeation 24 h after application.

pH of the Propranolol Creams

To measure the pH of the PHCs (1, 3, and 5%), the electrode of a pH meter (Docu-pH meter, Sartorius AG, Niedersachsen, Germany) was inserted into a 20 g sample.

Ductility of the Propranolol Creams

Ductility was evaluated using a parallel-plate viscometer (Kumagai Riki Kogyo Co., Ltd., Tokyo, Japan). A PHC sample (1, 3, or 5%) was placed in a cylindrical hole (0.5 cm³) at the center of the viscometer, and the loading plate was dropped on the sample. The diameter of the spread sample (D_∞, cm) was measured 180 s later. The yield value (YV, dyne/cm²) was calculated using the following formula:

  

(1)

where W represents the mass of the loading plate (115 g), V represents the sample volume (0.5 cm³), and g_n represents the standard acceleration of free fall (980 cm/s²).

Drug Content in the Propranolol Creams

For each PHC sample (100 mg, 1, 3, or 5%), 10 mL of a mixture of purified water and methanol (1 : 1) and 1 mL of a methanol solution of furosemide (1 mg/mL) were added. The resultant mixture was agitated using a vortex mixer. Purified water was then added to obtain a total volume of 100 mL. This solution was filtered through a hydrophobic polytetrafluoroethylene membrane filter (TORAST™ Disc, Shimadzu GLC Ltd., Tokyo, Japan) and analyzed by HPLC.

Stability Test

Each PHC sample (20 g, 1, 3, and 5%) was placed into an ointment container (polypropylene, MI Chemical Co., Ltd.). The storage conditions were 25 °C and 56% relative humidity (RH). The samples were evaluated immediately after preparation and after 3 months of storage. The test items included changes in visual appearance, drug content, pH, and ductility. In addition, PHCs provided to the patients (1 and 3%) were collected and stored at room temperature in the patients’ homes or an examination room of our hospital. The drug content of the PHCs was measured using HPLC.

HPLC Measurement Conditions

Propranolol was analyzed using HPLC (Shimadzu Corporation, Kyoto, Japan). The HPLC system consisted of an online degassing unit (DGU-20A3), solution sending unit (LC-20AD), column oven (CTO-20AC), autosampler (SIL-20AC), photodiode array UV visible detector (SPD-M20A), and system controller (CBM-20A). The column used was CAPCELL PACK C18 (3.0 × 150 mm, 3 µm, Shiseido Co., Ltd., Tokyo, Japan) and was set at 40 °C. Purified water was added to 3.5 mL of triethylamine to obtain a total volume of 500 mL. Phosphoric acid was added to achieve a pH of 3.0. This solution was mixed with acetonitrile at a ratio of 65 : 35, and the resultant mixture was used as the mobile phase. The flow rate was 0.3 mL/min, the measurement time was 10 min, the detection wavelength was 291 nm, and the injection volume was 10 µL. The analysis software used was the LC solution (version 1.25; Shimadzu Corporation).

Cases

Infants with superficial IHs were treated with PHCs at the outpatient clinic of Iwata City Hospital (Shizuoka, Japan) between October 2016 and August 2017. Data on demographics, laboratory tests, treatment courses, and IH lesions of the infants were obtained from electronic medical records. We obtained approval from the Institutional Review Board of Iwata City Hospital and informed consent from the parents of all infants.

Statistical Analysis

Statistical analyses were performed using the GraphPad Prism software (version 5.0; GraphPad, CA, U.S.A.). The results are expressed as the mean ± standard deviation. Statistically significant differences were determined using Tukey’s and Dunnett’s multiple comparison tests. A p-value of less than 0.05 was considered to indicate a significant difference.

Results

In Vitro Skin Permeability Assay of the Propranolol Creams and Gels

Figure 1 shows the cumulative permeation amount of propranolol creams (PHCs) and gels (PCVPG, PHPMCG, and PGGG) 24 h after application to pig ear skin in the in vitro skin permeability assay. When the 1% propranolol formulations of cream and gel were compared, the cumulative amounts of propranolol that permeated the PCVPG, PHPMCG, PGGG, and PHC were 0.8, 8.0, 21.1, and 16.5 µg, respectively. Significantly more propranolol permeated the PHC and PGGG than the PCVPG (p < 0.05). Furthermore, the comparison of the permeation amount between the 1, 3, and 5% PHCs showed a concentration-dependent increase in the cumulative permeation amount. The cumulative permeation amount for the 5% PHC was 1.9 times higher than that for the 1% PHC (Fig. 1).

Fig. 1. In Vitro Skin Permeation Profiles until 24 h after Application of Propranolol Cream and Gels

Propranolol cream (hydrophilic cream, PHC) and gel formulations (carboxyvinyl polymer, PCVPG; hydroxypropyl methylcellulose, PHPMCG; gellan gum, PGGG) were applied to pig skin, and the in vitro skin permeability was measured using Franz-type diffusion cells (effective diffusional area: 3.14 cm², receptor volume: 17 mL). The values represent the cumulative amount of propranolol. Columns show the mean ± standard deviation of 3 (PCVPG, PHPMCG, and PGGG) and 6 (PHC) determinations. Asterisks indicate a significant difference compared with propranolol cream and gel formulations using Tukey’s multiple comparison test, * P < 0.05.

Pharmaceutical Evaluation of the Propranolol Creams

The PHCs (1, 3, and 5%) appeared white immediately after preparation and no separation was observed. Table 2 shows the results of the pharmaceutical evaluation (drug content, pH, and ductility) of the PHCs (1, 3, and 5%). The drug content after preparation of the 1, 3, and 5% PHCs ranged from 99 to 103% of the theoretical content. The measured content was comparable to the theoretical content. All PHCs were mildly acidic. The YV, which indicates ductility, was higher as the propranolol concentration in the PHCs increased.

Table 2. Drug Content, pH, and Ductility of Propranolol Creams (PHC, 1, 3, and 5%) Initially (at Preparation) and after 3 Months of Storage at 25 °C and 56% RH

PHC	Drug content (mg/g)	pH	Yield value (dyne/cm2)
Initial (at preparation)
1%	10.0 ± 0.1 (100%)	3.90 ± 0.04	371 ± 29
3%	29.8 ± 0.2 (99%)	3.68 ± 0.08	471 ± 34
5%	51.5 ± 0.9 (103%)	3.66 ± 0.02	543 ± 41
After 3 months of storage (25 °C, 56% RH)
1%	10.2 ± 0.1 (102%)	3.79 ± 0.04	425 ± 35
3%	31.4 ± 0.3 (105%)	3.66 ± 0.05	588 ± 85
5%	51.7 ± 0.6 (103%)	3.70 ± 0.04	677 ± 49

PHC, propranolol hydrophilic cream; RH, relative humidity. Drug content data are provided as the mean ± standard deviation (n = 4) and percentage of the formulation. Data on pH and ductility are provided as the mean ± standard deviation (n = 4).

The PHCs (1, 3, and 5%) were stored at 25 °C and 56% RH for 3 months. None of the PHCs showed either separation or coloring, and no change in their appearance was observed. No significant changes were observed in any of the test items (i.e., drug content, pH, or ductility) 3 months after preparation (Table 2).

In addition, the drug content of the PHCs (1 and 3%) that were provided to the patients was measured and subsequently returned to their attending physicians. Each PHC was stored in the patients’ homes or in an examination room for up to 12 months. As shown in Fig. 2, the drug content of the 1 and 3% PHCs decreased over time. It was 97.0% of the theoretical content at 6 months after preparation and 89.8% at 12 months after preparation.

Fig. 2. Relationship between Drug Content and Time after Preparation in 1% Propranolol Cream (A) and 3% Propranolol Cream (B) Returned from the Patient

Each point represents data of propranolol creams returned from the patients (1%, n = 18; 3%, n = 13). Dotted line shows the 90% level of drug contents.

Cases of Infants Administered Topical Propranolol Cream

In all three patients examined, none of the IHs were located in life-threatening areas. The patients had not received any treatment for IH before the start of the application of the PHCs. The PHCs were applied twice daily as a thin layer onto the entire surface of the IH by gently rubbing with a fingertip. Table 3 shows the demographics of the patients examined (Cases #1 to #3), and Fig. 3 shows images of the IH lesions.

Table 3. Demographics and Descriptions of Treatment Lesions of Hemangioma in Three Cases Treated with the Propranolol Cream

Case	Sex	Age (months) at start of administration	Height (cm) at start of administration	Weight (kg) at start of administration	Location and type of hemangioma	Size of hemangioma at start of therapy (mm)
#1	Female	13	77.5	9.02	Upper lip and a superficial hemangioma	9 × 8
#2	Female	11	67.2	7.47	Left forearm and a superficial hemangioma	8 × 6
#3	Female	3	59.0	6.31	Right ankle joint and multiple type of hemangioma	Not measurable

Size of hemangioma at the start of therapy is provided as the length × width.

Fig. 3. Images of the Infantile Hemangiomas before and after the Start of Application of Propranolol Cream in Three Patients

Patients were instructed to apply propranolol cream (1 and 3%) twice a day in a thin layer to the infantile hemangioma. Case 1 was a 13-month-old girl with a superficial hemangioma on the upper lip. Upper, before treatment. Lower, 10 months after propranolol cream treatment. Case 2 was an 11-month-old girl with a superficial hemangioma on the left forearm. Upper, before treatment. Lower, 12 months after propranolol cream treatment. Case 3 was a 3-month-old girl with multiple types of hemangiomas on the right ankle joint. Upper, before treatment. Lower, 5-months after propranolol cream treatment.

Case #1

Case #1 was a 13-month-old girl. IHs (one site, 9 × 8 mm) were observed on the upper lip, and application of 1% PHC was started. The IH became discolored after 1 month of application. Because no change in the lesion was observed between 1 and 2 months of application, the 1% PHC was switched to 3% PHC. Subsequently, the IHs gradually disappeared. After 10 months of application, the size of the IH lesion decreased to 7 × 7 mm, and the IH was discolored and became almost indistinguishable from the surrounding skin. Thus, treatment was completed.

Case #2

Case #2 was an 11-month-old girl. IHs (one site, 8 × 6 mm) were observed on the left forearm, and application of 1% PHC was started. Because redness was noted on the left cheek of the patient after the start of application, her parent was concerned and brought her to our hospital (after 2 weeks of application). The pediatrician suspected an ADR to the PHC and suspended application for approximately 1 week. When application of the PHC was later resumed, redness on the left cheek disappeared. The physician considered that the PHC was unlikely to have caused the redness, and application was continued. Although the IHs tended to become discolored after 1 month of application, discoloration did not progress after 3 months of application. Thus, 1% PHC was switched to 3% PHC. After 12 months of application, although the size of the IH lesion remained unchanged (7 × 7 mm), the IH lesions were discolored compared to their appearance at the initial examination.

Case #3

Case #3 was a 3-month-old girl. Multiple types of IH were observed on the right ankle joint (size: unknown), and application of 1% PHC was started. The IHs tended to resolve after the application of PHC. Three months after the start of application, 1% PHC was switched to 3% PHC. The IHs were discolored from red at the initial examination to brown after 5 months of application, and the scars decreased.

Discussion

The present study aimed to elucidate the pharmaceutical profiles of propranolol cream and gel that were easily prepared with excipients readily available at hospitals and pharmacies. Because the target site of IHs is located in the region from the upper dermis to the subcutaneous adipose tissue,¹⁸⁾ propranolol, which is the active ingredient of these transdermal formulations, must be delivered to at least the dermis. To achieve the therapeutic concentration in the dermis, the drug needs to effectively permeate through the stratum corneum and epidermis, which represent the uppermost skin barrier. Thus, we performed an in vitro skin permeability assay to evaluate propranolol cream and gel. At a 1% propranolol concentration, the cream formulation made of hydrophilic cream and the gel formulation made of gellan gum showed higher permeability. This suggested that these formulations could be delivered to the pathological sections of IHs at high concentrations. Several transdermal formulations containing propranolol hydrochloride have been reported to date. Casiraghi et al. reported that the in vitro skin permeability of hydrophilic cream (oil-in-water base) is significantly higher than that of hydrophobic ointment (grease base) and lipophilic ointment (water-in-oil base).¹⁹⁾ Although there has been a report of a formulation using HPMC as a gel base,²⁰⁾ the present study results showed that the gellan gum-based gel generates better permeability than HPMC. Gellan gum promotes skin hydration, decreasing the barrier function of keratin.²¹⁾ This property is likely to be more advantageous for improved propranolol permeability. Stratum corneum permeability is increased by inflammation, so the drug transport may be increased because of IHs.²²⁾ Therefore, other formulations tested in this study could show drug efficacy against IHs. Further investigation of bases with better permeability is an interesting topic for future studies. While the transdermal formulations using hydrophilic cream and gellan gum were comparable in terms of permeability, the hydrophilic cream-based formulations were applied to the patients in the present study because they were easier to prepare and are widely used as pharmaceutical agents.

Because topical propranolol formulations are not commercially available, the present study was conducted based on the assumption that such formulations would be prepared at hospitals and pharmacies. We demonstrated through our preparation methods that formulations with consistent quality can be easily prepared without the use of special equipment. In the present study, the suspension of propranolol hydrochloride in a 10% PEG400 solution allowed us to prepare formulations, including the cream with a high propranolol concentration (5%), which had a drug content comparable to the theoretical content. Furthermore, the creams used in the present study were mildly acidic, and their pH was close to that of 4.1–5.8 on a healthy skin surface.²³⁾ Most commercially available ointments and creams are reported to have a YV of 42.1–1621 dyne/cm².²⁴⁾ Because the YVs of the creams prepared in the present study were close to these values, they appear to be as easy to use as commercially available ointments.

After the propranolol creams were stored at 25 °C and 56% RH for 3 months, no changes in appearance, such as separation or coloring, were macroscopically detected, and the drug content did not decrease. Although few studies have investigated the storage stability of such formulations, the results of the present study revealed that the storage stability of PHCs was sufficient for formulations prepared in clinical settings. In addition, we assume that once PHCs are provided to patients, they will be stored in general households under various conditions in terms of temperature, humidity, light shielding, and other factors. Thus, we measured the drug content of the PHCs provided to patients to confirm their stability. Although the drug content decreased over time, it remained at approximately 90% after 12 months of preparation. Propranolol is not affected by temperature or humidity but is unstable in light.²⁵⁾ However, our results showed no substantial changes in the pharmaceutical profiles of the PHCs prepared and stored at room temperature in the homes of the patients and the examination room. This suggests that PHC can be supplied as an in-house formulation and adequately applied.

In the present study, we examined three patients treated with PHC to investigate the clinical course of IH and adverse events after the application of PHC. After the PHC was applied for 5–12 months, the IHs were discolored in all patients. Tumor size also decreased in some patients. Furthermore, no adverse events caused by PHC were observed during application. Thus, PHC can reduce the incidence of systemic ADRs, which are major problems associated with the oral administration of propranolol, and the cream may be effective for growth suppression and involution in IHs. In two patients, 1% PHC was switched to 3% PHC to increase the amount of propranolol to be delivered, and the effect of PHC was enhanced. Although the in vitro skin permeability assay showed no significant differences between the 3 and 5% PHCs, the permeability increased in a concentration-dependent manner. Based on this, switching to a formulation with a higher drug concentration can be expected to enhance drug efficacy in clinical use.

Because the present study is a case series without a control group, we cannot rule out that the observed decrease in tumor size might be attributable to spontaneous resolution. The patients in the present study were aged 3–13 months. A previous study showed that in infants aged 1–5 months with IHs who were in the proliferation phase and required treatment, only 4% of the infants achieved complete or almost complete resolution of the target hemangiomas after 6 months without treatment.¹²⁾ Several clinical studies and case reports have been conducted to date that suggest that propranolol-containing cream and gel formulations are effective for the treatment of IHs.^14,15,17) Similar to the results of these studies, our results also suggest the efficacy of propranolol cream. In future, comparative studies with a placebo should be conducted. We believe that the elucidation of the association between the pharmaceutical profiles and efficacy of formulations used in such clinical studies will contribute to the provision of easy-to-use and safe formulations for patients.

Conclusion

We developed a simple method for preparing topical propranolol formulations using excipients available at hospitals and pharmacies. We characterized several commercially available cream bases and gels using an in vitro pig skin permeability assay. Our pharmaceutical evaluations indicated that propranolol creams can be prepared as a hospital formulation, have appropriate quality, and be stored for up to 3 months in clinical settings. Propranolol creams can permeate transdermally and suppress the growth of hemangiomas. This case series shows that topical propranolol treatment appears to be effective in reducing the incidence of systemic ADRs. Therefore, it is an effective alternative to oral propranolol for the treatment of IH.

Acknowledgments

The authors express their gratitude to Mr. Seiya Inagi and Ms. Yuka Ishizaka (University of Shizuoka) for their excellent technical assistance.

Conflict of Interest

The authors declare no conflict of interest.

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