Abstract
Exploring factors related to difficulties in extracting tablets or capsules from press‐through‐packages is essential for optimizing the dosage form. To achieve this, the involvement of patient insight is important. In the present study, the preferences of patients regarding drugs that are difficult to extract from their packaging were collected using an electronic medication notebook (‘harmo®’) based on dispensing data. We found that approximately 30% of respondents had difficulty removing tablets or capsules from their packaging, with 125 specific drugs identified as ‘hard to push out’. Independent factors related to ‘hard‐to‐push‐out’ drugs were female sex and feeling of weakness in the hands or fingers. Furthermore, several ‘hard‐to‐push‐out’ drugs had characteristics such as a spherical shape or small major axis or small major axis drug‐to‐pocket size ratio. The findings of this study may help improve the quality of drug packaging, thus enhancing the patients' medication experience.
Keywords: capsule, electronic medication notebook, patient preference, personal health record, size, tablet
1. INTRODUCTION
Tablets and capsules are widely used forms for oral medications. 1 , 2 Press‐through‐package (PTP) sheets are a type of blister package and the most common packaging for prescription and over‐the‐counter medications. 3 Oral drugs in PTP sheets are easy to handle and carry. However, older adults or people with hand or finger impairments may find it difficult to push tablets or capsules out of PTP sheets. 3 , 4 The European Medicines Agency published a reflection paper that lists medication appearance, swallowability, patient perception and any handling required before using medicines, especially in older adults. 5 Regarding patient‐related factors, female sex, older age, residence in an institution and some comorbidities or impairments were associated with a reduced ability to open drug containers. 6 While previous studies mainly focused on older subjects, 6 , 7 , 8 , 9 the factors related to the difficulty in extracting tablets and capsules from PTP sheets in relatively younger individuals remain unknown. Therefore, diverse perspectives and insights from a wide range of populations are needed. Kabeya et al. identified size‐related factors that increased the risk of difficulty in removing drugs from PTP sheets through a survey of marketing specialists of medical wholesalers. However, they did not directly determine patient preferences owing to the limitations of data collection methodologies. 10 Furthermore, a previous study conducted among the general adult population (50 participants aged 18–45 years) used 3D printing to create specific drug shapes to tackle dexterity issues. However, scores for handling the drug with the created shape were the lowest, and the need to involve more patients was highlighted when optimizing dosage form characteristics. 11
In Japan, medication notebooks are used for recording medications dispensed to patients. Previous studies have revealed the usefulness of medication notebooks for monitoring patients' health 12 and detecting contraindicated prescriptions or duplications. 13 , 14 Electronic medication notebooks are becoming increasingly popular to maintain records of patients' prescribed medicines by using a smartphone app. 15 The tools have the ability to be used for secondary purposes such as analysing the accumulated personal health records as big data, and questionnaires can be sent directly to patients through electronic medication notebooks. Thus, by leveraging the electronic medication notebook, it would be possible to conduct an analysis on a large patient cohort, linking their accumulated personal medical records, such as dispensing histories, in the electronic medication notebooks with their questionnaire responses. This approach is expected to lead to a more profound understanding of patient preferences for prescribed medication.
Therefore, the purpose of this study was to investigate patient factors related to difficulty in extracting tablets or capsules from PTP sheets based on data from electronic medication notebooks, which could help prevent medication recall errors due to patient memory uncertainty and fully understand patient preferences for prescribed medications, focusing on those identified as ‘hard to push out’.
2. METHODS
2.1. Questionnaire survey conducted using electronic medication notebooks (harmo®)
The questionnaire survey was delivered to electronic medication notebook (harmo®, harmo Co., Ltd., Tokyo, Japan) users who met the inclusion criteria from 23 to 29 March 2023. People aged 20 years or older who were prescribed either tablets or capsules within 90 days from 2 weeks prior to the survey distribution date (23 March 2023) were included in the survey. Patients' demographic data, such as sex, age (grouped by decade), medication dispensing and medical history, and history of side effects and allergies, were collected anonymously. The questionnaire contained the following items: consent for survey participation, whether the participant experienced difficulty in extracting tablets or capsules from PTP sheets (yes/no/not sure), specific names or characteristics of ‘hard‐to‐push‐out’ drugs corresponding to the previous question, and hand and finger condition (no problem/trembling/numbness/feeling of weakness/difficulty in bending fingers; multiple answers were allowed). ‘Hard‐to‐push‐out’ drugs were identified if a patient reported names or features of a specific medication as ‘hard to push out’ and had been dispensed the relevant drugs at least once. The sizes (major axis, minor axis, diameter and thickness; Figure 1) of the identified ‘hard‐to‐push‐out’ drugs were obtained from the package inserts of each medication. The prescription histories of diabetes, peripheral neuropathy and antirheumatic medications were identified if patients were prescribed medications with these disease indications at least once (Table S1). To increase the response rate, we presented the questions in a simple manner. Additionally, to streamline the response process, we sent notifications to all harmo® users about the questionnaire, including a link to the survey details through a smartphone app (Table S2).
FIGURE 1.
Parameters relating to the inside of press‐through‐package (PTP) pockets.
2.2. Statistical analysis
Patients' demographic data are expressed as categorical variables and were compared using the chi‐square test. Multivariable logistic regression analysis was conducted to determine the factors related to difficulty in extracting tablets or capsules from PTP sheets. Multivariable analysis employed variables deemed clinically relevant to the outcome. The age cutoff was determined using the receiver operating characteristic (ROC) curve and Youden index calculations (data not shown). Assessment of multicollinearity among the explanatory variables used in logistic regression analysis yielded variance inflation factor values ranging from 1.000 to 1.180, indicating the absence of multicollinearity issues. Model fit for the multivariable logistic regression analysis was assessed using the area under the ROC curve (AUC‐ROC). Statistical significance was set at P < .05. All statistical analyses were conducted with SAS ver. 9.4 (SAS Institute Inc., Cary, North Carolina, USA).
2.3. Ethics approval
This study involved a survey conducted using a self‐administered, anonymous web‐based questionnaire. Participants were asked to complete the questionnaire only if they consented to study participation and sharing of their personal health records. The protocol was approved by the ethics committee of the Keio University Faculty of Pharmacy (approval number 221111‐1).
3. RESULTS
The questionnaire was administered to 51 175 users of harmo®, of whom 1143 (2.2%) responded. After excluding respondents who answered ‘Not sure’ to the question ‘Do you experience difficulty in extracting tablets or capsules from PTP sheets?’ (n = 83), 1060 respondents were analysed. Of these 1060, 319 (30.1%) stated that they faced issues while extracting tablets or capsules from PTP sheets (Table 1).
TABLE 1.
Respondents' characteristics (n = 1060).
| Having difficulty in extracting tablets or capsules from PTP sheets | P‐value a | |||
|---|---|---|---|---|
| Yes (n = 319) | No (n = 741) | |||
| Sex | Male | 171 (53.6%) | 463 (62.5%) | .0068 |
| Female | 148 (46.4%) | 278 (37.5%) | ||
| Age | 20s | 4 (1.3%) | 15 (2.0%) | .2342 |
| 30s | 17 (5.3%) | 37 (5.0%) | ||
| 40s | 32 (10.0%) | 107 (14.5%) | ||
| 50s | 74 (23.2%) | 188 (25.4%) | ||
| 60s | 99 (31.0%) | 225 (30.4%) | ||
| 70s | 81 (25.4%) | 141 (19.0%) | ||
| 80s | 11 (3.5%) | 27 (3.6%) | ||
| 90s | 1 (0.3%) | 1 (0.1%) | ||
| Hand and finger condition b | No problem | 237 (74.3%) | 653 (88.1%) | <.0001 |
| Trembling | 16 (5.0%) | 14 (1.9%) | .0049 | |
| Numbness | 31 (9.7%) | 32 (4.3%) | .0006 | |
| Feeling of weakness | 51 (16.0%) | 41 (5.5%) | <.0001 | |
| Hard to bend fingers | 20 (6.3%) | 27 (3.6%) | .0568 | |
| Prescription history | Diabetes medications | 67 (21.0%) | 139 (18.8%) | .3969 |
| Medications for peripheral neuropathy | 72 (22.6%) | 121 (16.3%) | .0157 | |
| Antirheumatic medications | 13 (4.1%) | 14 (1.9%) | .0383 | |
Note: Bold indicates P < .05.
Abbreviation: PTP, press‐through‐package.
Chi‐square test.
Multiple answers allowed.
Based on the respondents' characteristics, the percentage of female participants who experienced difficulty in pushing tablets or capsules out of PTP sheets was found to be significantly higher than that of those who did not (46.4% vs. 37.5%, P = .0068, chi‐square test). There were no significant differences in age distribution between the two groups; however, there were intergroup differences in hand and finger conditions. A higher proportion of respondents who experienced difficulty in extracting tablets or capsules from PTP sheets were prescribed medications for peripheral neuropathy or antirheumatic medicines than those who were not (22.6% vs. 16.3%, P = .0157 and 4.1% vs. 1.9%, P = .0383, respectively, chi‐square test). The results of the multivariable analysis revealed that female sex and feeling of weakness in the hand or fingers were independently associated with having difficulty in extracting tablets or capsules from PTP sheets (odds ratio 1.412 and 2.382, respectively, Table 2). The multivariable logistic regression model's performance was assessed using the AUC‐ROC. The AUC‐ROC was 0.635, with 95% Wald confidence limits from 0.599 to 0.672, indicating limited discriminative ability.
TABLE 2.
Results of multivariable logistic regression analysis for difficulty in extracting tablets or capsules from press‐through‐package (PTP) sheets.
| Odds ratio | 95% CI | P‐value | ||
|---|---|---|---|---|
| Sex | Female | 1.412 | 1.098–1.814 | .0071 |
| Age | ≥60 | 1.069 | 0.834–1.369 | .6000 |
| Hand and finger condition** | No problem | 1.000 (reference) | ||
| Trembling | 1.444 | 0.714–2.918 | .3062 | |
| Numbness | 1.252 | 0.753–2.082 | .3871 | |
| Feeling of weakness | 2.382 | 1.559–3.638 | <.0001 | |
| Hard to bend fingers | 1.243 | 0.706–2.188 | .4513 | |
| Prescription history | Diabetes medications | 1.069 | 0.781–1.462 | .6785 |
| Medications for peripheral neuropathy | 1.308 | 0.961–1.779 | .0874 | |
| Antirheumatic medications | 1.747 | 0.864–3.531 | .1204 | |
Note: Bold indicates P < .05.
The subgroup analysis in younger age groups (the 50s or younger age group) has also been conducted, and feeling of weakness in the hand or fingers and the prescription history of medications for peripheral neuropathy were identified as factors related to ‘hard to push out’ (odds ratio 3.744 and 2.165, respectively, Table S3).
Based on responses from 159 respondents who provided the names or features of drugs that were difficult to extract from PTP sheets, 125 distinct drugs were identified as ‘hard to push out’. This information was linked to the dispensing data of the respondents. The most reported drug was esomeprazole capsules 20 mg (original, reported by nine respondents out of 161 those who were prescribed), followed by esomeprazole capsules 20 mg (generic brand, reported by five respondents out of 34). Eldecalcitol capsules 0.75 μg (generic brand A), eldecalcitol capsules 0.75 μg (generic brand B) and prednisolone tablets 5 mg (original) were each reported by four respondents out of 17, 8 and 85, respectively (Table S4). The sizes (major axis, minor axis, diameter and thickness) of the identified ‘hard‐to‐push‐out’ drugs obtained from the package inserts of each medication are described in Table S5. The major axis of the esomeprazole capsule 20 mg (original, generic brand A) was 11.40 mm, and the eldecalcitol capsule was 6.50 mm in diameter and spherical.
4. DISCUSSION
Our study aimed to identify the factors that contribute to difficulty in removing ‘hard‐to‐push‐out’ drugs from their packaging. We directly collected patient feedback on the difficulty in removing tablets or capsules from PTP sheets by using electronic medication notebooks, which are connected to dispensing data and help prevent recall errors. A previous study could not obtain the specific names of drugs that are difficult to extract from PTP sheets owing to its methodology. 10 In our present study, 159 respondents provided names or only characteristics of ‘hard‐to‐push‐out’ drugs. From among the names provided, we successfully identified 125 specific drugs' exact names and doses. One or more doses, brand names or trade names of ‘hard‐to‐push‐out’ drugs were missing in almost all responses; however, access to dispensing data enabled us to obtain specific drug names and doses. Additionally, previous studies on the difficulty in extracting tablets and capsules from PTP sheets mainly focused on older subjects. 6 , 7 , 8 , 9 In contrast, our study population covered a wide age group (those in their 20s to those in their 90s), with a substantial proportion (44.7%) younger than 60 years, allowing us to gather diverse perspectives and insights.
The multivariable analysis revealed that female sex and feelings of weakness in the hand or fingers were independently associated with difficulty in extracting tablets or capsules from PTP sheets. A previous study found that certain factors, such as female sex, were linked to the ability of older individuals with chronic illnesses to open medicine containers. 6 , 7 Female individuals experienced significantly greater difficulty in opening drug containers, including blister packages, than did male individuals. 7 On the basis of a previous study, 9 we included some comorbidity‐related prescriptions (neuropathy, rheumatoid arthritis and diabetes mellitus) as explanatory variables; however, there were no significant differences in the findings with and without these prescriptions among the overall population. Still, the prescription history of medications for peripheral neuropathy was only identified as a factor related to ‘hard to push out’ in younger age groups. To explore the impact of these factors, further investigation would be necessary.
Esomeprazole capsule, both in its original and generic forms, was the most reported drug that was difficult to push out. Kabeya et al. described the characteristics of ‘hard‐to‐use’ drugs as having smaller drug size (minor axis of 6.16 ± 1.27 mm or smaller) and smaller drug‐pocket size ratio (major axis ratio of 0.78 ± 0.13 or smaller or minor axis ratio of 0.74 ± 0.14 or smaller). 10 The minor axis of the esomeprazole capsules was 4.90 mm, which met the ‘smaller drug size’ criteria (minor axis) in that previous study. The major axis drug‐pocket ratios of esomeprazole capsules were 0.66 (original) and 0.68 (generic A) (data not shown), and the minor axis drug‐pocket ratios were 0.83 and 0.73, respectively. Therefore, the smaller size and drug‐pocket size ratio could be reasons for identifying the drug as ‘hard to push out’. Eldecalcitol capsules were the second most frequently reported ‘hard‐to‐push‐out’ drugs. They were 6.50 mm in diameter and spherical. A participant in a survey identified eldecalcitol as being ‘hard to push out’ and mentioned in the free comments section that they had accidentally dropped the drug after it rolled over. Capsule shape could make it difficult for patients to hold or grip it, leading to the perception of the drug being ‘hard to push out’. Research with semistructured interviews identified that small round tablets (≤7 mm in diameter) were challenging to remove from blisters or other packages. In addition, older people and their caregivers highlighted difficulties in handling small, round tablets, especially the least preferred 6‐ and 7‐mm round tablets, and caregivers referred to the potential for these to be dropped. Regardless of age, the difficulties associated with handling tablets were related to small, round tablets; caregivers preferred oval‐shaped tablets and caplets. 8
This study has some limitations. First, we could not obtain patient demographic data, such as medical history or comorbidities, owing to the limitations of electronic medication notebooks and the separation of prescribing and dispensing systems in Japan. Because of the restricted number of variables available in this study, the AUC‐ROC value of 0.635 indicates that our model has limited discriminative power. In addition, the data collected through electronic medication notebooks may be biased toward a specific population and has a low response rate (2.2% based on all harmo® users). However, out of 51 175 users, 4994 (9.8%) opened the notifications, and 1482 (2.9%) accessed the questionnaire. Therefore, the response rate based on the number of users who viewed the questionnaire was 77.1%. A survey using electronic medication notebooks revealed that relatively younger to middle‐aged individuals were more likely to participate than older individuals. Still, the 20s and 30s constitute less than 10%, and those aged 80s and 90s were very few. This may be because of the higher usage rate of electronic devices among younger individuals and the lower number of younger individuals who are prescribed medications. However, data on patients' perspectives regarding difficulties in extracting tablets and capsules experienced by younger to middle‐aged individuals are lacking. Therefore, this study may provide new insights into patients' preferences for handling oral drugs. In the interpretation of our results, it is important to note that while the P‐value for the odds ratio for female sex reporting difficulty is highly significant (P = .0071), the lower bound of the 95% confidence interval (1.098) is very close to the point of no effect (1.0). This proximity suggests that the observed association, although statistically significant, should be interpreted with caution. The potential for the loss of significance if the lower bound were to fall below or exactly at 1.0 highlights the need for careful consideration of the clinical relevance of our findings. Further studies with larger sample sizes may help to confirm and strengthen these associations.
In conclusion, female sex and feelings of weakness in the hand or fingers were factors independently associated with having difficulty in extracting tablets or capsules from PTP sheets, and ‘hard‐to‐push‐out’ drugs had characteristics of a small minor axis, small major axis drug‐pocket ratio and spherical shape.
AUTHOR CONTRIBUTIONS
Masami Tsuchiya, Hayato Kizaki, Shungo Imai and Satoko Hori designed the study. Masaki Asano, Yuri Shimizu, Hayato Kizaki, Shungo Imai and Satoko Hori created and evaluated the questionnaire. Masami Tsuchiya processed the data and performed the statistical analysis. Yukiko Ito, Makoto Tsuchiya, Ryoko Kuriyama, Nao Yoshida, Masanori Shimada and Takanori Sando supported questionnaire development, distribution, collection of responses and provision of personal health records. Masami Tsuchiya, Shungo Imai and Satoko Hori drafted and completed the manuscript. Tomo Ishijima and Satoko Hori supervised this study. Hayato Kizaki, Yukiko Ito, Makoto Tsuchiya, Ryoko Kuriyama, Nao Yoshida, Masanori Shimada, Takanori Sando and Tomo Ishijima reviewed the manuscript. All authors have approved the manuscript.
CONFLICT OF INTEREST STATEMENT
TS and TI are co‐CEOs of harmo Co., Ltd., which operates harmo®. YI, MT, RK, NY and MS are harmo Co., Ltd. employees. Other authors declare no conflicts of interest.
Supporting information
Table S1. The list of diabetes medications, medications for peripheral neuropathy, and antirheumatic medications.
Table S2. The sample of questionnaire (originally written in Japanese and translated into English).
Table S3. Results of subgroup analysis (multivariable logistic regression analysis for difficulty in extracting tablets or capsules from PTP sheets) in younger age groups (the 50s or younger, n=474).
Table S4. The list of “Hard‐to‐push‐out” drugs.
Table S5. The profiles of “Hard‐to‐push‐out” drugs.
ACKNOWLEDGEMENTS
We would also like to express our sincere gratitude to all the participants who responded to our survey.
Tsuchiya M, Imai S, Asano M, et al. Exploring the factors associated with difficulties in extracting tablets or capsules from press‐through‐package sheets. Br J Clin Pharmacol. 2025;91(2):479‐484. doi: 10.1111/bcp.16355
The authors confirm that the principal investigator for this paper is Satoko Hori and that they had direct clinical responsibility for patients.
Funding information The authors did not receive support from any organization for the submitted work.
DATA AVAILABILITY STATEMENT
The questionnaires and personal health record data used in this study are available upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1. The list of diabetes medications, medications for peripheral neuropathy, and antirheumatic medications.
Table S2. The sample of questionnaire (originally written in Japanese and translated into English).
Table S3. Results of subgroup analysis (multivariable logistic regression analysis for difficulty in extracting tablets or capsules from PTP sheets) in younger age groups (the 50s or younger, n=474).
Table S4. The list of “Hard‐to‐push‐out” drugs.
Table S5. The profiles of “Hard‐to‐push‐out” drugs.
Data Availability Statement
The questionnaires and personal health record data used in this study are available upon reasonable request.