Development of Sedative Chewing Lozenges Based on a Complex of Herbal Extracts and Glycine for Children

Introduction

The prevalence of insomnia among the pediatric population is estimated to be between 1% and 6% (Himelfarb & Shatkin, 2021; Bruni et al., 2024a). When concomitant conditions such as resistance to bedtime and nighttime awakenings are taken into account, the prevalence rises to 25-50% among preschool children (Reynolds et al., 2023; Bruni et al., 2024b).

In Russia, various neurotic and neurosis-like conditions are diagnosed in up to 2-12% of children, including attention deficit hyperactivity disorder (ADHD) and anxiety symptoms (Surushkina & Chutko, 2023). ADHD occurs in approximately 18% of school-aged children (more common among boys than girls) (Fraticelli et al., 2022). The development of higher mental functions may be delayed in children with ADHD, leading to decreased mental abilities and difficulty organizing activities (Nazarova et al., 2022; Claussen et al., 2024). Children with ADHD are often aggressive, unbalanced, insecure, and lonely, and may experience stress and anxiety (Hirota & King, 2023). Approximately 1.5 million children were born in Russia in 2020, and 180,000 may have neurotic disorders (Chutko et al., 2022). If these behaviors are repeated daily, there is cause for concern, especially for younger children who may struggle to cope with their emotions and become impulsive and hyperactive (Baklanov et al., 2020; Chan et al., 2022). Parents may deal with unreasonable mood swings, stuttering, tantrums, and sleep disorders, which can eventually lead to more serious functional changes in a child's body (Pelevin et al., 2018; Danielson et al., 2024).

This is why it is so important to address this problem among children. An innovative herbal preparation based on Melissa officinalis, Polemoniaceae, and glycine could be a great way to address these issues. It has a sedative effect on a child's nervous system, gently reducing reflex excitability without inhibiting the central nervous system (Ekambaram & Owens, 2021; Samatadze et al., 2022; Mathews et al., 2024). This leads to better sleep quality and normalisation, as well as increased mental activity and higher mental function (Bruni et al., 2021; Yang et al., 2023; Yeom & Cho, 2024; Mizzi & Blundell, 2025).

The primary advantages of this herbal medicine are its natural composition and minimal side effects. It is presented in a convenient and attractive form for children in the form of chewing tablets. The drug is free from artificial colors, flavors, preservatives, gluten, and GMOs. It can be used from the age of 3 years old.

Chewing plates are designed to be visually appealing, as well as tasty and colorful. This decision was made because children often refuse to take medicine with an unpleasant smell or taste when they are young.

The aim of this research was to develop and investigate a sedative herbal preparation based on Melissa officinalis (Melissa officinalis L.), Polemoniaceae (Polemonium caeruleum L.), and glycine in the form of chewable tablets.

Materials and Methods

To study the quality indicators of finished syrup, standard methods were used in accordance with regulatory requirements. An organoleptic assessment was performed according to GOST 6687.5-86 and the State Pharmacopoeia XV edition (Shikov et al., 2021; Zaki Dizaji et al., 2021; Chidambaranathan & Culathur, 2022). Before analysis, the syrup was diluted with drinking water in a 1:10 ratio. 25 mL of syrup was added to a 250 mL measuring cylinder. The volume was adjusted to the mark with water at 10-14°C, and the mixture was thoroughly mixed. Then, taste and aroma were evaluated immediately after pouring the Sample into a tasting glass (Fragedakis et al., 2023; Pavithra et al., 2023).

In addition to organoleptic properties, several physicochemical parameters were measured: density, refractive index, pH, viscosity, and microbiological purity (Gagnon et al., 2025). Density was measured using two parallel methods: pycnometric and hydrometric (Patel et al., 2022; Perrine et al., 2023; Sirohi et al., 2024). The pycnometric method involved weighing a clean and dry pycnometer, then filling it with distilled water up to a specific mark, followed by thermostating and reweighing it. This process was repeated using the test syrup. The hydrometric method involves placing the test liquid in a cylinder, carefully dipping a clean and dried hydrometer into it, and reading the scale after 3-4 minutes of immersion. Refractive index is measured using a refractometer (Canassa & Baldin, 2022; Bodo et al., 2023). A few drops of syrup are placed on the lower prism. Prisms are closed tightly, and readings are taken on the device's scale at a temperature of 20°C. pH is measured by the ionometric method (Divakaruni & Jastroch, 2022; Wilhelmy et al., 2022).

The viscosity of the liquid was determined using a capillary viscometer (Dunn et al., 2021; Macrì et al., 2023). To achieve this, a measured volume of liquid was placed in the elbow of the viscometer, and then it was installed in an upright position in a water bath at 20°C for 30 minutes to allow for temperature equilibrium. After the liquid level rose above the upper mark, the time it took for the liquid to flow between two marks on the viscometer was recorded. This time was averaged over three trials to get the mean expiry time for the test fluid. To calculate the relative viscosity of the syrup under investigation, we also measured the expiry time of a reference fluid. During the experiment, we observed that syrup demonstrated Newtonian flow behavior.

The microbiological purity of the syrup was assessed in accordance with the requirements of the State Pharmacopoeia XV edition for drugs of the third category (Reshetnikov & Barashkova, 2022; Chen et al., 2025). The total number of microorganisms (CFU) should not exceed 10³ per mL, the number of fungi should be 10², and the presence of E. coli is not allowed in 1 mL of syrup. Drops of syrup were applied to Petri dishes with nutrient agar and incubated at 37 °C for 24 hours. No visible growth of colonies was observed after this time. Additionally, purity tests were carried out: 5 mL of the drug was mixed with 45 mL of purified water, and the resulting solution did not react with chlorides, sulfates, calcium, or heavy metals (Fiodorova et al., 2022; Tbahriti et al., 2025).

Safety studies were also conducted in accordance with Technical Regulations 021/2011 of the Customs Union on Food Safety. To extract biologically active substances from plant materials, two methods were used to identify optimal conditions for maximum preservation of these substances (Zhang et al., 2020; Hudz et al., 2023; Poornachitra & Maheswari, 2023). The first method involved evaporating 200 mL of an aqueous solution in a porcelain cup on a water bath for 10 hours, until a powder was obtained. The second, more efficient method, utilized a vacuum rotary evaporator to evaporate the liquid solution in a round-bottom flask at a temperature of 50-60 °C in a heating bath and a steam temperature of 30-40 °C in the evaporator at a pressure of 50 mmHg, until a dry concentrate was achieved. This method produced a saturated yellow concentrate with a dry matter content of 70-72% and increased levels of flavonoids by 1.86 times and saponins by 14 times compared to the initial aqueous alcoholic extract.

The creation of a laboratory sample of phytopreparations in the form of sedative lozenges based on Melissa officinalis, Polemoniaceae, and glycine extracts was carried out using two methods. The first method involved adding 20 grams of gelatin to 200 ml of syrup made from plant extracts. The mixture was then allowed to swell, forming a block, and cooled in a refrigerator for four hours before being shaped into rectangular forms.

The second method was more complex and involved a percolation step. For this, 50 g of Polemoniaceae raw material and 50 g of Melissa officinalis raw material were placed in a percolator, along with 70% ethanol in a 1:2 ratio. The percolation process involved stages such as soaking, infusion (24 hrs), and actual percolating until the raw materials were depleted. The resulting percolate was then purified through settling and filtration. After that, alcohol was distilled using a distillation apparatus. The aqueous residue was then evaporated to a thick consistency using a vacuum evaporator at 50-60 °C and a pressure of 5 mmHg. The moisture content of the dry extract did not exceed 25%, and the heavy metal content was below 0.01%.

Next, the dry extract was dissolved in water to form a thick mass, from which bars could be formed. Lozenges could then be cut from these bars. The resulting dosage form was an elastic-plastic base with evenly distributed active ingredients designed for absorption. The lozenges were pale yellow in color, had a sweet and sour taste with a slight lemon scent, and had a smooth and uniform surface. The average dissolution time for one lozenge was 4 ± 0.66 minutes, which met the pharmacopoeial requirements (less than 15 minutes). The average weight of a lozenge was 1.40 ± 0.05 grams, and the weight loss during drying was 13.6% ± 0.1%. Figure 1 shows the formulation and manufacturing technology of lozenges.

Biological properties of the laboratory sample were tested in several stages. In the first stage, an experimental study was conducted on 10 sexually mature rats, divided into an experimental and a control group. Animals in the experimental group were given crushed lozenges containing Melissa officinalis extract at a dose of 2 mg and Polemoniaceae extract at 2 mg, as well as glycine at 10 mg. The control group was given a standard diet.

The effectiveness of the laboratory product was tested at the Republican Orphanage in Buinaksk. A study was conducted for 30 days on children aged 3-5 (7 boys and 3 girls) with mental disabilities, hyperactivity, aggression, and sleep disorders who were given ¼ of a lozenge 3 times a day after meals. Following the study, caregivers at the orphanage observed a decrease in the children's aggression and hyperactivity, as well as an improvement in their sleep patterns.

The taste qualities of lozenges were evaluated using the method of threshold concentrations and numerical indices developed by I. A. Egorov (Bakker, 2014; Samaranayake et al., 2024). The study involved 35 children aged 5-10 and 25 students who were divided into two groups. One group assessed the main taste sensations (sweet, sour, salty, bitter), while the other assessed the objective sensations (pleasant/unpleasant). The study used a blind method and followed standard tasting rules. As a result, the taste of the lozenge was determined to be sweet and sour with a pleasant aroma.

Throughout the study, subjects were interviewed daily and their pulse and blood pressure monitored. At the end of 30 days, participants reported decreased anxiety and stress, as well as improved sleep, mood, and memory, with no side effects, including nausea, vomiting, dizziness, or allergies. Pulse and blood pressure remained within normal limits for all participants.

Results and Discussion

As a result of the research, a laboratory sample of sedative lozenges was developed based on a dry extract of Melissa officinalis (Melissa officinalis L.), a dry extract of Polemoniaceae (Polemonium caeruleum L.), and glycine.

To ensure the stability and reproducibility of the composition, the main physico-chemical parameters of the intermediate product, syrup, were studied. Studies have shown that the resulting syrup is a clear, viscous liquid without sediment, turbidity, and foreign inclusions, with a faint lemon flavor and a slight bitter note in the taste (Table 1).

Table 1. Determination of organoleptic parameters

It was found that the density of the syrup is 1.305-1.315 g/ml, the refractive index is 1.452–1.455, and the hydrogen index (pH) is 4.5. The dynamic viscosity was [MPa·s]; 94 41 MPa·s, the yield index is 0.9886; the consistency index is 63.00 MPa·s, which characterizes the product as a Newtonian fluid and indicates the stability of its rheological properties under various loads. The most important stage was the assessment of microbiological purity and safety. The research results (Table 2) confirmed that the content of toxic elements, pesticides, and radionuclides in the Sample is significantly lower than the permissible levels established by TR CU 021/2011 "On Food Safety". Microbiological parameters also met the requirements of the Pharmacopoeia.

Table 2. The results of the conducted research

The results shown in Table 2 indicate that, in terms of safety, the tested samples of lozenges comply with TR CU 021/2011 "On Food Safety" (Appendices No. 2 (paragraph 2), No. 3 (paragraph 6, paragraph 10), No. 4 (paragraph 19))., which confirms the possibility of using the drug from the age of 3 (Mistry & Batchelor, 2017; Tbahriti et al., 2025).

The data obtained indicate that the developed formulation and technological process make it possible to obtain a stable intermediate product (syrup) that meets all regulatory requirements for organoleptic, physico-chemical, and safety indicators (Todorović et al., 2023; Banerjee et al., 2025). Vacuum drying of extracts at 60 °C, in contrast to evaporation in a water bath at 100 °C, allowed us to obtain a concentrate with a higher content of biologically active substances (flavonoids 1.86 times and saponins 1.4 times higher) and improved organoleptic properties (light brown color, transparency), which is consistent with the literature data on the thermal stability of many phytocomponents (Vega-Gálvez et al., 2021; Wang et al., 2021; Hou et al., 2024). Plant concentrates with a high dry matter content and preservation of the organoleptic characteristics of the initial product were obtained (Table 3).

Table 3. Comparative characteristics of the studied syrup of various concentration methods

During the tests on laboratory rats in the control group, reflex excitability was noted by 35% (p<0.05), an increase in sleep duration by 25% (p<0.05) was recorded, and an improvement in cognitive tests (maze) was noted: the passage time decreased by 20% (p<0.05) compared with the control group. The group (Casarrubea et al., 2016; Postu et al., 2019). No side effects (changes in water and food intake, signs of intoxication, allergic reactions) were detected during the 30-day experiment.

 The revealed sedative and anxiolytic effect is consistent with the pharmacological properties of the claimed components. Melissa officinalis is known to have moderate sedative properties, and Polemoniaceae is traditionally used in medicine due to its pronounced anxiolytic and sedative effects, which surpass valerian in activity (Shakeri et al., 2016; Brody et al., 2021; Petrisor et al., 2022). Glycine, being an inhibitory neurotransmitter, potentiates the action of phytocomponents (Adeva-Andany et al., 2018; Cen et al., 2022; Imenshahidi & Hossenzadeh, 2022). The absence of toxicity confirms the data obtained in the study of safety indicators.

For a preliminary assessment of human efficacy and tolerability, an open pilot study was conducted with the participation of 25 volunteer students (18-22 years old) with complaints of anxiety, stress, and sleep disorders.

During a pilot study on volunteers, a subjective assessment of the condition on a visual analog scale (VAS) after 30 days of taking lozenges (3 times a day) showed (Natan et al., 2022; Åström et al., 2023):

• A decrease in stress levels by 40% (p<0.01).
• A decrease in anxiety levels by 45% (p<0.01).
• Improvement of sleep quality (reduction of falling asleep time, reduction of nighttime awakenings) according to the PSQI questionnaire by 50% (p<0.01) compared with baseline indicators.
• Objective indicators (heart rate, blood pressure) remained within the physiological norm throughout the study.
• No adverse events (nausea, dizziness, allergic reactions) have been reported.

The data obtained indicate a good tolerance and a pronounced positive effect of the developed complex on the subjective state of people with increased psycho-emotional stress. It is important to note that the study was open and uncontrolled, which does not completely exclude the effect of the placebo effect. However, the severity of the effect and its correlation with the data from the preclinical experiment allow us to consider these results encouraging and serve as the basis for organizing further randomized, double-blind, placebo-controlled trials (RCTs).

Conclusion

Based on a comprehensive study, the formulation and technology of sedative chewing lozenges based on extracts of Melissa officinalis, Polemoniaceae, and glycine have been developed. It has been established that the use of vacuum drying ensures the safety of biologically active substances in the finished product. The conformity of the finished Sample with the requirements of the regulatory documentation on organoleptic and physico-chemical parameters has been confirmed. The compliance of the drug with the safety requirements according to TR CU 021/2011 has been proven, which justifies the possibility of use in children from the age of 3.

Experimental data convincingly demonstrate the pronounced sedative and anxiolytic activity of the developed complex. An in vivo model showed a statistically significant decrease in reflex excitability and an improvement in cognitive functions in animals. Pilot studies on volunteers have confirmed the good tolerability of the drug and its positive effect on the psycho-emotional state - there was a significant reduction in stress and anxiety levels, normalization of sleep. An important advantage of the developed form is its high organoleptic characteristics, which ensure good acceptability among the children's audience.

The high organoleptic characteristics of the lozenges have been determined, ensuring their acceptability to the target audience. The obtained results substantiate the prospects of using the developed phytopreparation in pediatric practice.

Acknowledgments: The authors would like to thank their mentor, Timur Algasanovich Ibragimov (Associate Professor of the Department of Pharmacy, Dagestan Medical State University, Makhachkala, Republic of Dagestan, Russia) for his professionalism and wisdom. The authors express their deep gratitude to the staff and pupils of the Republican Orphanage (Buinaksk, Republic of Dagestan, Russia) and the educational institution Kindergarten – Primary School No. 68 (Makhachkala, Republic of Dagestan, Russia), as well as students of Dagestan State Medical University (Makhachkala, Republic of Dagestan, Russia) for participating in the experiment.

Conflict of interest: None

Financial support: None

Ethics statement: This study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Dagestan State Medical University (Makhachkala, Republic of Dagestan, Russia). Informed consent was obtained from all adult subjects and from the parents or legal guardians of all child participants.