Revolutionizing Parkinson’s Treatment: The Evaluation of Sublingual Dosage Form

Introduction

Brief overview of Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative ailment impacting motor functions, characterized by symptoms including tremors, bradykinesia (slowed movement), rigidity, and postural instability.^1,2 The etiology of Parkinson's disease (PD) is attributed to the depletion of dopamine-producing neurons within the brain. The prevalence of Parkinson's disease exhibits regional variability; however, it is generally reported to affect approximately 1% of individuals aged 60 years and above, escalating to as much as 4% among those aged 80 years and above on a global scale.^3,4 Both the incidence and prevalence of PD are subject to the influence of genetic and environmental determinants, with a higher prevalence observed in males compared to females.³

Parkinson's disease, a neurodegenerative disorder, exerts its effects on both motor and non-motor functions. Fundamental motor symptoms encompass tremors, rigidity, bradykinesia (diminished movement speed), and postural instability, significantly impeding daily activities such as dressing, eating, and writing. Non-motor manifestations encompass depression, anxiety, sleep disturbances, cognitive and neurobehavioral irregularities, autonomic and gastrointestinal dysfunction, and pain.⁵ The progression of the disease introduces variations and fluctuations in symptoms, contributing to a distinctive symptomatic trajectory for each patient. Regrettably, non-motor symptoms tend to be under recognized and inadequately addressed, consequently intensifying disability, compromising the quality of life, and shortening life expectancy.⁶

Importance of advancements in medication delivery for Parkinson's treatment

The prevailing treatment modalities for Parkinson's disease (PD) encompass a spectrum of interventions, including oral pharmacotherapy, injections, and traditional approaches. A concise overview of the current treatment panorama, derived from the furnished review articles, is presented below.

Pharmacological Interventions

• Levodopa: This stands as the primary pharmacotherapeutic choice for addressing all motor symptoms, including tremor, in PD.
• Dopamine Agonists and Anticholinergics: Augmenting the treatment regimen with these medications demonstrates potential for further reduction in tremors.⁷
• Deep Brain Stimulation (DBS): Recognized as the most established advanced therapeutic modality, particularly beneficial in cases of advanced PD.⁷
• GLP-1 Receptor Agonists: Investigations into the viability of GLP-1 receptor agonists for PD treatment have been undertaken in certain studies.⁸
• Physical Exercise: Varied forms of physical exercise exhibit effectiveness in PD management, though the comparative advantages of distinct exercise types remain indeterminate.⁸ 
• Microelectrode Recording (MER) in DBS Surgery: Comparative studies have scrutinized the clinical outcomes associated with DBS surgery with and without microelectrode recording.⁹

Oral Tablets

Predominantly, the administration of medication for Parkinson's disease relies on oral tablets. This category encompasses a range of medications, including but not limited to levodopa, dopamine agonists, and MAO-B inhibitors.

Injections

In the advanced stages of the disease, injections such as apomorphine or the subcutaneous infusion of levodopa may be employed to address motor fluctuations.⁹

Additionally, a systematic review and meta-analysis had underscored the identification of atypical respiratory swallow patterns and respiratory pause durations in individuals afflicted by PD, holding implications for both the assessment and treatment of swallowing disorders.¹⁰ Furthermore, investigations into the experiences of treatment burden among individuals with PD and their caregivers have been conducted, elucidating factors influencing treatment burden and proposing potential strategies for alleviation.¹¹ These findings furnish nuanced insights into the diverse treatment modalities available for the management of Parkinson's disease, spanning from conventional oral medications to advanced therapeutic interventions such as deep brain stimulation. Ongoing research endeavours and clinical studies persist in enriching our understanding and refining the dynamic landscape of PD treatment.

The deficiencies inherent in conventional medication delivery approaches, characterized by delayed onset, fluctuating drug levels, and adverse effects, have instigated a quest for inventive alternatives. A selection of articles addresses the hurdles and constraints faced by patients using traditional medication delivery methods, presenting potential solutions. The chosen articles for review are as follows: 

1. Revolutionizing Healthcare Delivery: Scientific and Regulatory Complexities in Crafting mHealth Interventions - This publication delves into the constraints of conventional delivery mechanisms, emphasizing the transformative impact of mobile Health (mHealth) technologies. These technologies prove effective in administering interventions with self-service capabilities, fostering personalization, reducing provider burdens, and overcoming constraints related to care locations.¹²
2. Telemedicine in the Management of Cystic Fibrosis during the COVID-19 Era - This article recounts the implementation of telemedicine in caring for individuals with cystic fibrosis, shedding light on associated challenges. The discussion encompasses the frequent demands of visits for pulmonary disease monitoring, medication oversight, and the involvement of multidisciplinary provider teams.¹³
3. Quantitative Evaluation of Injectable Medication Delivery Practices - A study within this article quantifies the enhanced efficiency achieved with autoinjectors compared to alternative medication administration methods. The findings underscore limitations while illuminating potential implications stemming from the research.¹⁴
4. Guiding Policymakers in Developing Nations: Practices and Challenges of Geriatric Home Medication Review in Malaysia - A Qualitative Exploration - This work scrutinizes the complexities involved in providing geriatric home medication review, revealing significant impediments such as the absence of outcome monitoring, formal training deficiencies, and constraints within the workforce.¹⁵
5. Contemporary Principles, Hurdles, and Novel Metrics in pH-Responsive Drug Delivery Systems for Systemic Cancer Treatment - The content of this article revolves around the limitations associated with traditional chemotherapeutic agents and the impediments encountered in the development of pH-responsive drug delivery systems designed for systemic cancer therapy.¹⁶ These scholarly contributions offer valuable insights into the shortcomings of conventional medication delivery methods and propose innovative approaches to address and surmount these challenges.

Focus on the evaluation of sublingual dosage forms

Sublingual administration represents a distinct drug delivery route wherein medications are positioned beneath the tongue, facilitating absorption through the oral mucosa. This mode of delivery ensures swift onset of action and heightened bioavailability, as it circumvents hepatic metabolism. Sublingual tablets, designed to disintegrate rapidly, commonly incorporate super-disintegrant to achieve accelerated disintegration, improved dissolution, and enhanced bioavailability. This administration approach is frequently employed for drugs susceptible to extensive first-pass metabolism or degradation within the gastrointestinal tract.¹⁷

A comprehensive systematic review focusing on sublingual allergen immunotherapy underscores its efficacy in managing allergic respiratory diseases across diverse age groups, with a particularly noteworthy disease-modifying impact, notably evident with grass pollen extracts.¹⁸ In a separate investigation examining the application of dexmedetomidine sublingual film for acute agitation associated with schizophrenia and bipolar disorders, the findings highlight its innovative attributes, including a non-invasive route of administration, rapid absorption, and expeditious onset of effect, positioning it as a promising and novel treatment modality.¹⁹ Consequently, sublingual administration emerges as an auspicious alternative for the delivery of various medications, particularly catering to conditions necessitating rapid onset of action and augmented bioavailability.

Sublingual dosage forms are emerging as an innovative strategy for addressing Parkinson's disease (PD), particularly in the context of providing swift relief for motor fluctuations in advanced PD patients. Notably, sublingual apomorphine stands out as a pioneering sublingual rescue medication designed to alleviate OFF times in PD.²⁰ Clinical trials have underscored the safety and efficacy of sublingual apomorphine, with Phase II trials revealing that a noteworthy 100% of patients achieving a full ON response within 30 minutes, and 40% within 15 minutes. The mean duration of effect was reported as 50 minutes, and in subsequent Phase III trials, an impressive 77.3% of patients attained a full ON response. This rapid and efficacious profile positions sublingual apomorphine as a compelling option for managing motor fluctuations in PD.²⁰

The comprehensive review article titled "Sublingual apomorphine in treatment of Parkinson's disease: a review" serves as a valuable and thorough resource. It provides an extensive overview encompassing the development, pharmacology, safety, and efficacy of sublingual apomorphine in the context of PD treatment.²¹ This review proves instrumental in fostering a nuanced understanding of the rationale underpinning the exploration of sublingual delivery as an avenue for enhancing Parkinson's treatment strategies.²²

The primary objective of this review is to delve into the evolutionary trajectory of sublingual dosage forms in the therapeutic landscape of Parkinson's disease. This encompasses an in-depth exploration of the development, efficacy, and potential benefits associated with sublingual administration in alleviating the symptoms of Parkinson's disease. The overarching aim is to furnish a comprehensive and scholarly understanding of the advancements and significance of sublingual dosage forms in enhancing the overall treatment paradigm for Parkinson's disease. This comprehensive assessment extends to evaluating their influence on patient outcomes, adherence to prescribed regimens, and the broader spectrum of disease management. Through a meticulous academic lens, this review aspires to unravel the nuanced impact and contributions of sublingual dosage forms, offering insights into their potential to advance the care and management of individuals afflicted with Parkinson's disease.

Historical Perspective

The evolution of drug delivery methods has witnessed a transformation over time, with a contemporary emphasis on exploring unconventional approaches like transdermal patches and nasal sprays. Traditional routes such as oral, intravenous, intramuscular, and subcutaneous remain prominent, but the emergence of transdermal patches and nasal sprays has introduced novel dimensions to drug administration.²³

Parkinson's disease poses a significant challenge in the realm of neurological disorders, necessitating continuous exploration of novel drug delivery methods to optimize treatment outcomes. This comprehensive review delves into the efficacy of nasal spray and transdermal patches, offering a critical analysis of their ability to address key aspects such as drug level consistency, therapeutic effectiveness, and long-term tolerability. Studies encompassing diverse patient populations, drug formulations, and duration of treatment were included to capture a comprehensive view of the effectiveness of nasal spray and transdermal patches in Parkinson's disease management. Furthermore, methodological nuances and potential biases in the selected studies were considered to ensure a robust evaluation of the evidence.²⁴

Construction projects often employ different delivery methods based on project-specific requirements, costs, and timelines. In healthcare, the selection of delivery methods for pharmaceuticals involves considerations of bioavailability, patient compliance, and therapeutic efficacy. Drawing parallels between the two industries allows for a nuanced exploration of the criteria guiding the choice between traditional and alternative delivery methods in healthcare.²⁵

Limitations and challenges associated with existing dosage forms

The evolving understanding of the onset of action for antipsychotic and antidepressant drugs holds profound implications for patient care strategies. The long standing belief in delayed onset has potentially influenced the search for pertinent biological markers and the timing of crucial clinical decisions.²⁶ The conventional narrative surrounding antipsychotic and antidepressant drugs posits a delayed onset of therapeutic action, but recent empirical findings compel a re-examination of this temporal framework. Notably, a meta-analysis of existing studies challenges the established belief in the delayed onset of antipsychotic efficacy, suggesting an earlier commencement of therapeutic response than previously acknowledged.²⁷

By challenging this conventional wisdom, recent research compels a reconsideration of existing patient care protocols, urging a more dynamic and adaptive approach that aligns with the revised understanding of drug efficacy onset. This necessitates a thorough examination of the potential impact on patient outcomes and the broader landscape of quality of life considerations. Moreover, a scholarly contribution in the Encyclopedia of Psychopharmacology categorically dismisses the delayed-onset hypothesis, asserting that the onset of action may be early, if not immediate.²⁸

Parkinson's disease (PD) stands as a chronic and progressive neurodegenerative disorder primarily impacting the motor system. Levodopa, recognized as the most effective medication for PD treatment, presents challenges owing to its short half-life and a limited therapeutic window. The emergence of motor fluctuations, characterized by oscillations between optimal (ON periods) and suboptimal drug responses leading to symptom re-emergence or exacerbation (OFF periods), represents a prevalent complication of levodopa therapy.²⁹

Motor fluctuations, encompassing ON and OFF periods, is the predominant complication associated with levodopa therapy. ON periods denote optimal symptom control, while OFF periods signify suboptimal drug responses marked by symptom resurgence or aggravation. The pervasive nature of motor fluctuations is underscored by their occurrence in up to 50% of PD patients, with an alarming 80 to 100% prevalence rate after a decade of treatment.³⁰

Levodopa's inherent characteristics, including a short half-life and a narrow therapeutic window, contribute to the intricacies of its administration. The review delves into the complexities of levodopa pharmacokinetics, highlighting the multifactorial influences on absorption and metabolism. Additionally, an overview of ongoing clinical trials provides a glimpse into the promising strategies being explored for the effective management of motor fluctuations in Parkinson's patients. This collective exploration aims to contribute to the evolving understanding of this intricate facet of Parkinson's disease management, paving the way for enhanced therapeutic interventions and improved patient outcomes.^31,32

Need for alternative approaches to enhance treatment efficacy

Patient-Centered Care (PCC) emerges as a healthcare paradigm that intricately tailors treatment modalities to the distinctive needs of each patient, taking into meticulous consideration various elements such as age, comorbidities, and lifestyle factors. This approach signifies a departure from the conventional one-size-fits-all model, placing the patient at the core of the healthcare framework.³³

In order to actualize the tenets of PCC, a multifaceted approach involving multi-level strategies and tailored therapeutic educational interventions is imperative. These strategies span various dimensions of healthcare delivery, aiming to customize patient-centered care at multiple levels of interaction within the healthcare system.³⁴

The significance of PCC lies in its potential to revolutionize healthcare delivery by customizing care regimens, particularly for individuals grappling with multi-morbidity. This tailored approach not only augments overall patient satisfaction with healthcare services but also plays a pivotal role in enhancing both physical and social well-being. By prioritizing the unique requirements of each patient, PCC has the capacity to usher in a new era of patient-centric healthcare.³⁴

The potential efficacy of sublingual administration of medications, notably apomorphine and levodopa, presents a promising avenue for the management of Parkinson's disease, particularly in the mitigation of motor fluctuations and addressing perioperative requirements. Further investigation through rigorous research endeavours and clinical trials holds the potential to furnish additional elucidations regarding the utility and effectiveness of sublingual drug administration in the treatment paradigm for Parkinson's disease. Advancements in technology: Touch upon how technological advancements have paved the way for exploring new and more efficient drug delivery systems.³⁵

Method of Preparation

Direct compression method

The direct compression method serves as a prevalent technique in the preparation of sublingual tablets, wherein essential components such as aspartame (a sweetener) and avicel pH 102 (a diluents) are employed. In conjunction, super disintegrant, namely sodium starch glycollate, cross carmellose sodium, and cross povidone, are incorporated into the formulation. Magnesium stearate is included for lubrication purposes. The meticulous process involves passing the mixture through a standard sieve size of 60, ensuring precise amounts of the active ingredients and additives are homogenously blended using geometric dilution. Subsequently, magnesium stearate is introduced and thoroughly triturated. Diverse sublingual tablet formulations are crafted by varying the quantities of excipients. The culmination of this process involves compression using an 8 mm standard concave punch with a minipress table punching machine, resulting in the formulation achieving a total weight of 150 mg. This methodological approach to sublingual tablet preparation showcases a systematic and controlled methodology, allowing for the customization of formulations to meet specific requirements.³⁶

Evaluation

Weight variation

Randomly selecting 20 tablets from each batch, a digital weighing scale is employed to measure their net weight, and subsequently document the obtained values. The average weight derived from these tablets is utilized to ascertain the individual weights of each tablet. This method ensures a representative sampling of the batch and provides a reliable basis for evaluating the consistency and uniformity of tablet weights. By employing a random selection process and relying on average weights, the procedure aims to capture the overall characteristics of the batch, enabling researchers and pharmaceutical practitioners to draw meaningful conclusions about the manufacturing precision and quality control measures in place. This systematic and standardized technique contributes to the robustness and reliability of tablet weight assessments within the pharmaceutical industry.

Thickness

The diameter of each tablet is assessed utilizing a Vernier calliper. This measurement process involves positioning the tablet between the jaws of the calliper and subsequently sliding the scale arm to exert pressure against the stationary arm, allowing for the recording of the observed reading. This straightforward technique facilitates the precise determination of tablet diameters, ensuring accuracy in the dimensional characterization of the pharmaceutical product. The application of a Vernier calliper, renowned for its meticulousness and precision, is characterized by its exacting measurement capabilities and high level of accuracy. The clarity and simplicity of the procedure, as described, contribute to the reliability and reproducibility of diameter measurements, enhancing the overall quality control and assessment of pharmaceutical tablets.³⁷

Wetting time

In the experimental set up, the sublingual tablet is positioned between two layers of absorbent paper, which are subsequently inserted into a rectangular plastic dish measuring 11 cm by 7.5 cm. Following thorough saturation with distilled water, any excess water will completely drain from the dish. Subsequently, a stopwatch is employed to quantify the duration required for the water to permeate from the saturated absorbent paper to permeate the entire tablet. The use of absorbent paper ensures uniform wetting, creating an environment conducive to the evaluation of water diffusion dynamics through the sublingual tablet. The chosen rectangular plastic dish dimensions provide a standardized and controlled setting for the experiment. These investigations underscore the importance of wetting time in the development and assessment of sublingual tablets. When composing a review article, referencing these studies can underscore the critical role of wetting time as a key parameter in formulating and evaluating sublingual tablets. Furthermore, highlighting the utilization of wetting time as a quality control parameter in the pharmaceutical research and development of sublingual tablets provides a comprehensive perspective on its significance in this field.

Hardness

The magnitude of force applied perpendicularly across the diameter of a tablet, resulting in its fracture, is recognized as tablet hardness. This parameter serves as a critical indicator of the tablet's propensity to undergo breakage, chipping, and abrasion during handling and storage processes leading up to eventual use. The determination of tablet hardness for each formulation is done using a Monsanto Hardness Tester. Employing a specialized instrument such as the Monsanto Hardness Tester reflects a commitment to precision and standardization in the evaluation of this crucial parameter. The assessment of tablet hardness using this method contributes valuable insights into the mechanical strength and resilience of formulations, thereby informing pharmaceutical practices aimed at optimizing tablet quality and stability throughout various stages of production and utilization.³⁸

Disintegration test

Each individual tablet is placed within a 10 mL glass test tube possessing a 1.5 cm diameter, accompanied by the addition of 2 mL purified water. The time required for complete tablet dissolution is meticulously recorded through the use of a timer, while concurrent visual examination is conducted. To enhance the visual inspection process, the test tube is gently rotated at a 45^o angle without causing agitation, aiming to disperse any tablet particles that may have obscured undisintegrated remnants. The disintegration assessment is performed utilizing the disintegration apparatus typically employed in the United States Pharmacopeia (USP) disintegration test for oral tablets. Adhering to the USP guidelines, a stringent timeframe of a maximum of two minutes is allocated for the disintegration of sublingual tablets. This meticulous methodology ensures compliance with standardized testing procedures and offers a comprehensive evaluation of the disintegration characteristics of the tablets.³⁹

Dissolution test

The US Pharmacopeia (USP) Dissolution Test Apparatus Type II stands as the designated apparatus for conducting the dissolution test under consideration. The dissolution medium, comprising 500 mL of distilled water, serves as the controlled environment for the test. Samples are systematically extracted at predefined intervals during the dissolution process, and subsequent analysis of these samples is conducted using High-performance liquid chromatography (HPLC). In an academic context, the utilization of the USP Dissolution Test Apparatus Type II for this test signifies adherence to established regulatory standards, ensuring precision and reliability in the assessment of dissolution properties. The strategic sampling intervals and subsequent HPLC analysis contribute to a comprehensive understanding of the dissolution behaviour, providing valuable data for pharmaceutical research and quality control.⁴⁰

Drug content A subset of ten tablets is randomly chosen from the formulation, meticulously disintegrated to yield a powdered equivalent measured in milligrams of the active pharmaceutical ingredient. This powder is accurately transferred to 100 mL volumetric flasks containing the requisite pH solution, followed by thorough shaking to ensure complete amalgamation of the constituents. Subsequent to the addition of a solution to attain the prescribed volume, the mixture undergoes filtration. The drug content is quantified using a double beam UV-visible spectrophotometer, with one millilitre of the filtrate appropriately diluted for measurement. This entire procedure is iterated thrice, and the resultant values are averaged for a comprehensive assessment. The utilization of a double beam UV-visible spectrophotometer underscores a commitment to accurate and reliable analytical techniques. This approach adheres to established standards for pharmaceutical analysis, providing a scientific basis for evaluating the consistency and quality of the formulated medication.⁴¹

Angle of repose

The angle of repose is ascertained through the application of the funnel method, wherein a vertically adjustable funnel is employed to pour a mixture until it forms a cone with a maximum height (h). The determination of the angle of repose involves utilizing the formula θ = tan-1 (h/r), where r signifies the radius of the base of the cone, h represents its height, and θ denotes the angle of repose. The formula utilized for calculating the angle of repose encapsulates the geometric relationship between the heap's height, radius, and the resultant angle. The systematic and quantitative nature of the funnel method contributes to its utility and reliability in scientific investigations involving particulate matter.⁴²

Friability test

The friability test is conducted utilizing the Roche Friabilator, a specialized apparatus designed for this purpose. In this procedure, twenty tablets, initially weighed as Wo, are introduced into a plastic chamber that rotates at a speed of 25 revolutions per minute. The tablets undergo a combined impact of shock and attrition as they are dropped from a height of six inches with each revolution, subjected to a total of 100 revolutions. After completing the designated number of revolutions, the tablets are carefully dusted and reweighed as W. The percentage of friability is determined using the following formula.

% Friability = W0 - W / W0 × 100

In an academic context, the utilization of the Roche Friabilator for the friability test represents a standardized and controlled methodology in the evaluation of tablet durability. The formulation of the percentage friability calculation formula reflects a quantitative approach. This meticulous procedure contributes valuable data for pharmaceutical quality control, offering insights into the robustness of tablets during handling and transportation.^43,44

Conclusion

In conclusion, the evolving landscape of Parkinson's disease (PD) treatment has witnessed a diverse range of modalities, from traditional routes to innovative approaches such as injections, transdermal patches and nasal sprays. Among these, the sublingual mode of delivery, exemplified by sublingual apomorphine, stands out for its ability to ensure swift onset of action and enhanced bioavailability by bypassing hepatic metabolism. This review has provided a comprehensive exploration of the development, pharmacology, safety, and efficacy of sublingual apomorphine in PD treatment. While its potential benefits for drugs susceptible to extensive first-pass metabolism are evident, further insights into its utility and effectiveness await exploration through rigorous research and clinical trials. The continued investigation of sublingual drug administration holds promise in refining our understanding and expanding the treatment options available for individuals grappling with Parkinson's disease.

Conflict of interest

The authors declare no conflict of interest.

Acknowledgment

I want to express my sincere gratitude to Dr. M. Padmasree for her unwavering support and guidance throughout the review process of this article.