The Review on Innovations in Mouth Dissolving Films: Enhancing Drug Delivery and Patient Compliance

Mr. Faizan Ahmed¹, Mujahid Ahmed Haroon Rasheed², Pathan Junaid Moinuddin*² , Obaidurraheman Mohammed Saleem²

1.      Assistant Professor, Dept. of Pharmaceutical Chemistry, Royal College of Pharmaceutical Education and Research, Syne Khurd Malegaon.

2.       Final year B Pharmacy Royal College of Pharmaceutical Education and Research, Syne Khurd Malegaon.                  

       Email Id: pathanjunaid2021@gmail.com ,  Mobile no: 8788081031

INTRODUCTION

One prevalent type of episodic headache disease is migraine. Has a 1-year frequency of roughly 4% in children, 6% in adults, and 18% in women. Attacks that include different combinations of headache and gastrointestinal, autonomic, and neurological symptoms are what define it. (1) And also incapacitating type of primary headache, migraine affects about 12% of the studied Caucasian population. The majority of non-pharmacological migraine management involves lifestyle counselling to assist patients avoid situations that could set off an episode. (2) Headache location in a large cohort of patients. The most frequently encountered locations include the orbital, frontal, and temporal regions, with the least prevalent sites being diffuse and the vertex. A single location is infrequent. Hemi cranial location is present in two thirds of subjects and a quarter each are on the left side, right side, and both sides The headache locations exhibit considerable similarity across various migraine types, although certain distinctions exist. Variances in location and side tend to be apparent among patients under the age of 21 and those who are older. Gender, headache frequency, and the presence of aura contribute to differences in headache location. The location also demonstrates numerous correlations with triggers and various headache features. (3) With female-to-male ratios ranging from 2:1 to 3:1 and peaking in midlife, the distinguishing trait of migraines being notably more common in females than in males is well-documented worldwide. There is little information on how sex affects migraine symptoms, disability, and use of healthcare services. Regarding probable migraines (PM) and other severe headaches that fall outside the scope of migraines, little information is available. Differentiating between different types of severe headache problems may be made easier by being aware of the sex variations in these conditions. In a sizable US population sample, this study analyses the prevalence and clinical characteristics of migraine, PM, and other severe headaches between the sexes. (4) Over the course of more than ten years of use, botulinum toxin type A has been proven to be a well-tolerated choice for the preventive therapy of chronic migraine. (5)

TYPES OF MIGRAINE

1.         Common migraine, or aura-free migraine:

The most prevalent kind of migraine is this one. It usually affects one side of the head and causes moderate to severe headache discomfort. There isn't an aura (disturbances in vision or perception) before it.

Aura-driven migraine (classic migraine): The distinctive neurological signs or "aura" of a migraine with aura typically occur before the headache. Motor abnormalities, sensory alterations, and visual disturbances are all possible aura symptoms.

2.         Persistent Headache:

When a person has headaches 15 days a month or more for at least three months and at least eight of those headaches are migraines, that individual is diagnosed with chronic migraine.

3.      Period Pain:

Some women have migraines in the days preceding, during, or following their menstrual cycle, which is strongly related to their menstrual cycle.  

4.      Migraine Vestibular:

Vertigo and issues with balance and coordination are linked to vestibular migraines. People may feellightheaded and have trouble balancing during an attack.

5.      Migraine in the retina:

One-sided temporary blindness or vision loss is a rare form of migraine. Usually, the visual problems subside after less than an hour. Migraine Hemiplegic.

6.      Migraine Hemiplegic:

Before or during the headache, hemiplegic migraines induce momentary paralysis or weakness on one side of the body. Confusion, trouble speaking, and eyesight problems are among more symptoms.  

Fig. 1. Symptoms of Migraine

EPIDEMIOLOGY

Migraine is still a disorder that is significantly underdiagnosed and undertreated in the US. Despite being a very prevalent cause of temporary impairment, many people with migraine, including those who experience incapacitating headaches, have never sought medical attention for the issue. The highest prevalence is found in women, people between the ages of 25 and 55, and people from low-income households—at least in the United States. But prevalence is also high in other groups besides these. (6)

PATHOPHYSIOLOGY OF MIGRAINE

A group of confusing neurological disorders known as migraines have been linked to significant involvement of the brain and related tissues during an attack. (7). Pathogenesis of migraines is becoming increasingly well understood. Migraine is now considered to be more than just a vascular headache, but rather a complex and varied disorder of nervous system function due to improved characterization and identification of its clinical symptoms. Important new insights into its pharmacological mechanisms, anatomical and physiological aspects, and genetic reasons have been revealed by recent studies. Novel targets for migraine therapy have been made possible.

TREATMENT APPROACHES OF MIGRAINE

Triptans Promising new therapies for acute migraines have emerged that target the serotonin (5HT1F) and calcitonin gene-related peptide (CGRP) receptors. Other tactics, such as glutamate, GABAA receptors, transient receptor potential vanilloid (TRPV1) receptors, or a combination of 5-HT1B/1D receptors and neuronal nitric oxide production, have not, however, proven effective in clinical trials. One Of the novel therapeutic options, humanized antibodies against CGRP or the CGRP receptor show the greatest potential for the prevention of migraines. Furthermore, both invasive and non-invasive Neuromodulator techniques have promise as acute and preventive therapy; nevertheless, more investigation is required to find the best candidates and application procedures. (9) In the future, the management of migraine is anticipated to customize treatments according to the unique mechanisms of migraine that impact individual patients. (10)

Acute Treatment:

Ø  Pain Relief Medications:

Non-prescription medications like acetaminophen, ibuprofen, or aspirin can be used for immediate relief (OTC). Prescription triptans, such as sumatriptan, rizatriptan, or eletriptan, are designed to specifically target migraine symptoms.

Ø  Anti-Nausea Medications:

Medications like metoclopramide or prochlorperazine are effective in alleviating nausea associated with migraines.

Ø  Combination Medications:

Some medications, such as sumatriptan with naproxen sodium, combine pain relievers with antinausea components.

Ø  Preventive Measures:

Lifestyle Adjustments: Recognize and steer clear of triggers, including specific foods, beverages, insufficient sleep, stress, and hormonal changes. Establish consistent sleep patterns and employ relaxation techniques to manage stress.  Botox Injections:
Botox injections, approved by the FDA for chronic migraines, can be administered every 12 weeks.

Fig.2. Caffeine in Migraine (11)

MOUTH DISSOLVING FILM…….

In recent times, there has been a growing interest in fast dissolving films as a viable alternative to fast dissolving tablets. These films are specifically designed to dissolve rapidly upon contact with a moist surface, such as the tongue, within a few seconds. This unique characteristic allows consumers to take the product without the need for additional liquids, offering a distinct marketing advantage and promoting increased patient compliance. Since the drug is directly absorbed into the systemic circulation, the issues of degradation in the gastrointestinal tract and the first-pass effect can be circumvented. These features contribute to the widespread popularity and acceptance of this formulation, especially among pediatric and geriatric patients, as well as those who fear choking. Notably, over-the-counter films for pain management and motion sickness have been successfully commercialized in the US markets. (12) The inception of fast-dissolving drug-delivery systems date back to the late 1970s, offering an alternative to tablets, capsules, and syrups, particularly tailored for pediatric and geriatric patients facing challenges in swallowing conventional oral solid dosage forms. In response to this demand, various formats of orally disintegrating tablets (ODTs) were introduced commercially. The majority of ODT products were designed to dissolve in under a minute upon contact with saliva, forming a solution that could be easily ingested. Dissolvable oral thin films (OTFs) have emerged in recent years, originating from the confection and oral care markets, initially in the form of breath strips, and have gained widespread consumer acceptance for delivering vitamins and personal care products in a no manner. Companies possessing expertise in formulating polymer coatings containing active pharmaceutical ingredients (APIs) for transdermal drug delivery seized the opportunity to adapt this technology to OTF formats. Presently, OTFs stand as a well-established and embraced technology for the systemic delivery of APIs in over-the-counter (OTC) medications. Additionally, they are in the early- to mid-development stages for prescription drugs. (13)

CLASSIFICATION OF ORAL FILMS

7.       There are three different subtypes

8.      Flash release

9.      Mucoadhesive melt-away wafer

10.  Mucoadhesive sustained-release wafers

Table.2. Suitable candidates for Mouth Dissolving Films (16)

Table 1. Comparison between orally fast dissolving films and oral disintegrating tablets. (15)

AREAS COVERED

This review provides a comprehensive examination of the advantages of orally disintegrating films (ODFs), common excipients, and existing products in the market. It outlines the definition of ODFs and distinguishes them from other films and dosage forms. The text discusses potential manufacturing methods, considering that ODFs are not currently included in any pharmacopoeia, and explores various approaches to characterization and quality control. The review delves into the necessary characteristics, as well as the pros and cons of ODFs. Additionally, it addresses biopharmaceutical considerations, highlighting the potential of these films to improve drug bioavailability. (14)

SPECIAL FEATURES OF MOUTH DISSOLVING FILMS

Table 3. Generalized Detail of Different Ingredients of Oral Film (17)

MANUFACTURING METHODS (18)

Solvent casting Semisolid casting Hot melt extrusion

Solid dispersion extrusion Rolling

Fig. 5. Diagram of a solvent-casting film system

  SOLVENT CASTING METHOD

The solvent casting method involves the process of creating a film or coating by dissolving a substance in a solvent, spreading the solution onto a substrate, and allowing the solvent to evaporate. This technique is commonly used in various applications, such as film production and material processing. In this method, a solution is prepared by dissolving a substance in a solvent. The solution is then applied to a substrate, and the solvent is allowed to evaporate, leaving behind a thin film or coating of the dissolved substance. It's crucial to carefully control the solvent evaporation process to achieve the desired film thickness and quality. The resulting film can have various applications, ranging from biomedical films to industrial coatings. It's important to note that the solvent casting method requires precise control of parameters such as solvent type, concentration, and evaporation conditions to achieve the desired properties in the final product. Researchers and practitioners often fine-tune these parameters based on the specific requirements of their applications.

HOT MELT EXTRUSIO

Solvent casting is a commonly employed method for formulating orodispersible films, while hot melt extrusion (HME) is recognized for its substantial potential. Despite being considered a benchmark technology for its advantages in product development, process optimization, validation, and technology transfer, solvent casting has limitations such as the extensive use of solvents and the necessity to manage organic volatile impurities. The pharmaceutical industry is increasingly adopting HME due to its manifold benefits, including a solvent-free continuous process, reduced unit operations, and enhanced content uniformity. However, there have been limited initiatives in the development of hot melt extruded or dispersible films. In the HME process, the active pharmaceutical ingredient is typically blended in the solid state with polymer, plasticizer, and other excipients. The resulting semisolid blend undergoes extrusion, where the internal heater of the extruder melts the mixture. Following this, the molten mass passes through dies and, upon cooling, is shaped according to the specified product requirements.

Fig. 6. Diagram of a film extrusion system

It's crucial to carefully control the solvent evaporation process to achieve the desired film thickness and quality. The resulting film can have various applications, ranging from biomedical films to industrial coatings.

Fig. 7. Process of preparing mouth dissolving film

It's important to note that the solvent casting method requires precise control of parameters such as solvent type, concentration, and evaporation conditions to achieve the desired properties in the final product. Researchers and practitioners often fine-tune these parameters based on the specific requirements of their applications.

EVALUATION PARAMETERS:

1)  Organoleptic evaluation

2)  Mechanical properties

a) Thickness b) Dry test/tack test c) Tensile Strength d) Percent Elongation e) Tear Resistance

f) Young’s modulus g) Folding endurance

3)  Swelling properties

4)  Transparency

5)  Contact angle

6)  Assay/Content uniformity

7)  Disintegration time

8)  In-vitro Dissolution test

PATIENT ACCEPTANCE AND COMPLIANCE:

For a drug to exert its effectiveness, it is imperative that it reaches the designated site of action. Therefore, a pivotal determinant is patient adherence, as the absence of medication intake results in the failure to deliver the drug to its active site. Patient compliance poses a significant challenge, especially among children and the elderly. In specific scenarios where maintaining consistent blood levels is not critical, the requirement for a dosage form that is convenient for patients may be fulfilled by a rapidly dissolving intraoral tablet with an appealing taste and texture. (20)

 CLINICAL AND REGULATORY ASPECTS:

In the US FDA, when a product demonstrates bioequivalence to an existing oral counterpart, the regulatory pathway involves the Abbreviated New Drug Application (ANDA) process, with the exclusion of clinical studies as per section 505 (j) of the Food, Drug, and Cosmetic Act. For instance, when assessing comparative bioequivalence between an orally disintegrating tablet (ODT) and an orally dissolving film (ODF). Nevertheless, if the ODF exhibits a distinct pharmacokinetic profile, qualifying as a "new dosage form," compliance with the 505 (b) (2) process becomes necessary. This mandates the conduct of a new clinical study, potentially leading to a 3-year marketing exclusivity. Notably, preclinical toxicity studies are not mandated for identical molecules. In Europe, the approval for marketing authorization adheres to the guidelines of the European Medicine Evaluation Agency, with the option of adopting either the decentralization procedure or the mutual recognition process. (21)

ADVANTAGES:

1.      Convenient dosing.

2.      No water needed.

3.      No risk of chocking.

4.      Taste masking.

5.      Enhanced stability.

6.      Improved patient compliance.

7.      The drug enters the systemic circulation with reduced hepatic first pass effect.

8.      Site specific and local action.

9.      Availability of large surface area that leads to rapid disintegration and dissolution within oral cavity.

10.  Dose accuracy in comparison to syrup.

CONCLUSION:

In conclusion, innovations in mouth-dissolving films (MDFs) mark a significant leap in drug delivery, addressing formulation challenges and improving patient adherence. Advanced techniques, polymers, and novel technologies enhance mechanical properties, controlled release, and bioavailability. The integration of taste-masking strategies ensures better patient acceptance. MDFs represent a promising, patient-centric approach with potential to revolutionize oral drug delivery, warranting further research for practical implementation across diverse medical conditions.

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