INTRODUCTION:
In the realm of pharmaceuticals, the administration of drugs offers a spectrum of pathways to achieve therapeutic effects. The conventional route, widely practiced, involves oral ingestion, wherein the drug is taken by mouth, swallowed, and initially traverses the systemic circulation through the intricate membranes of the small intestine. This preference for oral drug administration stems from its inherent ease of use, rooted in the historical belief that orally delivered drugs, akin to food, are efficiently absorbed. Furthermore, oral medications typically take the forefront in new drug development and formulation.
This preference is primarily driven by considerations of patient compliance, the convenience of administration, and the cost-effective manufacturing processes involved.1
Yet, the potential for developing oral dosage forms encounters limitations when dealing with drugs that are poorly absorbed through the gastrointestinal (GI) tract. The journey of oral drug delivery is frequently impeded by an array of physiological and pharmaceutical challenges. These challenges are closely linked to the physicochemical properties of the drugs in question and the variability in GI conditions. These variables encompass transit time, the presence of food, pH levels, and enzymatic activity within the alimentary canal. Moreover, the formidable obstacle of extreme first-pass hepatic metabolism looms large, significantly curtailing the bioavailability of drugs administered orally. For certain drugs, like glibenclamide, the substantial first-pass hepatic metabolism renders oral administration incapable of achieving therapeutic concentrations.2
Recent years have witnessed remarkable breakthroughs in the realm of pharmaceutical technology. These advancements have ushered in significant alterations and improvements in systemic drug delivery through innovative administration methods. The conventional routes of drug administration, such as oral, intravenous (IV), and intramuscular (IM), have found themselves overshadowed by the emergence of cutting-edge controlled drug delivery systems.3
Innovative Approach to Buccal Drug Delivery:
The buccal region, nestled within the oral cavity, emerges as an enchanting avenue for drug administration with the potential for systemic delivery. It boasts a mucosal landscape richly veined with blood vessels, rendering it an accessible canvas for the seamless administration and subsequent release of pharmaceutical wonders. The allure of buccal drug delivery extends beyond mere accessibility, offering unparalleled patient compliance when compared to its pharmaceutical counterparts.4
Indeed, buccal drug delivery possesses a myriad of advantages that set it apart from conventional routes of administration:
1. Enhanced Bioavailability: By bypassing the perilous terrain of the hepatic portal system, buccal drug deliverybestows orally administered drugs with enhanced bioavailability, ensuring their swift and effective assimilation.
2. Shielded from Gastric Perils: Shielded from the corrosive clutches of the stomach's harsh environment, drugs delivered through the buccal mucosa remain untarnished, ensuring their integrity and efficacy.
3. Rapid Onset: The buccal mucosa's robust vascularity and high blood flow velocity usher in a rapid ascent of drug plasma concentrations, offering swift relief and therapeutic effects.
4. Ease of Administration: Administering drugs through the buccal route proves a hassle-free endeavor, eliminating the need for injections or traditional oral medications, thus enhancing patient convenience.
5. Flexible Discontinuation: Discontinuation of drug delivery through this route is a seamless process, offering flexibility and control as required by the patient's condition.
6. Patient Preference: Buccal drug delivery garners favor among patients, outshining parenteral, nasal, rectal, and vaginal routes with its ease and patient-friendliness.
7. Barrier-Free Mucosa: In stark contrast to transdermal systems, mucosal surfaces lack the formidable stratum corneum barrier. This absence propels transmucosal routes, like the buccal route, to the forefront of drug administration, bypassing the traditional hurdles faced by transdermal approaches.
In essence, the buccal region stands as a captivating conduit for drug delivery, redefining the landscape of pharmaceutical administration. Its advantages extend far beyond the boundaries of traditional routes, promising a future where drug delivery is not only effective but also tailored to meet the demands of modern medicine and patient preferences. Dose can be reduced which in turn reducesdose depending on side effects.5
Limitations of Buccal Drug Delivery:
Drug delivery through buccal mucosa has the following disadvantages:
· Drugs, that are precarious at buccal pH, cannot be administered by buccal route.
· The continuous secretion of saliva in buccal cavity may lead to dilution of the drug.
· Drugs having unpleasant taste, cannot be administered by this route.
· Buccal region offers small surface area for absorption of drug.
· Loss of dissolved drug due to swallowing of saliva.
· Eating and drinking may be restricted.
· Only those drugsare ideal candidate, which are absorbed by passive diffusion.6
Buccal Mucosa: A Route for Drug Delivery:
In the realm of oral drug delivery, we encounter a triad of distinct routes, each with its unique characteristics: buccal, local, and sublingual drug delivery. The choice among these routes hinges primarily on disparities in permeability and the intricate anatomy inherent to the diverse oral mucosal sites. In broad strokes, the permeability of the oral mucosa follows a descending order as follows: sublingual > buccal > palatal. This hierarchy is intricately linked to the degree of keratinization and the thickness of the mucosal tissues.
The sublingual route, with its exceptional permeability, emerges as a star player in swiftly ushering in drug absorption and enhancing bioavailability across a spectrum of pharmaceutical compounds. In contrast, the buccal mucosa, though certainly a noteworthy contender, falls short of the sublingual region's rapid absorption and heightened bioavailability.7
Yet, the buccal mucosa emerges as a formidable contender, bolstered by two pivotal distinctions. Firstly, its relatively less pervious nature lends itself admirably to sustained-release formulations. Secondly, the buccal mucosa's comparative immobility and its intricate network of smooth muscle render it a favored host for retentive devices tailored for oral mucosal drug delivery. Consequently, the buccal mucosa zone within the oral cavity emerges as the prime candidate for sustaineddrugdelivery, epitomizing an ideal route for pharmaceutical endeavors.
Figure 1: Structure of Oral Mucosa
Drug Transport Mechanism across the Buccal Mucosa:
The most of the drugs move across oral epithelia, by passive transport which is primarily ruled by the law of diffusion. The cellular structure of the oral mucosa suggests that there are two permeation pathways for passive transport across the oral mucosa aretranscellular and paracellular. The paracellular route involves the movement of drug molecules through intercellular spaces, while the transcellular route involves passage through the lipid bilayers of cell membranes.8
Figure 2: Drug Absorption pathways across buccal mucosa
Mucoadhesion:
Definition:
Bioadhesionis the situation in which two materials, from which one is of biological nature, are adhered together for long period of time with the help of interfacial forces. When the adhesion is to mucous membrane, the situation is called mucoadhesion.9
Mechanism of Mucoadhesion:
Mucoadhesion is a situation which involves three consecutive steps wetting, adsorption and interpenetration of polymer chains. Mucoadhesion mechanism consists of two steps, the contact stage and the consolidation stage as shown in Figure 3.
Contact stage: In this stage there is an intense contact occursbetween the mucous membrane and mucoadhesive molecule because of spreading and swelling of the mucoadhesive material.
Consolidation stage:
In thisstage the moisture present in the mucous membrane activates the mucoadhesive moleculesandplasticizes the system, which permit the fragmentation and link up of mucoadhesive materialwith the mucus membrane by the aid of weak van der Waals forces and hydrogen bonds.10
Figure 3: Mechanism of Mucoadhesion
Mucoadhesive Polymers:
These are the polymers which may be water-insoluble or soluble, adheres to the mucus surfaces due to the mutual adsorption and interpenetration. They play an essential role in designing mucoadhesive devices so as to increase the retention time at the desired site.These polymers can be divided into three categories:
· Polymers having hydrophilic groups that make hydrogen bond with alike groups on mucosal surface.
· Polymers that are electrostatic in nature and bind through nonspecific, non-covalent bond.
· Polymers that adhere to certain receptor site on the biological substrate.11-12
Mucoadhesive polymer should have the following properties:
1. The polymer must be nontoxic.
2. It should not irritate mucosa.
3. It should be bonded non-covalently with the mucus cell surface.
4. It should attach rapidly to the wet tissue.
5. It mustallow easy embodiment of the drug.
6. It should release the drugeasily without any hinderance.
7. The polymer shouldbestableon storage
8. Polymer must be stableduringshelf life of the mucoadhesive formulation.
9. Polymer must be economic so that the prepared formulation remains economic and competitive.13
Mucoadhesion's Game-Changing Role:
Mucoadhesive systems revolutionize drug delivery by establishing intimate contact between the drug formulation and the absorbing tissue, thereby potentially elevating drug concentration at a specific site and facilitating high drug flux through the absorbing surface. The ideal attributes of an oral adhesive system for systemic delivery include nonirritancy, a pleasant mouthfeel, strong mucoadhesion, high drug loading capacity, taste neutrality, and prolonged drug release. Recent advancements have seen the emergence of various mucoadhesive dosage forms for oral delivery, including adhesive tablets, gels, ointments, and patches.14,15
Buccal Patches/Films: A Promising Alternative:
Buccal patches or films represent a promising alternative to conventional tablets. They consist of thin laminates comprising a drug-holding matrix designed for controlled drug release, an impermeable backing layer, and a mucoadhesive layer for adhering to mucosal tissue. Patches or films offer several advantages over mucoadhesive tablets, including flexibility, reduced thickness, and enhanced comfort during use. Moreover, they address the issue of short retention time experienced by gels on the oral mucous membrane, which are susceptible to dilution, washing off, and elimination by saliva. In cases where localized drug delivery is needed for oral diseases, these mucoadhesive films also serve as protective barriers, reducing pain and promoting more effective disease management.16
Designing Buccal Mucoadhesive Devices:
The design of buccal mucoadhesive devices can be categorized into three primary types, as illustrated in Figure 4:
Type I: These devices consist of a single-layer structure comprising a drug-polymeric matrix with multidirectional drug release. However, this type of device is prone to greater drug loss due to inadvertent swallowing.
Type II: In this configuration, an impermeable backing membrane overlays the drug-polymeric matrix, preventing drug loss from the uppermost layer into the oral cavity.
Type III: Here, drug release occurs exclusively from one side adjacent to the buccal mucosa, thanks to a unidirectional release mechanism. This is achieved by shielding all film faces except the one in direct contact with the mucosa.
Figure 4: Design of buccal mucoadhesive device
Buccal Patch Systems: A Breakthrough in Drug Delivery:
Buccal patch systems represent a pioneering approach in drug delivery, offering a wide spectrum of possibilities ranging from simple erodible to nonerodible adhesive films. These patches can exhibit unidirectional or bi-directional drug release capabilities, making them a versatile solution for targeted therapy. The primary focus of these systems is to deliver medication effectively through the oral mucosa, revolutionizing the field of pharmaceuticals.
Exploring the Components:
1. Polymer Matrix or Matrices:
· Polymers play a pivotal role in buccal patch systems, controlling the rate of drug release with precision. The polymer matrix is crafted by incorporating the drug within the polymer base. Key considerations for selecting the ideal polymer include:
· Molecular weight and chemical composition conducive to drug diffusion.
· Ease of fabrication into the desired product.
· Non-toxic and non-irritant properties of both the polymer and its degradation products.
· Superior wetting, spreadability, bioadhesion, and biodegradability characteristics.
· Stability throughout the shelf life of the patch system.17
2. Drug:
· The chosen drug must possess specific qualities to excel in buccal delivery:
· A balanced blend of hydrophilic and lipophilic properties.
· Potency achievable with a daily dose of a few milligrams.
· A short half-life (t1/2).
· Susceptibility to hepatic first-pass metabolism or gastrointestinal degradation, making it suitable for buccal delivery.
· A pleasant taste profile.18
3. Mucoadhesives:
· Mucoadhesion is the cornerstone of mucoadhesive drug delivery systems. The polymers with excellent mucoadhesive properties are characterized by hydrogen bond-forming groups and high hydrophilicity. These polymers must also possess:
· High surface free energy to enhance mucosal surface wetting.
· Flexibility to penetrate the mucus network.
· Biocompatibility, non-irritant attributes, and economic feasibility.
· Natural, semi-synthetic, or synthetic origins, including cellulose derivatives, chitosan, polyacrylic polymers, sodium alginate, polyvinylpyrrolidone, and polyvinyl alcohol.19
4. Permeation Enhancers:
· Permeation enhancers, as excipients, expedite drug penetration through the buccal mucosa. These materials should be chemically inert, non-toxic, non-irritating, and safe. Permeation enhancers operate by:
· Modifying cell membrane fluidity.
· Altering cellular proteins, mucosal structure, and rheologic properties.
· Enhancing permeation through various mechanisms.
5. Backing Membrane:
The backing membrane serves as an impermeable barrier to prevent drug loss from the uppermost layer of the patch. It is typically created by casting a polymer solution into a thin, water-impermeable film. Materials suitable for backing membranes include polyester film, polyethylene film, polyolefin film, ethylcellulose, multiphor sheet, cellophane-325, and polyglassine paper.20
6. Plasticizer:
Plasticizers contribute to the softness and flexibility of buccal films. Commonly used plasticizers include propylene glycol, glycerol, PEG200, PEG 400, mineral oil, and castor oil. These additives also play a role in drug release by solvating the polymer and altering polymer-polymer interactions. The precise choice of plasticizer influences the elasticity and rigidity of the patch.
Innovative Methodology For Buccal Patch Preparation:
In our quest to develop high-quality buccal patches, we have employed two innovative methods, each designed to optimize drug delivery while minimizing the use of solvents. These methods ensure the uniformity and effectiveness of our patches.
1. Solventless Casting:
In this pioneering approach, we have eliminated the need for solvents in the patch creation process, enhancing safety and environmental sustainability. The steps involved in solventless casting are as follows:
· Precise amounts of polymers are accurately weighed and directly combined without the use of solvents.
· Subsequently, the drug, plasticizer, and penetration enhancer are incorporated into the polymeric blend.
· The resulting mixture is meticulously stirred and subjected to sonication until a clear and homogenous solution is achieved.
· This solution is then meticulously cast onto a backing membrane positioned within a petri dish.
· To prevent sudden solvent evaporation, an inverted funnel is employed as a cover.
· The petri dish is left to dry naturally at room temperature for a period ranging from 24 to 48 hours.
· Once dried, the patches are carefully removed and securely packed in aluminum foil.21
2. Direct Milling:
Our second pioneering method for buccal patch development avoids solvent usage entirely, ensuring an eco-friendly and efficient process. Here are the key steps involved in direct milling:
· Drug and excipients are mechanically combined without any reliance on liquid media. This is achieved either through direct milling or kneading, maintaining a solvent-free approach.
· Following mixing, the composite product is rolled onto a release liner until the desired thickness is achieved.
· To create a laminate suitable for die-cutting into patches of the desired dimensions and shapes, the backing material is ultimately laminated onto the release liner sheet.22
CHARACTERIZATION OF BUCCAL PATCHES:
To ensure the quality and performance of our buccal patches, a comprehensive characterization process is undertaken, which includes the following parameters:
1. Weight and Thickness Uniformity:
· Three patches from each formulation are individually weighed on an electronic balance, and the average weight is determined.
· Likewise, the thickness of three patches from each formulation is measured at three different positions using a micrometer screw gauge, and the average thickness is calculated.23
2. Folding Endurance:
The folding endurance of buccal patches is assessed by repeatedly folding a patch at the same location until it ruptures. The number of folds required to break or crack a patch is recorded.24
3. Surface pH:
· Three patches from each formulation are selected randomly and allowed to swell on an agar plate surface for two hours.
· A digital pH meter is employed to measure the pH of the patch surface.
4. Percentage Swelling:
· Individual patches from each formulation are weighed before and after being placed in petri dishes containing 20 ml of simulated pH 6.8 phosphate buffer for 1 hour.
· The percentage swelling (%S) is calculated using the formula: %S = (Wt - Wo / Wo) x 100, where Wt is the weight of the swollen patch after time t, and Wo is the initial weight at zero time.
5. Drug Content Uniformity:
· A patch is divided into three equal-sized pieces and placed in separate 100 ml volumetric flasks with 100 ml pH 6.8 phosphate buffer.
· After continuous stirring for 24 hours, the solutions are filtered, suitably diluted, and analyzed using a UV spectrophotometer to determine average drug content.25
6. Mucoadhesive Strength:
· Ex-vivo mucoadhesive strength is assessed using a modified physical balance and fresh porcine buccal mucosa.
· The detachment force, in grams, is recorded as the mucoadhesive strength.26
7. Residence Time (Ex-vivo Mucoadhesion Time):
· Ex-vivo mucoadhesion time is determined by monitoring the behavior of patches adhered to fresh porcine buccal mucosa.
· The time until complete detachment is recorded.27
8. In-vitro Drug Release:
The drug release from patches is evaluated using a USP dissolution test apparatus, with phosphate buffer (pH 6.8) as the dissolution medium.28
9. Ex Vivo Permeation Studies:
Permeation studies are conducted using freshly isolated porcine buccal mucosa in a Franz diffusion cell.29
10. Stability Studies:
Accelerated stability studies are conducted following ICH guidelines to assess the stability of the drug and dosage form over a 90-day period under varying conditions.
By adopting these innovative methods and rigorous characterization processes, we aim to produce buccal patches of the highest quality and efficacy for the benefit of our patients and the environment.30
CONCLUSION:
Buccal mucoadhesive patches offer various advantages when comes to administration, retention accessibility, economy, withdrawal, and patient acceptability. Adhesions of these mucoadhesive devices to mucus membrane raise the drug concentration gradient at the site of absorption and increase the bioavailability of systemically administered medications. In order to deliver drugs that are inefficient when taken orally, systemic drug administration through the buccal mucosa is a promising area for further study.Regardless of the various advantages of drug delivery through the buccal mucosa, this buccal route is still highly difficult due to some hurdles like limited area for absorption and the barrier characteristics of the buccal mucosa. The methods investigated to overcome such hurdles are design and use of ingredients that possess mucoadhesive and penetration-enhancing properties, which improve patient compliance and also assist in attaining prolongedand intimate contact of the drug with the buccal mucosa.
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Received on 13.09.2023 Modified on 10.02.2024
Accepted on 03.05.2024 © RJPT All right reserved
Research J. Pharm. and Tech 2024; 17(7):3445-3451.
DOI: 10.52711/0974-360X.2024.00539