Anatomic and Physiological Considerations[9]
Four sites within the buccal cavity have been used for drug administration. The four regions have varying permeability, which plays a role in the absorption of drugs across the oral mucosa. As seen in the four key areas are the buccal cavity, the lingual area, the palate and gingival region. The most commonly used sites for drug administration of the four mentioned above is the sublingual and buccal route. Using the sublingual route, the medicament is placed under the tongue, usually in the form of a rapidly dissolving tablet. The anatomic site for drug administration between the cheek and gingival is known as the buccal mucosa. The oral mucosa is composed of three layers. The first layer is the stratified squamous epithelium; underneath this layer lies the basement Membrane .The basement membrane overlies the lamina propria and submucosa.

Fig 3. : Mucousal region of mouth [10]

The constitution of the epithelium within the different sites of the oral cavity shows dissimilarity. The gingival and hard palate are exposed to mechanical stress during eating, hence the epidermis is keratinized in a similar manner as the skin. The epithelium in the soft palate, buccal and sublingual area is not keratinized, therefore not containing ceramides and acylceramides which are associated with providing a barrier function.[11]  The mucosa of the buccal and sublingual region have only small amounts of ceramide, and is thus more permeable when compared to other regions of the oral cavity.[12]  The presence of membrane coating granules (MCGs) accounts for the differences in permeability amongst the various regions of the oral mucosa. When cells go through differentiation from basal to flattened keratinous cells, MCGs are formed. At the apical cell surface, MCGs merge with the plasma membrane and their contents are discharged into the intercellular spaces. This occurs mainly in the upper one-third of the epithelium.  MCGs are present in both keratinized and nonkeratinised epithelia, however their composition is different. On the other hand, non-keratinised epithelium contains MCGs that are nonlamellar and include cholesterol, cholesterol esters and glycospingolipids

Fig 4 :  Composition of layers of mucosal epithelium

(a)  Keratinised    (b)  non kerantinised

A layer of mucus is present on the surface of the epithelial layer of cells. This plays a major role in cell-to-cell adhesion, oral lubrication, as well as mucoadhesion of mucoadhesive drug delivery systems .A major feature in the environment of the oral cavity is the presence of saliva. The salivary glands produce saliva, responsible for protecting the soft tissues from abrasion during the mastication of food Saliva plays an essential role in facilitating the disintegration of quick-disintegrating drug delivery systems [13]  the buccal and sublingual regions are different from each other in terms of anatomy, permeability to drug, and their ability to retain a drug delivery system for a desired duration. Although the buccal mucosa is less permeable than the sublingual mucosa and does not yield a rapid onset of action as seen with sublingual delivery, mucosa of the buccal area has an expanse of smooth and relatively immobile surface, which is suitable for placement of a retentive system. For buccal drug delivery, adhesion to the oral mucosa permits not only the intimacy of contact and the possibility of improved drug absorption, but also the ability to achieve an optimum residence time at the site of administration.[14] These characteristics make the buccal mucosa a more appropriate site for prolonged systemic delivery of drugs. The sublingual route is however more suitable for delivery systems formulated either as rapidly disintegrating matrices or softgels. These systems create a highly significant drug concentration in the sublingual region prior to systemic absorption across the mucosa.

Mode of Action

Fig 5. : Absorption through oral mucosal

The wafer quickly dissolves in the oral cavity, and the active ingredient can be absorbed into the blood - stream via the oral mucosa. The active ingredient, once absorbed by the oral mucosa, thus bypasses the liver’s first-pass effect, which improves bioavailability. Depending on the selected wafer type, the active ingredient’s release may also be delayed. In this case, it is absorbed after swallowing via the gastrointestinal tract.

Manufacturing of wafers[6]
The active ingredient in wafer is integrated into a polymer matrix. The typical size of an oral film is between 2cm2  to 10cm2 , with a thickness of 20 micrometre to 500 micrometre.Oral thin films can be composed of a single-layered system.The active ingredient  may be prsented within the wafer matix in either a dissolved an emulsified or a dispersed state.If required, it can also be bound in a complex form,for example,to enable taste masking.

Open Matrix-Type Wafers and Tablets
With the introduction of the Zydis® system[15]  in the late 1970s, the concept of quick disintegrating drug delivery systems gained much attention. It was the first of this class of delivery systems to be manufactured on a large scale. It is a freeze-dried wafer made from various standard tablet adjuvants. [16]  The wafer essentially works on the principle of forming an open network containing the active ingredient. The Zydis® manufacturing process. The freeze-dried tablet disintegrates within 2-3 seconds, releasing the active ingredient. The drug either forms dispersion or dissolves in the saliva, which is then swallowed and absorbed via the GIT.

Fig 6 :  Production of Zydis® lyophilized wafer [10]

The WOWTab® (With-Out-Water tablet) has been produce by Yamanouchi Pharmaceutical Co. Ltd. (Tokyo, Japan). This tablet is manufactured using conventional granulating and compression. The rapid disintegration is attributed to the blending of a low and high mold ability saccharide. The unique combination of saccharides provides sufficient mechanical strength as well as quick tablet disintegration.Fuisz Technology Ltd. (Chantily, Virginia, USA) developed the Flash Dose® tablet, which can dissolve in the patient’s mouth in less than 10 seconds. This has been achieved by the use of Shearformtechnology. The process involves a unique blend of sugars being placed in a fast spinning machine and subjected to flash heat. By this process, long cotton-like fibres called ‘floss’ are produced. The ‘floss’ is then cured by subjecting it to specific environmental conditions that induce crystallisation, at this stage crystallisation modifiers may also be added. The matrix is then blended with coated or uncoated microspheres containing the active drug. The floss is compressed using standard tabletting equipment.[17]

Fig 7 :  Manufacturing process of Flash Dose [10]

Of the various open matrix-type wafers on the market, the Zydis® system remains the most popular, as a result making lyophilisation the most frequently used process for the manufacture of these systems.

Preparation of wafers
For the formulation of a rapidly disintegrating wafer, a polymer with low gelation characteristics is desired.[18]  The gelation potential of polymers is highly dependent on its’ solubility.

1) Materials and Methods
Polymers utilised in the study include: sodium alginate, hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), pectin, polyethylene oxide (PEO), polyvinyl alcohol (PVA) (MW 124,000 - 186,000). Additionally, lactose and polystyrene cylindrical moulds of total volume 60.31mm³ (diameter 16mm and depth of 2.4mm) were utilised. Materials used in the preparation of simulated saliva were: Potassium Phosphate Monobasic (KH2PO4), Disodium Hydrogen Phosphate (Na2HPO4), Sodium Chloride (NaCl).

2) Preparation of wafers
Polymers suitable for oramucosal preparations were identified based on information provided in literature . A polymer  (1%w/v) and lactose as a bulking agent (6%w/v) was added to deionised water and mixed for 45 minutes. 1.5mL of the various polymer solutions were pipetted into the cylindrical cavities pre-oiled with mineral oil. The formulation was subjected to a freeze-phase in a freeze-dryer at -60°C for 2 hours. The drying-phase was executed at a pressure of 25 mtorr for 24 hours. Wafers were stored in glass jars with 2g of desiccant sachets.

Analysis of wafers

(1) Weight Uniformity
Weight uniformity was used to assess the reproducibility of wafer production process. Individual wafers were weighed, and standard deviations calculated. All experimentation was conducted in triplicate.The reproducibility of the production process was demonstrated by the low standard deviations (SD) calculated from the mass for each of the various polymer systems. Shows the results obtained from the various polymer wafer systems. Mean weight of wafers manufactured (N=3)

Polymer Mean (g)

± SD

HPC 0.126

± 0.0017

HPMC 0.122

± 0.0002

Pectin 0.134

± 0.0055

PEO 0.119

± 0.0045

PVA 0.118

± 0.0011

Sodium alginate 0.109

± 0.0007

Although the standard deviation of the samples is low, slightly higher values were observed for polymers such as pectin and PEO. This may be attributed to the high viscosity of the initial solution, and therefore greater variability in the production process.

(2) Gelation of Matrices
The main objective of this study was to formulate a rapidly dissolving wafer system. Thus the matrix formation characteristics required assessment and formed the basis for the selection of a suitable polymer. Gelation of the dosage form would delay the disintegration and ultimately the release of active substance. A novel method was developed in order to assess the matrix forming profiles of the wafers. Wafers were weighed before being placed in a Petri dish (diameter 85mm, depth 10mm) containing 20mL of simulated saliva (pH 7.1). The Petri dish was agitated for a period of 30 seconds on a Vortex Genie2 on the slowest setting. The contents of the Petri dish were sieved through a stainless steel mesh (pore size 1mm). The mass of the remaining residue was determined on a balance (and used to calculate the rate of matrix formation.The simulated saliva solution comprised 2.38g Na2HPO4, 0.19g KH2PO4 and 8g NaCl in 1000mL of deionised water. [19]

(3) Determination Limits for Formulation Variables
The lower and upper limits were determined using a trial and error method. Wafers of varying polymer and diluents concentrations (up to 30%w/v of each) were made and inspected visually. Polymers such as sodium alginate, pectin and PEO tended to form a gel-like substance when hydrated and agitated rather than undergo disintegration.

Sodium alginate produced the highest amount of residue, possibly due to its low water solubility. In sharp contrast, the highly hydrophilic polymers such as HPC were completely disintegrated within 30 seconds into small particles which were able to penetrate through the pores on the sieve. The mass of intact material after sieving of the various dissolved wafers tested. Based on the results obtained, HPC was identified as the most suitable polymer for the wafer system, because no residue was produced after 30 seconds of hydration and agitation in simulated saliva. This may be attributed to the fact that HPC is highly soluble in polar solvents and therefore undergoes disintegration rapidly without forming a gel residue, ensuring rapid matrix disintegration.

Fig 8 :  Mass of intact wafer after gelation studies using various polymers (N=3)

(4) Development of the Manufacturing Process
To establish the suitability of a mould in terms of ease of the system removal, well plates, blister packs and disposable polystyrene trays were assessed. To overcome problems of wafers sticking to the mould, various lubricant systems were considered. Magnesium Stearate, Span 60, Maize oil and mineral oil were evaluated for their anti-adhesive properties.It was also necessary to determine suitable timeframes for the lyophilisation process.



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