WAFERS TECHNOLOGY – A NEWER APPROACH TO SMART DRUG DELIVERY SYSTEM

ABOUT AUTHORS:
Papola Vibhooti *, Dr. Kothiyal Preeti
Shri Guru Ram Rai Institute of Technology & Sciences
Dehradun, Uttarakhand, India
*papola.vibhooti47@gmail.com

ABSTRACTS
The lyophilized wafer developed throughout this review is an effective and versatile drug delivery system for oramucosal application. This has been established from the extensive physicochemical and physic mechanical profiling conducted. Through a screening and selection of polymers, HPC had the lowest gelation characteristics and was therefore suitable for the development of the wafer system. Suitable excipient and polymer combinations were established which allowed for the development of rapidly disintegrating and prolonged release wafer systems. The wafer system containing HPC, lactose, mannitol and glycine had the ability to disintegrate within 30 seconds. The modified wafer system, consisting of pectin cross linked with zinc ions serving as the drug reservoir, and mucoadhesive polymer combination of pectin, carmellose and gelatin, provided effective release of model drug diphenhydramine hydrochloride over approximately six hours. The modification of this technology to provide a prolonged release mucoadhesive system seems promising. It is envisaged that this system will be applicable to many drugs requiring the extended release of bioactive material. Therefore, the lyophilized wafer matrices developed in this study are highly effective in the rapid delivery of drugs, using the oral route as a site of administration.

REFERENCE ID: PHARMATUTOR-ART-1908

Introduction ^[1]
Therapeutic value and pharmacoeconomic value have in recent years become major issues in defining health care priorities under the pressure of cost containment. ^[2] The improvement in drug therapy is a consequence of not only the development of new chemical entities but also the combination of active substances and a suitable Delivery system. The treatment of an acute disease or chronic illness is mostly accomplished by delivery of one or more drugs to the patient using various pharmaceutical dosage forms. Tablets, pills, capsules, suppositories, creams, ointments, liquids, aerosols, and injections are in use as drug carriers for many decades.

These Conventional types of drug delivery systems are known to provide a prompt release of the drug. Therefore, to achieve as well as to maintain the drug concentration within the therapeutically effective range needed for treatment, it is often necessary to take this type of drug several times a day, resulting in the significant fluctuation in drug levels.^[3] For all categories of treatment, a major challenge is to define the optimal dose, time, rate, and site of delivery. Recent developments in drug delivery techniques make it possible to control the rate of drug delivery to sustain the duration of therapeutic activity and/or target the delivery of drug to a special organ or tissue. Many investigations are still going on to apply the concepts of controlled delivery for a wide variety of drugs. ^[4]

The basic rationale for controlled drug delivery is to alter the pharmacokinetics and pharmacodynamics of pharmacologically active moieties by using novel drug delivery systems or by modifying the molecular structure and or physiological parameters inherent in a selected route of administration. It is desirable that the duration of drug action become more a design property of a rate - controlled dosage form and less, or not at all, a property of the drug molecules ’ inherent kinetic properties. ^[5]

The rationale for development and use of novel drug delivery systems may include one or more of the following arguments

Decrease the toxicity and occurrence of adverse drug reactions by controlling the level of drug and/or metabolites in the blood at the target sites.

Improve drug utilization by applying a smaller drug dose in a controlled – release form to produce the same clinical effect as a larger dose in a conventional dosage form.

Control the rate and site of release of a drug that acts locally so that the drug is released where the activity is needed rather than at other sites where it may cause adverse reactions.

Provide a uniform blood concentration and/or provide a more predictable drug delivery.

Provide greater patient convenience and better patient compliance by significantly prolonging the interval between administrations.

“Accelerating Success Through Strategic Innovation” ^[6]

“Wafers technology”

The oral mucosa provides the ideal application site for many active ingredients. Their diffusion into the dense network of capillaries ensures direct access to the blood stream –and excellent patient compliance.

Wafer – an innovative oral dosage form

New oral thin films, so-called wafers, thus creating new possibilities for action profiles and patient compliance.

Wafers are paper-thin polymer films used as carriers for pharmaceutical agents. The innovative dosage form is taken orally but does not require water or swallowing.

Effective absorption of active ingredient
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.

Positive aspects with wafers (industrial point of view):

Attractive dosage form with new active ingredients.
Improvement of established products.
Access to new indications by means of a new absorption profile even for existing active ingredients.
Optimization of bioavailability.
Increase patient compliance.
Innovative technology for product.
Increase of product appeal through innovative format.
Exclusivity and cutting edge technology position in the market through an step forward.

Advantages of wafers

Marketing availability till date^[7]
Ranbaxy Laboratories received import permission for marketing the US FDA approved product Gliadel (polifeprosan 20 with carmustine implant) Wafer. The company has signed an exclusive licensing agreement with BioPro Pharmaceutical, USA, to promote and market Gliadel Wafer in India. Gliadel Wafer is for the treatment of newly diagnosed high-grade malignant gliomas and recurrent glioblastoma multiforme. There is very limited data available on the incidence of brain tumours in India, according to unofficial sources, the estimated prevalence of CNS tumours in India is two to five new cases per 1,00,000 per year. Another source estimates the total number of cases to be around 21,000 per year. Glioblastoma multiforme constitutes about 60-65 percent of these primary brain tumours.

Type of wafers^[8]

Flash dissolved wafers
Melt away wafers
Sustained release wafers
Flash dispersed wafers

Fig 1: Difference between sustained release and flash-dispersal wafers

Fig 2 : Difference between flash dissolve and melt – away wafers

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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 Shearform^™technology. 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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Established Parameters of Formulation Variables
1) Concentration of HPC
Lower and upper limits were determined to be 1%w/v and 10%w/v respectively. The upper limit of 10%w/v was set because wafers of higher polymer concentrations were difficult to remove from the mould. Some wafers produced with polymer concentrations below 5%w/v collapsed. Less than 1%w/v of HPC was not sufficient to form the wafer matrix.

2) Concentration of Diluent
The concentration of the diluent would affect both the solubility and textural properties of the matrices. Lower and upper limits were determined to be 1%w/v and 5%w/v respectively. Concentrations of lactose higher than 5%w/v caused the wafer to be powdery and extremely fragile.

3) Type of Mould
A major problem that was encountered was the removal of the wafers from the moulds without disrupting the delicate structure. Polystyrene trays proved to be the most successful, with minimal deformation of the final product as these moulds could be easily split down the middle to release the wafer.

4) Type of Lubricant
As mentioned above, removal of the wafers from the mould was problematic. Mineral oil produced the greatest ease of removal of the product as compared to the other lubricants analyzed, imparting minimal hydrophobicity and having no effect on the taste of the final product as opposed to other substances such as maize oil.

5) Freeze-Drying Parameters
Although the wafers appeared to be dry after a period of 24 hours, ‘melting’ and discoloration of the matrices occurred on storage. This was attributed to moisture present within the products, indicating that the freeze drying process needed to be conducted for a longer period. In future processes, this was increased to 48 hours.

Concluding Remarks
It was necessary to gain a firm understanding of the key factors involved in the successful production of a lyophilised wafer system. HPC was selected as the most appropriate polymer of the seven that were assessed. It was expected that the type of diluent used in the wafer matrix would affect the disintegration rate of the wafers. Mannitol which is more quickly soluble than lactose will be included in the experimental design to assess its influence of this inclusion on the disintegration rate. The diluents will either be used on their own or in a 1:1 combination. To solve the problem of wafers collapsing, Seager (1998) recommended that glycine be used as a collapse protectant. Therefore, concentrations of up to 0.6%w/v will be included in subsequent formulations.The selection of a suitable polymer, determination of future formulation parameters and creation of problem-free manufacturing techniques formed the basis of this part of the study.

General Statistical Approach to Wafer Formulation
A Face Centered Central Composite design was developed with 5 factors and 4 centre points (Table 5.1).The equation for the design was as follows:
Response = b0 + b1*s + b2*t + b3*u + b4*v + b5*w + b6*s*s + b7*t*t + b8*u*u +

b9*v*v + b10*w*w + b11*s*t + b12*s*u + b13*s*v + b14*s*w + b15*t*u + b16*t*v + b17*t*w + b18*u*v + b19*u*w + b20*v*w

Where:

s = Polymer Concentration;

t = Diluent Type;

u = Diluent Amount;

v = Glycine Concentration; and

w = Fill Volume.

The responses that are generally measured are:

· Disintegration profiles;

· Rate of influx of simulated saliva into the matrix;

· Friability;

· Matrix yield value;

· Matrix tolerance;

· Matrix absorption energy;

· Matrix resilience; and

· Brinell Hardness Number (BHN).

Evaluation of CCF Responses

1) ANOVA Test
An Analysis of Variance (ANOVA) was conducted on the input variables of the wafers to determine which input variables had a significant effect on the recorded output properties of the wafers. The ANOVA was carried out using Essential Regression and Experimental Design V2.207 ^[20] . Only the linear terms were used to regress the data, since we were only interested in the effect that each input variable had on the measured output variables at a 95% confidence interval.

2) Disintegration Profiles
The definition of a fast melting (or disintegrating) tablet appeared in a compendia publication for the first time in 1998. However, neither the US Pharmacopeia north European Pharmacopeia have defined a specific disintegration test.^[21] As a result, a novel method was developed to assess and compare the disintegration profiles of the 30 samples manufactured according to the CCF. Wafers were weighed before being placed in a petri dish containing 20mL of simulated saliva. The dish was allowed to slowly agitate on a vortex mixer for a period of 20 seconds. The contents of the dish were sieved through a stainless steel mesh (pore size 1mm).Particles that were able to pass through the pores of the sieve were considered to be sufficiently disintegrated, while those captured by the sieve were termed the ‘residue’. The residue represents the portion of the wafer that was not sufficiently disintegrated. The residue was measured in both the hydrated and dry state. For wafers that were eroded very rapidly, the agitation time was reduced to 10 seconds. Tests were conducted in triplicate. Based on the measurements documented, the following information was calculated, providing a comprehensive disintegration profile for each wafer formulation:

Normalised Percentage Matrix Disintegrated per second (%/s)

Similar to the disintegration profiles, the influx of simulated saliva is calculated as a rate, allowing the various formulations to be compared on the unit percentage per second.

3) Friability
Rapidly disintegrating systems prepared by the process of lyophilisation are known for having the characteristic disadvantage of poor physical resistance (Dobetti, 2001). Problems anticipated as a result of this include: breakage of tablet edges during handling and the inability of the tablet to be ejected and removed from a conventional blister alveolus. These features need to be taken into consideration when determining the packaging of the product. Friabilty was measured using a Roche friabilator (Hoffman la Roche, Basel, Switzerland). The wafers (N=3) were accurately weighed before being placed into the friabilator. A rotation time of 4 minutes at 25 rpm was used. Tablets were removed and loose particles brushed off the surface. Wafers were re-weighed and the percentage weight loss was calculated.

4) Structural Analysis His study focuses on the characterisation of matrix resilience, energy of absorption, matrix yield value and matrix tolerance, using the TA.XTplus Texture Analyser fitted with a 5kg load cell.

Following method of structural analysis

1) Energy of Absorption
The energy of absorption is an indirect indication of the porosity of the wafers. A highly porous wafer will exhibit a greater value for the energy of absorption because energy is accommodated within the voids in the matrix. The energy of absorption is calculated by determining the area under the curve (AUC) of a profile illustrating force (N) and distance (m) Note that for the AUC, the units of Newton metre (Nm) are equivalent to Joules.

Fig 9: Calculation of energy of absorption (i.e. AUC)

2) Matrix Yield Value
This test is indicative of a surface phenomenon, providing information about the superficial, surface structure of the wafer. The matrix yield value is determined by creating a gradient between anchors 1 and 2. Anchor 2 represents the first point of major inflection on the force-distance profile. This is indicative of primary fracture of the wafer matrix which results in a reduction of force.

Fig 10 : Determination of matrix yield

3) Matrix Tolerance
On further application of force, the residual intact matrix undergoes complete fracture (Figure 5.3). The matrix tolerance value is indicative of the overall strength of the wafer. The second anchor indicates the point of maximum force. The gradient between anchors 1 and 2 in the matrix tolerance value. This indicates the point at which total collapse of the matrix occurs.

Fig 11 : Determination of matrix tolerance

4) Matrix Resilience
Matrix resilience profiles provide us with an understanding of the deformation characteristics and the ability of the wafer to withstand pressure. The calculation of matrix resilience is provided by the ratio of the AUC between anchors 2 and 3 and between anchors 1 and 2.

Fig 12 : Determination of matrix resilience

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5) BHN
The BHN is an indication of the force required to indent the surface of the wafer, and is thus a measure of the hardness of the surface of the wafer. BHN is calculated using the following equation.

Where:
D = Diameter of ball probe = 3.175mm
d = Depth of indentation = 0.25mm
F = Force

Fig 13 : Force – Distance profile for the computation of the BHN

Conclusions
The lyophilized wafer developed throughout this review is an effective and versatile drug delivery system for oramucosal application. This has been established from the extensive physicochemical and physic mechanical profiling conducted. Through a screening and selection of polymers, HPC had the lowest gelation characteristics and was therefore suitable for the development of the wafer system. Suitable excipient and polymer combinations were established which allowed for the development of rapidly disintegrating and prolonged release wafer systems. The wafer system containing HPC, lactose, mannitol and glycine had the ability to disintegrate within 30 seconds. The modified wafer system, consisting of pectin cross linked with zinc ions serving as the drug reservoir, and mucoadhesive polymer combination of pectin, carmellose and gelatin, provided effective release of model drug diphenhydramine hydrochloride over approximately six hours.

A successful, reproducible, manufacturing technique was established by the optimization of the lyophilisation cycle, employing mineral oil as a lubricant and polystyrene moulds providing wafers of suitable characteristics.

Characteristics that were critical to the mechanistic functioning of the wafer, such as rate of matrix disintegration, rate of simulated saliva influx and friability, were extensively elucidated to determine the effects of the formulation variables using ANOVA technology. A low concentration of polymer was associated with a high Disintegration rate, friability and influx of simulated saliva. As predicted, an increase in the amount of diluents present increased both the disintegration rate and friability.

The ANOVA method was used to present a comprehensive profile of the physic mechanical properties such as matrix yield value, matrix tolerance, matrix absorption energy, matrix resilience and Brinell hardness number.A firm understanding of the effects of formulation variables on the responses formed the corner stone of the optimization process. Although the DSC did not form a component of the optimization process, the information provided was integral in the determination of the effect of lyophilisation on the native ingredients. Through this analytical process, it was accepted that lyophilisation did not significantly alter the Tg.

The aim of this study, to consider formulation variables in the statistical optimisation of the lyophilised wafer system was achieved.

Future Prospects and Challenges^[22]
Historically, drug delivery has taken the form of injection, infusion, ingestion, and inhalation, with additional variations of each category. For example ingestion may be in tablet, capsule or liquid form; inhalation may be via use of a dry powder inhaler, an MDI, or a nebulizer. The challenge for both drug and drug delivery companies is to deliver both existing and emerging drug technologies in a manner that improves the benefits to the patients, healthcare workers and the healthcare system. Areas that are being targeted for improvements through device development includes:

• Improved efficacy

• Reduced side effects

• Continuous dosing (sustained release)

• Reduced pain from administration

• Increased ease of use

• Increased use compliance

• Improved mobility

• Decreased involvement of healthcare workers

• Improved safety for healthcare workers

• Reduced environmental impact (elimination of CFC’s)

To provide these benefits, a number of approaches are being (or in some cases have been) developed. The common thread running through the approaches is the concept of self-administered, targeted, sustained release with increased bioavailability. Determining which of the emerging approaches best meets stakeholder needs is a complex, multifaceted problem. Although ingestion is probably the most widely accepted form of delivery it presents difficulties for a number of important classes of drugs. Many drug delivery scientists view oral delivery as the ideal drug delivery method. In the case of proteins and peptides, historical oral delivery mechanisms can only delivery bioavailabities of a few percent. In some cases, dose limiting toxicity levels are caused by lack of selectivity.

In addition, due to the well known fragility and hygroscopicity of lyophilized products, an appropriate packaging system for the wafers need to be developed to ensure that the dosage form reaches the patient and is administered intact.

The modification of this technology to provide a prolonged release mucoadhesive system seems promising. It is envisaged that this system will be applicable to many drugs requiring the extended release of bioactive material.

Therefore, the lyophilized wafer matrices developed in this study are highly effective in the rapid delivery of drugs, using the oral route as a site of administration. The manufacturing process is simple and reproducible. A number of unique opportunities are presented for the formulation of a controlled release drug delivery system.

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