For the past few years, there has been an enhanced demand for more patient friendly and compliant dosage forms. So the demand for developing new technologies has been increasing annually, since the cost of developing new drug molecules is very high, pharmaceutical companies are focusing on the development of new drug dosage forms for existing drugs with improved safety and efficacy together with reduced dosing and the production of more cost effective dosage forms.
For most drug used to produce systemic effects, the oral still considered as the preferred way of administration because of its several advantages and high patient compliance when compared to many other routes. Tablets and hard gelatin capsules constitute a major portion of drug delivery systems that are currently available. For many patient groups such as the elderly, children and patients who are mentally retarded and unco-operative, nauseated, or on reduced liquid intake or diets have problems in swallowing these dosage forms.
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To overcome these problems, pharmaceutical technologists had developed a novel oral dosage form called as orally disintegrating tablets (ODTs) which disintegrate rapidly in saliva, within seconds, without the need to take it with water. Drug dissolution and absorption as well as onset of clinical effect and drug bioavailability may be greater than those observed from conventional dosage forms.
Even though chewable tablets have been on the market for few years, they are not the same as the new ODTs. Patients for whom chewing is difficult (or) painful can use these new tablets easily. ODTs can be used easily in children who have lost their Primary teeth and do not have full need for using of their permanent teeth.
Recent market studies indicates that more than half of the patient population prefers ODTs than other dosage forms and most patients would ask their doctors for ODTs( 70%), purchase ODTs( 70%), or prefer ODTs than regular tablets or liquids (>80%).
The US food and drug administration center for Drug Evaluation and Research (eDER) defined in the 'Orange Book' that an ODTs is a 'solid dosage' form containing medicinal agents, which disintegrates fastly, usually within seconds, when placed above the tongue. The significance of these dosage forms is highlighted by the European Pharmacopoeia with the adoption of term "Oro-dispersible Tablet" which says, it is a tablet that when placed in the oral cavity get disperse rapidly before swallowing. ODT products is used for treating diseases ranging from migraines (for which rapid onset of action is important) to mental illness (for which patient compliance is important for treating chronic diseases such as depression and Schizophrenia).
Developments in oral delivery of active ingredients include a number of technologies; many of it may classify as oral disintegrating tablets (ODTs). A number of companies are marketing products using various nomenclatures including ODT as well as in trademark names. A legal definition was established for the ODTS. In April of 2007, the FDA issued a draft guidance, Guidance for Industry: Orally Disintegrating Tablets. The definition says ODTs as solid oral preparations that disintegrate rapidly in the oral cavity with an in vivo disintegration time of approximately 30 seconds or less, as per USP disintegration test method. This definition provided a distinction from chewable, effervescent, or other immediate release tablets. The significance of the definition is to follow harmonization. So, as we look towards harmonization it becomes important to identify the problems that surround the technology and offer solutions for developing a new ODT formulation.
Marketing studies have shown that patients often prefer an ODT to conventional swallow tablets. Patients prefer ODTs based upon ease of swallowing, convenience (does not require water to administer), and the quicker onset of action with some compounds. However, from the consumer's perspective, ODTs should be palatable, effective, easy to use, and economical.
Pharmafreezeâ„¢ is a lyophilized system and PharmaburstTM is a patented, directly compressible system. The system is developed as per active ingredient considerations and required speed of oral disintegration. For selecting the appropriate system, one should consider dose, solubility, stability, and cost.
Taste of the active ingredient is a critical consideration and is independent of choosing a lyophilized or directly compressible tablet system. If a finished dosage form has good taste, the consumers may prefer the ODT to a conventional tablet blindly based upon the taste. If the product has an unpleasant taste, the consumer may prefer to manage with the inconvenience of swallow tablets.
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Poor taste can therefore neglect the benefits of the ODT, lead to non-compliance, and potentially lead to a failed product launch. Addition of flavors and masking agents alone may successful mask the objectionable taste of certain actives, namely low dose or those having moderate to low solubility. Other actives may require modifications needed for ODT applications. Methods to prevent drug dissolution in the oral cavity include pH modification, complexation, ion exchange, or often encapsulation. As popularity in ODTs has grown, so the demand for taste masking is increased.
In addition to drug solubility, permeability, and the factor of making a drug available in the oral cavity, it is important to consider the drug's therapeutic action. Many drugs have buccal, mucosal, or sub-lingual absorption properties before reaching the gastrointestinal tract. This could create bioequivalence problems. Oral absorption can avoid first pass metabolism and reduce side effects due to undesirable metabolite formation. Oral absorption results in higher availability and lowers the dose to achieve same therapeutic action as that of swallow tablet. By lowering the dose, the addition of less active per unit dose can lower the costs of these novel technologies. Oral absorption can lead to lowering the Tmax or result in faster onset of action and offer quick relief to the patient.
In some cases, increased bioavailability may not be needed. Examples may include developing a generic of a branded product or producing a line-extension in the existing branded product. When undesirable, the formulator may wish to use similar techniques that were discussed for taste masking. It is required to inhibit drug dissolution to prevent oral absorption. SPI Pharma offers a PharmacapsTM service where they can assist with problem of poor tasting drug and those which has high oral bioavailability. This service focuses on developing small active particles which are non-gritty, retard oral dissolution, avoid fracture of the particles under compaction, and also meet dissolution criteria. As per the FDA's classification on an ODT, tablets should target disintegration in approximately 30 seconds or less. Disintegration is done by using a USP disintegration apparatus in water or simulated saliva. An assumption is made that disintegration does not require the action of chewing or drinking liquids.
Disintegration by this method is challenge for many ODTs, since 30 seconds equates to less than 12 up and down motions of the apparatus. The test will prove not practical for products that disintegrate in a matter of a few seconds. SPI Pharma has developed the compressed tablets that disintegrate in 10 seconds or greater. This is done by using a basket fitted with proximity sensors to detect the absence of the tablet using conductivity. This removes human error potential and the problems in recording results so fastly in a cloudy suspension.
Another important required to meet the FDA's classification is develop a tablet that does not exceed 500 mg in weight. The rationale for supporting this demand is that "larger tablets may have an effect on patient safety and compliance". The verbiage is carefully constructed because the extent of component solubility can influence the acceptability of a larger tablet being labeled as an ODT. Both the PharmafreezeTM and PharmaburstTM platforms are soluble and thus tablets larger than 500 mg to be potentially classified as an ODT.
ODTs are also compressed tablets that basically depend upon the ingredients that have high solubility, wicking or swelling properties. The ingredients should allow sufficient compatibility and also rapid disintegration. This is done by adding highly soluble ingredients like sugars or sugar alcohols that produce a smooth melt and in case of ingredients like mannitol produce cool and sweet taste. It is likely that many ODTs could meet the 500 mg tablet weight exemption when given in the high solubility. Other ingredients found in ODTs may include microcrystalline cellulose that draws saliva into the dosage form for increasing saliva exposure to soluble surfaces and allowing rapid dissolution of the sugar or sugar alcohol components. Some ingredients like starches have the ability to expand in the presence of water making the product to disintegrate. In Pharmaburst's patented technology, tablets are durable and have a fast, smooth melt.
The ability to make fast disintegrating compressed tablets, with sufficient tablet hardness, yield tablet with low friability which is demonstrated in Figure 1. The figure shows PharmaburstTM placebo tablets having a 500 mg tablet weight and ranging from approximately 3.5 to 15.0 kp in tablet hardness.
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DESCRIPTION OF ORALLY DISINTERGRATING DOSAGE FORMS:
ODTs are distinguished from conventional sublingual tablets, buccal tablets and
lozenges that it requires more than a minute to dissolve in oral cavity. In the literature, ODTs also called as Oro disperse, mouth dissolving, quick dissolve, fast-melt, and freeze-dried wafers.
Freeze dried wafers are a quick dissolving thin matrix that contains a medicinal agent that does not require water for swallowing. To ensure physical stability, this fragile dosage form requires unit dose packaging. The water makes to disintegrate fastly in the oral cavity and releases the drug, which dissolves or disperses in saliva. When the saliva is swallowed, the drug is absorbed across the gastrointestinal tract (GIT).
An Orally Disintegrating Tablet (ODT) is a solid dosage forms that contains medicinal substances which disintegrates rapidly (within seconds). The drug is released, dissolved or dispersed in the saliva, and swallowed and then absorbed across the GIT.
A quick dissolving tablet (also known as a fast dissolving, fast - dissolving, fast melting or Oro-dispersing Tablet) is an oral tablet does not require water for swallowing. The tablets get dissolved within 60 seconds when placed in the mouth. The active ingredients are permeated through mucous membranes in the mouth and GIT and enter the systemic circulation. The pregastric drug absorption may bypass the digestive system and metabolism by the stomach acids and enzymes. The tablets are physically robust and can be packaged in multi-dose containers.
IDEAL PROPERTIES OF ODTs:
The ODT's performance depends on the technology used during their manufacture. The necessary property of such tablets is that the ability to disintegrate rapidly and disperse (or) dissolve in saliva, thereby preventing the need for water intake. Various technologies are developed to perform this unique function. An ideal ODT should meet the following criteria.
Requires no water for oral administration but has to get disintegrate and dissolve in the oral cavity within a few seconds.
Have sufficient strength to withstand the rigors of the manufacturing process and post manufacturing handling.
During drug loading allow high.
Insensitive to environmental conditions such as humidity and temperature.
Adaptable and amenable to existing processing and packaging machineries.
THE NEED FOR DEVELOPMENT OF ODTs:
Due to patient poor acceptance, compliance with existing delivery regimes, limited market size for drug companies and drug uses, coupled with high cost of disease management the need for non- invasive delivery system persists.
Orally disintegrating dosage forms are particularly suitable for patients, who are inconvenient to swallow traditional tablets and capsules with a glass of water. These include the following:
Pediatric and geriatric patient who have problems in swallowing or chewing solid dosage forms.
Patients who are not willing to take solid preparation due to fear of choking.
Very elderly patient who may not be able to swallow frequent dose of antidepressant.
An eight year old with allergies who desires a more convenient dosage form than
A middle aged woman undergoing radiation therapy for breast cancer may have
nausea to swallow her H2-blocker.
A patient with persistent nausea, who may be in journey, or has little access to water.
Increased bioavailability and faster onset of action are a major factor of these
formulations. Dispersion in saliva and in oral cavity causes pregastric absorption from some of the formulation and drug dissolves quickly buccal, pharyngeal and gastric regions are all areas of absorption for many drugs. Pregastric absorption prevents first pass metabolism. The safety profiles can be improved for drugs that produce significant amounts of toxic metabolism by first pass liver metabolism and gastric metabolism and for drugs that have a fraction of absorption in the oral cavity and pregastric segment of GIT.
CHALLENGES IN FORMULATING ODTs:
Amount of drug
Size of tablet.
MANUFACTURING AND MARKETING FACTOR:
Developing new drug delivery technologies and utilizing them in product development is critical for pharmaceutical industries.
It is common for pharmaceutical manufacture's to develop a given drug entity in a new and dosage form as a drug nears the end of its patient life,
A new dosage form allows a manufacturer to extend market exclusively, unique product differentiation, value added product line extension, and extent patient protection from a conventional dosage form.
Example: Eisai Inc. Launched Aricept ODT, a line extension of donepezil for Alzheimer's disease, in Japan in 2004 and in the US in 2005 in response to a generic challenge filled in the US by Ranbaxy.
APPROACHES TO ODT DEVELOPMENT:
Incorporating the appropriate disintegrating agent, maximizing the porous structure of the tablet matrix and using highly water soluble excipients in the formulation.
A technology that is originally developed a particular administration need can become quickly adopted as a part of a pharmaceutical company's product life cycle management strategy, that is what has happened with ODTS technologies.
ADVANTAGES OF ORALLY DISINTEGRATING TABLETS:
Bioavailability of drugs is increases when some drugs are absorbed from the mouth, pharynx and oesophagus as the saliva passes down into the stomach,
Pregastric absorption can result in improved bioavailability, reduced dosage, and improved clinical performance through a reduction of unwanted effects.
Ease of administration to patients who cannot swallow a tablet, such as pediatric, geriatric, mentally ill, disabled and uncooperative patients.
When compared to liquids convenience of administration and accurate dose.
No need of water to swallow the dosage form, which is highly convenient for patients who are traveling and do not have immediate access to water.
Good mouth feel property of ODTs helps to change the psychology of medication as "bitter pill" particularly in pediatric patients.
Provide advantages of liquid medication in the form of solid preparation.
Rapid dissolution of drug and absorption and rapid onset of action.
CHALLENGES IN FORMULATING ODTs:
Orally disintegrating drug delivery systems usually contain the medicament in a taste-masked form as most drugs are unpalatable. The active ingredients come in contact with the taste buds when delivery system get disintegrate or dissolve in oral cavity, hence, taste-masking of the drugs becomes critical to patient compliance.
In order to disintegrate in the oral cavity, ODTs are made of either very porous or soft-molded matrices and compressed into tablets with very low compression force, which makes the tablets friable and/or brittle, difficult to handle, and often requiring specialized peel-off blister packing that may increase the cost. Only few technologies can produce tablets that are sufficiently hard and durable to allow them to pack in multidose bottles, such as WowtabÂ® by Yamanouchi-Shaklee, and DurasolvÂ® by CIMA labs.
They need protection from humidity which calls for specialized product packaging because several orally disintegrating dosage forms are hygroscopic and cannot maintain physical integrity under normal conditions of temperature and humidity.
Amount of drug:
The application of technologies used for ODTs is limited to the amount of drug that can be incorporated into each unit dose. For lyophilized dosage forms, the drug dose must be lower than 400 mg for insoluble drugs and less than 60 mg for soluble drugs. This parameter is particularly challenging for formulating a fast-dissolving oral films or wafers.
Water-soluble drugs have various formulation challenges because they form eutectic mixtures, which inturn results in freezing-point depression and the formation of a glassy solid that may collapse upon drying because of loss of supporting structure during the sublimation process. Such collapse can be prevented by using various matrix-forming excipients such as mannitol and can induce crystallinity and hence, impart rigidity to the amorphous composite.
Size of tablet:
The degree of ease of taking a tablet depends on its size. It has been reported that the easiest size of tablet to swallow is 7-8 mm while the easiest size to handle was one larger than 8 mm. The tablet size and easy to handle is difficult to achieve.
Selection of ODT Drug Candidates:
Several factors must be considered for selecting drug candidates for delivery as ODT dosage forms. An ODT is formulated as a bioequivalent line extension of an existing oral dosage form. Under this circumstance, it is assumed that the absorption of a drug molecule from the ODT occurs in the postgastric GIT segments like the conventional oral dosage form. But this may not always be the case. An ODT may have different degrees of pregastric absorption and thus, the pharmacokinetic profiles will vary. Therefore, the ODT will not be bioequivalent to the conventional oral dosage form. For example, ODT formulations of selegiline, apomorphine, and buspirone have significantly different pharmacokinetic profiles when compared with the same dose administered in a conventional dosage form.
It is possible that these differences may be attributed to the drug molecule, formulation, or a combination of both. If significantly higher plasma levels have been observed, pregastric absorption leads to the prevention of first-pass metabolism and play an important role. This situation may have important ascepts for drug safety and efficacy, which may need to be addressed and assessed in a marketing application for an ODT. For example, safety profiles can be improved for drugs that produce a significant amount of toxic metabolites mediated by firstpass liver metabolism and gastric metabolism and for drugs that have a substantial fraction of absorption in the oral cavity and segments of the pregastric GIT.
Drugs having the ability to diffuse and partition into the epithelium of the upper GIT (log P > 1, or preferable > 2); and those able to permeate oral mucosal tissue are considered ideal for ODT formulations. Patients who take anticholinergic medications may not be the best patients for these drugs. Similarly, patients with Sjögren's syndrome or dryness of the mouth due to decreased saliva production may not be good patients for these tablet formulations. Drugs with a short half-life and frequent dosing, drugs which are very bitter or unacceptable taste and taste masking cannot be achieved or those require controlled or sustained release are unsuitable drug of rapidly dissolving oral dosage forms.
Researchers have formulated ODT for various therapy in which rapid peak plasma concentration is required to achieve the desired pharmacological response. These include neuroleptics, cardiovascular agents, analgesics, antiallergic, anti-epileptics, anxiolytics, sedatives, hypnotics, diuretics, anti-parkinsonism agents, anti-bacterial agents and drugs used for erectile dysfunction.
IMPORTANT CRITERIA FOR EXCIPIENTS USED IN THE FORMULATION OF ODTs:
It must be able to disintegrate quickly.
Their individual properties should not affect the ODTs.
It should not have any interactions with drug and other excipients.
It should not interfere in the efficacy and organoleptic properties of the product.
When selecting binder (a single or combination of binders) care must be taken in the final integrity and stability of the product.
The melting points of the excipients used will be in the range of 30-350C.
The binders can be liquid, semi liquid, solid or polymeric mixtures.
(Ex: Polyethylene glycol, coca butter, hydrogenated vegetable oils)
TECHNOLOGIES FOR PREPARING ODTS
The various technologies adopted to prepare ODTs are:
Freeze drying / Lyophilization
Cotton candy process
Oral films / waters
Freeze drying or lyoplilization:
It is a first generation techniques of preparing ODT, in which water sublimes from the product after freezing. The product obtained by this process dissolves more rapidly than other available solid products. The enhanced dissolution characteristic of the formulations by freeze drying process is because of the appearance of glossy amorphous structure to bulking agents and sometimes to drug also. The ideal drug characteristics for this process are relative water insolubility with fine particle size and good aqueous stability in suspensions. The main disadvantage associated with water-soluble drugs are formation of eutectic mixture, because of freeze point depression and formation of glassy solid on freezing which might collapse on sublimation. The addition of cryprotectants like mannitol, crystalforming materials induces crystallinity and imparts rigidity to amorphous material and can prevent collapse of structure and mask the bitter taste. The advantage of using freeze-drying process is that pharmaceutical substances can be processed at non elevated temperature, there by eliminating adverse thermal effects. However high cost of equipment and processing and the lack of resistance necessary for standard blister packs of the final dosage forms limits the use of this process.
Molding process involves moistening, dissolving, or dispersing the drug with a solvent then molding the moist mixture into tablets (compression molding with lower pressure than conventional tablet compression), evaporating the solvent from drug solution or suspension at ambient pressure (no vacuum lyophilization), respectively.
The molded tablets formed by compression molding are dried. As the compression force applied is lower than conventional tablets, the molded tablets results in highly porous structure, which increases the disintegration and dissolution rate of the product. However, further improvement in dissolution rate of the product can be done by passing the powder mixture through a fine screen. As molding process is employed usually with soluble ingredients (saccharides) it offers improved mouth feel and disintegration of tablets. The tablets prepared by this method have low mechanical strength, which results in erosion and breaking during handling.
As the processing solvent is evaporated during the spray drying technique it produces highly porous and fine powders. Spray drying process was developed by Allen and Wang to prepare the ODT. Hydrolyzed and non-hydrolyzed gelatin were used as supporting matrix, mannitol as bulking agent, sodium starch glycolate as superdisintegrant, citric acid and sodium bicarbonate were used to enhance disintegration and dissolution.
It involves softening of the active blend with the solvent mixture of water-soluble polyethylene glycol and methanol and subsequent expulsion of soft mass through extruder or syringe to get a cylinder of the product into even segments using heating blade to form tablets.
Abdelbary et al. prepared the ODT by incorporating a hydrophilic waxy binder (super polystate) PEG-6-Sterate.Superpolystate is a waxy material with an melting point of 33-370C and an hydrophilic lipophilic balance of 9. It acts as a binder and increases the physical resistance of tablets, and also helps in the disintegration of tablets as it melts in the mouth and solubilizes rapidly leaving no residue.
Super polystate was incorporated into the formulation of ODT by melt granulation technique where granules formed by the molten form of this material. Crystallized paracetamol was used as model drug and the formulation included mannitol as a water-soluble excipient and crosscarmellose sodium as disintegrating agent.
Phase transition process:
Kuno et al. examined the disintegration of ODT by Phase transition of sugar alcohols using erythritol (m.p.1220C), xylitol (m.p.93-950C), trehalose (970C), and mannitol (1660C).
Compressing a powder containing two sugar alcohols, one with high- and the other with low-melting points and subsequent heating at a temperature between their melting points produced the tablets. Because of low compatibility, the tablets are not sufficiently hard before the heating process. The tablet hardness was increased after heating process, due to increase of inter particle or the bonding surface area in the tablets induced by Phase transition of lower melting point sugar alcohol.
The presence of highly porous structure in the tablet matrix is the key factor for rapid disintegration of ODT. Volatile substances such as camphor can be used in tabletting process, which sublimated from the formed tablet to improve the porosity.
Koizumi et al. developed ODT utilizing camphor; which is a subliming material that is removed from compressed tablets prepared using a mixture of mannitol and camphor. Camphor was sublimated in vaccum at 800C for 30 min after preparation of tablets.
Zydis is a unique freeze dried oral solid dosage form that can be administered without water and it dissolves instantly on tongue in less than 3 sec. The drug is physically trapped in a water soluble matrix, and then freeze dried to produce a product that rapidly dissolves. The matrix consists of water soluble saccharides and polymer (gelatin, dextran, alginates) to provide rapid dissolution and to allow sufficient physical strength to withstand handling. Water is used during the process to produce porous units for rapid disintegration. Various gums are used to eliminate sedimentation problem of dispersed drug. Glycine prevents the shrinkage of zydis unit during the process and long term storage. As the zydis dosage form is weak in physical strength, unit is contained in peelable blister pack, which allows removal of product without damaging it. An ideal drug candidate for zydis should be chemically stable, water insoluble and of small particle size (Less than 50 microns). Water soluble drugs might form eutectic mixtures and does not freeze adequately, hence the dose is limited to 60mg. Larger drug particles might present sedimentation problem during processing.
It is CIMA lab's first fast dissolving formulation. Tablets are prepared by direct compression at low compression force to minimize oral disintegration and dissolution time. Orasolv technology is an example of slightly effervescent tablet that rapidly dissolve in mouth. The active medicaments are taste masked and dispersed in saliva due to the action of effervescent agents. It provides the pleasant sensation in the patient's mouth. The major disadvantage of Orasolv technology is its low mechanical strength. The tablets produced are soft and friable and need to be packaged in specially designed pack.
It is also a patented technology by CIMA lab, producing second generation ODT's. The tablets prepared by this technology contain drug, fillers, lubricant and tablets prepared by conventional equipments. Durasolv formulations have higher mechanical strength than its predecessors due to application of higher compaction pressure. Durasolv product is durable enough to be packed in either traditional blister pack or vials. It is one of the appropriate technologies for product requiring low amounts of active ingredients.
Wow tab technology:
It is patented by yamanouchi Wow means "without water". Wow tab is an intra buccaly soluble, compressed tablets consisting of granules made with saccharides of low and high mouldability. It is used to obtain a tablet of adequate hardness and fast dissolution rate. Mouldability is defined as the capacity of a compound to be compressed. Low mouldability means the compound shows reduced compressibility for tabletting and rapid dissolution rate. But for high mouldability compounds this condition is reversed. In this the active ingredients is mixed with low mouldability saccharides and then compressed into tablet. The wow tab formulation is stable to environment due to its significant hardness than zydis and Orasolv. Wow tab product is suitable for both conventional bottle and blister package.
Cotton candy technology:
It is patented by Fuisz. Cotton candy technology utilizes a unique spinning mechanism to produce floss like crystalline structure. This crystalline sugar can incorporate the active drug into a tablet. The final product has a high surface area for dissolution. Once placed on the tongue it disperses and dissolves quickly.
The oraquick ODT formulation utilizes a patented taste masking technology by K V Pharmaceutical Company, who claims that its taste masking technology i.e., microsphere technology (Micromask) has superior mouth feel over taste masking alternatives. The process of taste masking does not utilize solvents of any kind and so contributes to faster and superior efficient production. Tablet with significant mechanical strength without disrupting taste masking are obtained after compression. Oraquick claims quick dissolution in matter of seconds with good taste masking. There are no products yet in the market using oraquick technology, but KV pharmaceutical has products, having different classes of drugs such as analgesics, cough and cold, psychotics and ant infective, in developmental stage.
This is patented by Elan, King of Prussia. Nanocrystal technology constitutes lyophilization of colloidal dispersions of drug substance and water soluble ingredients filled into blister pockets. This method avoids manufacturing process such as granulation, blending and tabletting which is more advantages for highly potent and hazardous drugs. As manufacturing losses are uncommon, this process is useful for small quantities of drug.
This technology is based on preparation of floss that is known as shear form matrix, which is produced by subjecting a feedstock containing a sugar carrier by flash heat processing. In this process, sugar is together subjected to centrifugal force and to a temperature gradient, which raises the temperature of the mass to create an internal, flow condition, which permits part of it to move with respect of mass. The flowing mass exists through the spinning head that flings the floss. The floss produced is amorphous in nature so it is further downsized and recrystalised by various techniques to provide uniform flow properties and thus facilitate blending. The recrystalised matrix is then blended with other tablet excipients and an active ingredient. The resulting mixture is compressed into tablet. The active ingredient and other excipients can be blended with floss before carrying out recrystallisation. The shear form floss, when blended with the coated or uncoated microspheres, is compressed into flash dose or EZ chew tablets.
SPI Pharma, New castle, patents this technology. This utilizes the coprocessed excipients to develop ODT, which dissolves within 30-40 s. This technology involves dry blending of drug, flavor, and lubricant followed by compression into tablets. Tablets obtained have sufficient strength so they can be packed in blister packs and bottles.
Akina patents this technology. It utilizes the concept of formulating plastic granules and coprocessing at low pressure to produce strong tablets with high porosity. Plastic granules composed of:
Porous and plastic material
Water penetration enhancer, and Binder
The process involves usually mixing the porous plastic material with water penetration enhancer and followed by granulating with binder. The tablets obtained have excellent hardness and rapid disintegration time ranging from 15 to 30s depending on size of tablet. There are several commercial products available in market for orally disintegrating tablets.
Conventional tablet process:
The WOWTAB manufacturing technique is one successful method that features conventional tablet characteristics for ease of handling, packaging, and fast disintegration. The technology is based on a combination of new physically modified polysaccharides that have water dissolution characteristics that facilitate fast disintegration and high compressibility. The result is a fast-disintegrating tablet that has adequate hardness for packaging in bottles and easy handling.
The manufacturing process involves granulating low-moldable sugars (e.g.,Â mannitol, lactose, glucose, sucrose, and erythritol) that show quick dissolution characteristics with high-moldable sugars (e.g.,Â maltose, sorbitol, trehalose, and maltitol). The result is a mixture of excipients that have fast-dissolving and highly moldable characteristics. The drug can be added, along with other standard tableting excipients, during the granulation or blending processes. The tablets are manufactured at a low compression force followed by an optional humidity conditioning treatment to increase tablet hardness.
Floss-based tablet technology:
Floss-based tablet technology (e.g.,Â FlashDose, Biovail and Mississauga, ON, Canada) also is used to produce fast-dissolving tablets using a floss known as the shearform matrix. This floss is commonly composed of saccharides such as sucrose, dextrose, lactose, and fructose. The saccharides are converted into floss by the simultaneous action of flash-melting and centrifugal force in a heat-processing machine similar to that used to make cotton candy. The fibers produced are usually amorphous in nature and are partially recrystallized, which results in a free-flowing floss. The floss is mixed with an active ingredient and excipients followed by compression into a tablet that has fast-dissolving characteristics.
COUNSELING POINTS FOR ODTs
Pharmacists are in the ideal position to become familiar with the different technologies and educate their patients on what to expect upon taking their first dose. The majority of patients receiving ODT preparations have little understanding of this new dosage form. Patients may be surprised when tablets begin to dissolve in the mouth. The might expect a faster onset of action. Clarification from the pharmacist can avoid any confusion or misunderstanding. As with all dosage form technologies, some patient populations are better served by their use than others. Patients who concurrently take
anticholinergic medications may not be the best candidates for these drugs. Although no water is needed to allow the drug to disperse quickly and efficiently, most technologies utilize the body's own salivation. Decreased volume of saliva may slow the rate of dissolution / disintegration and decrease the bioavailability of the product. Although chewable tablets have been on the market for some time, they are not the same as the
new ODTs. Patients for whom chewing is difficult or painful can use these new tablets easily. ODT's can be used easily in children who have lost their primary teeth, but do not have full use of their permanent teeth. Patients may mistake ODT for effervescent tablets. Pharmacists may wish to stress the difference between the use of quick dissolving and effervescent tablets.
Industrial applications include the following:
To develop an orally disintegrating dosage forms and to work with existing disintegrants
To further improvise upon the existing technology of ODTs
To optimize the blend of disintegrants or excipients to achieve ODTs
To select and develop proper packaging material and system for enhanced stability of the product and also develop a cost-effective product
To arrive at various taste-masking agents and prepare palatable dosage forms thereby increasing patient compliance
To develop disintegrants from different polymers which are used as coating materials by certain modifications and use them for formulating ODTs.
These dosage forms may be suitable for the oral delivery of drugs such as protein and peptide-based therapeutics that have limited bioavailability when administered by conventional tablets. These products usually degrade rapidly in the stomach. Should next
generation drugs be predominantly protein or peptide based, tablets may no longer be the dominant format for dosing such moieties. Injections generally are not favored for use by patients unless facilitated by sophisticated auto-injectors. Inhalation is one good alternative system to deliver these drugs, but the increased research into biopharmaceuticals so far has generated predominantly chemical entities with low molecular weights. The developments of enhanced oral protein delivery technology by ODTs which may release these drugs in the oral cavity are very promising for the delivery of high molecular weight protein and peptide.
Stavudine (2'-3'-didehydro-2'-3'-dideoxythymidine, d4T, brand name Zerit) is a nucleoside analog reverse transcriptase inhibitor (NARTI) active against HIV.
Stavudine is a nucleoside analog reverse transcriptase inhibitor (NARTI) active against HIV. Stavudine was approved by the FDA in 1994 for adults and in 1996 for pediatric use and again as an extended-release version for once-a-day dosing in 2001. When HIV infects a cell, reverse transcriptase copies the viral single stranded RNA genome into a double-stranded viral DNA. The viral DNA is then integrated into the host chromosomal DNA which then allows host cellular processes, such as transcription and translation to reproduce the virus. RTIs block reverse transcriptase's enzymatic function and prevent completion of synthesis of the double-stranded viral DNA thus preventing HIV from multiplying.
Stavudine is an analog of thymidine. It is phosphorylated by cellular kinases into active triphosphate. Stavudine triphosphate inhibits the HIV reverse transcriptase by competing with natural substrate, thymidine triphosphate. It also causes termination of DNA synthesis by incorporating into it. Simultaneous use of AZT is not recommended,as it can inhibit the intracellular phosphorylation of stavudine. Other anti-HIV drugs do not possess this property.
Indications: In combination with other antiretroviral agents, is suggested for the (HIV)-1 treatment.
Dosage and Administration:
The dose interval between ZERIT (stavudine) should be 12 hours. It can be taken with or without food.
Adult Patients: ZERIT can be given to adult patients with renal failure with an adjustment in dosage.
Pediatric Patients: In pediatric patients the urinary clearance is also a major route of excretion and clearance of stavudine will be altered in children with renal impairment. There are inadequate data to suggest a specific dose adjustment of ZERIT in this type of patients.
The major adverse reactions are the following:
lactic acidosis and severe hepatomegaly with steatosis
neurologic symptoms and motor weakness