challenges in development of orally disintegrating and dispersible tablets
TRANSCRIPT
CONTENTS IntroductionAdvantages over conventional tablet dosage formsChallenges in formulation and developmentMaterials requiredMechanism of drug releaseFormulation techniques Conventional methods Patented technologiesMarketed productsEvaluation testsFuture developmentsConclusionReferences
INTRODUCTIONDefinitions of ODTs:
According to US FDA:
“A solid dosage form containing medicinal substance, which disintegrates rapidly usually within a matter of seconds, when placed upon the tongue”.
According to European pharmacopoeia:
“A tablet that is to be placed in the mouth where it disperses rapidly before swallowing”.
Terminologies for ODTsRapidly dissolving tablets are also known as
Melt in Mouth tablets
Mouth dissolving tablets (MDT)
Fast disintegrating tablets (FDT)
Orally disintegrating tablets
Rapid disintegrating tablets (RDT)
Oro dispersible tablets (ODT)
Quick dissolving tablets.
Advantages over the conventional dosage form No risk of choking.
Requires no water intake.
Overcomes unacceptable taste of the Drugs.
Quick disintegration and dissolution of the dosage form. Facilitates faster onset of therapeutic action. Improved bioavailability can be achieved.
Avoids First Pass Metabolism due to pregastric absorption.
Ideal dosage form for Peadiatric and geriatric patients.
Ease of administration for patients who are mentally ill, disabled and un co-operative.
Challenges in the product design, formulation and manufacture of ODTs.
PalatabilityMechanical strengthAmount of drugSize of tabletHygroscopicityAqueous solubilityShort half-lifeCost of the tablet
PALATABILITY
As most of the drugs are unpalatable, orally disintegrating drug delivery
systems usually contain the medicament in a taste masked form.
Delivery systems disintegrate or dissolve in patient’s oral cavity, thus
releasing the active ingredients which come in contact with the taste buds;
hence taste masking of drugs become critical to patient compliance.
General taste masking technologies in oral solid dosage forms:1. Taste masking with hydrophilic vehicleHydrophilic vehicles- carbohydrates, proteins, gelatin, ZeoliteIon Exchange resins- Indion 204, 214, 224, 234CyclodextrinsFlavors, sweeteners, amino acids.
2. Taste masking with lipophilic vehicleEx: fats, fatty acids.
3. Miscellaneous masking agentsEx: Effervescent agents, Rheological modifications, salt
preparations, solid dispersions etc.
Detection threshold of sensors compared to Human receptorsPharmaceutical taste assessment requires human test panel that
increases time and money to the development process. During the last decade, a
multisensor system and a device for the liquid analysis that can be
collected under the term “Electronic tongue” was developed.
TasteTaste Taste basic Taste basic substancesubstance
Human tongueHuman tongue Electronic Electronic tonguetongue
SweetnessSweetness SucroseSucrose 1x101x10-2-2 2x102x10-6-6
Bitterness Bitterness CaffeineCaffeine 0.7x100.7x10-3-3 1x101x10-6-6
Sourness Sourness HClHCl 9x109x10-4-4 5x105x10-6-6
The active moiety in pharmaceutical product cannot be therapeutically beneficial unless it has preference and acceptance by the patient. Thus, pleasant taste is important for the therapeutic success of the drug formulation.
Human tongue with taste receptors.
Sample Electronic tongue
Objectives of electronic tongue:
Identification between bitter, sweet and sour substances by using electronic tongue.
Separating the different substances eliciting the same taste (sour, bitter, sweet).
Identify drug preparations containing active substance and placebo substance.
Quantification of the effect of taste masking of bitter
substances by sweet ones.
MECHANICAL STRENGTH In order to allow ODTs to disintegrate in the oral cavity, they
are made of
either very porous and soft-molded matrices or 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 add to the cost.
AMOUNT OF DRUGApplication of technologies used for ODTs is limited by the
amount of
drug that can be incorporated into each unit dose.
In case of Lyophilized dosage forms, drug dose must be less than 400mg – insoluble drugs less than 60mg -- soluble drugs
This parameter is particularly challenging when formulating a fast-dissolving oral films.
SIZE OF TABLETThe degree of ease when 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.
Therefore, the tablet size that is both easy to take and easy to handle is
difficult to achieve
HYGROSCOPICITYSeveral orally disintegrating dosage forms are hygroscopic
and cannot
maintain physical integrity under normal conditions of temperature and
humidity. Hence, they need protection from humidity which calls for
specialized product packaging.
AQUEOUS SOLUBILITYWater soluble drugs pose various formulation challenges because they form
eutectic mixtures, which result in freezing point depression and the formation of a glassy solid that may collapse upon drying because loss
of
supporting structure during the sublimation process.
This collapse can be prevented by using various matrix-forming excipients
like Mannitol which induces crystallinity and hence impart rigidity to the
amorphous composite.
SHORT HALF-LIFEODTs being immediately releasing dosage forms and the
absorption of
maximum amount of dose takes place in the pre-gastric region, these have
sort half life.
This character may render drug unsuitable for delivery as prolonged release
or sustained release dosage form.
COST OF THE TABLET
As ODTs are easily fragile, these products require special unit-dose
packaging which may add to the cost of the dosage form.
Drug
Excipients
THE IDEAL CHARACTERISTICS OF DRUG
For disintegration and dissolution in oral cavity i.e., the pre-gastric absorption from an ODT include,
1. No bitter taste2. Dose lower than 20mg3. Small to moderate molecular weight4. Good solubility in water and saliva5. Partially nonionized at the oral cavity’s pH.6. Ability to diffuse and partition into the epithelium of
upper GIT.7. Ability to permeate oral mucosal tissue.
EXCIPIENTS
FILLER
Eg: More potent drugs like codeine are required in very low amount which
require diluent such as lactose to makeup volume of drug.
Various fillers used are Lactose,
Directly compressed spray dried mannitol,
Sorbitol, Calcium carbonate,
Pregelatinised starch, Magnesium trisilicate,
Al(OH)3 etc.
SUPERDISINTEGRANTS
Eg: Cross povidone, Crosscarmellose sodium,Sodium starch glycolate,calcium carboxy methyl
cellulose,Alginates, Micro crystalline cellulose, Amberlite IRP 88, Guargums, Modified corn starch, Pregelatinized starchChitin chitosanSmecta
BINDERS
Acacia
Cellulose derivatives
Gelatin
Polyvinyl pyrollidine
Tragacanth
ANTIFRICTIONAL AGENTS
GLIDANTS corn starch, talc,
silica derivatives
LUBRICANTS Stearic acid,
magnesium stearate, talc, PEG, liquid paraffin
ANTIADHERENTS talc, corn starch,
colloidal silica, sodium lauryl sulphate.
OTHER EXCIPIENTSCOLOURS Eg: Carotene, chlorophyll, brilliant blue, Indigotene,
Erythrosine
FLAVOURING AGENTS Eg: Menthol, Vanilla, Liquorice, Citrus fruits flavour, Anise
oil, Clove oil, Pippermint oil, Eucalyptus oil.
SWEETENERS Eg: Natural- Mannitol, Lactose, Sucrose, Dextrose Artificial- Saccharin, Aspartame, Cyclamate
MECHANISMS OF DRUG RELEASEThe drug releases from the FDT due to the action of super
disintegrants and generally by swelling of the porous matrix.
MECHANISM OF SUPERDISINTEGRANTS
Due to deformation
Due to disintegrating particle/repulsive forces
Capillary action and porosity (wicking)
Chemical reaction (acid-base)
DEFORMATION AND REPULSION a. Deformation b. Repulsion
WICKING AND SWELLING a. Wicking b. Swelling
FORMULATION TECHNIQUES
COVENTIONAL TECHNIQUES
Tablet moulding
Direct compression Spray drying
Sublimation
Freeze drying (or) Lyophilization Mass extrusion
Cotton candy process
Tablet MoldingMolded tablets are prepared by using water soluble ingredients so
that the
tablets dissolve completely and rapidly.
The powder blend is moistened with a hydro-alcoholic solvent and is
molded into tablets under pressure lower than that used in Conventional
tablet compression. The solvent is then removed by air-drying.
Eg: Benadryl, Fastmelt(diphenhydramine citrate, pseudoephidrine HCl) – Allergy, sinus
DIRECT COMPRESSIONEasiest way to manufacture tablets is direct compression.
Low manufacturing cost, conventional equipments and limited number of
processing steps led this technique to be a preferable one.
However disintegration and dissolution of directly compressed tablets
depend on single or combined effect of disintegrant, water
soluble
excipients and effervescing agents.
SPRAY DRYINGSpray drying can produce highly porous and fine powders that dissolve
rapidly.
The formulations are incorporated by hydrolyzed and non hydrolyzed
gelatins as supporting agents, Mannitol as Bulking agent, sodium starch
glycolate or crosscarmellose sodium as disintegrating and an acidic material (e.g. citric acid) and / or alkali material (e.g. I sodium bicarbonate) to enhance disintegration and dissolution.
Tablet compressed from the spray dried powder disintegrated within 20 seconds when immersed in an aqueous medium
SUBLIMATIONTo generate porous matrix in ODTs, volatile ingredients are
incorporated in the formulation which is subjected to sublimation (by vacuum drying) leaving behind the porous matrix.
FREEZE DRYING OR LYOPHILIZATION
It is a process in which water is sublimed from the product after freezing.
Lyophilization is a pharmaceutical technology which allows drying
of
HEAT SENSITIVE DRUG and biological at low temperature under
conditions that allow removal of water by sublimation.
Lyophilization results in preparations, which are highly porous, with a very
high specific surface area, which dissolves rapidly and show improved
absorption and bioavailability.
MASS EXTRUSIONThis technology involves softening the active blend using the solvent
mixture of water soluble polyethylene glycol, using methanol and expulsion
of softened mass through the extruder or syringe to get a cylinder of the
product into even segments using heated blade to form tablets.
The dried cylinder can also be used to coat granules of bitter tasting drugs
and thereby masking their bitter taste.
COTTON CANDY PROCESS Cotton candy process is also known as “candy floss” process and forms
the
basis of the technologies such as Flash Dose (Fuisz technology).
An ODT matrix is formed from saccharides or polysaccharides processed
into amorphous floss by a simultaneous action of flash melting and
centrifugal force.
The matrix is cured or partially recrystallised to provide a compound with
good flow properties and compressibility. The candy floss can then be milled
and blended with active ingredients and Excipients and subsequently
compressed into ODT. Limitation: The high processing temperature limits the use of this
technology to Thermo stable compounds only
PATENTED TECHNOLOGIES
Zydis Technology
Orasolv Technology
Durasolv Technology
Wow tab Technology
Flash Dose Technology ( Ceform Technology )
Flash Tab Technology
Oraquick Technology
Quick-Dis Technology
Nanocrystal Technology
ZYDIS TECHNOLOGYA Zydis tablet is produced by lyophilizing or freeze-drying the drug in
a
matrix usually consisting of gelatin. The product is very lightweight and
fragile, and must be dispensed in a special blister pack.
Patients should be advised not to push the tablets through the foil film, but
instead peel the film back to release the tablet. The Zydis product is made to
dissolve on the tongue in 2 to 3 seconds.
Eg: Maxalt-MLT (rizatriptan benzoate) - Migraine
ORASOLV TECHNOLOGY
In this system active medicament is taste masked.
It also contains effervescent disintegrating agent.
Tablets are made by direct compression technique at low compression force in order to minimize oral dissolution
time.
Eg: Remeron ( mirtazapine) - Depression
DURASOLV TECHNOLOGYThe tablets made by this technology consist of a drug, fillers and a
lubricant.
Tablets are prepared by using conventional tableting equipment and have
good rigidity. These can be packed into conventional packaging system like
blisters.
Eg: Fazaclo (clozapine) - antipsychotic
WOWTAB TECHNOLOGYYamanauchi pharmaceutical company patented this technology.
‘Wow’ means ‘without water’. The active ingredients may constitute up to
50% w/w of the tablet.
In this technique, saccharides of both low and high mouldability are used to
prepare the granules. Mouldability is the capacity of a compound to be
compressed.
Eg: Fast melt (diphenhydramine citrate, pseudoephidrine HCl) – allergy & sinus
FLASH DOSE TECHNOLOGYThis technology is patented by Fuisz.
A sugar based matrix, called ‘Floss’ is used, which is made up of a
combination of excipients (crystalline sugars) alone or in combination with
drugs.
Eg: Nurofen meltlet, a new form of Ibuprofen, as a mouth-dissolving tablet is the first commercial product prepared by this technology and launched by Biovail Corporation.
FLASH TAB TECHNOLOGYPrographarm labs have a patent over this technology.
In this technology, microgranules of the taste-masked active drug are used.
Micro granules may be prepared by using conventional techniques like coacervation, micro encapsulation, and extrusion-spheronisation. All these processes utilize conventional tabletting technology.
These taste-masked micro crystals of active drug, disintegrating agent, a swelling agent and other excipients like soluble diluents etc are compressed to form a multiparticulate tablet that disintegrates rapidly.
Eg: Excedrin Quick Tabs (acetaminophen, caffeine) – head ache
DRUGS INCORPORATED IN ODTsAnalgesics and Anti-inflammatory Agents Anthelmintics Anti-gout Agents Anti-hypertensive Agents Anti-malarials Anti-migraine Agents Anti- muscarinic Agents Anti- neoplastic Agents and Immunosuppressant's Anti- protazoal Agents Anti-thyroid Agents ß-Blockers Cardiac Inotropic Agents Corticosteroids Diuretics Anti- parkinsonian Agents Gastro-intestinal Agents Histamine H,-Receptor Antagonists etc…
PREFORMULATION STUDIES
Compatability studies = FTIR / DSC
Angle of repose Ө = tan -1 (h/r)
Determination of Bulk density = W / Vo
Tapped density = W / Vf
Hauser’s Ratio= Tapped density/Bulk density
compressibility index : CI = 100 (Vo – Vf )/ Vo
Moisture content
Some of the Marketed ODTs in India
Name of productName of product Active IngredientActive Ingredient
Feldene MeltFeldene Melt Piroxicam(10-20 mg)Piroxicam(10-20 mg)
Zyprexa ZydisZyprexa Zydis Olanzapine (5, 10, 15 or 20 mg)Olanzapine (5, 10, 15 or 20 mg)
Nimulid -MDNimulid -MD NimesulideNimesulide
Claritin ReditabClaritin Reditab Micronized LoratadineMicronized Loratadine
Pepcid RPDPepcid RPD Famotidine (20-40 mg)Famotidine (20-40 mg)
EVALUATION TESTS
WEIGHT VARATION TEST I.P. procedure for uniformity of weight was followed,
twenty tablets were taken and their weight was determined individually and collectively on a digital weighing balance. The average weight of one tablet was determined from the collective weight.
The weight variation test would be a satisfactory
method of determining the drug content uniformity
FRIABILITY TESTThe pharmacopoeial limit of friability test for a tablet is not
more than 1% using Tablet friability apparatus, carried out at 25 rpm for 4 min (100 rotations).
This test is again not applicable for lyophilized and flash dose tablets, but is always recommended for tablets prepared by direct compression and moulding techniques to ensure that they have enough mechanical strength to withstand the abrasion during shipping and shelf life.
Percentage friability = 100(initial weight-final weight)/initial weight
WETTING TIME AND WATER ABSORPTION RATIO
Wetting time and water absorption ratio reported the use of a piece of double folded tissue paper placed in a Petri dish containing 6 ml of water. One tablet was placed on this paper and the time for complete wetting of tablet was noted as wetting time. The wetted tablet was then weighed and the water absorption ratio, R, was determined according to equation.
R = 100 (Wa−W b) /Wb
Wb and Wa are the weights of tablet before and after water absorption
HARDNESS TEST
The tablet tensile strength is the force required to break a tablet by compressing it in the radial direction and is measured using a tablet hardness tester.
Monsanto hardness tester Phyzer type hardness tester
MOISTURE UPTAKE TEST
The test can be carried out by keeping ten tablets along with calcium chloride in a desiccator maintained at 37 °C for 24 hrs to ensure complete drying of the tablets.
The tablets are then weighed and exposed to 75% RH, at room temperature for 2 weeks. The required humidity can be achieved by keeping saturated sodium chloride solution in the dessicator for 24 hrs.
The tablets are reweighed and the percentage increase in weight is recorded. If the moisture uptake tendency of a product is high, it requires special dehumidified area for manufacturing and packing.
MEASUREMENT OF TABLET POROSITY
The mercury penetration porosimeter can be used to measure the tablet
porosity which is a relative assessment of the degree of water penetration in
the formulation, responsible for its fast disintegration.
IN-VITRO DISPERSION TIMEThe test is performed by placing two tablets in 100 ml
water and stirring it gently, till the tablets get completely disintegrated.
The formulation is considered to form a smooth dispersion if the complete dispersion passes through a sieve screen with a nominal mesh aperture of 710 μm without leaving any residue on the mesh.
IN-VITRO DISINTEGRATION TESTThis test are carried out by using any one of the following
method
Tablet disintegration apparatus
Modified dissolution apparatus (as per J.Pharm)
Disintegration Test on Shaking Water Bath
Disintegration Test with Rotary Shaft Method
Disintegration Test using Texture Analyzer
Disintegration Test using Electro Force
DISINTEGRATION APPARATUS
Apparatus with wire basket in a beaker.
DISINTEGRATION USING TEXTURE ANALYZERThe in vitro disintegration behavior of fast dissolving
systems manufactured by the main commercialized technologies was studied using the texture analyzer (TA) instrument.
IN-VITRO DISSOLUTION STUDY
The dissolution method for oral disintegrating tablets is the same as that of conventional tablets.
USP 2 paddle apparatus is most suitable and common choice for dissolution test of oral disintegrating tablets, where the paddle speed is 50 rpm is used.
The USP 1 (basket) apparatus may have certain application for such tablets but is used less, frequently due to specific physical properties of tablets.
Specifically tablet fragments or disintegrating tablet masses become trapped on the inside top of the basket spindle where little or no effective stirring occurs, yielding irreproducible results in dissolution profiles.
FUTURE DEVELOPMENTSODTs can offer several biopharmaceutical advantages over
conventional solid dosage forms such as,
Improved efficacy
Require small amount of the drug to be effective
Offer better drug bioavailability
ODTs may be suitable for oral delivery of drugs such as proteins and peptide based therapeutics that has limited bioavailability when administered by conventional tablets.
Because drugs delivered in ODTs may be absorbed in the pre gastric sites of highly permeable buccal and mucosal tissues of the oral cavity, they may be suitable for delivering relatively low-molecular weight and highly permeable drugs.
CONCLUSION
Orally disintegrating tablets (FDTs) have better patient acceptance and compliance and may offer improved biopharmaceutical properties, improved efficacy, and better safety compared with conventional oral dosage forms.
Prescription FDT products initially were developed to overcome the difficulty in swallowing conventional tablets with water among pediatric, geriatric, and psychiatric patients with dysphagia.
Future possibilities for improvements in FDTs and drug delivery are bright, but the technology is still relatively new.
REFERENCES1. International journal of research in Ayurveda and Pharmacy.2. Journal of Chemical and Pharmaceutical Research, 2009,
1(1): 336-341.3. The Indian Pharmacist, Volume 3, Issue 19, p.72-75 (2004).4. United States Pharmacopoeia 24/NF 19. The Official
Compendia of Standards. Asian ed. Rockville, MD: United States Pharmacopoeial Convention Inc; 2000:1913-1914.
5. Bentham science Publishers- Recent patents on Drug delivery and Formulations, Volume 4, Number 3, November 2010.
6. Aulton’s Pharmaceutics- The design and manufacture of medicines, Edited by Michael E.Aulton- 3rd Edition, 2008.
7. FDA, Guidance for Industry: Orally Disintegrating Tablets Draft Guidance, (Rockville, MD, April 2007).
8. Review article- Recent Patents and Trends in Orally Disintegrating Tablets by Farhan A. AlHusban, Amr M. El-Shaer, Rhys J. Jones and Afzal R. Mohammed