A REVIEW: FAST DISSOLVING DRUG DELIVERY SYSTEM

ABOUT AUTHORS:
Rahul Ratnakar*¹, Lakshmi Goswami², Dr. Preeti kothiyal
¹Persuing M.Pharma
²Lecturer/guide
^1,2Shri Guru Ram Rai Institute of Technology & Science,
P.O. Box - 80, Patel Nagar,
Dehradun 248001, Uttarakhand, India.
rhl.ratnakar@gmail.com

ABSTRACT
Oral delivery is currently the gold standard in the pharmaceutical industry where it is regarded as the safest, most convenient and most economical method of drug delivery having the highest patient compliance ^[1]. Mouth dissolving tablets are solid dosage forms containing drugs that disintegrate in the oral cavity within less than one minute the development of mouth dissolving tablets formulation is emerging and gaining popularity because it is easy to administer and leads to better patient compliance ^[2]. These are novel types; of tablets that disintegrate/dissolve/ disperse in saliva within few seconds’. According to European Pharmacopoeia, the ODT should disperse/disintegrate in less than three minutes. The basic approach used in development of MDT is the use of superdisintegrants like Cross linked carboxymelhylcellulose (Croscarmeliose), Sodium starch glycolate (Primogel, Explotab) (Polyplasdone) etc. which provide instantaneous disintegration of tablet after putting on tongue, thereby releasing the drug in saliva ^[3]. MDTs can be administered anywhere and anytime, without the need of water and are thus quite suitable for children, elderly and mentally disabled patients. This is seen to afflict nearly 35% of the general population and associated with a number of conditions, like parkinsonism, mental disability, motion sickness, unconsciousness, unavailability of water etc. To overcome such problems, certain innovative drug delivery systems, like ‘Mouth Dissolving Tablets’ (MDT) have been developed ^[4].

REFERENCE ID: PHARMATUTOR-ART-1939

INTRODUCTION

Definition
A fast-dissolving drug delivery system, in most cases, is a tablet that dissolves or disintrigrants in the oral cavity without the need of water or chewing. Most fast-dissolving delivery system films must include substances to mask the taste of the active ingredient. This masked active ingredient is then swallowed by the patient’s saliva along with the soluble and insoluble excipients.These are also called melt-in-mouth tablets, repimelts, porous tablets, oro-dispersible, quick dissolving or rapid disintegrating tablets.

An ideal Properties of FDT6
Require no water for oral administration, yet dissolve / disperse/ disintegrate in mouth in a matter of seconds.

Have a pleasing mouth feel. Have an acceptable taste masking property. Be harder and less friable Leave minimal or no residue in mouth after administration Exhibit low sensitivity to environmental conditions (temperature and humidity). Allow the manufacture of tablet using conventional processing and packaging equipments^[5].

Advantages of MDT
a. No need of water to swallow the tablet ^[6].

b. Can be easily administered to pediatric, elderly and mentally

disabled patients.

c. Accurate dosing^[7] as compared to liquids.

d. Dissolution and absorption of drug is fast, offering rapid onset of action.

e. Bioavailability of drugs is increased^[8]as some drugs are absorbed from mouth, pharynx and esophagus through saliva passing down into the stomach^[9].

f. Advantageous over liquid medication in terms of administration as well as

g. transportation

h. First pass metabolism is reduced, thus offering improved bioavailability and thus reduced dose and side effects.

i. Free of risk of suffocation due to physical obstruction when swallowed, thus

j. offering improved safety.

1. Suitable for sustained/controlled release actives^[10].

2. Allows high drug loading ^[3].

Disadvantage^[11,12]:
* Fast dissolving tablet is hygroscopic in nature so must be keep in dry place.

* Some time it possesses mouth feeling.

* MDT requires special packaging for properly stabilization & safety of stable product.

* The tablets usually have insufficient mechanical strength. Hence, careful handling is required

* The tablets may leave unpleasant taste and/or grittiness in mouth if not formulated properly ^[2].

Challenges in formulating Fast dissolving tablets

Palatability
As most drugs are unpalatable, FDTs usually contain the medicament in a taste-masked form. Upon administration, it 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 the drugs becomes critical to patient compliance^[13].

Mechanical strength
In order to allow FDTs 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. Only Wow tab and durasolv technologies can produce tablets that are sufficiently hard and durable to allow them to be packaged in multi-dose bottles.

Hygroscopicity
Several orally disintegrating dosage forms are hygroscopic and cannot maintain physical integrity. The application of technologies used for FDTs is limited by the amount of drug that can beincorporated into each unit dose. For lyophilized dosage forms, the drug dose must be less than 400 mg for insoluble drugs and 60 mg for soluble drugs. This parameter is particularly challenging when formulating a fast-dissolving oral films or wafers^[14,20].

Amount of drug
The application of technologies used for FDTs is limited by the amount of drug that can beincorporated into each unit dose. For lyophilized dosage forms, the drug dose must be less than 400 mg for insoluble drugs and 60 mg for soluble drugs. This parameter is particularly challenging when formulating a fast-dissolving oral films or wafers ^[15].

Aqueous solubility
Water-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 of loss of supporting structure during the sublimation process. Such collapse sometimes can be prevented by using various matrix-forming excipients such as mannitol than can induce crystallinity and hence, impart rigidity to the amorphous composite^[16] .

Size of tablet The ease of administration of 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 ^[3].

Conventional Techniques^[11] :

Disintegrates addition: Disintegrate addition technique is one popular techniques for formulating Fast-dissolving tablets because of its easy implementation and cost-effectiveness. The basic principle involved in formulating Fast-dissolving tablets by disintegrates addition technique is addition of superdisintegrants in optimum concentration so as to achieve mouth dissolving along with the good mouth feel.

Molding: In this method, molded 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. Molded tablets are very less compact than compressed tablets. These possess porous structure that enhances dissolution.

Freeze drying: A process in which water is sublimated from the product after freezing. Lyophilization is a pharmaceutical technology which allows drying of heat sensitive drugs 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 dissolve rapidly and show improved absorption and bioavailability.

Sublimation: The slow dissolution of the compressed tablet containing even highly water-soluble ingredients is due to the low porosity of the tablets. Inert solid ingredients that volatilize readily (e.g. urea, ammonium carbonate, ammonium bicarbonate, hexa methelene tetramine, camphor etc.) were added to the other tablet ingredients and the mixture is compressed into tablets. The volatile materials were then removed via sublimation, which generates porous structures. Additionally, several solvents (e.g. cyclohexane, benzene) can be also used as pore forming agents.

Spray-Drying: Spray 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 cross carmellose 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.

Mass-Extrusion: This 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 geta 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.

Direct compaction: Direct compration method is the easiest way to manufacture tablets. Conventional equipment, commonly available excipients and a limited number of processing steps are involved in direct compression. Also high doses can be accommodated and final weight of tablet can easily exceed that of other production methods. Directly compressed tablet's disintegration and solubilization depends on single or combined action of disintegrants, water soluble excipients and effervescent agent.

Patented Technology^[11,17]:

Flashtab Technology: Prographarm laboratories have patented the Flashtab technology. Tablets prepared by this system consist of an active ingredient in the form of micro crystals. Drug micro granules may be prepared by using the conventional techniques like coacervation, micro encapsulation, and extrusion spheronisation. All the processing utilized conventional tabletting technology.

Wowtab Technology: Wowtab Technology is patented by "Yamanouchi Pharmaceutical Co. " WOW means "Without Water ". In this process, combination of low mouldability saccharides and high mouldability saccharides is used to obtain a rapidly melting strong tablet. The active ingredient is mixed with a low mouldability saccharide and granulated with a high mouldability saccharide and compressed into tablets followed by moisture treatment. Thus tablets obtained showed adequate hardness and rapid disintegration

Orasolv Technology: Orasolv Technology has been developed by "CIMA" labs. 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. Conventional blenders and tablet machine is used to produce the tablets. The tablets produced are soft and friable and packaged in specially designed pick and place system.

Durasolv Technology: Durasolv is the patented technology of "CIMA" labs. The 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. Durasolv is an appropriate technology for products requiring low amounts of active ingredients. This 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 ^[2].

Criteria for Drug Selection^[2,18]:
* The ideal characteristics of a drug for in vivo dissolution from an MDT include:-
• No bitter taste.
• Dose lower than 20mg.
• Small to moderate molecular weight.
• Good stability in water and saliva.
• Partially non-ionized at the oral cavities pH.
• Ability to diffuse and partition into the epithelium of the upper GIT.
• Ability to permeate oral mucosal tissue.

* Unsuitable drug characteristic for MDT:-
• Short half-life and frequent dosing.
• Very bitter or otherwise unacceptable taste because taste masking cannot be achieved.
• Required controlled or sustained release.

Super Disintegrants Used in MDTs^[12,19]:
As day’s passes, demand for faster disintegrating formulation is increased. So, pharmacist needs to formulate disintegrants i.e. Superdisintegrants which are effective at low concentration and have greater disintegrating efficiency and they are more effective intragranularly. This superdisintegrants act by swelling and due to swelling pressure exerted in the outer direction or radial direction, it causes tablet to burst or the accelerated absorption of water leading to an enormous increase in the volume of granules to promote disintegration.

Various types of Super disintegrants used are as follows –
* Crosspovidone
* Microcrystalline cellulose
* Sodium starch glycollate
* Sodium carboxy methyl cellulose or cross carmelose sodium
* Pregelatinzed starch
* Calcium carboxy methyl cellulose
* Modified corn starch. Sodium starch glycollate has good flowability than crosscarmellose sodium.

Factors to be considered for selection of superdisintegrants:
* It should produce mouth dissolving when tablet meets saliva in the mouth
* It should be compactable enough to produce less-friable tablets.
* It can able to produce good mouth feel to the patient. Thus, small particle size is preferred to achieve patient compliance.
* It should has good flow since it improve the flowability of the total blend^[2].

Promising Drugs to be in corporated In Fast Dissolving Tablets^[22-24]

Analgesics and Anti-inflammatory Agents:
Aloxiprin, Auranofin, Azapropazone, Benorylate, Diflunisal, Etodolac, Fenbufen, Fenoprofen Calcim, Flurbiprofen, Ibuprofen, Indomethacin, Ketoprofen, Meclofenamic Acid, Mefenamic Acid.

Anthelmintics :
Albendazole, Bephenium Hydroxynaphthoate, Cambendazole, Dichlorophen, Iverrnectin, Mebendazole, Oxarnniquine, Oxfendazole, Oxantel Embonate

Anti-Arrhythmic Agents:
Amiodarone, Disopyramide, Flecainide Acetate, Quinidine Sulphate.

Anti-Epileptics:
Beclamide, Carbamazepine, Clonazepam, Ethotoin, Methoin, Methsuximide, Methylphenobarbitone, Oxcarbazepine, Paramethadione, Phenacemide, Phenobarbitone

Anti-Fungal Agents:
Amphotericin, Butoconazole Nitrate, Clotrimazole, Econazole Nitrate, Fluconazole, Fiucytosine, Griseofulvin, Itraconazole, Ketoconazole, Miconazole, Natamycin, Nystatin, Sulconazole Nitrate.

Anti-Muscarinic Agents:
Atropine, Benzhexol, Biperiden, Ethopropazine, Hyoscine Butyl Bromide, Hyoscyarnine, Mepenzolate Bromide, Orphenadrine, Oxyphencylcimine, Tropicamide.

Anti-Neoplastic Agents And Immunosuppressants:
Aminoglutethimide, Amsacrine, Azathiopnne, Busulphan, Chlorambucil, Cyclosporin, Dacarbazine, Estramustine, Etoposide, Lomustine, Melphalan, Mercaptopurine, Methotrexate, Mitomycin, Mitotane, Mitozantrone, Procarbazine, Tamoxifen Citrate, Testolactone .

Future prospects of MDT^[4,21]
Mouth dissolving tablets can offer several biopharmaceutical advantages such as improved efficiency over conventional dosage forms. For example, they require smaller amounts of active ingredient to be effective, improve absorption profiles, and offer better drug bioavailability than regular tablets and capsules. In addition, MDTs 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. Because drugs delivered in MDTs may be absorbed in the pregastric 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. Future possibilities for improvements in MDTs and drug delivery are bright, but the technology is still relatively new. Several drug delivery technologies that can be leveraged on improving drug therapy from MDTs have yet to be fully realized.

Preformulation Studies

Bulk Density^[25,26]:
Apparent bulk density was determine by pouring the 5 gram of powder into a 100 ml granulated cylinder. The bulk volume (V) poured drug was determined. The bulk density was calculated using the formula. ρb = M / V

Tapped Density^[25,26]:
Weight 5 g. of powder and placed in a measuring cylinder. Measuring cylinder containing known mass (5 gm) of powder was tapped for 100 times or fixed time. The minimum volume (Vt) occupied was measured. The tapped density was calculated using following formula. ρt = M / Vt

Compressibility Index^[26,27]:
The simplest way for measurement of free flow of powder is compressibility, a indication of the ease with which a material can be induced to flow is given by Compressibility Index. The value below 15% indicates a powder with give rice to good flow properties, whereas above 25% indicate poor flowability. Which is calculated follows. % C.I. = ρt - ρb ρt ? 100

Hausner ratio^[26]:
Hausner ratio is an indirect index of ease of powder flow. Hosner ratio is the ratio of tapped density to bulk density. Lower the value of Housner ratio better is the flow property. Powder with Housner ratio less than 1.18, 1.19, 1.25, 1.3- 1.5 and greater the 1.5 indicate excellent, good, passable, and very poor, respectively. It is calculated by following formula. Hausner ratio = ρt ρt

Porosity^[25,28]:
Percent relative porosity (ε) was obtained using the relationship between apparent density (ρapp) and true density (ρtrue) which is calculated by following formula. ε = ( 1 - ρapp / ρtrue) ? 100

Voide Volume^[25]:
Voide volume(V) was obtained by difference between bulk volume(Vb) and tapped volume (Vp).Voide volume can be calculated by following formula.

Angle of repose^[26,28]:
The angle of repose was determined using funnel method. Funnel that can be fit vertically with stand at 6.3 cm. height. The opening end of funnel are closed with thumb until drug are poured. The 5 gm of powder was poured into funnel that can be raised vertically until a maximum cone hight (h) was obtained. Radius of the heap (r) was measured and the angle of repose (?) was calculated using the formula.

Evaluation of Mouth dissolving Tablets By-

Thickness^[29]:
Tablet thickness can be measured using a simple procedure. 5 tablets were taken and their thickness was measured using Varnier calipers.

Hardness^[27,30]:
It is the force required to break a tablet by compression in the radial direction, it is an important parameter in formulation of mouth dissolve tablets because excessive crushing strength significantly reduces the disintegration time.In the present study the crushing strength of the tablet was measured us-ing Pfizer hardness testers. An average of three observations is reported.

Uniformity of weight^[31,27]:
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.

Disintegration time^[31]
The test was carried out on 6 tablets using the apparatus specified in I.P.-1996 distilled water at 37ºC ± 2ºC was used as a disintegration media and the time in second taken for complete disintegration of the tablet with no palatable mass remaining in the apparatus was measured in seconds

In-vitro drug release^[31]:
The development of dissolution methods for ODTs is comparable to the approach taken for conventional tablets, and is practically identical. Dissolution conditions for drugs listed in a pharmacopoeia monograph, is a good place to start with scouting runs for a bioequivalent ODT. Other media such as 0.1N HCl and buffers (pH - 4.5 and 6.8) should be evaluated for ODT much in the same way as their ordinary tablet counter parts. The USP 2 Paddle apparatus is used for this purpose which is the most suitable and common choice for orally-disintegrating tablets, with a paddle speed of 50 rpm commonly used. Typically the dissolution of ODT is very fast when using USP monograph conditions; hence slower paddle speeds may be utilized to obtain a profile. The USP 1 Basket apparatus may have certain applications but sometimes tablet fragments or disintegrated tablet masses may become trapped on the inside top of the basket at the spindle where little or no effective stirring occurs, yielding irreproducible dissolution profiles.

Friability test^[32,27]:
Friability of the tablets was determined using Roche friability (Electrolab, Mumbai). This device subjects the tablets to the combined effect of abrasions and shock in a plastic chamber revolving at 25 rpm and dropping the tablets at a height of 6 inches in each revolution. Preweighed sample of tablets was placed in the friabilator and were subjected to 100 revolutions. Tablets were de dusted using a soft muslin cloth and reweighed. The friability (f) is given by the formula. f = (1- W0 / W) × 100 Where, W0 is weight of the tablets before the test and W is the weight of the tablet after the test.

In-vitro dispersion time test^[29]:
To determine dispersion time 10 ml measuring cylinder was taken in which 6 ml distilled water was added and tablet was dropped in it. Time required for complete dispersion was determined.

Wetting time ^[29,31]:
Five circular tissue papers of 10 cm diameter are placed in a petridish with a 10 cm diameter. Ten millimeters of water-containing Eosin, a water-soluble dye, is added to petridish. A tablet is carefully placed on the surface of the tissue paper. The time required for water to reach upper surface of the tablet is noted as a wetting time.

Water absorption ratio1^[31]:
A piece of tissue paper folded twice was placed in a small Petri dish containing 6 ml of water. A tablet was put on the paper & the time required for complete wetting was measured. The wetted tablet was then weighed. Water absorption ratio (R), was determined using following equation, R = 10 ( Wa /Wb) Where- Wb is weight of tablet before water absorption & Wa is weight of tablet after water absorption.

Accelerated Stability study^[31]:
The Orally disintegrating tablets are packed in suitable packaging and stored under the following conditions for a period as prescribed by ICH guidelines for accelerated studies. (i) 40 ± 1 °C (ii) 50 ± 1°c (iii) 37 ±1 ° C and Relative Humidity= 75% ± 5% The tablets were withdrawn after a period of 15 days and analyzed for physical characterization (Visual defects, Hardness, Friability, Disintegrations, and Dissolution etc.) and drug content. The data obtained is fitted into first order equations to determine the kinetics of degradation. Accelerated stability data are plotting according Arrhenius equation to determine the shelf life at 25 ° C.

Packaging^[12]:
Packaging special care is required during manufacturing and storage to protect the dosage of other fast-dissolving dosage forms. Quick-dispersing and/or dissolving oral delivery systems, the system can be packaged using various options, such as single pouch, blister card with multiple units, multipleunit dispenser, and continuous roll dispenser, depending on the application and marketing objectives.

CONCLUSION:
The basic principle involved in formulating fast dissolving tablets is by maximizing the pore structure . a vacuum-drying technique was adopted in the present investigation after addition of a subliming agent to increase porosity of the tablets The main focus of this category of drug is basically on paediatric and geriatric populations and patients suffering from heart disease as these provide instant relieve from the attack as taken by the patient itself without water as it dissintigerates rapidly within the saliva which help in quick recovery and helpful to those patients founding difficulty in swallowing of tablets, as fdt has a potential advantage on conventional dosage form as the increases the bioavailability and onset of action of the drugs .the key ingredient of the formulation is the addition of a super disintigerating agent in optimum concentration which provide rapid disintigeration along with excellent mechanical strength . the product offers a promising future potential because of the availability of new technologies along with strong market acceptance and patient demand Several drug delivery technologies that can be leveraged on improving drug therapy from these dosage forms.

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