RECENT TRENDS IN ORAL DRUG DELIVERY: MOUTH DISSOLVING TABLETS

About Authors:
Soniya^1*, Tarun Parashar¹, Satyanand Tyagi², Patel Chirag J³, Rishikesh Gupta^4
1*Department of Pharmaceutics, Himalayan Institute of Pharmacy and Research, Rajawala, Dehradun, Uttarakhand, India-248002.
²President, Tyagi Pharmacy Association & Scientific Writer (Pharmacy), Chattarpur, New Delhi, India-110074.
³Department of Pharmaceutics, Maharishi Arvind Institute of Pharmacy, Mansarovar, Jaipur, Rajasthan, India-302020.
⁴Institute of Pharmacy, Bundelkhand University, Jhansi, Uttar Pradesh, India-284128.
*soniyarani487@gmail.com 08006939832/09999261031

ABSTRACT:
To obviate the problems associated with conventional dosage forms, mouth dissolving tablets have been developed having good hardness, dose uniformity, easy administration, faster disintegration without water and serves as the first choice of dosage form for pediatrics, geriatrics and traveling patients. Mouth dissolving tablets (MDTs) are also known as fast melting tablets, fast disintegrating tablets, fast dissolving/dispersing tablets or melt in mouth tablets.This article gives a brief review of mechanism of action, technologies used now a day for MDTs,Some of promising drug candidates for MDT and evaluation parameters MDTs.Due to wide significance of MDT, this drug delivery system may lead to better patient compliance and ultimate clinical output.

Reference Id: PHARMATUTOR-ART-1543

INTRODUCTION
Oral routes of drug administration have wide acceptance up to 50-60% of total dosage forms. Solid dosage forms are popular because of ease of administration, accurate dosage, self-medication, pain avoidance and most importantly the patient compliance.

The most popular solid dosage forms are being tablets and capsules; one important drawback of this dosage forms for some patients, is the difficulty to swallow. Drinking water plays an important role in the swallowing of oral dosage forms.

Often times people experience inconvenience in swallowing conventional dosage forms such as tablet when water is not available, in the case of the motion sickness (kinetosis) and sudden episodes of coughing during the common cold, allergic condition and bronchitis. For these reason, tablets that can rapidly dissolve or disintegrate in the oral cavity have attracted a great deal of attention [1, 2].Mouth dissolving tablets are not only indicated for people who have swallowing difficulties, but also are ideal for active people. The concept of Mouth Dissolving Drug Delivery System emerged from the desire to provide patient with more conventional means of taking their medication. Taste-masking is of critical importance in the formulation of an acceptable rapidly dispersing or dissolving oral dosage forms [1, 3]. Some drugs are absorbed from the mouth, pharynx and esophagus as the saliva passes down into the stomach. In such cases, bioavailability of drug is significantly greater than those observed from conventional tablets dosage form. The advantage of mouth dissolving dosage forms are increasingly being recognized in both, industry and academics [4, 5].

DIFFICULTIES WITH EXISTING ORAL DOSAGE FORM

1. Patient may suffer from tremors therefore they have difficulty to take powder and liquids. In dysphasia physical obstacles and adherence to an esophagus may cause gastrointestinal ulceration.
2. Swallowing of solid dosage forms like tablet and capsules and produce difficulty for young adult of incomplete development of muscular and nervous system and elderly patients suffer from dysphasia. Liquid medicaments (suspension and emulsion) are packed in multi-dose container; therefore achievement of uniformity in the content of each dose may be difficult.
3. Buccal and sublingual formation may cause irritation to oral mucosa, so patients refused to use such medications.
4. Cost of products is main factor as parenteral formulations are most costly and discomfort.
5. Liquid medicaments (suspension and emulsion) are packed in multidose container; therefore achievement of uniformity in the content of each dose may be difficult [1, 3, 5].

ADVANTAGES OF MDT
1.      Achieve increased bioavailability/rapid absorption through pre-gastric absorption of drugs from mouth, pharynx & esophagus as saliva passes down.
2.      Administration to the patients who cannot swallow, such as the elderly, bedridden patients, patients affected by renal failure & patients who refuse to swallow such as pediatric, geriatric & psychiatric patients.
3.      Convenient for administration and patient compliant for disabled, bedridden patients and for travelers and busy people, who do not always have access to water.
4.      The risk of chocking or suffocation during oral administration of conventional formulations due to physical obstruction is avoided, thus providing improved safety.
5.      Good mouth feel property helps to change the perception of medication as bitter pill particularly in pediatric patients.
6.      Cost effective.
7.      Easy transportation [3, 4, 6].

DISADVANTAGE OF MDT
1.      Fast dissolving tablet is hygroscopic in nature so must be keep in dry place.
2.      MDT requires special packaging for properly stabilization & safety of stable product.
3.      Some time it possesses mouth feeling [5, 6].

IDEAL PROPERTIES OF MDT

An ideal MDT should:
1.      Not require water to swallow and should dissolve or disintegrate in the mouth within a few seconds.
2.      Be compatible with taste masking and other excipients.
3.      Allow high drug loading.
4.      Exhibit low sensitivity to environmental conditions like temperature and humidity.
5.      Leave minimal or no residue in the mouth after oral administration.
6.      Have a pleasing mouth feel.
7.      Have sufficient strength to withstand the rigors of the manufacturing process and Post manufacturing handling.
8.      Allow the manufacture of tablets using conventional processing and packaging equipment at low cost [2, 4, 6].

SUPERDISINTEGRANTS
Disintegrating agents are substances routinely included in the tablet formulations to aid in the breakup of the compacted mass when it is put into a fluid environment. They promote moisture penetration and dispersion of the tablet matrix. In recent years, several newer agents have been developed known as “Superdisintegrants”. These newer substances are more effective at lower concentrations with greater disintegrating efficiency and mechanical strength. On contact with water the superdisintegrants swell, hydrate, change volume or form and produce a disruptive change in the tablet. Effective superdisintegrants provide improved compressibility, compatibility and have no negative impact on the mechanical strength of formulations containing high-dose drugs [3, 6].

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MECHANISM OF SUPERDISINTEGRANTS
1.    Swelling
Perhaps the most widely accepted general mechanism of action for tablet disintegration is swelling. Tablets with high porosity show poor disintegration due to lack of adequate swelling force. On the other hand, sufficient swelling force is exerted in the tablet with low porosity. It is worthwhile to note that if the packing fraction is very high, fluid is unable to penetrate in the tablet and disintegration is again slows down [4, 7].

2.    Porosity and capillary action
Disintegration by capillary action is always the first step. When we put the tablet into suitable aqueous medium, the medium penetrates into the tablet and replaces the air adsorbed on the particles, which weakens the intermolecular bond and breaks the tablet into fine particles. Water uptake by tablet depends upon hydrophilicity of the drug/excipients and on tableting conditions. For these types of disintegrants maintenance of porous structure and low interfacial tension towards aqueous fluid is necessary which helps in disintegration by creating a hydrophilic network around the drug particles [8].

3.    Due to disintegrating particle/particle repulsive forces
Another mechanism of disintegrants attempts to explain the swelling of tablet made with ‘nonswellable’ disintegrants. Guyot-Hermann has proposed a particle repulsion theory based on the observation that nonswelling particle also cause disintegration of tablets.
The electric repulsive forces between particles are the mechanism of disintegration and water is required for it. Researchers found that repulsion is secondary to wicking [8, 9].

4.    Due to deformation
During tablet compression, disintegrated particles get deformed and these deformed particles get into their normal structure when they come in contact with aqueous media or water. Occasionally, the swelling capacity of starch was improved when granules were extensively deformed during compression. This increase in size of the deformed particles produces a breakup of the tablet. This may be a mechanism of starch and has only recently begun to be studied [7, 9].

NEWER MANUFACTURING TECHNOLOGIES USED NOW A DAYS FOR MDTs

1.      Freeze drying/Lyophilization
Lyophilization can be used to prepare tablets that have very porous open matrix network into which saliva rapidly moves to disintegrate lyophilized mass after it is placed in mouth. The drug is entrapped in a water soluble matrix which is freeze dried to produce a unit which rapidly disperses when placed in mouth. Apart from the matrix and active constituents, the final formulation may contain other excipients, which improve the process characteristics or enhance the quality of final product. These include suspending agents, wetting agents, preservatives, antioxidants, colors and flavors. The preferred drug characteristics for freeze drying formulations are water insoluble, low dose, chemically stable, small particle size and tasteless. Corveleyn and Remon investigated the influence of various formulation and process parameters on the characteristics of rapidly disintegrating tablets in lyophilized form using hydrochlorothiazide as a model drug. They have concluded that maltodxtrins are useful in the formulation of fast dissolving tablets made by freeze-drying. Lyophilization is relatively expensive and time consuming manufacturing process. Other drawback includes fragility, which make the use of conventional packing difficult and poor stability during storage [1, 10].

2.      Moulding
Moulded tablets are designed to facilitate fast absorption of drugs through the mucosal lining of mouth by inclusion of water-soluble ingredients. The advantage of this system is that it has a porous structure which enhances dissolution (thereby enhanced bioavailability) and decreased first pass metabolism of certain drugs.

As moulding process is employed usually with soluble ingredient (saccharides) which offers improved mouth feel and disintegration of tablets. However, moulded tablets have low mechanical strength, which results in erosion and breakage during handling. The main concern about these molded tablets is their mechanical strength, which can be achieved by using binding agents. The spray congealing of a molten mixture of hydrogenated cottonseed oil, sodium carbonate, lecithin, polyethylene glycol and an active ingredient into a lactose based tablet triturate form was used to prepare the taste masked drug particles. As compared to the lyophillization technique, tablets produced by the molding technique are easier to scale up for industrial scale manufacturing [6, 10].

3.      Spray Drying
In this technique, gelatin can be used as a supporting agent and as a matrix, mannitol as a bulking agent and sodium starch glycolate or croscarmellose or crospovidone are used as superdisintegrants. Tablets manufactured from the spray-dried powder have been reported to disintegrate in less than 20 seconds in aqueous medium. The formulation contained bulking agent like mannitol and lactose, a superdisintegrant like sodium starch glycolate & croscarmellose sodium and acidic ingredient (citric acid) and/or alkaline ingredients (e.g. sodium bicarbonate). This spray-dried powder, which compressed into tablets showed rapid disintegration and enhanced dissolution [9, 11].

4.      Sublimation
To generate a porous matrix, volatile ingredients are incorporated in the formulation that is later subjected to a process of sublimation. Highly volatile ingredients like ammonium bicarbonate, ammonium carbonate, benzoic acid, camphor, naphthalene, urea, urethane and phthalic anhydride may be compressed along with other excipients into a tablet. This volatile material is then removed by sublimation leaving behind a highly porous matrix. Tablets manufactured by this technique have reported to usually disintegrate in 10-20 sec. Even solvents like cyclohexane, benzene can be used as pore forming agents [11].

5.      Direct Compression
Direct compression represents the simplest and most cost effective tablet manufacturing technique. MDT can be prepared by using this technique because of the availability of improved excipients especially super-disintegrants and sugar based excipients.

(a) Super-disintegrants: The rate of disintegration gets affected by the addition of superdisintegrants and hence the dissolution. Other ingredients like water-soluble excipients and effervescent agents also increase the disintegration.

(b) Sugar based excipients: The sugar based excipients which are commonly used are especially bulking agents (like dextrose, fructose, lactilol, maltilol, maltose, mannitol, sorbitol, starch hydrolysate, polydextrose and xylitol) which display high aqueous solubility and sweetness, and hence impart taste masking property and provide pleasing mouth feel. Mizumito et al classified sugar-based excipients into two types on the basis of molding and dissolution rate:
Type 1 saccharides (lactose and mannitol) exhibit low mouldability but high dissolution rate.

Type 2 saccharides (maltose and maltilol) exhibit high mouldability but low dissolution rate [6, 9, 12].

6.      Nanonization
A recently developed Nanomelt technology involves reduction in the particle size of drug to nano size by milling the drug using a proprietary wet-milling technique. The nanocrystals of the drug are stabilized against agglomeration by surface adsorption on selected stabilizers, which are then incorporated into MDTs. This technique is especially advantageous for poorly water soluble drugs. Other advantages of this technology include fast disintegration/dissolution of nanoparticles leading to increased absorption and hence higher bioavailability and reduction in dose, cost effective manufacturing process, conventional packaging due to exceptional durability and wide range of doses (up to 200mg drug per unit) [1, 13].

7.      Mass-extrusion
This technology involves softening of the active blend using the solvent mixture of water soluble polyethylene glycol and methanol and expulsion of softened mass through the extruder or syringe to get a cylindrical shaped extrude which are finally cut into even segments using heated blade to form tablets. This process can also be used to coat granules of bitter drugs to mask their taste [6, 14].

DRUG CANDIDATES FOR MOUTH DISSOLVING TABLETS [3, 5, 15, 16]

Table 1:Some of promising drug candidates for Mouth Dissolving Tablets

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EVALUATION [17, 18]

1. Weight variation test:
Randomly selected 20 tablets were taken and their individual weights & the average weight of 20 tablets were determined. The deviation of each individual tablet from the average weight was calculated and compared with the standard values given in Pharmacopoeia.

2.      Tablet hardness:
The tablet hardness is defined as the force applied diametrically of the tablet to break the tablet. It is determined by taking six tablets from each formulation by a Monsanto hardness tester.

3.      Friability:
It is determined by taking six tablets from each formulation with the help of Roche Fribrilator. After that the pre-weighed six tablets were rotated at 25 rpm for 4 minutes. The tablets were reweighed after removal of the fine particles using 60 mesh and the percentage of weight loss is calculated.

% friability = (Loss in weight/ Initial weight) ×100

4.      Disintegration test:
Disintegration time was measured in artificial saliva (pH 5.8) of 900 ml, without disc at 37 ± 5 ?C temperature. The disintegration time of six individual tablets is recorded and from this the average weights are calculated and the time in seconds recorded for complete disintegration of the tablet.

5.      In-Vitro dissolution Studies:
The release of drug from the fast dissolving tablet is determined by using USP dissolution testing apparatus. It is performedusing 900 ml of artificial saliva (pH 5.8) at 37 ± 0.5?c at 50 rpm. The samples are withdrawn at frequent intervals and those are analyzed by measuring the absorbance of the diluted sample. Other medias are also used such as 0.1 m HCl and buffer pH 4.5 are used.

6.      Wetting time:
It is mainly related to the disintegration properties of tablets. It is determined by a tablet is placed on piece of tissue paper folded twice and kept in a Petridis (Internal diameter = 6.5 cm) containing 6 ml of water and the time for complete wetting was measured. The lower wetting time implies the quick disintegration of the tablet.

7.      Taste or mouth feel: Healthy human volunteers were used for evaluation of mouth feel of the tablet. One tablet was evaluated for its mouth feel. Panels of 5 members evaluate the mouth feel by time intensity method. Sample equivalent to 40 mg was held in mouth for 10 seconds and the opinion is rated by giving different score values. (0: good, 1: tasteless, 2: slightly bitter, 3: bitter, 4: awful).

DISCUSSION AND CONCLUSION
MDTs have better patient acceptance and compliance and may offer improved biopharmaceutical properties, improved efficacy, and better safety compared with conventional oral dosage forms. In combination with other technologies such as modified release and micro encapsulation, MDTs will continue to provide enhanced commercial and therapeutic benefits.  The successful marketed MDTs have good taste and rapid release properties. Several drug delivery technologies that can be leveraged on improving drug therapy from MDTs have yet to be fully realized.

ACKNOWLEDGEMENT
As a corresponding author, My Self, Soniya is highly thankful to my Parents and Teachers for their moral support and encouragement. Last but not the least, thanks to Almighty god for showering his blessings best owned on me.

REFERENCES
1.    Kuchekar B.S., Atul, Badhan C. and Mahajan H.S., “Mouth dissolving tablets: A novel drug delivery system”, Pharma Times, 2003; 35: 7-9.
2.    Parkash V., Maan S., Deepika Y.S.K., Hemlata and Jogpal V., “Fast disintegrating tablets: Opportunity in drug delivery system”, J Advanced Pharma Techno & Res, 2011; 2(4): 223-35.
3.    Bradoo R., “Fast Dissolving Drug Delivery Systems”, JAMA India, 2001; 4(10): 27-31.
4.    Panigrahi D., Baghel S. and Mishra B., “Mouth dissolving tablets: An overview of preparation techniques, evaluation and patented technologies”, J Pharm Res, 2005; 4(3): 35-38.
5.    Rish R.K., “A review on fast dissolving tablets techniques”, The Pharma Review, 2004; 2: 32.
6.    Giri T., Tripathi D. and Maunder R., “Formulation aspects in the development of Orodispersible tablets: an Overview” Int J Pharm and Pharm Sci, 2010; 2(3): 38-42.
7.    Seager H., “Drug-deliver Products and the Zydis Fast dissolving Dosage Form”, J Pharm Pharmacology, 1998; 50: 375-82.
8.    Arunachalam A., Karthikeyan M., Ashutoshkumar S. and Konam K., “Fast Dissolving Drug Delivery System: A Review”, J Global Trends in Pharma Sci, 2010; 1(1): 92-110.
9.    Lachmann, L., Liebermann, H.A. and Kiang, J.L.: “The theory and practice of Industrial Pharmacy”, Varghese Publishing House, 3rd Edition, 1998: 430-440.
10.    Prajapati B.G. and Ratnakar N., “A Review on Recent patents on Fast Dissolving Drug Delivery System”, Int J PharmTech Res, 2009; 1(3): 790-798.
11.    Bagul U., Kishore G., Patel N. and Alphale S., “Evaluation of sublimed fast melting tablet”, Int. Journal of Pharmaceutical sciences, 2010; 2(2): 76-80.
12.    Chang R., Guo X., Burnside B.A. and Couch R., “Fast-dissolving tablets”, PharmTech 2000; 24(6): 52-58.
13.    Yourong F., Shicheng Y., Seong H.J., Susumu K., and Kinam P., “Orally Fast Disintegrating Tablets: Developments, Technologies, Taste-Masking and Clinical Studies”, Critical Reviews™ in Therapeutic Drug Carrier Systems 2004; 21(6):433-475.
14.    Kaushik D., Dureja H. and Saini T.R., “Mouth Dissolving Tablets: A review”, Indian Drugs, 2004; 41(4): 187-193.
15.    Ashish P., Mishra P., Main P., Harsoliya M.S. and Agrawal S., “A review on - Recent advancement in development of rapid disintegrating tablet”, URP Journal, 2011; 1(1): 1-8.
16.    Shukla D., Chakraborty S., Singh S. and Mishra B. “Mouth dissolving tablet I: An overview of formulation technology”, J Sci Pharm 2008; 77: 327-341.
17.    Abdelbary G., Prinderre P., Eouani C., Joachim J., Reynier J.P. and Piccerelle P., “The preparation of orally disintegrating tablets using a hydrophilic waxy binder”, Int J Pharma, 2004; 278(2): 423-33.
18.    Kamal S, Pooja M, Surender V, Navneet S and Ajay K. Mouth dissolving tablets: An overview on future compaction in oral formulation technologies. Der Pharmacia Sinica, 2010, 1(1): 179-187.

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