The Oral Route Of Drug Administration Biology Essay

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There is different type of route of administrations oral route, parenteral route, sublingual route, rectal route, vaginal route, nasal route, inhalation, cutaneous route, transdermal route.

The oral route of administration most preferable route of administration including solutions, suspensions, emulsions, pastes, and tablets, capsules, powders, granules, premix. Tablets are solid dosage forms made with suitable API and excipients. Tablet usually compressed with a number of adjuncts including diluents, binders, disintegrants, antiadherent, colorants and flavouring. After compression tablets may be coated with various materials. Tablets and capsules are popular dosage form due to ease of self administration, pain avoidance, versatility, patient compliance and easy manufacturing. Tablets may vary in size, shape, weight and in other as depending on their intended use and method of manufacture.

With Active ingredient number of excipient added for different purposes. Mostly filler, disintegrant, binder, glidant, lubricant, sorbent, flavour, and colourant added as excipients. Tablet is manufactured with direct compression, wet granulation or dry granulation. Direct compression is simplest method for manufacturing. To improve flow properties of mixture or mechanical strength granulation process require. Wet granulation is used to improve flow, compressibility, bio-availability, homogeneity, electrostatic properties, and stability of solid dosage forms.

There are different types of tablets - 1 and 2

Uncoated tablets include normal compressed tablets which contain API and excipients. Other one is multiply tablets has more than one layer of different material to staged drug release, chemical-physical incompatibility and for different appearance.

Coated tablets: compressed tablets may be coated with mixtures of different substances.

Sugar coated tablets coated with sugar layer to protect the inserted drug from the environment and mask bitter taste of drug. Sugar coating process is time consuming and required expertise during process.

Film coated tablets are coated with a thin layer of polymer which give better appearance as like film. This process has advantage over sugar coating. Tablet can be designed at which dissolve the desired location by this process. Film coating protects from environmental conditions.

Enteric coated tablets are coated with special material to release in to intestine and prevent stomach effect on tablet for enhance drug absorption and reduce gastric irritation. Enteric coating is beneficial over drug which irritating in stomach or which destroys at low pH.

Effervescent tablets are compressed tablets contain drug and carbonates or hydrogen carbonates which release gas in contact with water. Effervescent tablets are dissolved in water before administration.

Buccal and sublingual tablets are flat oval shaped tablets to be placed in the buccal pouch or beneath the tongue for absorption through oral mucosa. Buccal tablets are designed to release slowly while sublingual tablets are dissolving promptly.

Chewable tablets are chewed or allowed to dissolve in the mouth contain flavouring agent for taste. Chewable tablets are prepared by using mannitol, sorbitol, or sucrose as binders and fillers, and colors and flavours to enhance their appearance and taste. Normally antacid tablets are more desirable because antacid require large dose so it may give swallowing problem.

Molded tablet are prepared by molding instead of compression. Tablet triturates are small molded tablet they are very soft and designed to rapid dissolution.

Mouth dissolving or disintegrating tablets normally dissolved in the mouth within 1 minute.

Extended release tablets also called as controlled release tablets. This type of tablet release slowly so that it absorbed by body over a time period from single dose. So its produce continuous therapeutically effect. Continues and consistent release of medicine is the main advantage of extended release tablets.

Vaginal tablets are uncoated, pear or ovoid tablet inserted into vagina for local effect. They normally contain antibacterial or antiseptic drugs.

Dental cones are used after a tooth extraction to be place in the empty pouch which normally contain antibacterial drug, coagulant or astringent to avoid infection and decrease bleeding. Dental cones released slowly.

Implants: Implants also referred as a depot tablets. These tablets are inserted into subcutaneously for long period and constant release of drug. Main demerits are it requires surgical technique for administration and discontinue as well. There may be chance of tissue toxicity.

Mouth dissolving tablets:

Tablets dosage forms are not suitable for poor solubility drugs, drugs that needed onset of action or have serious side effects. Drug with bitter taste, sensitive to oxygen or atmospheric moisture are not suitable for direct compression it may require encapsulation (3).

The oral route of administration especially Swallowing of formal tablet and capsule is unmanageable (4) in paediatric, elderly patients and dysphasia patients associated with stroke, Parkinson's disease, AIDS, thyroidectomy and other neurological disorders including cerebral palsy.

An estimated 35% of the general population, and an additional 30-40% of elderly institutionalized patients and 18-22% of all persons in long-term care facilities, suffer from dysphagia (5).

Liquid medicaments (suspension and emulsion) are packed in multidose container; therefore achievement of uniformity in the content of each dose may be difficult. Possibility of breakage, leakage during transport and preservative are other problems. Buccal and sublingual formation may cause irritation to oral mucosa, so patients refused to use such medications.

Administration of drug would be affected by some physiological effects of gastrointestinal system and first pass metabolism by hepatic enzymes thus clinical effect of drug may be reduce with tablet and capsule and other oral dosage form.

Cost of products due to sterile environment and painful administration is main factor as parenteral formulations are most costly and discomfort. Mouth dissolving tablets are perfect over all this type of problems.

Mouth dissolving tablets are also known by different name as ordispersible tablets, rapid disintegrating tablet, fast dissolving tablet, rapimelts, porous tablets and etc. The European Pharmacopoeia defines the term "orodisperse" as a tablet that can be placed in the mouth where it disperses rapidly before swallowing (6). Fast dissolving tablets are designed to dissolve within few seconds in contact with saliva. Other excipients are added to increase the disintegration of tablets into oral cavity in three minutes and these tablets are termed fast-disintegrating tablets.

Mouth dissolving tablet took simply by placing them on the tongue. Tablets are designed to disintegrate or dissolve quickly on contact with saliva, thus no need of water for swallow or no need to chew tablet. Less frequently, they are designed to be absorbed through the buccal and oesophageal mucosa as the saliva passes into the stomach. This leads to increase the bioavailability by avoiding first pass liver metabolism (3). This type of drug delivery is becoming popular day by day due to its numerous advantages. Maximizing the porous structure of the tablet matrix and introducing an adequate disintegrating agent and use of highly water soluble excipients make it to dissolve rapidly.

Ideal Mouth dissolving tablet should - (7)

Ease to administration to paediatric, mental ill or elderly who refuse to swallow a tablet.

Not require water to swallow.

Dissolve or disintegrate within matter of second.

Be compatible with taste masking.

Have mouth pleasing taste.

Leave minimum or no residue after administration in mouth.

Have low sensivity to environmental condition as humidity and temperature.

Not be either too hard or fragile.

Allow high drug loading.

Convenience of administration and accurate dosing as compared to liquid dosage form.

Be adaptable and comfortable to existing processing and packaging machinery.

Allow using suitable processing and packaging at low cost for manufacturer.

Advantages

Rapid dissolution and absorption which may produce onset of action.

Masked taste of API helps to change the primary view of ''bitter tablet'' especially for children

Pre-gastric absorption can result in improved bioavailability and low amount of dosage allow less unwanted side effects..

No need of water to swallow, which highly attract to travelling patient. It is good marketing point to profit for pharmaceutical company as well.

Limitations (8)

If something wrong in formula the tablet may leave unpleasant taste and /or grittiness.

Drug with high loading dosage create problem in formulation.

Careful handling require during manufacturing due to insufficient mechanical strength.

Challenges in the formulation of oral disintegrating tablets

Mechanical strength and disintegration time: Mechanical strength is primary challenge while maintain disintegration time of MDTs. Fragile tablet will have chance of breaking during transport or handling by the patients while hard tablet don't exists low disintegrating time.

Taste masking: MDTs are completely dissolved in mouth so masking bitter taste of API is important to avoid patient compliance and acceptance for dosage from.

Mouth feel: Particle after dissolution of MDT should be as small as possible. This problem can be solved by addition of flavours and cooling agents as like menthol improve the mouth feel.

Sensitivity to environmental conditions: As most of materials used in mouth dissolving tablet are intended to dissolve in minimum quantity of water, MDT should exhibit low sensitivity to environment conditions.

Selection of drug

The ideal drug used for mouth dissolving tablet should not bitter in taste, have enough stability in water and saliva, minimum dose lower than 20mg, nonionised at the oral cavity pH and small to moderate molecular weight. While short halftime and repeated dosing type of drug is not suitable for orally disintegrating tablets. Physical properties of the active ingredient are also helpful factor to consider tablet design.

Ingredients to be used for Fast dissolving tablets:

Active pharmaceutical ingredient and different excipients used in the FDDTs should allow quick release of the drug, resulting in faster dissolution. Understanding chemistry of these excipients is important to prevent interaction with the API. Cost of these excipients is also important for formulators. The temperature of the excipient should be preferably around 30-35C for faster melting properties. Smaller particle size of the excipients gives a better smooth surface which improve physical properties and better mouth feel.

Many additives will also show their secondary functions as like some diluents or fillers may help to tablet dissolution and most effective lubricants are water repellent by their nature, which may delay both disintegration and dissolution.

Disintegrants are also essential to ensure quick disintegration and high dissolution rates (9). Disintegrants are agents which increasing surface area and promoting a more rapid release of the drug substance for the breakup of the tablet into smaller fragments in aqueous environment. Swelling of particle, porosity, wicking, deformation and severe mechanism of action suggested for disintegrants. However two main processes involved in during disintegration (10).

1. Disintegrants that facilitate water uptake:

This type of disintegrants helps to transport of liquids into the pores of the tablet which leads to break into fragments. One of the substances are surface active agents that increase the wetting of the solid and the penetration of the liquid into the pores of the tablet other are working by using capillary forces.

2. Disintegrants that will rupture the tablet: swelling of the disintegrant particle causes rupturing of tablet.

Fast dissolving requires quick absorption of water in to the centre of tablets. Thus, Tablets have open pore structures inside is very important for making fast dissolving tablets.

To get sufficient effect of disintegrant, tablet surface must be comfortable to wetting. High proportion of hydrophobic drug can effect disintegrating time.

DISSOLUTION OF DRUGS FROM TABLETS.

From reference (11)

The required concentration the superdisintegrant can be used according to critical concentration of disintegrant. Superdisintegrant are decrease the disintegration time by various mechanisms. Factors such like Disintegration, compactability, mouth feel and flow should be considered when selecting super disintegrant.

Generally superdisintegrant are used at 2-5 wt % of the tablet in normal tablet formulation. In case of MDTs quantity of disintegrant should be higher for great flow with direct compression. To produce enough robust tablets compactable disintegrant should be chosen.

Crosspovidone, microcrystalline cellulose, sodium starch glycollate, sodium carboxy methyl cellulose, and modified corn starch should be used as superdisintegrant.

Sometimes gas producing disintegrants are used for extra fast disintegration. Commonly mixtures of citric and tartaric acid with carbonates or bicarbonates are used.

Binder keep the formula together so right choice binder is important to keep the integrity and stability of tablet. Starch, sucrose, gelatine are common binder.

Bulking agent or Diluents or fillers: Diluents give bulk to formulation to prepare tablets in desired shape. Most common filler is lactose.

Selection of diluents in MDT is paramount for taste and better mouth feel. Filler should be chemically inert, non-hygroscopic, biocompactible, have good biopharmaceutical properties, and less cost (10).

Bulking agents used in this type of preparation should be more sugar based to improve textural characteristic. The examples of bulking agents include calcium carbonate, magnesium carbonate, calcium phosphate, calcium sulphate, pregelatinzed starch, magnesium trisilicate and aluminium hydroxide. Mannitol, polydextrose, lactitol and starch hydrolysate are sugar based bulking agents.

Lubricants improve the flow properties of mixture in the hopper. It also prevent sticking and reduce friction between the tablet and die. Magnesium stearate widely used lubricant. Lubricants give a sheen to final tablets. Stearic acids, magnesium stearate, zinc state, calcium state, talc, liquid paraffin, magnesium lauryl sulphate, colloidal silicon dioxide.

Sweeteners added to mask taste of API and good taste and flavour. Pharmaceutical grade sachharides such as Mannitol, sucrose, lactose, glucose, and xylitol have been used in MDTs.

Colourant give identification and reduce patient compliance.

Various technologies:

The different technologies used for preparation of mouth dissolving tablet.

Freeze drying

Cotton candy process

Molding

Sublimation

Spray drying

Mass extrusion

Nanonization

Phase transition process

Direct compression

Freeze drying or lyophilisation

The manufacture of mouth dissolving tablets using lyophilisation involves a series of procedures. In this process preparation of aqueous solution or suspension placed in to tablet size moulded blister followed by specially designed freezing process. These blisters are than carried to freeze dryer for removing moistu (3). Disadvantage of using this process is time consuming and expensive. Special packaging required due to poor stability and fragility of final product.

Zydis and Quicksolv is unique patent technology base upon freeze-dried technology.

Cotton candy process

Matrix of polysaccharides or saccharides has been produced by simultaneous action of flash melting and spinning. This matrix has better flow properties and compressibility. Then this candy matrix is milled and blended with active ingredient and compressed to tablet.

High dose of drug and improved mechanical strength can be achieved by this process but high process temperature limits the use of this process (12).

Molding

Tablet made from this process contain water-soluble ingredients so the tablets dissolve rapidly and completely. Flashtab is invented process by ethypharm based upon molding.

Powder is incorporated with hydro alcoholic solvent followed by compression at low pressure in molded plates to form a wetted mass. The solvent is than removed by air drying. The tablet made by this technique has less mechanical strength.

Sublimation

Readily volatilize solid ingredients are added to other tableting agents, then mixture is compressed to make tablets. These tablets are then subjected to sublimation to crate porous tablets.

Spray drying

Spray drying can produce highly porous and fine powders that dissolve quickly. In this technique, particular support matrix produced by spray drying. This matrix mixed with drug and compressed into tablets. This tablet disintegrated within 20 second in aqueous medium. (13)

Mass extrusion

In this technology the active blend made soft by adding water soluble polyethylene glycol and methanol and pass this blend to syringe or extruder to get a cylinder of product. Then cylinder finally cut in to tablet shape using heated blade. The dried cylinder can also be used to coat granules for taste masking.

Nanonization

Recently developed technology involves reduction in the particle size of drug to nanosize by wet milling technique. The nanocrystals of the drug are stabilized against agglomeration by surface adsorption on stabilizers, which are then incorporated in to MDTs. This technique is very useful for poorly soluble drugs.

Phase transition process

Compress the mixture of Low and high melting point sugar alcohol with active ingredient to make tablet. Then heating tablet at temperature between low and high melting point of sugars.

Direct compression

Porosity and wetting of water into tablets are important criteria to ensure quick dissolution of drug which depend upon mechanical strength of tablet. And another side fragility of tablet is also important.

As described above many techniques are available for manufacturing of mouth dissolving tablet but this techniques are time consumable, costly and special equipments are needed. Tablets made from direct compression method have good mechanical strength but low disintegration time (14). This process is very simple. Just few steps is involved milling, powder mixing and tableting. Wet or dry granulation does not require. This method reduces production time and cost. High doses can be adapted. Conventional equipment and commonly available excipient can be use for direct compression.

Tablets are made by compressing a formulation containing a drug or drug with excipients on tablet compressing machine. There are two types of tablet punching machine either single punch or multi punch rotary machine.

The type and quantity of disintegrant is primary cause for satisfactory quality of tablet in direct compression. OROSOLV and DURASOLV (15) patents from CIMA labs have been described evolution of carbon dioxide as a disintegration mechanism.

Some precaution during direct compression is to avoid air entrapment because it causes the capping, splitting, or laminating of tablets. Forced feeders can reduce air entrapment, making the filler powder more dense and amenable to compaction.

Evaluation of MDTs:

There are different standard has been set regards to tablets in different pharmacopoeias. The following standard test including:

General appearance

Size and shape

Tablet thickness

Weight variation

Hardness

Friability

Wetting time and water absorption ratio

Disintegration time

Dissolution time

General appearance

The appearance of the tablet is important criteria. Standard size, shape, good colour, marking on the tablet, surface roughness and colour homogeneity of tablet is all exceptions of the patients and measure of quality.

Size and shape

The size of tablet frequently related with administered dose. Small size of tablet is easy for swallow. Capsule shaped tablet is more convenience for high dose materials with high compression weight is also needed (11).

Organoleptic properties

Uniformity of colour is important for appearance for rich quality appeal. One study (16) shows that patients presume thought about test depends upon shape and size of tablets. For example, orange colour tablets will be sour, blue tablets have bitter taste. So, right choice of colour is important factor.

The presence of an odour in a batch of tablet suggest stability problem however it could be characteristic of the drug or added sweetener or flavour. Taste of product is also important factor consider to patience acceptance.

Friability and Hardness

It is also referred as crushing strength. Hardness of tablets depends upon applied compression force during manufacturing process and the characteristic of the granulation. Enough hardness of tablet is necessary to avoid damage during storage, transportation, and handling. Too hard tablet may result in less disintegrating time but if is too soft, it may not capable for later process as like coating or packaging and shipping procedures.

Disintegration testing is an important part of testing during production to ensure batch to batch uniformity.

Dissolution test

Dissolution study of tablet in vitro is important tool.

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