Comparison of Oral Drug Administration Strategies

Abstract

In this literature assignment the oral route of administration will be discussed and further studied. Particular formulations such as tablets (including chewable as well as buccal tablets), capsules, oral solutions, suspensions and emulsions which can be applied by using this selected route will be compared and any differences or/and similarities between those will be identified. Oral formulations are usually the most convenient for both children and adults and therefore should be the first choice for example pain management etc or generally when required. Speed of absorption (in the oral route it may be slow depending on the preparation and the stomach contents) and duration of effect (slower release compared to other routes for a prolonged effect) are also some of the factors under investigation in this study. According to the advantages and disadvantages of these different formulations it would be useful to identify which is the most preferable formulation by patients followed by specific examples/drugs which are administered orally.

Introduction

Different drugs require different routes of administration and therefore different dosage forms are produced in order the appropriate absorption to be achieved through the suitable form of the drug. Each substance is absorbed in a different way by the human body. Hence different administration routes are provided and recommended for each substance under which the dose of the drug will be absorbed, delivered and distributed more effectively.

The two major classes where through the drug can enter the human body are enteral and parenteral routes. In the enteral route the drug passes directly into the Gastrointestinal tract. Enteral route includes sublingual (under the tongue), oral (swallowing) as well as absorption of the drug through the rectum. On the other hand parenteral routes involve intravascular (the drug is administered into the blood stream), intramuscular (skeletal muscle), subcutaneous (into subcutaneous tissues) and inhalation routes of administration (where the drug is absorbed through the lungs).

Parenteral routes, Routes of Drug Administration, RL Copeland,

PH.D., Department of Pharmacology

Topical preparations include those that result to either mucosal membranes (such as eye drops, nasal) or skin (dermal and transdermal for local and systemic action respectively).

The physical characteristics of the drug, its rate of absorption or/and release as well as the possibility of the need of high concentrations at particular sites are some basic key factors that determine the route of administration for each drug. It should be also mentioned that more than one route of administration can be advisable for the substance/drug depending on the patient’s condition.

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According to researches it has been proved that the oral route is the most popular route of administration between those that were referred above. This is due to its simplicity, convenience and safety provided. However, there are some disadvantages of the oral route of drug administration involving the long time the drug needs in order to show an effect as well as the interaction of drug substances with enzymes and/or secretions of the gastrointestinal tract. Gastric emptying time as well as the alteration of pH levels into the gastrointestinal tract are factors to investigate in order to achieve maximum absorption of the drug through the oral route.

Discussion

Tablets

Nowadays, one of the most common dosage forms produced by pharmaceutical industries and preferred by the majority of patients is undoubtedly tablets. The category of compressed tablets is the most popular dosage form in use. Tablets are used for either systemic drug delivery or for local drug action as well. They are more preferable than any other dosage form as they are taken orally by patients, which is a convenient and safe way of drug administration and are more stable compared to liquids (physical and chemical stability). Different types of tablets (regarding their shape, size and drug dose) require a different formulation in order to be produced as each category has different properties and alterations may be needed in the choice of excipients each time and in methods used. That means that every tablet is a different situation and as a result different steps should be followed.

Tablets have enough advantages in comparison to other dosage forms. First of all they are easier to handle and the preparation procedure offers an accurate dosing of the drug. The possibility of mass production makes production of tablets cheaper and their chemical and physical stability is obviously better compared to liquid dosage forms. Tablets are also compliant with the majority of patients.

Disadvantages of tablets are noticed when they are dispensed especially in the elderly and paediatrics where swallowing difficulties are observed. They also belong to the category of slow-acting dosage forms (first-pass effect). Finally their poor bioavailability in combination with the decrease in PH over the time complete the most important disadvantages and create points for improvement.

The compressed tablet is the most popular, versatile but most technically difficult dosage form as well. According to European Pharmacopoeia (3rd edition, 1997) tablets are “solid preparations each containing a single dose of one or more active ingredients and obtained by compressing uniform volumes of particles”. Million tablets are dispensed on a daily basis in the pharmacies all over the UK. Hence pharmacists should be completely aware of how they are made and the steps that follow during the production stage before they reach in the dispensary area of pharmacies.

First of all, tablets are called pills by the majority of people. However this name is technically incorrect as tablets are made by compression whereas pills are an ancient solid dose forms prepared by hand into spherical particles about 4 to 6mm in diameter.

As it was said above, tablets are made by a process of compression and that is their basic difference compared to pills. There are two main types of press in tablet production: the single -punch press (or eccentric press) and the rotary press (or multistation press). There is one more type, called hydraulic press (used more in research and development work) which requires a more specialized equipment.

The first very important factor for investigation in tablet formulation is compressibility. Because the majority of drugs do not have very good compression properties on their own usually require the addition of excipients. Low dose tablets (dose less than 50mg) are used to be prepared by direct compression whereas high dose ones (dose more than 50mg) by using wet granulation technique. Compression properties could be understood better by studying the behaviour of elastic, plastic or fragmenting tablets under compression.

Good flow (or alternatively flowability) is the next attribute for investigation. In order to succeed that, tablets require the addition of different excipients (and not only the active drug) such as lubricants, glidants, binders, disintegrants, antiadherents etc. Depending on the drug and the dose of the tablet each time (preparation of low or high dose tablets), different excipients are used. Excipients however, can affect powder’s properties; hence pharmaceutical industries need to study very well them and their properties in order to avoid any possible errors during the tableting process.

325mg aspirin tablets, by Ragesoss, E. Johnson, 2010

Tablets can be controlled by weight. The whole tablet’s weight combines the weight of the active drug (drug dose) and the weight of the excipients added after it. “Tableting process relies on consistent volumetric filling of the die space set by the bottom punch”.

Uniformity of tablets can be tested in two ways; weight variation or content uniformity test. Weight variation test occurs for high dose tablets (dose > 50mg) that are uncoated and contain at least 50 % of the active ingredient (drug). On the other hand, content uniformity test is used for coated tablets which contain again the same percentage (at least 50%) of the single active ingredient.

In tablet manufacturing, tablets are prepared by powder compression. By that way particles are placed very close to each other and finally a defined size and shape is given. During compression procedure a die and two punches (upper and lower) are used. First of all die is a tool that is used by pharmaceutical industries for cutting or shaping materials by using press. On the other hand, punch is used to describe a hard metal rod which has two different ends; a shaped tip and a blunt butt. The compressive force is applied by the upper punch while the lower one moves at the same time up and down within the tip.

The image below describes the whole process from the time that the powder is moved to the die till the tablet is formed.

The sequent of events involved in the formation of tablets. Pharmaceutics – The science of dosage form design, edited by M.E, Aulton Second edition

Coming back to flowability, good flow depends on both active ingredients and the excipients added in the powder mix. The good flow of a powder mix can be ensured by measuring the angle of repose or consolidation index. If flow properties are not very good, then lubricants and glidants are the most appropriate excipients for the improvement of the flow. It should also be noted that only glidants are able to improve a powder’s flow. Lubricants just decrease the extinction of friction and by that way the flow becomes better.

More especially, by the addition of a lubricant the coefficient of friction between the die wall and the tablet during ejection is reduced and by that way the powder has a better flowability. Magnesium stearate is the most commonly used lubricant especially for tablets and functions as an antiadherent. That means that by its addition, it prevents ingredients from picking and sticking to manufacturing equipment during the compression of chemical powders into solid tablets. It is also hydrophobic and reduces the compressibility of many formulations.

On the other hand, glidants are added mainly to the dry powders to improve flowability. In general the addition of a glidant or lubricant or both of them can affect the excipient’s/powder’s flowability and bulk density. These additions can have great results and turn powders with a very poor flow to powders with a good flow.

Apart from lubricants and glidants, formulation of tablets requires the use of other excipients as well. The filler for example which acts as a bulking agent, is used in order to increase the bulk volume of the powder and hence the size of the tablet when the dose of the active ingredient is too low (low dose of a potent drug requires the incorporation of a substance). An ideal filler has to be chemically inert, biocompatible, non-hygroscopic, soluble, compactible, quite tasty and not of very high cost. The filler used most widely is lactose as its properties look enough like the ideal filler’s one.

The addition of a disintegrant also ensures that the tablet when will be in contact with liquid will break up into small fragments. This promotes quick drug dissolution. During disintegration, the liquid comes in contact with the solid and penetrates the pores of the tablet. Afterwards the tablet breaks slowly into smaller fragments. Two categories of disintegrants exist: those that facilitate water uptake (e.g. surfactants) and that rapture the tablet (e.g. starch).

Sticking or picking properties of tablets depend on the addition of antiadherents. Antiadherents reduce adhesion between the powder and the punch faces. Lots of lubricants can be used as antiadherents. Talc or starch have also similar properties. Magnesium stearate which is the most commonly used lubricant (especially for tablets) functions as an antiadherent as well. That means that by its addition, it prevents ingredients from picking and sticking to manufacturing equipment during the compression of chemical powders into solid tablets. It is also hydrophobic and reduces the compressibility of many formulations.

Pharmaceutical industries can involve flavouring agents and colourants during tableting procedure too. First of all, a flavouring agent by its addition either gives a more pleasant taste in the tablet or mask an unpleasant one. Flavouring agents cannot be added prior to an operation involving heat as they are usually thermolabile. Usual flavouring agents are essential oils such as anise and cardamom, vanilla or peppermint.

Colourant is the last excipient could be added during wet massing method in order to produce high dose tablets. General knowledge of colourants involve tablets identification and patients compliance. Even if colouring procedure finishes during coating stage, the colourant chosen could be added prior to compaction as well. Opacifiers like Titanium oxide and Inorganic materials like Iron oxide are characteristic colourant examples.

The choice of the appropriate excipients depends on the type of the tablet as different excipients give different properties. So chewable tablets are not designed to disintegrate since mechanical action is supplied by the patient. Hence there is no need for disintegrants to be contained in to the relevant formulation. Although the drug is immediately released in the mouth, it is swallowed and absorbed from the stomach. Colouring and flavouring is also needed especially in the presence of antacids.

Effervescent tablets are dissolved in a glass of water before administration. Plenty of analgesics use this specific type and during this process disinitegration and dissolution are facilitated due to carbon dioxide liberation. Effervescent tablets have a rapid bioavailability and cause less stomach irritation. However extra protection from moisture is required in packaging.

Finally extended – release tablets have been designed in order to release the drug dose over 12-24 hours until the drug to result to Gastrointestinal tract. They are classified according to the mechanism of drug release (e.g. erosion, dissolution, diffusion etc).

Capsules

The second most common dosage form administered via the oral route are capsules. Capsules which are solid dosage forms are distinguished into two categories; hard gelatine capsules and soft gels. Soft gelatine shells are consisted of less gelatine compared to hard gelatine ones (43%), 37% of glycerine and 20% of water. On the other hand, in hard gelatine shells no glycerine is added and larger amount of gelatine is obviously used. Although both capsule types are widely used, soft gels have some more advantages due to the accuracy and precision of dose that they offer, the accuracy of fill volume as well as the fact that they are preferred for high dose poorly compressible drugs. Generally speaking both capsule types are from the dosage forms that can be massively produced in a manufacturing scale and achieve appropriate dose in combination with the preferable size, shape and colour.

Hard gelatin capsules Soft gelatin capsules

Capsules are more stable than liquid dosage forms and as it was mentioned above they contribute to accurate dosing. Such as with tablets, they are quite easy to administer and any unpleasant tastes can be easily masked. Capsules’ release properties can be managed and further studied and it is also possible light resistant capsules to be produced. Patients compliance is another important issue too.

The basic disadvantages are pretty much the same with those of tablets. Capsules as tablets are not indicated for people with swallowing difficulties including the elderly and children. They are also unsuitable for very small children and the use of animal gelatine in their formulation process might be an important religious issue.

The aim of developing a capsule formulation is first of all to prepare a capsule with accurate dosage, good bioavailability, stability, elegance and facility in the production stage.

In capsule formulation is very important the mixture that will be added into the capsules to have been blended very well and being 100% homogenous. Disintegrants are usually included in capsule formulation in order to “help” capsule’s contents to be distributed in the stomach.

Aqueous solutions cannot be filled in hard gelatin capsules because water softens the gelatin and destroys the capsules. However, there are some exceptions of a few aqueous solutions (included oils) that can be added in hard gelatin capsules.

In general, capsules are consisted of two main parts: the body and the cap. Almost all of the pharmaceutical companies that produce hard gelatin capsules use gelatine produced by ingrained bovine spongiform encephalopathy. This material is a good film former, soluble in water and is able to fluid in GI at normal body temperature without to release any of the ingredients of the capsule.

Capsules are available in a variety of sizes and the appropriate size is chosen each time according the fill volume of the ingredients.

Capsule sizes

In hard gelatine capsules and generally in capsules, there is one extra step compared to tablets; that is the dissolution of the capsule shell. When the capsule will pass through the GI and will be placed in a dissolution medium at approximately 37οC, the gelatin will start gradually to dissolve. So, firstly the cap and afterwards the body will start to “melt”, and as a result the dissolution medium will penetrate into the capsule ingredients.

Oral Solutions

Solutions are from the oldest dosage forms used in pharmaceutical formulations. Their strongest advantage is based on the fast and high absorption of soluble medicinal products. Being from the simplest formulations to prepare concerning both time and cost, solutions are still one of the “leading” dosage forms due to their application in patients with swallowing difficulties and their easy administration. For example they are administered in geriatrics, in paediatrics as well as in patients in intensive care or patients suffering from psychiatric problems. Solutions are divided in oral solutions (elixirs, linctuses, syrups, mixtures, draughts, spirits and paediatric drops), in external solutions (lotions, liniments, external applications and collodions), in gargles and mouthwashes as well as in enemas and douches.

Care pholcodine oral solution BP

Focusing on the oral solutions, they contain a liquid which is characterized by its homogeneity and in which one or more active ingredients have been dissolved. Contrary to suspensions, in solutions there is no need for shaking before use. Most times, water is the preferred vehicle due to its multiple properties. Solutions offer immediate absorption of the drug and the drug dose can be also shaped regarding the patient’s needs.

On the other hand, the drug stability is importantly affected in solutions and unpleasant tastes cannot be so easily masked as in other dosage forms (for example in tablets). As with suspensions, solutions do not offer a convenient transport due to possible container breakages. Other disadvantages involve the use of a measuring device in order to administer the appropriate dose to the patient which further requires a relevant technical accuracy. Finally, the fact that some of the drugs are poorly soluble enables the creation of a vehicle which usually consists of water and a variety of other solvents in order the chosen drug to be dissolved.

Solubility which is an important factor to investigate in solutions, is directly connected to particle size, stirring, viscosity and temperature. Physical and chemical stability are other factors that need to be taken in consideration while dealing with the formulation of this specific dosage form.

Oral Suspensions

Generally speaking suspensions cover a wide range of pharmaceutical products involving enemas, ear drops, inhalations etc. Focusing on the suspensions administered via the oral route (mixtures for oral use) at least one of the active ingredients is suspended in a vehicle. According to the British Pharmacopoeia oral suspensions are “oral liquids containing one or more active ingredients suspended in a suitable vehicle. Suspended solids may slowly separate on standing but are easily redispersed”. Suspensions are an alternative way of drug administration which would not be so convenient for use if taken in other dosage forms (e.g. tablet). They are preferred from patients who experience swallowing difficulties and they are indicated for paediatric or/and geriatric use.

Paracetamol oral suspension

Some of the advantages of suspensions over other pharmaceutical formulations involve the palatability and stability that can be achieved using insoluble drugs. As it was mentioned above it is easier to swallow suspended insoluble powders and the absorption stage will be really faster that any other solid dosage forms which require dissolution before absorption.

On the other hand, shaking is necessary before use and most times the dose is not as accurate as in equivalent solution. The disperse system can be also affected depending on the storage conditions. Finally it is not so easy to transport suspensions and extra caution is needed due to possible container breakages in this specific dosage form.

Suspensions are further categorized into diffusible and indiffusible ones. Diffusible suspensions use light insoluble (or very slightly soluble) powders which during shaking require longer time to disperse uniformly (compared to indiffusible suspensions) in order to be made up to an accurate dose. Light Kaolin BP and Magnesium Trisilicate BP are some common diffusible powders which are completely insoluble in the water. Calamine BP and Zinc oxide BP are some of the commonly used indiffusible powders (heavy powders which are not soluble in the vehicle). One of the basic differences between these two categories is that in indiffusible suspensions a suspending agent is added for facilitating the vehicle to be thickened.

Oral Emulsions

British Pharmacopoeia states that “oral emulsions are oral liquids containing one or more active ingredients. They are stabilised oil-in-water dispersions, either or both phases of which may contain dissolved solids. Solids may also be suspended in oral emulsions. When issued for use, oral emulsions should be supplied in wide-mouthed bottles”.

Q-LAX Oral emulsion

Generally speaking the term “emulsion” is connected to applications with external use, lotions and creams. However pharmaceutically it is used for preparations that are used to be administered via the oral route. Emulsions are dispersions of oil in water or the opposite. Tiny droplets indicate the dispersed phase. Therefore the use of an emulsifying agent is necessary in order to assure that the oil phase is normally dispersed in the presence of water. Oral emulsions are usually “oil-in-water” whereas those that are intended for external use are usually “water-in-oil” respectively.

As in suspensions, the artificial palatability of unpalatable drugs in emulsions is a strong advantage. It is also quite easy to flavour the aqueous phase and the sensation or/and the taste of the oil is something that can be easily removed. This dosage form has an increased rate of absorption and can combine even two incompatible ingredients (one in oily and another one in the aqueous phase).

Passing to the disadvantages, some similarities can be identified between emulsions and solutions. The first one is the use of a measuring device in order to administer the appropriate dose to the patient which requires a relevant technical accuracy. Stability can be affected depending on the storage conditions and as in suspensions (but not in solutions), a good shake of the preparation is required before administration. As it was mentioned twice above, emulsions, suspensions and solutions do not offer a convenient transport due to possible container breakages. Finally in emulsions cracking can be caused due to the microbial contamination of the preparation.

Although emulsions are a very helpful and useful dosage form in pharmaceutics, they are widely used more in external preparations than in internal ones (via the oral route).

Conclusion

Different drugs are administered via different routes of administration. Criteria such as either the speed or the efficiency with which the drugs act are decisive in order to choose the most appropriate route of administration and consequently the dosage form. More specifically, in terms of the oral route of drug administration different dosage forms were analyzed, discussed and their advantages and disadvantages were compared. Of course it is pointless to say that one of these dosage forms which are taken orally (tablets, capsules, oral suspensions, solutions and emulsions) is the best as each one covers specific aspects and purposes and is used under different circumstances. Tablets is the most commonly used dosage form with a very interesting as well as complicated manufacturing background. They are available in different types (e.g. immediate, modified release etc) and they are most preferable by patients. Capsules is another solid dosage form which is also preferred by patients. Tablets and capsules as solid preparations share common advantages. However patients compliance is their strongest one. When tablets or capsules cannot be swallowed then the use of other oral dosage forms such as solutions, suspensions or emulsions is necessary. Swallowing difficulties can be found especially in the elderly, in children or in patients in intensive care or with psychiatric support. Solutions and suspensions are used more widely than emulsions intended for internal use (via the oral route). Basic differences between those focus on palatability and stability of the preparation. To summarise it needs to be mentioned that it is not up to the formulator to decide the route of administration of each drug. This is solely determined by the physical characteristics of the drug itself, absorption and release factors.