Understanding Drug Delivery Systems And Dosage Forms Biology Essay

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For many decades, the treatment of an acute disease or a chronic illness has been mostly accomplished by the delivery of drugs to the patients using various pharmaceutical dosage forms such as tablets, capsules, pills, suppositories, creams, ointments, aerosols and injectables. Even today these conventional drug delivery systems are the primary pharmaceutical products commonly seen in the prescriptions and which are available as over- the- counter medicines. The method by which a drug is delivered can have a significant effect on its efficacy. The slow progress in the treatment of certain disease has suggested a growing need for a multidisciplinary approach to the delivery of drugs to their target sites. Recently, several technical advancements have resulted in the development of new techniques are capable of controlling the rate of drug delivery, sustaining the duration of therapeutic activity & / or targeting the delivery of drug to a tissue. These are referred to as novel drug delivery system. (Chein Y. W., 1992; Bandyopadhyay A.K., 2008 )

1.2. ORAL DRUG DELIVERY SYSTEM (Brahmankar D. M., 2006; Bankar G.S and Rhodes C.T., 2009)

An ideal drug delivery system (DDS) should aid in the optimization of drug

Therapy by delivering an appropriate amount to the intended site and at a desired rate. Hence, the DDS should deliver the drug at a rate dictated by the needs of the body over the period of treatment. An oral drug delivery system providing a uniform drug delivery can only partly satisfy therapeutic and biopharmaceutical needs, as it doesn't take in to account the site specific absorption rates within the gastrointestinal tract (GIT). Therefore there is a need of developing drug delivery system that release the drug at the right time, at the specific site and with the desired rate.

1.3. CONVENTIONAL DOSAGE FORMS (Ansel C., et al., 2007)

Conventional peroral dosage form is assumed to be one that is designed to release rapidly the complete dose of drug contained therein immediately following administration. The administration of a drug by either intravenous injection or an extravascular route (orally, intramuscularly, rectally) does not maintain the drug blood levels within the therapeutic range for an extended period of time. The short duration of action is due to the inability of conventional dosage forms to control temporal delivery.

Therefore to achieve as well as to maintain the drug concentration within the therapeutically effective range needed for the treatment, an alternative approach is to administer the drug repetitively using a constant dosing interval, as in a multiple-dose therapy. In this case the therapeutic drug blood level reached and the time required reaching that level depends on the dose and dosing interval.

There are several potential problems inherent in multiple dose therapy;

It is inconvenient for the patient and can result in missed doses, made up doses and non- compliance with the regimen.

Toxic levels may be produced if an attempt is made to maintain drug blood levels in the therapeutic range for longer periods by, for eg increasing the initial dose of an i.v injection.

Causes sequential therapeutic blood level peaks and valley associated with the taking of each dose on schedule and more than once daily.

When doses are not administered on schedule, the resulting peaks and valleys reflect less than optimum drug therapy. Example,

If doses are administered too frequently, minimum toxic concentration (MTC) of drug may be reached, with toxic side effects resulting.

If doses are missed, periods of subtherapeutic drug blood levels or those below the minimum effective concentration may results with no benefits to the patient.


Figure 1.1: A hypothetical plasma concentration Vs time profile from conventional multiple and single doses of sustained and controlled delivery formulations.


To overcome the potential problem associated with congenital drug therapy modified release system were developed and can be divided into following categories

1) Delayed release

2) Sustained release

3) Controlled release

4) Site Specific release

1.5. ORAL SUSTAINED DRUG DELIVERY (Williams L and Wilkins ., 2005 )

The concept of sustained release formulation was developed to eliminate the need for multiple dosage regimens particularly for those drugs requiring reasonably constant blood levels over a long period of time. In addition it also been adopted for those drugs that need to be administered higher doses, but where too rapidly a release is likely to cause undesirable side effects / Eg, the ulceration that occurs when HCl is released rapidly in the gastrointestinal tract.

There are many definitions of sustained release but the simplest definition is "Any drug or dosage form or medication that prolongs the therapeutic activity of drug''. The overall objective is that, once the drug-carrier material has been injected or otherwise implanted or taken orally into the body, the drug is released at a predetermined rate for some desired period of time.

The United States Pharmacopoeia has adopted the term extended release whereas the British Pharmacopoeia has adopted the term slow release. United States Food and Drug Administration has adopted the term Prolonged release. However the literature survey indicates that the most widely used terms today are sustained release & controlled release.

If the system is successful in maintaining constant drug levels in the blood or target tissue, it is considered as a controlled release system. If is unsuccessful at this but nevertheless extended the duration of action over that achieved by conventional delivery. It is considered as a prolonged release system.

In general, the goal of sustained of sustained release dosage form is to maintain therapeutic blood or tissue levels of drug for an extended period. This is usually accomplished by attempting to obtain zero order release from the dosage form. Sustained release system generally do not attain this type of release and provides drug in a slow first order fashion.

1.5.1. ADVANTAGES OF SUSTAINED RELEASE DOSAGE FORMS (Brahmankar D. M., 2006; Vyas S.P., 2002)

Enhanced patient compliance and convenience due to less frequency of administration.

Reduction in fluctuation in steady state- state levels and therefore better control of disease condition and reduced intensity of local or systemic side effects.

Less dose is required (reduction in total dose).

Produces more uniform drug effect.

Increase safety margin of high potency drug due to better control of plasma drug concentration.

Patient required short treatment and possibility of self medication.

Reduction in health care costs through improved therapy.


Poor in vitro-in vivo correlation.

Possibility of dose dumping due to food, physiologic or formulation variables.

Reduced potential for dosage adjustment of drugs normally administered in varying strengths.

Patient variation.

Termination of drug action is difficult in case of toxicity, poisoning or hypersensitivity reactions.


The biopharmaceutical evaluation of a drug for potential use in controlled release drug delivery system requires knowledge on the absorption mechanism of the drug form the G.I. tract, the general absorbability, the drug's molecular weight, solubility at different pH and apparent partition coefficient.

Table 1.1: It shows parameters for drug selection



Molecular weight/ size

< 1000


> 0.1 mg/ml for pH 1 to pH 7.8

Apparent partition coefficient


General absorbability

From all GI segments


Should not be influenced by pH and enzymes

Absorption mechanism


The pharmacokinetic evaluation requires knowledge on a drug's elimination half- life, total clearance, absolute bioavailability, possible first- pass effect, and the desired steady concentrations for peak and though.

Table 1.2: It shows Pharmacokinetic parameters for drug selection



Elimination half life

Preferably between 0.5 and 8 h

Total clearance

Should not be dose dependent

Elimination rate constant

Required for design

Apparent volume of distribution Vd

The larger Vd and MEC, the larger will be

the required dose size.

Absolute bioavailability

Should be 75% or more

Intrinsic absorption rate

Must be greater than release rate

Toxic concentration

Apart the values of MTC and MEC, safer

the dosage form. Also suitable for drugs

with very short half-life.


The drug properties that influence the incorporation of the drug into a sustained release dosage form can be classified as:-

Physicochemical properties

Biological properties

Physicochemical properties are those that can be determined by in vitro experiments. Biological properties are those that result from typical pharmacokinetic studies of absorption, distribution, metabolism, and elimination characteristics of drugs.

Table 1.3: Drug properties suitable for sustained release (Bandyopadhyay A.K., 2008; Robinson J.R. and Lee V.H.L., 1987; Banker G.S and Christopher T.R., 2002)



1) Physicochemical properties

Dose Size

If dose is greater than 0.5 g it is a poor candidate for a sustained release system since the product size will be exceptionally large.

Ionization , pKa, and aqueous solubility

Most drugs are weak acids or bases. Since the unchanged form of a drug preferentially permeates across lipid membranes, the relationship between the pKa of the compound and the absorptive environment is important. Drugs existing largely in ionized form are poor candidates. Extremes in aqueous solubility will be undesirable. For drugs with low water solubility, they will be difficult to incorporate in sustained release mechanism. The lower limit is 0.1 mg/ml. Drugs with very high solubility are equally difficult to incorporate. pH dependant solubility will be another problem.

Partition Coefficient

Drugs with a relatively high partition coefficient are predominantly lipid solubility and consequently, have very low aqueous solubility. Furthermore these compounds can usually persists in the body for longer periods, because they can localize in the lipid membrane of cells. The value of K at which optimum activity observed is 1000/1 in octanol /water.

Drug Stability

As sustained release systems are designed to release their contents over much of the length of GI tract, drugs, which are unstable in environment of intestine, may demonstrate decreased bioavailability, are poor candidates for sustained release.

2) Biological Properties


Drugs that are slowly absorbed or absorbed with variable absorption rate are poor candidates for sustained release systems. Lower limit on absorption rate constant is 0.25 h -1.


Drugs with high apparent volume of distribution, which in turn influences rate of elimination are poor candidates.


Drugs that are significantly metabolized before absorption, either in the lumen or tissue of the intestine, can show decreased bioavailability from slower releasing dosage forms. As the drug is released at a slower rate to these regions, less total drug is presented to the enzymatic process during a specified period, allowing more complete conversion of drug to its metabolite. As long as location, extent, and rates of metabolism are known and the rate constant(s) for the processes are not too large, successful sustained release systems can be developed.

Duration of action

The biological half-life and hence duration of action plays a major role. Drugs with biological half-life less than 2 hrs should not be used. At the other extreme a drug with half-life of greater than 8 hrs have inherently sustained action.

Therapeutic range

Drugs with narrow therapeutic range require precise control over the blood levels of the drug, placing a constraint on sustained release dosage form.

Biological half-life

The biological half life and duration of action of drug obviously plays a major rule in considering a drug for SR systems. Drugs with a very short half life (>2 hr) require large amounts of drug to maintain sustained effects and drugs with longer life (<8hrs) because their effects are already sustained.

1.5.5. Approaches For Sustained Release Formulations (Ansel c., 2009)

Coated beads, granules and microspheres.

Multitablet system.


Embedding drug in slowly eroding or hydrophilic matrix system.

Embedding drug in inert plastic matrix.

Complex formation.

Ion exchange resins.

Osmotic pump.

1.5.6. DESIGN AND FABRICATION OF ORAL SYSTEMS (Brahmankar D.M. and Jaiswal S.B.,1995; Robinson J.R. and Lee V.H.L., 1987; Chein Y W., 1992)

The majority of oral controlled release systems rely on dissolution, diffusion or a combination of both mechanisms, to generate slow release of drugs into the gastrointestinal milieu. The following techniques are employed in the design and fabrication of oral sustained release dosage forms.

1. Dissolution controlled release

Encapsulation dissolution control,

Matrix dissolution control.

2. Diffusion Controlled Release

Reservoir devices,

Matrix devices.

3. Diffusion and dissolution controlled systems.

4. Ion-exchange resins.

5. pH - independent formulations.

6. Osmotically controlled release.

7. Altered density formulations.

Dissolution-controlled Systems:

Drug with a slow dissolution rate will demonstrate sustaining properties, since the release of the drug will be limited by rate of dissolution. This being the case, SR preparations of drugs could be made by decreasing their dissolution rate. This includes preparing appropriate salts or derivatives, coating the drug with a slowly dissolving material, or incorporating it into a tablet with a slowly dissolving carrier. The dissolution process at steady state, is described by Noyes-Whitney equation,

dc/dt = KDA(Cs-C) = D/h A(Cs-C)

Where, dc/dt = Dissolution rate.

KD = Diffusion co-efficient

A = surface area of the dissolving solid

Cs = Saturation solubility of the solid.

C = Concentration of solute in bulk solution.

H = Thickness of diffusion layer.

Encapsulation dissolution control :

These methods generally involve coating individual particles of drug with a slow dissolving material. The coated particles can be directly compressed into tablets as in space tabs or placed in capsules as in spansule products.

Since the time required for dissolution of the coat is a function of thickness and aqueous solubility, sustained action can be obtained by employing a narrow or a wide spectrum of coated particles of varying thickness respectively.

Matrix dissolution control :

Those methods involve compressing the drug with a slowly dissolving carrier into a tablet form. Here the rate of drug availability is controlled by the rate of penetration of dissolution fluid into the matrix.

This in turn can be controlled by porosity of the tablet matrix, the presence of hydrophobic additives and wettability of granule surface.

Diffusion controlled systems:

Basically diffusion process shows the movement of drug molecules from a region of higher concentration to one of lower concentration. Diffusion systems are characterized by the release rate being dependent on its diffusion through an inert membrane barrier. Usually this barrier is an insoluble polymer

Membrane reservoir diffusion controlled

The core of the drug is encapsulated within a water insoluble polymeric material. The drug will partition in to the membrane and diffuse in to the fluid surrounding the particle or tablet. Cellulose derivatives are commonly used in the reservoir types.

Ficks first law of diffusion describes the diffusion process.

J= -D dc/dx.

D = diffusion coefficient in area/time

dc/ dx = change of concentration 'c' with distance 'x'


Figure 1.2: It shows Schematic representation of reservoir diffusion controlled drug release reservoir.


Zero order delivery is possible; release rate varies with polymer type.


Systems must be physically removed from implant sites.

Difficult to deliver high molecular weight compounds.

Increased cost per dosage unit, potential toxicity if system fails.

Matrix diffusion controlled

It this system a solid drug is dispersed in an insoluble matrix. The rate of drug release is controlled by the rate of diffusion of drug and not by the rate of solid dissolution. In this model, drug in the outside layer exposed to bath solution is dissolved first and then diffuses out of the matrix. The following equation describe the rate of release of drug dispersed in an inert matrix system have been derived by Higuchi,

dQ/dt =(DACS/2t)1/2

where 'A' is the total amount of the drug in the device, 'D' is the diffusion coefficient of the drug in the polymer, 'Cs' is the solubility of the drug in the polymer and't' is time.


Figure 1.3: It shows Release of drug dispersed in an inert matrix system


Easier to produce than reservoir or encapsulated devices, can deliver high molecular weight compounds.


Cannot provide zero order release, removal of remaining matrix is necessary for implanted system.

Dissolution and Diffusion - Controlled release system

Normally, therapeutic systems will never be dependent on dissolution only or diffusion only. In practice, the dominant mechanism for release will over shadow other processes enough to allow classification as either dissolution rate limited or diffusion controlled.

Partially soluble membrane system:

DrugThe drug is encapsulated in a partially soluble polymer (a polymer that has domains that dissolve with time). The drug diffuses through the pores in the polymer coat. For example, a cellulose acetate and HPMC mixture is coated on to the drug particles.

DrugGigg GI fluids

Figure 1.4: It shows partially soluble membrane system..

Matrix system:

Matrix system encapsulate the drug in a membrane coating, where dissolution of the drug in the fluid that penetrates in to the core and diffusion of the drug from the core across the polymer membrane makes for a diffusion and dissolution controlled system.

The drug is sparingly soluble in this case, so the release rate is slow and has significant influence on the diffusion of drug across the membrane.


Easier to produce than reservoir devices.

Can deliver high - molecular weight compounds.

Removal from implant sites is not necessary.


Difficult to control kinetics owning to multiple process of release.

Potential toxicity of degraded polymer .

Ion Exchange Systems

These are salts of cationic or anionic exchange resins or insoluble complexes in which drug release results from exchange of bound drug ions that are normally present in GI fluids.

The use of ion exchange resins to prolong the effect of drugs is based on the principle that positively or negatively charged therapeutic molecules combined with appropriate resins yield insoluble poly salt resonates.

Osmotically controlled systems

This device is fabricated as tablet that contains water soluble osmotically active drug, of that was blended with osmotically active diluents by coating the tablet with a cellulose triacetate barrier which functions as a semi permeable membrane. A laser is used to form a precision orifice in the barrier, through which the drug is released due to development of osmotic pressure difference across the membrane, when it is kept in water.


Figure 1.5: It shows osmotically controlled systems


Zero order release rates are obtainable.

Preformulation is not required for different drugs.

Release of drug is independent of the environment of the system.


System can be much more expensive than conventional counter parts.

Quality control is more extensive than most conventional tablets

pH independent formulations:

A buffered controlled release formulation is prepared by mixing a basic or acidic drug with or more buffering agents, granulating with appropriate pharmaceutical excipients and coating with GI fluid permeable film forming polymer. When GI fluid permeates through the membrane the buffering agent adjusts the fluid inside to suitable constant pH thereby rendering a constant rate of drug release.


Figure 1.6: It shows drug delivery from environmentally pH sensitive release systems

G. Altered density formulations:

Several approaches have been developed to prolong the residence time of drug delivery system in the gastrointestinal tract.

High-density approach

Low-density approach

1.5.7. MATRIX SYSTEMS: (Robinson J.R. and Lee V.H.L., 1987; Vyas S.P. and Roop K. Khar., 2008; Michael E Aulton., 2007)

Matrix system is formulated in such manner as to make the contained drug available over an extended period following administration. A typical controlled release system is designed to provide constant or nearly constant drug levels in plasma with reduced fluctuations via slow release over an extended period of time. In practical terms, an oral controlled release should allow a reduction in dosing frequency as compared to when the same drug is presented as a conventional dosage form.

On the Basis of Retardant Material Used: Matrix tablets can be divided in to 5 types.

1. Hydrophobic Matrices (Plastic matrices)

In this method drug is mixed with an inert or hydrophobic polymer and then compressed in to a tablet. Sustained release is produced due to the fact that the dissolving drug has diffused through a network of channels that exist between compacted polymer particles. 

Examples of hydrophobic matrices include polyethylene, polyvinyl chloride, ethyl cellulose and acrylate polymers and their copolymers.

The rate-controlling step in these formulations is liquid penetration into the matrix. The possible mechanism of release of drug in such type of tablets is diffusion. Such types of matrix tablets become inert in the presence of water and gastrointestinal fluid.

2. Lipid Matrices:

These matrices prepared by the lipid waxes and related materials. Drug release from such matrices occurs through both pore diffusion and erosion. Carnauba wax in combination with stearyl alcohol or stearic acid has been utilized for retardant base for many sustained release formulation.

3. Hydrophilic Matrices:

The formulation of the drugs in gelatinous capsules or more frequently, in tablets, using hydrophilic polymers which have high gel formation capability became a particular interest in the field of controlled release. Infact a matrix is defined as well mixed composite of one or more drugs with a gelling agent (hydrophilic polymer). These systems are called swellable controlled release systems.

The polymers used in the preparation of hydrophilic matrices are divided in to three broad groups

1. Cellulose derivatives: methylcellulose, hydroxyl ethyl cellulose; hydroxyl propyl methylcellulose (HPMC) and sodium carboxy methylcellulose.

2. Noncellulose natural or semisynthetic polymers: agar-agar; carob gum; alginates; molasses; polysaccharides of mannose and galactose; chitosan and modified starches.

3. Polymers of acrylic acid: Carbopol 934, the most used variety.

4. Biodegradable Matrices:

These consist of the polymers which comprised of monomers linked to one another through functional groups and have unstable linkage in the backbone. They are biologically degraded or eroded by enzymes generated by surrounding living cells or by non enzymatic process in to olegomers and monomers that can be metabolised or excreted.  

Examples are natural polymers such as proteins and polysaccharides; modified    natural polymers; synthetic polymers such as aliphatic poly (esters) and poly anhydrides.

5. Mineral Matrices:

These consist of polymers which are obtained from various species of seaweeds. Example is Alginic acid which is a hydrophilic carbohydrate obtained from species of brown seaweeds (Phaephyceae) by the use of dilute alkali. 

Advantages of the matrix systems (Robinson J.R. and Lee V.H.L., 1987)

• Easy to manufacture.

• Versatile, effective and low cost.

• Can be made to release high molecular weight compounds.

• Reproducible release profile.

• Since the drug is dispersed in the matrix system, accidental leakage of the total drug component is less likely to occur, although occasionally and cracking of the matrix material can cause unwanted release.

Disadvantages of the matrix systems (Robinson J.R. and Lee V.H.L., 1987)

The remaining matrix must be removed after the drug has been released.

The drug release rates vary with the square root of time. Release rate continuously diminishes due to an increase in diffusional resistance and/or a decrease in effective area at the diffusion front.


There are many approaches for preparing matrices for sustained drug delivery.

Table 1.4: summarizes common approaches for the same. (Lachman L.,et.al.,1991)





Melt Granulation

Granules prepared by melting all the ingredients together and then screening the congealed mass through appropriate mesh.

Useful for enhancing solubility and hence dissolution of poorly water soluble drugs and for modifying release characteristics of drugs delivered transdermally.

1. No need of solvents.

2. Fewer processing steps.

3. No need of high compression.

4. Uniform dispersion of fine particles occurs.

5. Stability at varying pH and moisture levels

1.High energy requirement.

2. Not suitable for thermosensitive materials including low melting binders.

3.Not suitable for blends containing high melting binders, thermosensitive drugs and/ or additives.

Direct Compression

Drug embedded matrices prepared by direct compression of blend of drug and additives and release retardant

1. More economic due to fewer steps, less equipments & less labour.

2. Less time consuming.

3. No batch-to-batch variation.

4. Useful for moisture sensitive and thermosensitive drugs.

1. Segregation of particles.

2. Not suitable for drugs having large doses.

3. Development of static charges during blending.

4. Difficulty in uniform distribution of color.



Granules containing drug are prepared using adhesive properties of binders.

1. Less energy is required.

2. Useful for thermosensitive drugs.

1. Solvents are required.

2. High compression is required.

1.6.1. BRONCHITIS (Tripathi K.D., 2004; Robbins and Cotran )

Bronchitis is a respiratory disease in which the mucous membranes of the bronchial passages in the lungs become inflamed. As the irritated membrane swells and grows thicker, it narrows or shuts off bronchial tubes, resulting in coughing spells accompanied by thick phlegm and breathlessness. It occurs in Bronchial tubes which starts from the trachea and terminate at the alveoli in the lungs .


Acute bronchitis (lasting less than 6 weeks)

Chronic bronchitis ( reoccurring frequently for more than two years).

Picture of the anatomy of the lungs

Fig 1.7: It shows respiratory system


Acute bronchitis is usually bronchitis that is short-termed is due to infection such as cold. The bronchitis lasts about two weeks and people recover with no permanent damage to the bronchial tree. Acute bronchitis usually comes on quickly and gets better after several weeks.


Cough that produces yellow or green mucus

Burning sensation in the chest


Sore throat




Acute bronchitis mostly caused by a viral infection (90%) that causes the inner lining of the bronchial tubes to become inflamed .Common viruses include the rhinovirus, respiratory syncytial virus (RSV), and the influenza .

Bacteria (10%) can also cause bronchitis (a few examples include, Mycoplasma, Pneumococcus, Klebsiella, Haemophilus).

Chemical irritants (for example, tobacco smoke, gastric reflux, solvents) can cause acute bronchitis.

Figure 1.8: It shows Pathophysiology of acute bronchitis


Chronic bronchitis is a serious long-term disorder which is characterized by a productive( wet) cough that is persistent with sputum production for atleast three months in a three consecutive years, in the absence of any other identifiable cause. In chronic bronchitis, there is inflammation and swelling of the lining of the airways that lead to narrowing and obstruction of the airways. The inflammation stimulates production of mucus, which can cause further obstruction of the airways and increase the likelihood of bacterial lung infections.

Chronic bronchitis , on the other hand occurs in people who smoke and , together with emphysema, is known as chronic obstructive pulmonary disease(copd).

Figure 1.9: It shows normal and infected bronchi


chronic cough with sputum production


dypsnea ( shortness of breath)

blue tinged lips

ankle, feet, and leg swelling



It is the most common factor that impairs mucociliary defence mechanism and leads to overactivity of mucus producing glands.

Statistics from the US Centers for Disease Control and Prevention (CDC) suggest that about 49% of smokers develop chronic bronchitis and 24% develop emphysema/COPD. Some researchers suggest that about 90% of cases of chronic bronchitis are directly or indirectly caused by exposure to tobacco smoke.


Continuous exposure to various pollutants like industrial effluents, vehicle smoke, fire smoker etc , and occupational exposure to organic or inorganic dusts may result in copd.


Repeated infection of respiratory tract (eg: viral infection, common cold) especially in infancy may lead to chronic bronchitis.


Inborn deficiency of a body protein, called alpha, antitrypsin result s in easy damage of alveoli to develop emphysema.

Preventive Care:

The best way to prevent chronic bronchitis is to avoid smoking and to stay away from air pollutants. For acute bronchitis, taking steps to avoid colds and respiratory infections.

Treatment Approach:

Acute bronchitis from a virus generally clears up on its own within 7 - 10 days. Using a humidifier, taking a cough medicine that contains an expectorant (something that helps "bring up" mucus). If a bacterial infection is the culprit, need to take antibiotics.


Bronchodilators -- increase airflow by dilating airways and made free to breathe.

Corticosteroids -- reduce inflammation they are usually used to treat moderate to severe COPD.

Cough medicines -- Two types of cough medicines, cough suppressants (for a dry cough) or expectorants (for a wet, productive cough that brings up mucus) can be used.