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Oral route of drug delivery is considered as the most popular and flexible route for the drug delivery system (Vyas SP & Khar R.K, 2006).Controlled drug delivery systems had been encouraged to avoid the draw back of fluctuating drug levels produced by conventional dosage forms.
Sustained drug delivery system was aimed to release the medication in a prolonged rate to maintain plasma drug level (N.K. Jain, 2002). The drugs having shorter half life are suitable for the sustained drug delivery system. The main objective in designing sustained delivery system is to reduce dosing frequency and there by increasing the action. The drug molecules shows better sustained drug release profile in matrix systems by different mechanisms. (Gilbert S. Banker & Christopher T. Rhodes, 2002)
The introduction of matrix tablet as a sustained release had made a new phase for the novel drug delivery system. Hydroxypropyl methylcellulose was the mostly used hydrophilic polymer to prolong the drug release pattern due to its gelling property, rapid hydration and good compressibility property.
The different grades of hydroxypropylmethylcellulose were available for the design of sustained drug delivery system. The viscosity range of the Hydroxypropyl methylcellulose aid in the percentage release rate of drug release. The low viscosity range polymer cause increase in the drug release. The hydrophilic matrix system the mechanism of drug release occurs mainly by diffusion and erosion. ( Saptarshi Dutta et al., 2009)
Sustained release dosage forms (Robinson JR)
The system designed achieve a prolonged therapeutic effect by continuous drug release and maintaining accurate concentration in blood over extended period of time in blood after single dose administration.
The basic rationale of sustained release drug was to alter the pharmacokinetic and pharmacodynamics of active drug moiety by modifying drug molecular structure. The sustained level of the medication was obtained by controlling the plasma blood level and less frequent dosing.
Theory of Sustained Release Concept (Lachman et al., 1987)
The blood level oscillation characteristics of multiple dosing of conventional dosage form was avoided with formulating drug with sustained release dosage form. The major advantage in the design of the sustained drug dosage form was that the total amount drug for administration can be reduced and there by maximizing the availability with minimum dose.
The safety margin of the high potency drug can be increased and the side effects can be reduced. The sustained release form enables reliability of the drug therapy. In the designing of sustained release dosage form the properties of the drug blood level time profile characteristics of multiple dosing therapy of immediate release dosage form was evaluated.
The pharmacokinetic model of preoral sustained release drug dosage form consists of maintance dose and loading dose. The maintance dose is the slowly available portion of the dose and the loading dose is the immediately releasing portion. To obtain constant drug level the rate of drug absorption must made equal to its rate of elimination. The fabrication of sustained release product was very difficult and involves physicochemical parameters and pharmacokinetic behaviour of drug. (A.K. Bandyopadhyay, 2008)
Fig: 1 Pharmacokinetic model of preoral sustained release drug dosage form
Terminology (Remington, 1997)
Non-immediate release delivery system may be conveniently divided into the 3 categories .
1. Delayed release
2. Sustained release
A. Controlled release
B. Prolonged release
3. Site specific targeting
4. Receptor targeting
1. Delayed release (Remington, 1997)
These systems are those that use repetitive, intermittent dosing of a drug from one or more immediate release units incorporated into a single dosage form. Examples of delayed release system include repeat action tablet and capsules and enteric-coated tablets where time release achieved by barrier coating.
2. Sustained release (Yie W. Chein 1992)
Sustained release system implies to the pharmaceutical dosage form formlated for retardation of release of therapeutic agent such that its appearance in the systemic circulation was delayed or prolonged and its plasma profile was sustained in duration. The onset of pharmacologic action was delayed and duration of therapeutic effect also delayed.
A. Controlled release (Yie W. Chein 1992)
The system that implies predictability and reproducibility in the drug release kinetics which means release of drug ingredient from controlled drug delivery system proceeds at a rate profile that is not only predictable kinetically but also reproducible from one point to another.
B. Prolonged release (Remington, 1997)
The prolonged release system provide slow release of a drug at a rate which will provide a longer duration of action than a single dose of the normal dosage form. The initial dose was not included in prolonged release formulation in comparison to the sustained release dosage form.
3. Site specific release (Remington, 1997)
These systems refer to targeting of a drug directly to a certain biological location. In this case of site specific release the target is adjacent to or in the diseased tissue or organ.
4. Receptor Targeting (Remington, 1997)
These systems refer to targeting of a drug directly to a certain biological location. In this case the targeting and receptor targeting system specify the spatial
aspect of drug delivery and are also considered to be controlled drug delivery systems.
Fig: 2 Plasma drug concentration time profile from conventional multiple dosing and controlled delivery formulation
Advantages of sustained drug therapy (Remington, 1997)
All sustained release product share the common goal of improving drug therapy and the improvement in drug therapy is represented by different advantages are the followings.
Better minimize in compliance from the side of patient.
Increased efficiency in treatment
Control condition most promptly
Decreasing the drug dosing between each interval
Minimize or eliminate systemic side effects
Improve bioavailability of some drugs
Better response in the dosing interval
The drug accumulation reduced in chronic drug therapy
Decreasing patient compliance problems is an highlighting advantage of sustained release therapy. The most important criteria for sustained drug therapy is improved efficiency in treatment. The result of obtaining constant drug blood level from a sustained release system is to achieve promptly the desired effect and maintain it for an extended period of time. In addition the method by which sustained release is achieved can improve the bioavailability of some drugs.
Disadvantages of sustained drug therapy ( Lachman et al., 1987)
Administration of sustained release therapy dose permits prompt termination of therapy
The physician has less flexibility in adjusting sustained release dosage regimen.
More costly process and equipment are involved in manufacturing many sustained release dosage form
Dose dumping due to sustained release.
Delay in drug release cause poor in vitro and in vivo corelationship
The drug release time period was slowed by gastrointestinal residence time.
The drugs molecules having short half life was not accepted for sustained release dosage forms.
Physicochemical properties for sustained release drug delivery system (Robinson JR) The proper drug release mechanism of a sustained drug delivery system depends upon its physicochemical and biological properties. The optimized design of a sustained release dosage form depends upon the nature of drug diposition.
A. Physiochemical Properties (Robinson JR)
1. Aqueous solubility
The drugs having low aqueous solubility usually cause limited gastrointestinal transit time of the undissolved drug and there by bioavailability problems will occur. The solubility affects the dissolution rate of the dosage regimen also. The drug showing low solubility and slow dissolution rate sustains the blood level by absorption controlled dissolution. The slightly soluble form a drug with high solubility was one of the methods for the preparation of sustained drug release systems.
2. Partition coefficient
Partition coefficient affects the permeation of drug across the biological membrane diffusion of drug across the matrix system. The drugs showing high partition coefficient are lipid soluble and having very low aqueous solubility. Drugs showing higher or lower level of the aqueous solubility are not suitable for the sustained drug dosage form.
3. Drug stability
The drug stability was affected by the degradation of enzyme and the acid hydrolysis. The drugs showing unstability in small intestine are poor candidates for sustained drug deliver system. The metabolizing enzyme present in the area of site of action was a unwanted factor in sustained drug release system.
4. Protein binding
Increased protein binding to the plasma cause increase in half life and not needed of sustained dosage form. The binding of drugs to the mucin cause increase in absorption. The factors mediated for the protein binding to the plasma are hydrogen bonding and vander waals force of attraction.
6. Molecular size and Diffusivity
In sustained drug delivery system the drug diffuses through a matrix system. The rate of diffusion denoted by the diffusion coefficient and depends upon the molecular weight. The important factor that mediates the rate of diffusion was the molecular weight of polymers.
B. Biological Factors
The biological factors play an important role in design of the sustained drug release system. The biological properties evaluate the ADME characteristics of drug for multiple dosing.
The extend of absorption was the rate limiting step in the sustained drug release system. The drug should be uniformly absorbed to maintain the constant blood level. The extend of absorption of a delivery system depend upon the bioavailability and by absorption of fraction of the total dose.
The distribution of drug component depends upon ratio of drug concentration and apparent volume of distribution. The dosing of the sustained release formulation depend upon the value of the volume of distribution.
Metabolic change of a drug molecule into a inactive form carried out in the sustained release system design. The metabolic factors affecting the sustained release
dosage form design are fluctuating blood level due to first pass metabolism.
4. Half life of drug
The half life of drug was depend upon clearance and volume of distribution. The drugs with short half life are suitable for the sustained drug release medication. The factors that cause deviation of half life are metabolism, elimination and distribution. The frequent administration of dose is needed in the case of drugs with short half life.
5. Side effect and safety of the drug
The safety margin of the drug was determined by the therapeutic index. The main advantage of the sustained release dosage form was the minimization of the side effect. The safety of the drug administered increases with the increase of therapeutic index.
Matrix Tablet (Sunil Kamboj et al., 2009)
A matrix is an inert solid substance in which the drug molecule is uniformly distributed. A matrix may be formed by fusing the drug and the matrix material together. The matrix protects the drug from rapid dissolution and the active drug diffuses out slowly with respect to time. The hydrophilic matrix tablet makes drug release through diffusion and erosion mechanism. The hydrophobic matrix tablet in which drug is dispersed uniformly in a matrix. The drug release was controlled depend upon the solubility property by dispersing the drug in a swellable hydrophilic matrix system or in insoluble monolithic matrix system.
Classification of Matrix Tablets (Sunil Kamboj et al., 2009)
Based on the use of retardant material the matrix tablets can classified into 5 types.
1. Hydrophobic Matrix tablet
In this technique of sustained release from an oral dosage form the drug is mixed with an inert or hydrophobic polymer and then compressed into a tablet. The sustained release is obtained by dissolving drug and was diffused through a network of channels that exist between compacted polymer particles.Â The materials used as inert or hydrophobic matrices consist polyvinyl chloride, polyethylene, ethyl cellulose and ammonio methacrylate copolymers.
The rate controlling phase in these formulations is the solvent penetration into the matrix. The possible mechanism of drug release in the hydrophobic matrix tablet was by diffusion. Hydrophobic matrix tablet consist of porous and nonporous matrix systems.
2. Hydrophilic matrix tablets
The drug molecules are combined with the polymer and erode slowly in body fluids. Hydroxy propyl methyl cellulose is commonly used polymer in the hydrophilic matrix tablets.
In the hydrophilic matrix system the use of cellulosic polymer cause gel formation on the surface of polymer and cause tablet erosion with continuous release of drug. The polymers commonly used in the hydrophilic matrixes are classified into three categories
Cellulose derivatives- hydroxyethylcellulose, Methylcellulose 4000 cPs, Hydroxypropylmethylcellulose grades like K4M, K100M, 5cPs, 15cPs and Sodium carboxymethylcellulose.
Semi synthetic polymers- Modified starches, Alginates and Chitosan
Acrylic acid Polymers -Carbopol 934
3. Wax matrix tablets
The drugs are embedded into can be matrix by spray congealing in air, and blend congealing in an aqueous media. The congealing process use with or with out the aid of surfactants. The wax matrix components are prepared from the blend of powdered ingredients.
4. Gum type matrix tablets
In this type of matrix system the excipients produce gel like consistency in presence of water and the dispersion of the active drug of the tablet was maintained by gel barrier. For example xanthagum and sodium alginate in water soluble polysaccharides used in gum type matrix systems.
kinetic release mechanism from matrices:
The drug release from the polymer matrices occurs by the permeation of the water into the matrix system. The release mechanism follows by diffusion and erosion mechanism.
1. Zero order kinetics: (Paulo Costa & Jose Manuel Sousa Lobo, 2001)
The zero order drug release denotes concentration independent drug release mechanism from the system. The graph was plotted by taking a cumulative % drug release Vs time.
K0 = zero order rate constant
t = time in hours
The equation fitted to dissolution data by linear regression analysis denotes below
Qt = Q0 + K0 t
Qt = Particle dissolved in time t.
Q0 = Initial amount of drug in the solution part.
K0 = rate constant of zero order release.
2. First order kinetics: 28,23
The first order kinetic model plotted by log cumulative of % drug remaining versus time.The equation for concentration dependent drug release from the system
log C = log C0 - Kt /2.303
C0 = initial concentration.
K = first order constant.
3. Hixson Crowell's cube Root equation: 28
Hixson Crowell derived equation to correlate drug release from the system by the mechanism of erosion or by the change of surface area and diameter of particle. The graph was obtained by plotting cube root of % drug remaining Vs time in hours.
Q0 1/3 - Qt 1/3 = KHC Xt
Qt = Amount of drug released with time t.
Q0 = Initial amount of drug molecule.
K HC = Rate constant of Hixson model.
4. Higuchi's square Root of time Equation31, 30
The graph was obtained by plotting % Cumulative drug release Vs square root of time. The drug release was depend upon the fickian diffusion and describe the release from the swellable insoluble matrix system.
Q = Kt Â½
K= constant reflecting design variable system.
t= time denoted by hours
5. Korsmeyer And Peppas Model29
This equation demonstrates the the swelling nature and the polymeric hydration of the polymer.
= fraction of drug release with respect to time
K = release rate constant
n = diffusion release exponent
In the case of cylindrical shape matrix tablet the release mechanisms of solute depend upon diffusion exponent23.
n = 0.45 for Fickian model diffusion
0.45<n < 0.89 for anomalous diffusion or non Fickian diffusion
n = 0.89 case II transport
n = 1 or > 1 for super case II transport
Matrix system (Donald L wise,2005)
The mostly used matrix system consists of hydrophilic matrix system and hydrophobic matrix system. In the matrix system the active drug was embedded in the polymer matrix and was uniformly distributed.
The hydrophilic matrix system consists of swellable and erodible matrix system. The hydrophobic matrix system consists of homogenous and heterogeneous matrix system. The heterogeneous model matrix system includes monolithic, erodible and degradable matrices.
Mechanism of drug release from hydrophilic matrix system (Donald L wise,2005)
The hydrophilic matrix system in which the drug release occur two mechanisms such as diffusional release and relaxation release. The erosion mechanism also mediated for the drug release other than diffusion process. The erosion of the matrix system followed by the relaxation process creates total release of the drug. In the case of sparingly soluble drug the mechanism involves absorption of water and desorption of the drug molecule by the mechanism of swelling controlled diffusion.
The hydrophilic matrix system consist of glassy polymer with swellable property make contact with water cause reduction of glass transition temperature. The changes in the temperature cause the change of the glassy polymer region into a rubbery phase26. The drug diffuses out through the rubbery region by swelling and cause release into the external medium. The fickian model does not follow this type of release mechanism through this rubbery region. The release of the drug was mediated through a gel like diffusional barrier.
The fickian diffusion mechanism in which the release kinetics was controlled by the force made by potential gradiant by relaxational process and phase transition occurs by the stress in the polymers. The non fickian release system was mainly by the diffusion and erosion mechanism.
During the release of drug from the matrix system three fronts are mediated for the release process by diffusion and erosion. The eroding front in which the separation of the matrix from the releasing region. The drug release occurs simultaneously with the intake of aqueous medium.
Fig: 3 Internal uptake of solvent in the matrix system
The glassy core was separated from the swelling portion by the swelling front. The diffusional front found in the outer region of the swollen matrix in the case of the sparingly soluble drug. In the case of swelling front the intake of solvent cause the movement and the dissolution process. The matrix tablet drug release kinetics depend upon the diffusion front and erosion front.
The uniformity of drug distribution play a major role in proper release kinetics. The osmotic pressure also play an important role in uptake of solvent to the polymer system.
Fig: 4 Representation of burst release in zero order kinetics
The hydrophilic matrix tablet mainly show initial burst of release by surface release and depend upon the time for gel barrier formation. The release mechanism depends upon the physical and chemical characteristics of the drug material and the polymer. (Mario Grassi & Gabriele Grassi,2005)
Advantages of hydrophilic matrix system: (Ansel, 2005)
A hydrophilic matrix system consists of a drug dispersed in polymer and release drug by swelling of polymer with diffusion and erosion process. The advantages of hydrophilic matrix system are the following,
The excipient incorporated in the hydrophilic matrix system was generally safe.
High drug loadings can be incorporated into sustained drug release system.
The hydrophilic matrix system was easily prepared by direct compression or wet granulation method.
The different drug release kinetics followed like zero order, first order and bimodal release.
The release depends on both diffusion and erosion and not totally dependent on gastrointestinal motility.
5.0 DISEASE PROFILE
URINARY TRACT INFECTION (R.S Satoskar et al., 2002)
Urinary tract infection was a common disorder affecting all stages of age and in both gender. Urinary tract infection is defined as a condition in which persistence of actively multiplying bacteria in urine and which have the potential to invade the tissues of the urinary tract and adjacent structures. The urinary tract infection shows clinical syndromes consist of urethritis, cystitis, pyelonephritis and prostatitis. The syndromes associated with the urinary tract infections are due to the inflammatory responses by the microbial invasion.
Fig 5 Urinary system anatomic sites
The most common type of urinary tract infection is acute cystitis affecting the lower urinary tract with symptoms of dysuria, frequency and urgency in urination. Upper urinary tract infection involves kidney and referred to as pyelonephritis. The majority of urinary tract infections are caused by Escherichia coli. Urinary tract infections are represented in acute and chronic form. Inadequately treated acute infections may lead to chronic pyelonephritis.
Symptoms and signs (HL Sharma, KK Sharma, 2008)
The symptom of urinary tract infections varies with age and the part of the urinary system that was affected. The symptoms of urinary tract infection in children include diarrhea, loss of appetite, nausea and vomiting, fever and abdominal pain.
The most common symptoms of a urinary tract infection are frequency of urination, burning with urination and abdominal pain. An upper urinary tract infection may cause additionally present with flank pain and fever. Lower urinary tract infections in adults include symptoms like haematuria, inability to urinate and malaise.
Symptoms of a lower urinary tract infection or bladder infection20
Pain in the lower back region
Burning sensation while urination
Pressure in the lower abdomen
Presence of blood in urine
Symptoms of an upper urinary tract infection (Joseph T. Dipro, et al., 1996)
Pain in the waist
The signs of urinary tract infections include foul smelling urine and cloudy urine.
Causes of Urinary tract infection (Vinay kumar et al.,)
In women the urinary tract infections usually caused by bacteria that live on the skin near the rectum or vagina. These bacteria invades through the urinary tract and cause infections in the bladder or other parts of the urinary tract. In men the urinary tract infection are rare and usually shows an abnormal urinary tract or enlarged prostate.
Other causes (Vinay kumar et al.,)
Kidney stones that may cause blockage of free flow of urine.
Cystocele - relaxing of the bladder and vaginal area can causes pools of urine to remain in the bladder itself.
Diverticula - infections that develop on the inside wall of the urethra.
Urethral stenosis - preventing an easy flow of urine by narrowing of the urethra.
Epidemiology (Mary Anne Koda & Lloyd Yee Young, 2001)
The invasion of urinary tract infections shows difference according to the age and gender. Urinary tract infection represents a range of graph in severity from asymptomatic infection to acute pyelonephritis. Females are susceptible more to the risk of urinary tract infection due to the anatomic and physiologic differences. The incidence of urinary tract infection in neonates is about 1% and most of the neonatal case occurs in males.
Microbiology (Joseph T. Dipro, et al., 1996)
Organisms causing UTI are derived primarily from the aerobic members of the fecal flora. The majority of uncomplicated urinary tract infections are due to Gram- negative bacilli Escherichia coli. The other Gram negative organisms include Proteus mirabilis and Klebsiella, Aerobacter and Pseudomonas aeruginosa. Enterococci, Streptococci and Staphylococci account for small percentage of chance only. Mixed infection occurs mainly in chronic cases of urinary tract infection
Pathogenesis (Joseph T. Dipro, et al., 1996)
The urinary tract infection occurs by three a pathway by which bacteria invades into kidney. The three possible pathways for urinary tract infection are ascending, hematogenous pathways.
A. Hematogenous pathways (Joseph T. Dipro, et al., 1996)
Infection of the renal parenchyma of kidney by bacteria from distant foci in the course of infective endocarditis. The hematogenous infections are occurred mostly in urethral obstruction. The organisms invading the hematogenous pathways include Staphylococcus aureus, Candida, Salmonella and the infections with gram negative organism occurs rarely with kidney.
B. Ascending pathways (Joseph T. Dipro, et al., 1996)
Ascending infection is the common cause of pyelonephritis. The first step in ascending infection involves colonization of coliform bacteria in the distal urethra.
Due to the colonization the bacteria adhere to the mucosal epithelial cells of urethra. The urethral catheterization cause invasion of bacteria through the ascending route.
The abnormalities of urinary tract like bladder dysfunction, incomplete voiding, increased residual volume of urine cause bacterial accumulation. The vesicoureteral reflux cause by the vesicoureteral valve that permit the bacteria to ascend the ureter into the renal pelvis. The effect of vesicoureteral reflux cause obstruction in urinary tract and cause invasion of bacteria.
Diagnosis (Mary Anne Koda & Lloyd Yee Young, 2001)
The diagnosis of urinary tract infection was done by culture of urine sample. The presence of hematuria and proteinuria indicates complicated cystitis.
The urine leukocyte esterase test is the sensitive for detecting the bacteria. The sensitivity for urine leukocyte esterase was high for detecting more than 10 leukocytes cells/Âµl.
Indirect methods include detecting the presence of urine nitrite. The formation of nitrite by reduction of nitrate present in urine by bacteria.
Radiographic studies like ultrasound, intravenous pyelography are mentioned to the individuals having abnormality in the urinary system or in individuals not respond to drug therapy.
Classification of Urinary tract infection (R.S Satoskar et al., 2002)
A. Based on the factors trigger urinary tract infection
1. Uncomplicated Urinary Tract Infection
The uncomplicated infections are in which the normal flow of urine interfered due to the structural and neurologic abnormalities. The uncomplicated infections are associated with bacterial infection mostly by Escherichia coli.
2. Complicated Urinary Tract Infection
Complicated Urinary tract infections in which abnormality of urinary tract caused by obstruction or neurologic deficit that alter the normal flow of urine. The complicated urinary tract infection also caused by bacterial infection also. The chance of recurrence of urinary tract infection was in individual if the abnormalities persist.
3. Recurrent Urinary Tract Infection
Recurrence is a common stage after the complicated and uncomplicated Urinary tract infections. Recurrence occurs mainly due to the persisting problems associated with urinary system. The stage of recurrence is often called as reinfection or relapse.
A reinfection starts after the prior treatment of drug therapy and it is difficult to correlate between the reinfection and relapse. The relapse mainly caused by the same organism and often related to the kidney infection and structural abnormalities.
B. Based on the anatomic site of infection
1. Lower urinary tract infection
The lower urinary tract mainly affects urinary bladder and with symptoms like dysuria, frequency and urgency of urination. The lower urinary tract infection includes cystitis, urethritis and prostatitis.
Cystitis occurs in the lower urinary tract including the bladder and urethra. The surface of the bladder is affected in most cases. Chronic infection occurs if infections persist.
The infection affecting the urethra is known as urethritis. The urethritis mainly caused by bacterial infection.
2. Upper urinary tract infection
The upper urinary tract infection usually associated with kidney and referred as pyelonephritis.
When the lower urinary tract infection spreads to the kidney it is called pyelonephritis. The symptoms of pyelonephritis consist of fever, flank pain and tenderness.
C. Based on the symptoms and levels of infection (Joseph T. Dipro, et al., 1996)
1. Asymptomatic Urinary Tract Infection
The condition in which there is no symptom of infection but colonization of bacteria in the urinary tract is called asymptomatic urinary tract infections and also known as asymptomatic bacteriuria.
2. Acute Urethral Syndrome
The individuals with symptoms of urinary tract infection with very less bacterial counts and the condition is called acute urethral syndrome. The infection mainly caused by Escherichia coli.
Drug for urinary tract infection (F.S.K Barar, 2000)
1. Urinary tract antiseptics
Quinolines: Nalidixic acid, Clinoxacin, Enoxacin, Norfloxacin, Ciprofloxacin
Nitrofurans : Nitrofurantoin, Furazolidone
Sulfonamides : Trimethoprim - sulfamethoxazole
Pencillins : Ampicillin, Amoxicillin
Cephalosporins : Cephalexin, Cefixime
Aminoglycosides : Streptomycin ,Gentamicin
Treatment of urinary tract infections (Joseph T. Dipro, et al., 1996)
The most of the urinary tract infections was caused by gram negative bacteria. The most of the antimicrobial for urinary tract infection attains higher concentration in urine. In lower urinary tract infection the antibacterial action was attained in urine and in upper tract infection the antibacterial activity is needed in kidney tissue.
A. Drugs for acute pyelonephritis uncomplicated
Trimethoprim80 mg + sulfamethoxazole 400 mg OD for 14 days
Norfloxacin 400mg OD for 14 days
Ciprofloxacin 250 mg BD for 7 days
B. Drugs for uncomplicated cystitis
Nitrofurantoin 50-100 mg BD for 7 days
Trimethoprim80 mg + sulfamethoxazole 400 mg OD for 3 days
Norfloxacin 400mg OD for 3 days
Ciprofloxacin 250 mg BD for 3 days
C. Drugs for recurrent infections
Nitrofurantoin 100 mg QID for 6 months
Trimethoprim 50 - 100 mg OD for 14 days