FORMULATION AND EVALUATION OF AMOXICILLIN TRIHYDRATE MODIFIED RELEASE DOSAGE FORMS
RATIONALE FOR STUDY
* Bacterial regrowth occurs rapidly after this antibiotic concentration fall below bacterial Minimum Inhibitory Concentration (MIC). Therefore should prevent drug free interval between doses from being long enough for the bacterial pathogen to resume growth.
* Continuous administration of amoxicillin decreases the toxicity.
* Kinetics of bactericidal effect is slow and requires prolonged maintenance of effective concentration of drug.
* A smaller total antibiotic dose is required to achieve the same pharmacodynamic endpoint by continuous infusion in comparison to intermittent infusion.
* Elevation of beta lactum concentration demonstrates increased bacterial killing, only until finite points which tends to be about 4times the MIC. Further elevation is not increase bactericidal potency. It decreases potency.
* A direct correlation exists between times the beta lactum antibiotic concentration is maintained above therapeutics concentration, so continuous administration advantage.
* Tissue penetration of these drugs is not correlated with serum concentrations, i.e. elevation of serum drug concentration will not contribute much in cases where the pathogen is located intracellularly.
* Beta lactum antibiotics exhibit short half life values, which demand frequent drug administration. Therefore continuous administration is beneficial.23
* The concept of delivering the drugs after a well defined lag phase leads to the development of more than one pulse (multiple pulses) delivery systems. The multiple pulse delivery system offers advantages over biological resistance to antibiotics. Spore forming bacteria in the dormant phase are more prone to getting killed.24
RATIONALE FOR DRUG SELECTION
* It is broad spectrum antibiotic. So kill both gram negative and gram positive bacteria.
* Limited range of non β?lactam antibacterials was available; most had certain limitations in terms of toxicity.
- E.g.sulphonamides (rashes and renal toxicity); streptomycin and kanamycin (ototoxicity and nephrotoxicity); chloramphenicol (bone marrow aplasia); erythromycin (gastrointestinal side effects); tetracyclines (concentrate in developing bones and teeth) colistin (neuro and nephro?toxicity).
- A number of beta?lactams, penicillins: penicillin G and V (gastric acid labile), ampicillin, methicillin (nephrotoxicity) cephalosporins: cephaloridine and cephalothin (nephrotoxicity).
* It is better absorbed than ampicillin when given by mouth.
* Absorption is not affected by the presence of food in the stomach.
* Various study reports showed that amoxicillin was effective against variety of micro?organisms with MIC ranges 0.06 μg/ml?4 μg/ml for most of the micro?organisms ( eg: Staphylococcus aureus, H.influenza, S.pneumonia, S.pyogene i.e. responsible for tonsilitis/pharyngitis. )20
* Penicillin antibiotics need to have chemical structures added to increase their acid stability.
* It is better absorbed than ampicillin when given by mouth.
* The incidence of gastrointestinal, hepatic and haematological side effects is significantly higher for amoxicillin/clavulanic acid than amoxicillin alone.
* Amoxicillin/clavulanic acid seems to be associated with a higher risk of Stevens-Johnson syndrome, purpura and hepatitis than amoxicillin alone.
* Amoxicillin/clavulanic acid have low stability than amoxicillin alone.25
In view of these objectives extensive literature review was done and was reported in the next chapter “Literature Review”.
3.1 REVIEW OF DRUG
PHYSICOCHEMICAL PROPERTIES 26, 27, 28
Drug Name:-AMOXICILLIN TRIHYDRATE
Chemical name:- (6R)-6-(a -4-hydroxyphenyl-D- glycylamino)penicillanic acid trihydrate.
Description:- White or almost white, crystalline powder.A broad-spectrum semisynthetic antibiotic similar to ampicillin except that its resistance to gastric acid permits higher serum levels with oral administration.
Solubility:- Slightly soluble in water, in ethanol (95%) and in methanol; practically insoluble in chloroform, in ether and in fixed oils. It is soluble in dilute solutions of acids and of alkali hydroxides. (water solubility : 3430 mg/L)
Storage condition:- Store in tightly-closed containers in a cool place. Amoxicillin should be kept in the container it came in, tightly closed, and out of reach of children. Capsules and tablets of amoxicillin are crystalline in structure, so they should be stored at room temperature and away from excess heat and moisture (not in the bathroom). The liquid medication preferably should be kept in the refrigerator, but it may be stored at room temperature.
Melting range:-194 oC
Heavy metals:-Not more than 20 ppm
PHARMACODYNAMICS 29, 30, 31, 32
Amoxicillin is a moderate-spectrum antibiotic active against a wide range of Gram-positive, and a limited range of Gram-negative organisms. It is usually the drug of choice within the class because it is better absorbed, following oral administration, than other beta-lactam antibiotics.
Amoxicillin is stable in presence of gastric juices and it also produces less gastric disturbance and has the same antibacterial activity as ampicillin. It is a drug of choice in treatment of typhoid, meningitis, endocarditis, septicaemia, peritonitis and gonorrhoea. Another advantage of amoxicillin is that it penetrates equally well in to the purulent and mucoid sputum in distinction to ampicillin which does not cross the bronchial mucosa.
Amoxicillin is in the free acid form is a white crystalline powder sparingly soluble in water, It is stable in acid solution and thus can be given by mouth. It is well absorbed and produces high serum levels.
Peak serum concentrations are obtained within 60 to 90 minutes after drug administration. Animal studies demonstrated that amoxicillin is distributed evenly throughout the body tissues and is concentrated in the liver and kidneys. Small quantities enter the non infected cerebrospinal fluid. Administration of high doses results in proportionate increase in serum levels in patients with normal renal function. The drug is excreted in an active form in urine.
PHARMACOLOGY29, 30, 31, 32
Mechanism of action:-
Amoxicillin binds to penicillin-binding protein 1A (PBP-1A) located inside the bacterial cell well. Penicillins acylate the penicillin-sensitive transpeptidase C-terminal domain by opening the lactam ring. This inactivation of the enzyme prevents the formation of a cross-link of two linear peptidoglycan strands, inhibiting the third and last stage of bacterial cell wall synthesis. Cell lysis is then mediated by bacterial cell wall autolytic enzymes such as autolysins; it is possible that amoxicillin interferes with an autolysin inhibitor.
Bactericidal; inhibit bacterial cell wall synthesis. Action is dependent on the ability of penicillins to reach and bind penicillin-binding proteins (PBPs) located on the inner membrane of the bacterial cell wall.
The more rapid bactericidal activity is linked with a different effect on the growing cells. Thus while ampicillin and some other antibiotics such as cephalexin interfere primary with septation, resulting initially in elongated filamentous forms of gram negative bacteria, amoxicillin causes rapid interference with the cell wall leading to the formation of spheroplasts and lysis.
The cell wall of bacteria is essential for the normal growth and development. Peptidoglycan is a heteropolymeric component of the cell wall that provides rigid mechanical stability by virtue of its highly cross linked lattice work structure. In gram positive organism the cell wall is 50 to 100 molecules thick, while in gram negative micro organisms it is only 1 or 2 molecules thick. The biosynthesis of peptidoglycan involves about thirty bacterial enzymes and may be considered in three stages, which are as follows:
* The first stage involves the precursor formation which takes place in cytoplasm. The product, uridinediphosphate (UDP) accumulates in the synthesis of this compound is the addition of a dipeptide. D-alanyl-D alanine.
* During reactions of the second stage, UDP acetylmuramylpentapeptide and UDP acetylglucoseamine is linked to form a long polymer. To form this species, the sugar pentapeptide is first attached by a pyrophosphate bridge to a phospholipid in the cell membrane. The second sugar is then added, followed by the addition of five glycine residue as a branch of the heteropentapeptide. The molecule is then assumed to flip across the cell membrane such that the peptidoglycan precursor faces the periplasm. The completed unit is then cleaved from the membrane bound phospholipid.
* The final stage involves the completion of the cross link. This is accomplished by a transpeptidation reaction that occurs outside the cell membrane. The transpeptidase itself is membrane bound. The terminal glycine residue of the pentaglycine bridge is linked with the fourth residue of the pentapeptide (D-alanine) releasing the fifth residue (also D-alanine). It is this last step in peptidoglycan synthesis that is inhibited by the beta lactam antibiotics.
The lysis of bacteria that usually folloes their exposure to beta lactam antibiotics ultimately dependent on the cell wall autolytic enzymes i.e. autolysins. The relationship between inhibition of penicillin binding proteins (PBP) activity and activation of autolysins is unclear. Some evidence suggests that exposure of bacteria to beta lactam antibiotics results in the loss of an inhibitor of the autolysins.
Bata lactam antibiotics can interfere with cell wall synthesis only in growing cells, but presumably this antibiotics can bind to the transpeptidase and related enzymes even in resting cells thus inhibiting the terminal stages of cell wall synthesis if growth is subsequently resumed (Selwyn, 1980).
For the treatment of infections of the ear, nose, and throat, the genitourinary tract, the skin and skin structure, and the lower respiratory tract due to susceptible (only b-lactamase-negative) strains of Streptococcus spp. (a- and b-hemolytic strains only), S. pneumoniae, Staphylococcus spp., H. influenzae, E. coli, P. mirabilis, or E. faecalis. Also for the treatment of acute, uncomplicated gonorrhea (ano-genital and urethral infections) due to N. gonorrhoeae (males and females).
· Infections of the ear, nose, and throat
Due to Streptococcus species. (α- and β-hemolytic isolates only), Streptococcus pneumoniae, Staphylococcus spp., or Haemophilusinfluenzae.
· Infections of the genitourinary tract
Due to Escherichia coli, Proteus mirabilis, or Enterococcus faecalis.
· Infections of the skin and skin structure
Due to Streptococcus spp. (α- and β-hemolytic isolates only), Staphylococcus spp., orE.coli.
· Infections of the lower respiratory tract
Due to Streptococcus spp. (α- and β-hemolytic isolates only), S. pneumoniae,Staphylococcus spp., or H. influenzae.
· Gonorrhea, acute uncomplicated (ano-genital and urethral infections in males and females) due to Neisseria gonorrhoeae.
· Triple therapy for Helicobacter pylori with clarithromycin and lansoprazole
· Dual therapy for H. pylori with lansoprazole
Contraindicated in patients with known serious hypersensitivity to amoxicillin or to other drugs in the same class or patients who have demonstrated anaphylactic reactions to beta-lactams.
Probenecid decreases the renal tubular secretion of amoxicillin. Probenecid may result in increased and prolonged blood levels of amoxicillin. The clinical relevance of this finding has not been evaluated.
* Other Antibiotics
Chloramphenicol, macrolides, sulfonamides, and tetracyclines may interfere with the bactericidal effects of penicillin. This has been demonstrated in vitro; however, the clinical significance of this interaction is not well documented.
* Oral Contraceptives
As with other antibiotics, amoxicillin may affect the gut flora, leading to lower estrogen reabsorption and potentially resulting in reduced efficacy of combined oral estrogen/progesterone contraceptives.
In case of overdose, discontinue medication, treat symptomatically, and institute supportive measures as required. If the overdose is very recent and there is no contraindication, an attempt at emesis or other means of removal of drug from the stomach may be performed. A prospective study of 51 pediatric patients at a poison-control center suggested that overdosages of less than 250 mg/kg of amoxicillin are not associated with significant clinical symptoms and do not require gastric emptying.
Interstitial nephritis resulting in oliguric renal failure has been reported in a small number of patients after overdosage with amoxicillin.
Crystalluria, in some cases leading to renal failure, has also been reported after amoxicillin overdosage in adult and pediatric patients. In case of overdosage, adequate fluid intake and diuresis should be maintained to reduce the risk of amoxicillin crystalluria.
Renal impairment appears to be reversible with cessation of drug administration. High blood levels may occur more readily in patients with impaired renal function because of decreased renal clearance of amoxicillin. Amoxicillin may be removed from circulation by hemodialysis.
PHARMACOKINETICS29, 30, 31
Rapidly absorbed after oral administration.
Amoxicillin plasma protein binding is approximately 20%. The substance remains extracellular. The tissue concentrations depend on the circulation in those tissues and on the quantity of extracellular fluid. Amoxicillin diffuses adequately into the sputum, mucosa, bone tissue and aqueous humor of the eye to produce therapeutically active levels.
The concentrations in the bile are two to four times higher, or even higher than those in the blood. In the amniotic fluid and umbilical cord blood 25-30% of the mother's blood levels are attained. Amoxicillin diffuses poorly into the cerebrospinal fluid of patients with normal meninges. In inflamed meninges the concentrations are approximately 20% of those found in the blood.
Hepatic metabolism accounts for less than 30% of the biotransformation of most penicillins.
Most of the amoxicillin is excreted unchanged in the urine; its excretion can be delayed by concurrent administration of probenecid.Amoxicillin is primarily eliminated via the kidneys, largely (ca. 80%) via tubular excretion, for the remainder (ca. 20%) via glomerular filtration.
Approximately 60% of an orally administered dose of amoxicillin is excreted in the urine within 6 to 8 hours. Detectable serum levels are observed up to 8 hours after an orally administered dose of amoxicillin.
Volume of distribution:- 0.3 L/kg
Half life:-61.3 min
Plasma Protein Binding:-In blood serum, amoxicillin is approximately 20% protein-bound
Dose:-The equivalent of 750 mg to 4.5 g of amoxycillin daily, in divided doses.
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