The present invention is an improvement of the invention disclosed and claimed in main patent
application no. 330/KOL/2006.
More particularly the improvement relates a pharmaceutical suspension dosage form comprising
greater than 80 mg/ml and not more than 150 mg/ml of Cefixime and pharmaceutically
acceptable excipients
FIELD OF THE INVENTION
The present invention relates to pharmaceutical suspension dosage form comprising greater than
80 mg/ml and not more than 150 mg/ml of Cefixime and pharmaceutically acceptable excipients.
BACKGROUND OF THE INVENTION
Cefixime is a semi synthetic cephalosporin antibiotic for oral administration. It was first disclosed
in U.S. Pat. No. 4,409,214 by Fujisawa Corporation, Japan.
It has a bactericidal action and the mechanism of action is based on inhibition of bacterial cell
wall synthesis.
It is indicated for the treatment of infections caused by various gram--positive and gram-negative
organisms chiefly uncomplicated urinary tract infections caused by E. coli and P. mirabilis, otitis
media caused by H. influenza, M. catarrhalis and S. pyogenes, acute bronchitis and exacerbations
of chronic bronchitis caused by S. pneumonia and H. influenza. It is also indicated for
uncomplicated gonorrhea caused by N. gonorrhea. It is one of the most prescribed drugs for
pediatric use.
Cefixime as a drug is poorly soluble in water. From the point of view of bioavailability, the
preferred form of administration of sparingly soluble medicaments such as beta lactam antibiotics
is often an aqueous suspension. Cefixime, given orally, is about 40%-50% absorbed whether
administered with or without food.
Children 12 years of age or younger receive, e.g., about 8 mg of Cefixime/kg of body weight each
day. The recommended dose can be administered alternatively all at once or divided into 2 single
doses (e.g., about 4 mg of Cefixime/kg of body weight in the morning and evening). An increase
in the daily dose to 2.X6 mg of Cefixime/kg of body weight is possible depending on the severity

and the location of the infection. Adults and children above 12 years of age may receive 400 mg
of Cefixime each day. The recommended daily dose may be administered alternatively all at once
or divided into 2 single doses (in the morning and evening). The dose should be reduced for
patients with distinctly impaired renal function.
Solid dosage forms such as tablets and capsules have certain disadvantages since they have to
disintegrate in the gastrointestinal tract and then the medicament has to dissolve before it can be
absorbed, thus leading to slower absorption as compared to that of the suspension dosage form
and also the absorption is less than the suspension dosage form leading to bioequivalence issues.
Also, certain patient populations such as pediatrics and geriatrics have difficulty in swallowing
tablets and capsules, and there is a practical limit to the size, and therefore the dose, that can be
swallowed.
The oral suspension dosage forms have certain advantages over the above mentioned dosage
forms especially in population segments such as pediatrics and geriatrics who have problems in
swallowing the solid dosage forms. Further The oral suspension dosage form produces average
peak concentrations approximately 25%-50% higher than the conventional tablets. The area
under the time versus concentration curve is greater by approximately 10%-25% with the oral
suspension than with the conventional tablet after doses of 100 to 400 mg, when tested in normal
adult volunteers.
U.S. Pat. No. 4,079,138 by American Home Products Corporation describe a permanent
suspension with a non-aqueous basis as vehicle for active substances, which are sensitive to
hydrolysis.
U.S. Pat. No. 5,776,926 by Merck discloses Cefixime compositions in the form of non-aqueous
suspensions.
Cefixime is currently available in a number of different formulations in various strengths for
adult and pediatric patients, for example as tablets comprising 200 mg and 400 mg Cefixime and
as oral suspension comprising 100 mg/5 ml Cefixime.
In some patient population the compliance for the currently available oral suspension is low due
to requirement of dosing greater than 100 mg in certain disease conditions. Lack of availability of
a oral suspension dosage form comprising greater than 100 mg/5 ml cefixime leads to low
compliance rates. This is due to multiple dosing required leading to low compliance rates (e.g.
spillage).
There is a need to develop a higher strength oral suspension in unit dose for improving the patient
compliance and for reducing the frequency of dosing.
Further there is also a need to develop a concentrated oral suspension of Cefixime which
incorporates higher amount of drug per unit volume of the suspension so as to avoid multiple
administration.
OBJECTS OF THE INVENTION
The object of the invention is to provide a suspension dosage form comprising a unit dose greater
than 100 mg/5 ml and not more than 400 mg/5 ml of Cefixime and pharmaceutical ly acceptable
excipients.
The principal object of the invention is to provide a suspension dosage form consisting essentially
a unit dose of 200 mg/5 ml of Cefixime and pharmaceutically acceptable excipients.
Another object of the invention is to provide a suspension dosage form comprising Cefixime,
wherein the said new suspension strength 200 mg/5 ml is bioequivalent to suspension 2X100
mg/5 ml comprising Cefixime trihydrate marketed under the name of "Suprax".
Another object of the present invention is to provide a method of treating acute bacterial otitis
media, pharyngitis, tonsillitis, acute and chronic bronchitis with a oral suspension of cefixime
wherein said suspension form consists essentially of an unit dose of 200 mg/5 ml of Cefixime and
pharmaceutically acceptable excipients.
Yet another object of the invention is to provide a method of uncomplicated urinary tract
infections and gonorrhea with a oral suspension of cefixime wherein said suspension form
consists essentially of an unit dose of 200 mg/5 ml of Cefixime and pharmaceutically acceptable
excipients.
Yet another object of the present invention is to provide a suspension dosage form comprising
greater than 80 mg/ml and not more than 150 mg/ml of Cefixime.
Yet another object of the present invention is to provide a suspension dosage form comprising
Cefixime 100 mg/ml which is bioequivalent to 200 mg/5 ml of currently available marketed
suspension of Cefixime.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides for an oral suspension comprising a unit dose of greater than 100
mg/5 ml and not more than 400 mg/5 ml of Cefixime.
In preferred embodiment the present invention provides for an oral, pharmaceutical suspension
composition comprising Cefixime 200 mg/5 ml. In another embodiment the present invention
provides for an oral, pharmaceutical suspension composition comprising Cefixime 200 mg/5 ml
which is bioequivalent to a suspension dosage form of Cefixime 2X100 mg/5 ml marketed under
the trade name of Suprax.
The term Cefixime as used herein also denotes the various salt forms of Cefixime including the
commonly used trihydrate salt form.
The term "oral suspension" includes within its scope but is not limited to compositions selected
from the group consisting of pellets for suspension which can be coated or uncoated, granules for
suspension, in the form of a unit dose packet (sometimes referred to in the art as a "sachet"), in
the form of a suspension made from a unit dose packet, in the form of a powder for oral
suspension, in the form of a dose sipping device and in the form of an oral suspension per se
(liquid suspension) and combinations of these e.g. coated pellets filled in a dose sipping device or
in a sachet. It is noted that when a unit dose packet is constituted, it is probably mainly in the
form of a suspension if reconstituted according to directions, although the extent of suspension
versus solution depends on a number of factors such as pH.
Preferred oral, pharmaceutical suspension compositions comprising Cefixime are in the form of
powder for suspension. The powder for suspension can be reconstituted and administered in the
form of drops.
The oral, pharmaceutical suspension composition can additionally comprise of at least one
excipient depending upon the dosage form e.g. whether as pellets or as granules for suspension
and so on. The excipient can be one or more selected from the group consisting of diluents,
sweeteners, viscosity enhancing agents, dispersing agents, preservatives, flavoring agents and the
like. One excipient can perform more than one function.
Diluents include, but are not limited to, sucrose, sorbitol, xylitol, dextrose, fructose, malitol, sugar
potassium, aspartame, saccharin, saccharin sodium, and mixtures thereof. A preferred diluent of
the present invention is sucrose. Diluents can also be used as sweetener.
Suitable sweeteners include, but are not limited to, natural sweeteners such as sugars e.g.
fructose, glucose, sucrose, sugar alcohols such as mannitol, sorbitol or mixtures thereof and
artificial sweeteners such as sodium saccharine, sodium cyclamate and aspartame.
The term "viscosity enhancer," as used herein, refers to an agent or a mixture of agents that
increases the thickness of a liquid thereby keeping the active ingredient suspended to allow
accurate dosing. Viscosity enhancers include, but are not limited to, xantham gum, guar gum,
acacia, alginic acid, sodium alginate, propylene glycol alginate, povidone, carbomer, salts of
carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethyl cellulose, hydroxypropyl
cellulose, hydroxypropyl methylcellulose, bentonite, polydextrose, carrageenan, sucrose, sorbitol,
xylitol, dextrose, fructose, malitol, gelatin, tragacanth, a polyvinyl alcohol, cetearyl alcohol,
colloidal silicon dioxide and mixtures thereof. A preferred viscosity enhancer of the present
invention is xantham gum.
Dispersing agents include, but are not limited to, colloidal silicon dioxide and surfactants,
wherein the surfactant is used alone or as an admixture with one or more surfactant.
Combinations of colloidal silicon dioxide with one or more surfactants can also be used.
The term "flavoring agent," as used herein, refers to an agent or a mixture of agents that adds
flavor to a mixture. Flavoring agents include, but are not limited to, artificial strawberry flavor,
banana flavor and artificial cream flavor. A preferred flavoring agent of the present invention is
strawberry flavor.
The term "preservative," as used herein, refers to an agent or mixture of agents that is used to
protect a composition against antimicrobial (e.g., yeast, mold, bacteria) activity. Preservatives
include, but are not limited to, sodium benzoate, benzoic acid, ethylenediaminetetraacetic acid,
sorbic acid, benzethonium chloride, benzalkonium chloride, bronopol, butyl paraben, methyl
paraben, ethylparaben, propyl paraben, thiomerosol, sodium propionate, chlorhexidine,
chlorobutanol, chlorocresol, cresol, imidurea, phenol, phenylmercuric salts, potassium sorbate,
propylene glycol, and mixtures thereof. A preferred preservative of the present invention is
sodium benzoate.
All these excipients can be used at levels well known to the persons skilled in the art. The oral
suspension compositions can be prepared by means well known to those skilled in the art.
The application of the invention can be seen by the following non limiting examples:
Example 1
Cefixime for oral suspension, 200 mg / 5mL
Brief Manufacturing Process:
Sift Cefixime and sucrose separately through suitable screen. Also sift other excipients like
xanthan gum, colloidal silicon dioxide, sodium benzoate and strawberry flavor. Cefixime and the
above excipients are milled with approximately 20% quantity of total sucrose.
All the excipients along with the drug are loaded in a blender and blended for specified period of
time.
Bioequivalence Study
A bioequivalence study was carried out using the suspension (Test) comprising Cefixime 200
mg/5 ml as prepared in Example 1 against the commercially available oral suspension "Suprax"
(Reference) using twenty-five healthy human volunteers.
A 10 ml of the reference product was administered with 5 ml of the test product.
The bioequivalence data for this study is shown below in Table 1. The study was monitored in
terms of the AUC and Cmax achieved with the test product and reference product. AUCs are
plots of serum concentrations of Cefixime along the ordinate (Y-axis) against time on the
abscissa (X-axis). Generally, the values for AUC represent a number of values taken from all the
subjects in a population and are, therefore, mean values averaged over the entire population.
Cmax, the observed maximum in a plot of serum level concentration of Cefixime (Y-axis) versus
time (X-axis) is likewise an average value. The ratios of the log transformed mean values for
Cmax and AUC for the test and reference product (T/R ratio) is a measure of the bioequivalence
between the test and reference product. Values between 80 and 125% for the 90% Confidence
Intervals of these ratios indicate bioequivalence as recommended by the USFDA.
Table 1
n = 25
From the results of this study we can conclude that Cefixime suspension 200 mg/5 ml suspension
exhibits bioequivalence to that of the marketed suspension formulation "Suprax" 2X100 mg/5 ml.
Thus, this invention provides a pharmaceutical suspension composition comprising Cefixime 200
mg/5 ml, which when administered in humans demonstrates an AUC and Cmax for Cefixime
which is substantially equivalent to the AUC and Cmax obtained with twice the dose of an oral
suspension formulation comprising Cefixime trihydrate marketed under the name of "Suprax" is
administered to humans.
As used herein, the term "substantially equivalent" means that the two products are bioequivalent
within the framework of the guidelines for bioequivalence recommended by the USFDA as
already elaborated earlier.
Thus, this invention also provides for a method of achieving bioequivalence between a new
suspension dosage form of Cefixime 200 mg/5 ml and a suspension comprising Cefixime 100
mg/5 ml.
Example 2
Cefixime for oral suspension, 100 mg /mL
Example 3
Cefixime for oral suspension, 150 mg /mL
Brief Manufacturing Process:
Mill Cefixime through communiting mill and sift milled Cefixime through #60 mesh on a
mechanical/vibratory sifter. Sift Sucrose, Strawberry flavor, xanthan gum, colloidal silicon
dioxide, sodium benzoate, Sucralose through #30 (ASTM) screen using mechanical/vibratory
sifter. Blend Cefixime and all the excipients for 30 minutes and fill the blend in HDPE bottles as
per current approved packaging docket.
Bioequivalence Study
A bioequivalence study was carried out using the suspension (Test) comprising Cefixime
100mg/ml as prepared in Example 2 against the commercially available oral suspension "Suprax"
(200mg/5mL: Reference) using twenty-four healthy human volunteers under fasting and fed
conditions.
For this bioequivalence study, an open label, crossover design was planned as per the applicable
regulatory requirements based on the pharmacokinetics of the drug.
The bioequivalence data for this study is shown below in Table 2 and 3. The study was monitored
in terms of the AUC and Cmax achieved with the test product and reference product. Values
between 80 and 125% for the 90% Confidence Intervals of these ratios indicate bioequivalence as
recommended by the USFDA.
Table 2
Table 3
From the results of this study we can conclude that Cefixime 100 mg/ ml suspension exhibits
bioequivalence to that of the currently marketed suspension formulation "Suprax" 200 mg/5 ml.
We Claim:
1. A suspension dosage form of Cefixime comprising greater than 80mg/ml and not more
than 150mg/ml of Cefixime and pharmaceutically acceptable excipients.
2. The suspension dosage form of claim 1 comprising lOOmg/ml of Cefixime and
pharmaceutically acceptable excipients.
3. The suspension dosage form of claim 1, wherein the pharmaceutically acceptable
excipients include diluents selected from the group consisting of sucrose, sorbitol, xylitol,
dextrose, fructose, maltitol, aspartame, saccharin, saccharin sodium, and mixtures thereof.
4. The suspension dosage form of claim 1, wherein the pharmaceutically acceptable
excipients include sweeteners selected from the group consisting of fructose, glucose,
sucrose, mannitol, sorbitol, sodium saccharine, sodium cyclamate and aspartame and
mixtures thereof.
5. The suspension dosage form of claim 1, wherein the pharmaceutically acceptable
excipients include viscosity enhancing agents selected from the group consisting of
xanthan gum, guar gum, acacia, alginic acid, sodium alginate, propylene glycol alginate,
povidone, carbomer, salts of carboxymethylcellulose, methylcellulose, ethylcellulose,
hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,
bentonite, polydextrose, carrageenan, sucrose, sorbitol, xylitol, dextrose, fructose,
maltitol, gelatin, tragacanth, polyvinyl alcohol, cetearyl alcohol, colloidal silicon dioxide,
and mixtures thereof.
6. The suspension dosage form of claim 1, wherein the pharmaceutically acceptable
excipients include dispersing agents selected from the group consisting of colloidal
silicon dioxide and surfactants.
7. The suspension dosage form of claim 1, wherein the pharmaceutically acceptable
excipients include flavoring agents selected from the group consisting of strawberry
flavor, banana flavor, cream flavor and mixtures thereof.
8. The suspension dosage form of claim 1, wherein the pharmaceutically acceptable
excipients include preservatives selected from the group consisting of sodium benzoate,
benzoic acid, ethylenediaminetetraacetic acid, sorbic acid, benzethonium chloride,
benzalkonium chloride, bronopol, butyl paraben, methyl paraben, ethylparaben, propyl
paraben, thiomerosol, sodium propionate, chlorhexidine, chlorobutanol, chlorocresol,

cresol, imidurea, phenol, phenylmercuric salts, potassium sorbate, propylene glycol, and
mixtures thereof.
9. The suspension dosage form of claim 1 wherein the dosage form includes powder for
suspension, pellets or granules for suspension, and liquid suspension.
10. A suspension dosage form of Cefixime comprising lOOmg/ml of Cefixime wherein said
suspension is bioequivalent to 200mg/5 ml of currently available marketed suspension of
Cefixime trihydrate under fast and fed conditions.
11. A suspension dosage form of Cefixime comprising lOOmg/ml of Cefixime and
pharmaceutically acceptable excipients adapted for treating a subject having acute
bacterial otitis media, pharyngitis, tonsillitis, acute bronchitis or chronic bronchitis.
12. A suspension dosage form of Cefixime comprising lOOmg/ml of Cefixime and
pharmaceutically acceptable excipients adapted for treating a subject having
uncomplicated urinary tract infections, gonorrhea or both.
Dated this 8th day of June 2011.

A pharmaceutical suspension dosage form comprising greater than 80 mg/ml and not more than
150 mg/ml of Cefixime and pharmaceutically
acceptable excipients.