Technical field of the invention
The present invention relates to dispersible pharmaceutical compositions
comprising cefditoren pivoxil and processes for the preparation thereof.
Background
Solid dosage forms which are swallowed, such as tablets and capsules, provide
accurate dosage and avoid taste problems; but since they have to disintegrate in
the gastrointestinal tract and the medicament has then to dissolve before it can
be absorbed, absorption tends to be slower than from a suspension, and may be
less than complete. Also, some patients have difficulty swallowing tablets and
capsules, and there is a practical limit to the size, and therefore the dose, that
can be swallowed.
Cefditoren pivoxil, a semi-synthetic cephalosporin antibiotic for oral
administration is a prodrug which is hydrolyzed by esterases during absorption,
distributed in the circulating blood as active cefditoren and is indicated in the
treatment of acute bacterial exacerbation of chronic bronchitis, communityacquired
pneumonia, pharyngitis/tonsillitis and uncomplicated skin and skinstructure
infections.
From the point of view of bioavailability, the preferred form of administration of
sparingly soluble medicaments such as cefditoren pivoxil is often an aqueous
suspension. However, there are problems associated with this form of
administration. For example, such preparations in multidose form may have a
limited shelf life; and usual methods of dose measurement lack accuracy.
Suspensions are refrigerated to prevent the loss of potency and therefore are
inconvenient while traveling. Further, skills for precise measurement of the
correct dose are required. The bitter taste of many such medicaments is also a
drawback.
Single dose powders for reconstitution in sachet form, and dispersible tablets,
offer the advantages of suspensions without the problems of instability,
measurement inaccuracy, difficulty in swallowing, or size limitation. In general,
dispersible tablets are advantageous in that they combine the accuracy of
dosage associated with tablets, with the optimum bioavailability of suspensions.
They may also accommodate larger doses than swallow tablets or capsules.
One of the important requirements of dispersible solid dosage forms are that they
should disperse in an aqueous solution within a short period of time, for example,
less than one minute, to form a smooth suspension without any coarse lumps.
An intraorally disintegrating tablet preparation is described in the International
Publication No. WO93/12769, which is obtained by suspending a drug, lactose,
and mannitol in aqueous agar solution, filling the resulting suspension in a
molding pocket or the like, and drying the molding under reduced pressure. This
molding shows quick disintegration but is more fragile than usual tablets so that it
is readily cracked, chipped, etc. and a long time is required for its production;
thus the process for production is poor in productivity.
In Japanese Patent Laying-Open No.6-218028(1994) and Japanese Patent
Laying-Open No.8-19589(1996), a process for production of a tablet preparation
is described, where moist powder after kneading is filled in the tablet molding
well for wet shaping followed by drying. The resulting tablet preparation, being
porous and having a moderate void fraction, shows quick disintegration. However
the industrial productivity of this process for production is poor because a wet
material with low fluidity is filled and compressed so that the amount filled in each
well varies greatly and a special dryer is necessary.
US Patent No. 5,837,292 and 4,886,669 also describe fast disintegrating and fast
dissolving compositions.
Various processes are used for preparing dispersible tablets. However, a need
exists for a cost effective, rapid operation process for producing dispersible
pharmaceutical compositions comprising cefditoren pivoxil, which provide for
ease of oral administration and result in a suspension which has a smooth mouth
feel without any gritty particles.
Summary
In one general aspect there is provided a water-dispersible tablet comprising:
(a) therapeutically effective amount of cefditoren pivoxil,
(b) at least one disintegrant,
(c) at least one surfactant, and
(d) one or more pharmaceutically acceptable excipients,
wherein the ratio of the disintegrant to cefditoren pivoxil is about 1:1 to
about 1:25 and the ratio of disintegrant to surfactant is about 2:1 to
about 50:1.
Particularly the ratio of the disintegrant to cefditoren pivoxil is about 1:2 to about
1:10 and the ratio of disintegrant to surfactant is about 2:1 to about 20:1.
Cefditoren pivoxil used herein may be amorphous or crystalline.
Amorphous cefditoren pivoxil may be prepared as described in our co-pending
Indian Patent Application No's. 236/DEL/2004, 207/DEL/2005 and
2176/DEL/2006 which relate to a process of preparing amorphous cefditoren
pivoxil.
Disintegrant may be selected from a wide range of materials such as starches,
celluloses, aligns, gums, cross-linked polymers and clays.
Suitable examples of disintegrant comprise sodium starch glycolate, cross-linked
polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, calcium
carboxymethyl cellulose, alginic acid and alginates, pregelatinised starch, starch
and starch derivatives, microcrystalline cellulose, low-substituted hydroxypropyl
cellulose, swellable clays, smectite, attapulgite, montmorillonite, bentonite,
magnesium aluminium silicate, cyclodextrins and combinations thereof.
Particularly sodium starch glycolate, cross-linked sodium carboxymethyl
cellulose, cross-linked polyvinyl pyrrolidone, low-substituted
hydroxypropylcellulose etc. are used.
Surfactants/wetting agents may be selected from both non-ionic and ionic
(cationic, anionic and zwitterionic) surfactants suitable for use in pharmaceutical
compositions.
Suitable examples of surfactants include polyethoxylated fatty acid esters,
polyethylene glycol fatty acid esters, alcohol-oil transesterification products,
polyglycerized fatty acids, polyethylene glycol sorbitan fatty acid esters, sugar
esters, polyoxyethylene-polyoxypropylene block copolymers, ionic surfactants,
derivatives of fat soluble vitamins, and mixtures thereof.
Pharmaceutically acceptable excipients are selected from one or more of
diluents, lubricants, glidants, alkalizing agents, sweeteners, colorants and
flavoring agents.
Water-dispersible tablet can be prepared by conventional techniques, for
example either by direct compression, roller compaction or by wet granulation
techniques.
In another embodiment the water-dispersible tablet is prepared by a process
comprising the steps of:
(A) blending cefditoren pivoxil with a surfactant and one or more
pharmaceutically acceptable excipients;
(B) blending a disintegrant with the material of step (A) and
compressing to obtain the water-dispersible tablet,
wherein the ratio of the disintegrant to cefditoren pivoxil is about 1:1 to about
1:25 and the ratio of disintegrant to surfactant is about 2:1 to about 50:1.
In another embodiment the water-dispersible tablet is prepared by a process
comprising the steps of:
(A) blending cefditoren pivoxil with an aqueous solution/dispersion of a
surfactant and one or more pharmaceutically acceptable excipients;
(B) drying the material of step (A);
(C)blending a disintegrant with the material of step (B) and
compressing to obtain the water-dispersible tablet,
wherein the ratio of the disintegrant to cefditoren pivoxil is about 1:1 to about
1:25 and the ratio of disintegrant to surfactant is about 2:1 to about 50:1.
In yet another embodiment the water-dispersible tablet comprises one or more of
the following features. For example, the water-dispersible tablet may disperse to
form a solution, or non-gritty suspension or slurry, in less than about three
minutes.
In another embodiment the water-dispersible tablet may be compressed using
suitable tooling to produce a scored tablet. Scored tablets may be easily divided
into smaller pieces to provide a lower dose. In particular, the tablet may be
scored through its center so that it can be easily divided into two equal halves.
In another aspect there is provided a method of treating acute bacterial
exacerbation of chronic bronchitis, community-acquired pneumonia and
pharyngitis/tonsillitis comprising administering a dispersible pharmaceutical
composition comprising a therapeutically effective amount of cefditoren pivoxil, at
least one disintegrant, at least one surfactant and other pharmaceutically
acceptable excipients.
The details of one or more embodiments of the inventions are set forth in the
description below. Other features, objects, and advantages of the invention will
be apparent from the description and claims.
Description
The preparation of dispersible tablets requires the formulator to understand the
physicochemical incompatibilities of the active as well as to find suitable
excipients to be added. The dispersible tablets are characterized by:
(a) high speed of disintegration in water, and
(b) uniformity of dispersion of the particles into which they disintegrate.
The properties and the quality of the formulated tablet depend largely upon the
excipients that are incorporated, making the selection of such excipients an
important step in the process.
The present invention relates to a water-dispersible tablet comprising cefditoren
pivoxil, a disintegrant, a surfactant and pharmaceutically acceptable excipients
and processes for the preparation thereof.
The term 'therapeutically effective amount' used herein is intended to provide
from about 25 mg to about 2000 mg of cefditoren pivoxil. This dose may be
administered once daily or in divided doses several times daily.
Disintegrant may be selected from a wide range of materials such as starches,
celluloses, aligns, gums, cross-linked polymers and clays. These agents create
an increase in the surface so that the active is released very quickly. The
disintegrants used may be swelling types, wicking types, super disintegrants, gas
producing or those having a combination of two or more properties. The
disintegrants may be added intragranularly or extragranularly or at both stages.
Examples of disintegrants include sodium starch glycolate, cross-linked
polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, calcium
carboxymethyl cellulose, alginic acid and alginates, pregelatinised starch, starch
and starch derivatives, microcrystalline cellulose, low-substituted hydroxypropyl
cellulose, swellable clays, smectite, attapulgite, montmorillonite, bentonite,
magnesium aluminium silicate and combinations thereof. Particularly sodium
starch glycolate, croscarmellose sodium, crospovidone, low-substituted
hydroxypropylcellulose etc. or their combinations are used. Disintegrants may
constitute from 1 % to 15% w/w of the tablet.
Surfactants/wetting agents include both non-ionic and ionic (cationic, anionic and
zwitterionic) surfactants suitable for use in pharmaceutical compositions. These
include polyethoxylated fatty acid esters, polyethylene glycol fatty acid esters,
alcohol-oil transesterification products, polyglycerized fatty acids, polyethylene
glycol sorbitan fatty acid esters, sugar esters, polyoxyethylene-polyoxypropylene
block copolymers, ionic surfactants, derivatives of fat soluble vitamins, and
mixtures thereof.
Suitable examples include sodium lauryl sulphate, sodium dodecyl sulphate,
polyoxyethylene castor oil derivatives, for example, TWEENS, polyoxyethylenepolyoxypropylene
block copolymers, for example, POLOXAMER, or mixtures
thereof.
Selection of an optimum amount of disintegrant is desired for the quick
disintegration of the dispersible tablet into granules and further into individual
particles. Use of an excessively great amount of disintegrant may make the tablet
extremely moisture sensitive, and fragile. On the other hand lower amounts of
disintegrant may delay complete disintegrations. The ratio of the disintegrant to
cefditoren pivoxil ranges from about 1:1 to about 1:25. Particularly the ratio
ranges from about 1:2 to about 1:10. The ratio of disintegrant to surfactant is
about 2:1 to about 50:1. Particularly, the ratio ranges from 2:1 to 20:1. The use of
the disintegrant along with the drug and the surfactant in this ratio, results in the
formation of softer, more porous granules that can disintegrate in aqueous
solution to give a smooth suspension, avoiding the presence of coarse lumps.
The term 'pharmaceutically acceptable excipient' as used herein includes all
physiologically acceptable excipients used in the pharmaceutical art of
dispensing.
Suitable pharmaceutically acceptable excipients comprise those excipients acting
in one or more capacities as diluents, lubricants, glidants, alkalizing agents,
colorants and flavoring agents.
Suitable diluents include those excipients which facilitate compression and
provide strength. Diluents may be selected from one or more of lactose, starch,
sugar alcohols such as mannitol, sucrose, hydroxyl propyl cellulose,
microcrystalline cellulose, calcium carbonate, dicalcium phosphate and mixtures
thereof.
Particularly, a mixture of diluents is used, wherein one of the diluents is mannitol
and the other is microcrystalline cellulose. Mannitol forms low density matrix that
disintegrates rapidly and also provides a cooling sensation. Microcrystalline
cellulose provides appropriate fluidity and compressibility characteristics.
Suitable lubricants and glidants include, but are not limited to, colloidal
anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc,
hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax,
yellow beeswax and white beeswax.
Suitable alkalizing agents include, but are not limited to, sodium chloride, sodium
hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide,
ammonia, tertiary sodium phosphate, diethanolamine, ethylenediamine, Nmethylglucamine
or L-lysine and their mixtures.
The coloring agents and flavoring agents of the present invention may be
selected from any FDA approved colors and flavors for oral use.
Suitable flavoring agents include synthetic and natural flavors.
The water-dispersible tablet may further contain sweeteners.
Suitable sweetening agents may be selected from a wide range of materials such
as water soluble sweetening agents, water-soluble artificial sweeteners,
dipeptide based sweetening agents and mixtures thereof.
Water soluble sweetening agents encompass monosaccharides, disaccharides
and polysaccharides, such as xylose, ribose, glucose, mannose, galactose,
fructose, dextrose, sucrose, maltose, corn syrup and sugar alcohols such as
sorbitol, mannitol, xylitol, and mixtures thereof.
Water soluble artificial sweetening agents encompass free acid form of
saccharine and its soluble salts such as sodium or calcium saccharine salts,
cyclamate salts, acesulfame, aspartame and mixtures thereof.
The ingredients discussed above may be formed into water-dispersible tablet by
conventional techniques, for example either by direct compression, or first
slugging some of the ingredients, milling the slugs, blending with the remaining
ingredients and then compressing as appropriate. Water-dispersible tablet may
also be prepared using wet granulation techniques.
The water-dispersible tablet may be compressed using suitable tooling to
produce scored tablet. Scored tablets may be easily divided into smaller pieces
to provide a lower dose. In particular, the tablet may be scored through its center
so that it can be easily divided into two equal halves.
The pharmaceutical composition of the invention may be packaged in unit dose,
rolls, bulk bottles, blister packs and combinations thereof without limitation.
Preferably the composition is in unit dose form. The amount of medicament in a
unit dose will depend on the condition to be treated and the assay of the
medicament. The unit dose will be repeated according to the usual regime of the
medicament.
A method of treating acute bacterial exacerbation of chronic bronchitis,
community-acquired pneumonia and pharyngitis/tonsillitis is provided comprising
administering a water-dispersible tablet comprising cefditoren pivoxil, wetting
agents/surfactants, disintegrant and other pharmaceutically acceptable
excipients.
The following example illustrates various aspects of the present invention. This
example is for illustration only and should not be construed as limiting the scope
of the invention.
1. Cefditoren pivoxil (Amorphous form), mannitol, aspartame, sodium lauryl
sulphate, colour, sodium chloride and flavor were mixed in a rapid mixer
granulator.
2. Hydroxy propyl Cellulose and cross-linked carboxymethyl cellulose
sodium were mixed separately.
3. Material of step (1) was blended with material of step (2).
4. Colloidal Silicon Dioxide and Microcrystalline cellulose were blended with
material of step (3) for 15 minutes.
5. Magnesium Stearate was blended with material of step (4) for 15 minutes
and compressed.
The chemical and physical stability of cefditoren pivoxil in the water-dispersible
tablet prepared according to Example given above in Table 1 under accelerated
stability conditions of 40°±2°C and 75±5% relative humidity (RH), were evaluated
on the basis of assay and disintegration time measured between initial and 3-
month time points. The stability results for three months (M) at 40°C/75% RH are
given below in the tables 2 and 3.(Table Removed)

WE CLAIM:
1. A water-dispersible tablet comprising:
(a) therapeutically effective amount of cefditoren pivoxil,
(b) at least one disintegrant
(c) at least one surfactant, and
(d) one or more pharmaceutically acceptable excipients,
wherein the ratio of the disintegrant to cefditoren pivoxil is about 1:1 to
about 1:25 and the ratio of disintegrant to surfactant is about 2:1 to
about 50:1.
2. The water-dispersible tablet of claim 1, wherein the ratio of the
disintegrant to cefditoren pivoxil is about 1:2 to about 1:10 and the ratio of
disintegrant to surfactant is about 2:1 to about 20:1.
3. The water-dispersible tablet of claim 1, wherein cefditoren pivoxil is
amorphous or crystalline.
4. The water-dispersible tablet of claim 1, wherein the disintegrant is
selected from starches, celluloses, aligns, gums, cross-linked polymers
and clays.
5. The water-dispersible tablet of claim 1, wherein the surfactant is selected
from non-ionic and ionic surfactants.
6. The water-dispersible tablet of claim 5, wherein the surfactant is selected
from polyethoxylated fatty acid esters, polyethylene glycol fatty acid
esters, alcohol-oif transesterification products, polyglycerized fatty acids,
polyethylene glycol sorbitan fatty acid esters, sugar esters,
polyoxyethylene-polyoxypropylene block copolymers, ionic surfactants,
derivatives of fat soluble vitamins, and mixtures thereof.
7. The water-dispersible tablet of claim 1, wherein the pharmaceutically
acceptable excipients are selected from one or more of diluents,
lubricants, glidants, alkalizing agents, sweeteners, colorants and flavoring
agents.
8. The water-dispersible tablet of claim 7, wherein the diluent is selected
from lactose, starch, sugar alcohols such as mannitol, sucrose,
hydroxypropyl cellulose, calcium carbonate, microcrystalline cellulose,
dicalcium phosphate and mixtures thereof.
9. The water-dispersible tablet of claim 7, wherein the lubricants and glidants
are selected from colloidal anhydrous silica, stearic acid, magnesium
stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of
fatty acids, microcrystalline wax, yellow beeswax and white beeswax.
10. The water-dispersible tablet of claim 1 , wherein the tablet can be prepared
by techniques comprising direct compression, roller compaction or by wet
granulation techniques.