CO-PRECIPITATED AMORPHOUS CEFDITOREN PIVOXIL AND DOSAGE
FORMS COMPRISING THE SAME
Field of the Invention
The field of the invention relates to co-precipitated amorphous cefditoren pivoxil
dosage forms and processes for their preparation.
Background of the Invention
Cefditoren pivoxil, which is a pivaloxymethyl ester of cefditoren, is a third
generation cephalosporin derivative belonging to the class of 3-(2-substituted vinyl)
cephalosporin, which was first developed by Meiji Seika of Japan with the aim of
producing active cephalosporins with potent and broad-spectrum activity (U.S. Patent No.
4,839,350). Cefditoren pivoxil is highly active, not only against a variety of gram-positive
and gram-negative bacteria, but also against some resistant strains of bacteria. Chemically,
cefditoren pivoxil is chemically known as [6R-[3(Z),6a,7b(Z)]]-7-[[(2-amino-4-
thiazolyl)(methoxyimino)acetyl]amino]-3-[2-(4-methyl-5-thiazolyl)ethenyl]-8-oxo-5-thial-
azabicyclo[4.2.0]oct-2-ene-carboxylic acid, pivaloyloxy-methyl ester.
Crystals of cefditoren pivoxil are known to have high purity, high heat stability and
in addition satisfactory stability even when stored under high humidity conditions (U.S.
Patent No. 6,294,669). Crystals of cefditoren pivoxil, however, have low solubility in
water and thus have not been very suitable for oral administration.
In general, for medicinal compounds which are sparingly soluble in water, the
solubility or dissolution rate thereof is known to greatly affect the absorption of these
compounds in vivo. Thus, many reports were presented on how to improve the watersolubility
of such medicinal compounds, which are sparingly soluble in water. One of the
reported proposals is a method in which a medicinal compound sparingly soluble in water
is converted into an amorphous substance, thus to improve the solubility of the compound
in water.
It is known that an amorphous substance generally has a higher solubility in water,
as compared with that of the corresponding crystalline substance. Therefore, the
conversion of crystalline form of cefditoren pivoxil into an amorphous substance having
higher water solubility is expected to improve its therapeutic efficacy and thus can be
advantageously used.
U.S. Patent No. 6,342,493 describes a process for preparing orally administrable
compositions that include particles composed of a homogeneous mixture of a
crystallographically stable, amorphous, water soluble substance of cefditoren pivoxil and a
water soluble high molecular weight polymer. The process involves mixing crystalline
cefditoren pivoxil and a water soluble, high molecular weight polymer in an acidic
solution followed by basification of the acidic solution to precipitate a yellow-colored
powdery composition that contains amorphous cefditoren pivoxil and high molecular
weight polymer. Many technical problems are believed to exist in this process, such as the
need for strict production controls and requirements to carry out the operation.
WO 02/87588 discloses another method of conversion of crystalline cefditoren
pivoxil to amorphous form by grinding crystalline cefditoren pivoxil in the presence of a
pharmaceutically acceptable organic polymeric compound.
In the present invention we have found that amorphous cefditoren pivoxil can be
obtained by preparing a solution of crystalline cefditoren pivoxil in a solvent, optionally
adding a wetting agent, dispersing a water insoluble carrier in this solution and removing
the solvent.
Summary of the Invention
In one general aspect there is provided a process for preparing an amorphous form
of cefditoren pivoxil having a higher water-solubility. The process includes preparing a
solution of crystalline cefditoren pivoxil in one or more solvents; dispersing one or more
water insoluble carriers in the solution; and removing the solvent. The amorphous
cefditoren pivoxil and one or more water insoluble carriers are co-precipitated from the
solution.
Embodiments of the process may include one or more of the following features.
For example, the solution may be prepared in an organic solvent and may include one or
more of ketones, such as acetone; alcohols, such as methanol, ethanol, isopropyl alcohol;
and chlorinated hydrocarbons, such as methylene chloride.
The water insoluble carrier may be one or more of crospovidone, colloidal silicon
dioxide, macrocrystalline cellulose, cross-linked sodium carboxymethylcellulose, starch,
carboxymethylcellulose calcium, calcium carbonate, dibasic calcium phosphate, and
combinations thereof and, in particular, the water insoluble carrier may be crospovidone or
colloidal silicon dioxide, or combinations thereof. The weight ratio of cefditoren pivoxil to
water insoluble carrier may be from about 1:0.1 to about 1:2.
Removing the solvent may include, for example, one or more of distillation,
distillation under vacuum, evaporation, and spray drying.
The process may further include processing the mixture with one or more
pharmaceutically inert excipients. The pharmaceutically inert excipients may be one or
more of fillers, buffering agents, binders, disintegrants, coloring agents, flavoring agents,
lubricants, glidants, plasticizers, and preservatives. The process may further include
forming one or more of a tablet, a capsule, and a powder.
In another general aspect there is provided a process for preparing an amorphous
form of cefditoren pivoxil having a higher water-solubility. The process includes
preparing a solution of crystalline cefditoren pivoxil in one or more solvents; adding one
or more wetting agents; dispersing one or more water insoluble carriers in the solution;
and removing the solvent. The amorphous cefditoren pivoxil, one or more wetting agents,
and one or more water insoluble carriers are co-precipitated from the solution.
The wetting agent may be one or more of propylene glycol, hydroxypropyl
cellulose, hydroxypropyl methylcellulose, poloxamers, polyethylene glycols and tweens.
In another general aspect there is provided a pharmaceutical composition for oral
administration that includes a co-precipitated mixture of amorphous cefditoren pivoxil and
one or more water insoluble carriers.
Embodiments of the pharmaceutical composition may include one or more of the
following features. The water insoluble carrier may be one or more of crospovidone,
colloidal silicon dioxide, microcrystalline cellulose, cross-linked sodium
carboxymethylcellulose, starch, carboxymethylcellulose calcium, calcium carbonate,
dibasic calcium phosphate, and combinations thereof and, in particular, the water insoluble
carrier may be crospovidone or colloidal silicon dioxide, or combinations thereof.
In another general aspect there is provided a pharmaceutical composition for oral
administration that includes a co-precipitated mixture of amorphous cefditoren pivoxil,
one or more wetting agents, and one or more water insoluble carriers.
The wetting agent may be one or more of propylene glycol, hydroxypropyl
cellulose, hydroxypropyl methylcellulose, poloxamers, polyethylene glycols and tweens.
The pharmaceutical composition may further include one or more
pharmaceutically inert excipients. The one or more pharmaceutically inert excipients may
be one or more of fillers, buffering agents, binders, disintegrants, coloring agents,
flavoring agents, lubricants, glidants, plasticizers, and preservatives.
The pharmaceutical composition may be a solid dosage form and the solid dosage
form comprises one or more of tablets, capsules, and powders, and, in particular, may be a
tablet.
The weight ratio of cefditoren pivoxil to water insoluble carrier may be from about
1:0.1 to about 1:2.
In another general aspect there is provided a method for the treatment of bacterial
infections in a mammal. The method includes administering a pharmaceutical composition
that includes a co-precipitate of amorphous cefditoren pivoxil and one or more water
insoluble carriers, and one or more of pharmaceutically acceptable excipients.
In another general aspect there is provided a co-precipitate of amorphous
cefditoren pivoxil and one or more water insoluble carriers. Embodiments of the coprecipitate
may include any one or more of the following features or the features described
above. For example, the weight ratio of cefditoren pivoxil to water insoluble carrier may
be from about 1:0.1 to about 1:2.
In another general aspect there is provided a co-precipitate of amorphous
cefditoren pivoxil, one or more wetting agents, and one or more water insoluble carriers.
The details of one or more embodiments of the invention are set forth in the
description below. Other features, objects, and advantages of the invention will be
apparent from the description and claims.
Detailed description of the Invention
The term 'amorphous' as used herein means a solid state in which cefditoren
pivoxil molecules gather together with a pharmaceutically acceptable organic polymeric
compound without forming crystals having a regular special configuration, more
specifically, a solid state in which the amorphous form can be confirmed by conventional
powder X-ray diffractometry. Specifically, the crystalline cefditoren pivoxil exhibits sharp
diffraction peaks, whereas the co-precipitate of amorphous cefditoren pivoxil and one or
more water insoluble carriers according to the present invention does not substantially
exhibit any X-ray diffraction peaks.
In one embodiment, amorphous cefditoren pivoxil may be prepared by a process
that includes forming a solution of cefditoren pivoxil in one or more solvents, dispersing a
water insoluble carrier into the solution, and removing the solvent by spray drying, thereby
co-precipitating the amorphous cefditoren pivoxil and water insoluble carriers.
The spray dryer used for drying the solution may be any of the conventional spray
driers known in the art including nozzle type, disc type or jet type. Based on the selection
of spray dryer, the various process parameters may be varied.
The solvent may be, for example, one or more of ketones, such as acetone;
alcohols, such as methanol, ethanol, isopropyl alcohol; and chlorinated hydrocarbons, such
as methylene chloride.
Examples of water insoluble carrier may include one or more of crospovidone,
colloidal silicon dioxide, microcrystalline cellulose, cross-linked sodium
carboxymethylcellulose, starch, carboxymethylcellulose calcium, calcium carbonate and
dibasic calcium phosphate, and combinations thereof. More particularly, the water
insoluble carrier is crospovidone, or colloidal silicon dioxide, or combinations thereof.
The weight ratio of cefditoren pivoxil to water insoluble carrier may vary from about 1:0.1
to about 1:2.
The wetting agents are the substances, usually surface-active agents, which reduce
the surface tension of a liquid and thereby increase its adhesion to a solid surface. Due to
poor dispersibility in solvents, the pharmaceutical composition containing cefditoren
pivoxil may optionally include a wetting agent. The wetting agent wets the particles of
cefditoren pivoxil such that when the solvent evaporates, the particles of cefditoren pivoxil
which precipitate are tiny and do not aggregate.
Examples of wetting agents may include one or more of propylene glycol,
hydroxypropyl cellulose, hydroxypropyl methylcellulose, poloxamers, polyethylene
glycols and tweens.
The amorphous cefditoren pivoxil prepared as generally described above may be
further processed with one or more pharmaceutically inert excipients to prepare
pharmaceutical compositions. The term "pharmaceutical composition" includes solid
dosage forms such as one or more of tablets, capsules, and powders that are formulated by
conventional methods of admixture such as one or more of blending, filling, and
granulation. Of course, other formulation methods also may be used. The dosage form
may be optionally coated with one or more film forming polymers.
In one embodiment, the cefditoren pivoxil tablet may be prepared by blending a
spray dried, co-precipitated mixture of cefditoren pivoxil and water insoluble carriers with
diluents and disintegrants, mixing the blend with lubricant and glidants, directly
compressing the mixed blend in a suitable tableting machine, and coating with one or
more film forming polymers.
In alternative embodiments, dry granulation and wet granulation techniques may
be used for preparing cefditoren pivoxil tablets.
Coating may be performed by applying one or more film forming polymers with or
without other pharmaceutically inert excipients. This may be done as a solution or
suspension using any conventional coating technique known in the prior art, such as spray
coating in a conventional coating pan or fluidized bed processor, or dip coating.
Suitable film forming polymers include one or more of ethylcellulose,
hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose,
carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, cellulose
acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose
acetate trimellitate, waxes, methacrylic acid polymers such as Eudragit® RL and RS, and
mixtures thereof. The coating can also be performed using any commercially available
ready to coat preparations such as opadry-AMB, opadry-white, opadry-clear, etc.
Suitable solvents used for making a solution/suspension of film forming polymer
include one or more of methylene chloride, isopropyl alcohol, acetone, methanol, ethanol,
water and mixtures thereof.
In another embodiment, cefditoren pivoxil capsules may be prepared by blending
the spray dried, co-precipitated mixture of cefditoren pivoxil and water insoluble carrier
with other pharmaceutically inert excipients and filling into suitably sized hard gelatin
capsules.
The term "pharmaceutically inert excipient" as used herein includes one or more of
fillers, buffering agents, binders, disintegrants, coloring agents, flavoring agents,
lubricants, glidants, plasticizers and preservatives for pharmaceutical compositions.
Suitable fillers may include one or more of corn starch, lactose, white sugar,
sucrose, sugar compressible, sugar confectioners, glucose, sorbitol, calcium carbonate,
calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline
cellulose, silicified microcrystalline cellulose, cellulose powdered, dextrates, dextrins,
dextrose, fructose, kaolin, lactitol, mannitol, sorbitol, starch, starch pregelatinized, sucrose
and mixtures thereof.
Examples of buffering agents include one or more of sodium citrate, sodium
tartarate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium
polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium
hydrogenphosphate, dipotassium hydrogenphosphate, trisodium phosphate, tripotassium
phosphate, sodium acetate, potassium metaphosphate, and other sodium and potassium
salts.
Examples of binders include methyl cellulose, hydroxypropyl cellulose,
polyvinylpyrrolidone, gelatin, gum Arabic, ethyl cellulose, polyvinyl alcohol, pullutan,
pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol or mixtures
thereof.
Examples of disintegrants include starch, croscarmellose sodium, crospovidone,
sodium starch glycolate or mixtures thereof.
Examples of lubricants and glidants include colloidal anhydrous silica, stearic acid,
magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty
acids, microcrystalline wax, yellow beeswax, white beeswax and the like.
The coloring agents of the present invention may be selected from any FDA
approved colors for oral use.
The amorphous cefditoren pivoxil composition according to the present invention
may be used as antibacterial agents. Bacteria referred to herein include, for example grampositive
bacteria such as staphylococcus and streptococcus, gram-negative bacteria such as
Escherchia coli, Branhamella catarrhalis, Klebsiella, Proteus, and Haemophilus
influenzae, and anaerobes such as Peptostreptococcus, Propionibacterium acnes, and
Bacteriocides.
Further, the composition according to the present invention is useful for the
prophylaxis or therapy of diseases induced by gram-positive bacteria or gram-negative
bacteria.
The pharmaceutical composition according to the present invention may be used
by any administration route so far as the high dissolvability of the amorphous cefditoren
pivoxil can be utilized, for example by oral administration, intraoral administration,
parenteral administration, topical administration, or rectal administration. The
pharmaceutical composition according to the present invention is particularly administered
orally.
The amorphous Cefditoren pivoxil compositions according to the present invention
may be administered in combination with other medicines, for example, other antibacterial
agents.
The following examples illustrate various aspects of the present inventions. These
examples are for illustration only and do not limit the scope of the inventions.
Examples 1-4:
Amorphous cefditoren pivoxil 1
Ingredient
Cefditoren pivoxil
Crospovidone
Propylene Glycol
Acetone
Quantity
20 g
20 g
l g
2000 ml
Propylene glycol was dissolved in acetone. Cefditoren pivoxil was added to the solution
formed and crospovidone was dispersed in it. The solvent was removed to obtain the
amorphous cefditoren pivoxil.
Amorphous cefditoren pivoxil 2
Ingredient
Cefditoren pivoxil
Colloidal silicon dioxide
Hydroxypropyl cellulose
Acetone
Quantity
20 g
3.0 g
1.2 g
2000 ml
Hydroxypropyl cellulose was dissolved in acetone. Cefditoren pivoxil was added to the
solution formed and colloidal silicon dioxide was dispersed in it. The solvent was removed
to obtain the amorphous cefditoren pivoxil.
Amorphous cefditoren pivoxil 3
Ingredient
Cefditoren pivoxil
Colloidal silicon dioxide
Acetone
Quantity
l g
0.15 gm
100ml
10
Cefditoren pivoxil was dissolved in acetone and colloidal silicon dioxide was dispersed in
it. The solvent was removed to obtain the amorphous cefditoren pivoxil.
Amorphous Cefditoren pivoxil 4
Ingredient
Cefditoren pivoxil
Colloidal silicon dioxide
Hydroxypropyl methylcellulose
Dichloromethane
Isopropyl alcohol
Quantity
l g
0.15 gm
0.06 gm
20ml
5ml
Hydroxypropyl methylcellulose was dissolved in a mixture of dichloromethane and
isopropyl alcohol. Cefditoren pivoxil was added to the solution formed and colloidal
silicon dioxide was dispersed in it. The solvent was removed to obtain the amorphous
cefditoren pivoxil.
Example 5:
Tablets containing amorphous cefditoren pivoxil 1
Ingredient
Amorphous Cefditoren pivoxil 1
D-Mannitol
Hydroxypropylcellulose
Crosscarmellose sodium
Magnesium stearate
Purified Water
Percent w/w
74.92795
3.631124
1.152738
20.17291
0.115274
q.s
Coating
Hydroxypropyl methylcellulose E - 5
Titanium Dioxide
PEG 400
Purified Water
q.s.
1. Amorphous Cefditoren pivoxil 1 and mannitol were granulated with a solution of
hydroxypropylcellulose in water.
2. The wet granules were dried in a fluid bed drier, passed through a screen and then
subjected to sizing.
3. Crosscarmellose sodium and magnesium stearate were passed through a screen,
blended with the blend of step 2 and the total mixture was compressed into tablets.
4. The tablets were coated with the coating composition in the coating pan.
Example 6:
Tablets containing amorphous cefditoren pivoxil 2
Ingredient
Amorphous Cefditoren pivoxil 2
D-Mannitol
Crospovidone
Polyvinyl pyrollidone K-30
Sodium lauryl sulphate
Magnesium stearate
Purified Water
Percent wAv
61.99116
12.51919
22.09816
2.037683
0.655967
0.697837
q.s
Coating
Hydroxypropyl methylcellulose E - 5
Titanium Dioxide
PEG 400
Purified Water
q.s.
1. Amorphous cefditoren pivoxil 2, sodium lauryl sulphate and mannitol were
granulated with a solution of polyvinyl pyrrolidone in water.
2. The wet granules were dried in a fluid bed drier, passed through a screen and then
subjected to sizing.
3. Crospovidone and magnesium stearate were passed through a screen, blended with
the blend of step 2 and the total mixture was compressed into tablets.
4. The tablets were coated with the coating composition in the coating pan.
Example 7:
Tablets containing amorphous cefditoren pivoxil 3
Ingredients Percent w/w
Intragranular
Amorphous Cefditoren pivoxil 3
Mannitol
Crosscarmellose sodium
Sodium Polyphosphate
Hydroxypropylcellulose
Purified Water
51.72414
17.41379
12.06897
0.689655
1.551724
q.s.
Extragranular
Crosscarmellose sodium
Magnesium Stearate
Total
12.06897
1.034483
96.55172
Coating
Hydroxypropyl methylcellulose E - 5
Titanium Dioxide
PEG 400
Purified Water
Total
q.s.
100
1. Amorphous cefditoren pivoxil 3, mannitol, sodium polyphosphate and
intragranular croscarmellose sodium were granulated with a solution of
hydroxypropylcellulose in water.
2. The wet granules were dried in a fluid bed drier, passed through a screen and then
subjected to sizing.
3. The extragranular croscarmellose sodium and magnesium stearate were passed
through a screen, blended with the blend of step 2 and the total mixture was
compressed into tablets.
4. The tablets were coated with the coating composition in the coating pan.
Example 8:
Tables containing amorphous cefditoren pivoxil 4
Ingredients Percent w/w
Intragranular
Amorphous Cefditoren pivoxil 4
Mannitol
Crosscarmellose sodium
Sodium Polyphosphate
Hydroxypropyl methylcellulose
Purified Water
51.72414
17.41379
12.06897
0.689655
1.551724
q.s.
Extragranular
Crosscarmellose sodium
Magnesium Stearate
Total
12.06897
1.034483
96.55172
Coating
Hydroxypropyl methylcellulose E - 5
Titanium Dioxide
PEG 400
Purified Water
Total
q.s.
100
1. Amorphous cefditoren pivoxil 4, mannitol, sodium polyphosphate and
intragranular croscarmellose sodium were granulated with a solution of
hydroxypropyl methylcellulose in water.
2. The wet granules were dried in a fluid bed drier, passed through a screen and then
subjected to sizing.
3. The extragranular croscarmellose sodium and magnesium stearate were passed
through a screen, blended with the blend of step 2 and the total mixture was
compressed into tablets.
4. The tablets were coated with the coating composition in the coating pan.
In vitro dissolution study:
In vitro release of cefditoren pivoxil from tablets as per composition of Example 5, 6, 7
and 8 were studied in 900 ml water, using USP Dissolution Apparatus (Paddle Type II), at
50 rpm. The results are listed in Table 1.
Table 1: In vitro release of Cefditoren pivoxil from tablets
Time
15
30
60
Percentage (%) of cefditoren pivoxil dissolved
Example 5
21.6
28.3
32.5
Example 6
18.3
22.8
25.5
Example 7
25.4
26.2
35.1
Example 8
23.7
27.6
29.0
While the present invention has been described in terms of its specific
embodiments, certain modifications and equivalents will be apparent to those skilled in the
art and are included within the scope of the present invention.

WE CLAIM:
1. An amorphous Cefditoren pivoxil composition comprising:
a co-precipitated mixture of amorphous Cefditoren pivoxil and one or more water
insoluble carriers.
2. The amorphous Cefditoren pivoxil composition according to claim 1, wherein the ratio of
Cefditoren pivoxil to water insoluble carrier is from about 1:0.1 to about 1:2.
3. The amorphous Cefditoren pivoxil composition according to claim 1, wherein further comprising
one or more wetting agent.
4. The amorphous Cefditoren pivoxil composition according to claim 1, wherein the water insoluble
carrier comprises one or more of crospovidone, colloidal silicon dioxide, microcrystalline
cellulose, cross-linked sodium carboxymethylcellulose, methylcellulose, starch,
carboxymethylcellulose calcium, calcium carbonate and dibasic calcium phosphate and
combinations thereof.
5. The amorphous Cefditoren pivoxil composition according to claim 3, wherein the wetting agent
comprises one or more of propylene glycol, hydroxypropyl cellulose, hydroxypropyl
methylcellulose, poloxamers, polyethylene glycols and tweens.
6. The amorphous Cefditoren pivoxil composition according to claims 1 or 3, wherein further
comprising one or more pharmaceutically inert excipients.
7. The amorphous Cefditoren pivoxil composition according to claim 6, wherein the one or more
pharmaceutically inert excipients comprise one or more of fillers, buffering agents, binders,
disintegrants, coloring agents, flavoring agents, lubricants, glidants, plasticizers and
preservatives.
8. The amorphous Cefditoren pivoxil composition according to claims 1 or 3, wherein the
pharmaceutical composition is a solid dosage form comprising one or more of tablets, capsules
and powders.
9. A process for preparing an amorphous Cefditoren pivoxil comprising Cefditoren pivoxil, and a
water insoluble carrier, the process comprising:
(a) preparing a solution of Cefditoren pivoxil by dissolving crystalline Cefditoren pivoxil in one
or more organic solvents;
(b) dispersing one or more water insoluble carriers in the solution; and
(c) removing the solvent, whereby the amorphous Cefditoren pivoxil and one or more water
insoluble carriers are co-precipitated from the solution.
10. A pharmaceutical composition comprising amorphous Cefditoren pivoxil substantially as
described and illustrated herein.