U.S. patent application number 10/241640 was filed with the patent office on 2003-01-23 for stabilized cefuroxime axetil.
Invention is credited to Sherman, Bernard Charles.
Application Number | 20030017214 10/241640 |
Document ID | / |
Family ID | 4164022 |
Filed Date | 2003-01-23 |
United States Patent
Application |
20030017214 |
Kind Code |
A1 |
Sherman, Bernard Charles |
January 23, 2003 |
Stabilized cefuroxime axetil
Abstract
Solid pharmaceutical compositions comprising cefuroxime axetil
as active ingredient and a zinc salt as stabilizer.
Inventors: |
Sherman, Bernard Charles;
(Willowdale, CA) |
Correspondence
Address: |
IVOR M. HUGHES, BARRISTER & SOLICITOR,
PATENT & TRADEMARK AGENTS
175 COMMERCE VALLEY DRIVE WEST
SUITE 200
THORNHILL
ON
L3T 7P6
CA
|
Family ID: |
4164022 |
Appl. No.: |
10/241640 |
Filed: |
September 12, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10241640 |
Sep 12, 2002 |
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09621676 |
Jul 24, 2000 |
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6485744 |
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Current U.S.
Class: |
424/643 ;
514/202 |
Current CPC
Class: |
A61K 31/546 20130101;
A61K 9/2009 20130101; A61K 9/1611 20130101; A61K 9/1623
20130101 |
Class at
Publication: |
424/643 ;
514/202 |
International
Class: |
A61K 031/545; A61K
033/32 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 29, 1999 |
CA |
2,280,925 |
Claims
What is claimed is:
1. A solid pharmaceutical composition comprising cefuroxime axetil
and a zinc salt.
2. A composition of claim 1, wherein the zinc salt is zinc
chloride.
3. A composition of claim 1 or 2, wherein the amount of zinc salt
is from about 0.1 part to about 4 parts per 100 parts cefuroxime
axetil by weight.
4. A composition of claim 1 or 2, wherein the amount of zinc salt
is from about 0.2 to about 2 parts per 100 parts cefuroxime axetil
by weight.
5. A composition of claim 1 or 2, wherein the amount of zinc salt
is about 1 part per 100 parts cefuroxime axetil by weight.
6. A composition of any of claims 1 to 5, in the form of a
tablet.
7. A composition of any of claims 1 to 5, in the form of powder or
granules for oral suspension.
8. A process of stabilization of cefuroxime axetil comprising the
step of addition of a zinc salt to the cefuroxime axetil.
9. A process of claim 8, wherein the cefuroxime axetil and zinc
salt are both dissolved in solvent and the solvent is
evaporated.
10. A process of claim 8 or 9, wherein the zinc salt is zinc
chloride.
Description
BACKGROUND
[0001] Cefuroxime axetil is an antibiotic effective against a wide
spectrum of microorganisms when administered orally.
[0002] Solid compositions for oral administration comprising
cefuroxime axetil are presently available commercially in the form
of tablets, and as powders for oral suspension.
[0003] There are substantial difficulties in the production of
satisfactory solid compositions comprising cefuroxime axetil.
[0004] One problem is that it is difficult to make compositions for
oral administration which provide high bioavailability; that is to
say, that are well absorbed from the gastrointestinal tract into
systemic circulation. In particular, if the cefuroxime axetil is in
crystalline form, it exhibits poor water solubility and hence poor
absorption.
[0005] U.S. Pat. No. 4,820,833 discloses that absorption can be
improved by using cefuroxime axetil in pure amorphous form instead
of crystalline form.
[0006] U.S. Pat. No. 4,897,270 further discloses that absorption
from film coated tablets can be improved by formulating the tablets
such that, when a tablet is ingested, the film coating ruptures
rapidly in the gastrointestinal fluid, and the core then
disintegrates immediately.
[0007] Canadian patent no. 2209868 discloses that, instead of using
cefuroxime axetil in pure amorphous form, excellent dissolution and
absorption can also be achieved by using cefuroxime axetil in the
form of a co-precipitate of cefuroxime axetil and a water-soluble
excipient.
[0008] A second problem in formulating satisfactory solid
compositions comprising cefuroxime axetil is that cefuroxime axetil
is relatively unstable in the presence of many common excipients
(i.e. inactive ingredients) used to make solid pharmaceutical
compositions.
[0009] The object of the present invention is to provide a means of
stabilizing cefuroxime axetil, so as to reduce the rate of
degradation of cefuroxime axetil in solid pharmaceutical
compositions.
DESCRIPTION OF THE INVENTION
[0010] It has been surprisingly found that cefuroxime axetil can be
stabilized by admixture with a zinc salt, preferably zinc
chloride.
[0011] Compositions of the present invention will thus be solid
pharmaceutical compositions comprising cefuroxime axetil as active
ingredient and a zinc salt as stabilizer.
[0012] The amount of zinc salt in the composition will preferably
be from about 0.1 to about 4 parts per 100 parts cefuroxime axetil
by weight; more preferably from about 0.2 to about 2 parts per
hundred parts cefuroxime axetil by weight; and most preferably
about one part per hundred parts cefuroxime axetil by weight.
[0013] In order to enable maximum bioavailability, the cefuroxime
axetil in the composition will preferably be in pure amorphous form
or in the form of a co-precipitate with a water-soluble
diluent.
[0014] The zinc salt may be added to the composition at any point
in the process of production of the composition.
[0015] However, when the cefuroxime axetil is used in pure
amorphous form or in the form of a co-precipitate, the zinc salt
will preferably be added, in the process of making the pure
amorphous cefuroxime axetil or the co-precipitate, in order to get
a more intimate mixture of the zinc salt with the cefuroxime
axetil.
[0016] In the case of pure amorphous cefuroxime axetil, the process
of manufacture will preferably be to dissolve the zinc salt along
with the cefuroxime axetil in suitable solvent and then evaporate
the solvent, preferably by spray-drying, in order to produce
amorphous material comprising cefuroxime axetil and a small amount
of zinc salt intimately mixed therein.
[0017] Similarly, in the case of a co-precipitate, the process will
preferably be to dissolve the cefuroxime axetil, water-soluble
diluent, and zinc salt together in suitable solvent and evaporate
the solvent, again preferably by spray-drying to produce an
amorphous co-precipitate comprising the cefuroxime axetil,
water-soluble diluent, and zinc salt.
[0018] The amorphous material comprising cefuroxime axetil and zinc
salt, or cefuroxime axetil, water-soluble diluent, and zinc salt,
will then be further processed into the final solid composition
which, as aforesaid, may be a tablet, or a powder or granules for
oral suspension; that is to say, powder or granules to which water
is to be added to provide a suspension for pediatric use.
[0019] The invention will be further illustrated by the following
examples, which are intended to be illustrative but not limiting of
the scope of the invention.
[0020] Solutions were made by dissolving cefuroxime axetil,
sorbitol and zinc chloride in acetone and water in the proportions
shown.
1 Example Example Example Example #1 #2 #3 #4 Cefuroxime axetil 90.
90. 90. 90. Sorbitol 10. 9.6 9.0 8.0 zinc chloride 0 0.4 1.0 2.0
Acetone 400 400 400 400 Water 100 100 100 100 600 600 600 600
[0021] Each of the solutions of examples 1 to 4 was then
spray-dried to produce an amorphous co-precipitate comprising 90%
cefuroxime axetil by weight.
[0022] On a dried basis, the percentage of zinc chloride by weight
was nil in example 1, 0.4% in example 2, 1% in example 3, and 2% in
example 4.
[0023] In each case, the spray-dried co-precipitate was further
processed by mixing the co-precipitate with other ingredients in
the following proportions.
2 Co-precipitate 694. Crospovidone 358. Zinc stearate 8. 1060.
[0024] In each case, the mixture was then compressed into tablets
of weight 1060 mg per tablet. Each tablet thus contained 694 mg of
co-precipitate, which in turn comprised 90%.times.694 mg or 624.2
mg of cefuroxime axetil, which is equivalent to about 500 mg of
cefuroxime. The crospovidone is a disintegrant, and the zinc
stearate is a lubricant to prevent sticking to the tooling in the
tabletting process.
[0025] The tablets of each of these examples were then subjected to
an accelerated stability trial, in which samples were stored at
60.degree. C. for 7 days. The samples were then tested to determine
the amount by which related impurities (i.e. degradation products)
increased during the 7 days at 60.degree. C. The results were as
follows:
3 Example Example Example Example #1 #2 #3 #4 % zinc chloride in 0%
0.4% 1% 2% co-precipitate increase in RC1 0.29% 0.12% 0.06% 0.05%
increase in other 0.09% 0.11% 0.11% 0.17% impurities increase in
total 0.38% 0.23% 0.17% 0.21% impurities RC1 is delta-2-cefuroxime
axetil.
[0026] It can be seen that the increase in RC1 upon storage at
60.degree. C. for 7 days was 0.29% for the tablets of example 1,
which contained no zinc chloride. The increase was less for
examples 2, 3, and 4, but not significantly less for example 4 than
for example 3.
[0027] On the other hand, the increase in other impurities was more
rapid as the level of zinc chloride is increased. The increase in
total impurities was the least for example 3, which had 1% zinc
chloride in the co-precipitate.
[0028] Since the co-precipitate of example 3 comprised 90%
cefuroxime axetil, and 1% zinc chloride, the most preferred amount
of zinc chloride is concluded to be about 1 part per 100 parts
cefuroxime axetil by weight.
* * * * *