U.S. patent application number 11/230057 was filed with the patent office on 2006-01-26 for antimicrobial porous component based on a polymer material grafted with benzalkonium units.
This patent application is currently assigned to Laboratoire Chauvin S.A.. Invention is credited to Jacques Lacombe, Mohammed Naji, Bernard Pages.
Application Number | 20060016739 11/230057 |
Document ID | / |
Family ID | 8849760 |
Filed Date | 2006-01-26 |
United States Patent
Application |
20060016739 |
Kind Code |
A1 |
Naji; Mohammed ; et
al. |
January 26, 2006 |
Antimicrobial porous component based on a polymer material grafted
with benzalkonium units
Abstract
The invention concerns an anti-microbial porous part based on a
polymeric material grafted at the surface and in its volume with
ammonium motifs with anti-microbial and/or bactericidal and/or
fungicide activity, preferably benzalkonium. The invention is
characterized in that it has a porosity sufficiently high to enable
a liquid with compatible viscosity to pass through its structure
and sufficiently low to trap contaminating germs within said
structure.
Inventors: |
Naji; Mohammed;
(Montpellier, FR) ; Pages; Bernard; (Montbazin,
FR) ; Lacombe; Jacques; (Castelnau Le Lez,
FR) |
Correspondence
Address: |
Bausch & Lomb Incorporated
One Bausch & Lomb Place
Rochester
NY
14604-2701
US
|
Assignee: |
Laboratoire Chauvin S.A.
Montpellier Cedex
FR
|
Family ID: |
8849760 |
Appl. No.: |
11/230057 |
Filed: |
September 19, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10258832 |
Feb 26, 2003 |
|
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PCT/FR01/01290 |
Apr 26, 2001 |
|
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11230057 |
Sep 19, 2005 |
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Current U.S.
Class: |
210/106 |
Current CPC
Class: |
A61J 1/145 20150501;
A01N 33/12 20130101; A01N 25/34 20130101; A61F 9/0008 20130101;
A01N 33/12 20130101; A01N 2300/00 20130101; A01N 25/34 20130101;
A61J 1/1456 20150501; A01N 25/10 20130101; A01N 33/12 20130101 |
Class at
Publication: |
210/106 |
International
Class: |
B01D 24/46 20060101
B01D024/46; B01D 29/62 20060101 B01D029/62 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 28, 2000 |
FR |
00/05532 |
Claims
1-14. (canceled)
15. A porous antimicrobial component formed of a polymer material
in the form of a sinter and grafted at its surface and in its bulk
with ammonium units having at least one of antimicrobial activity,
bactericidal activity and fungicidal activity.
16. The porous component of claim 15, wherein the polymer material
is derived from a polymer comprising units of formula (I)
--[CH.sub.2--CH(Ar)]-- (I) in which Ar represents a chain of
formula:
--Ph--CH.sub.2--N.sup..sym.(CH.sub.3).sub.2R,X.sup..crclbar. (II)
or --Ph--CH.sub.2--X (III) in which: R represents a
C.sub.2-C.sub.15 alkyl, Ph is a phenyl unit, and the ion X.sup.- is
a pharmaceutically acceptable anion, with chains of formula II
being present in an amount that is sufficient to give said polymer
material antimicrobial, bactericidal or fungicidal properties.
17. The porous component of claim 16, wherein the polymer is a
polystyrene partially grafted with dimethyltetradecylamine
units.
18. The porous component of claim 17, wherein the polystyrene is
grafted to a molar percentage of 15% to 30% of benzalkonium
units.
19. The porous component of claim 15, which has a porosity of
between 5 and 30 microns.
20. A bottle for packaging a liquid solution, comprising a
distribution nozzle that includes a porous component of claim
15.
21. The bottle of claim 20, wherein the liquid solution is a
solution for food, medicinal or dermatological use.
22. The bottle of claim 20, wherein the bottle is for packaging an
ophthalmic solution.
Description
[0001] The present invention relates to the field of packaging
liquid solutions for which it is desired to ensure no microbial
contamination. The fields for which the present invention is more
particularly intended are those of pharmacy and especially that of
ophthalmology.
[0002] In general, any liquid solution of the therapeutic and
especially ophthalmic field is packaged in a device of bottle type
adapted with a nozzle to distribute this solution. This nozzle is
hermetically sealed until the time of use, so as to protect the
packaged solution against any risk of contamination, in particular
by microorganisms from the ambient atmosphere.
[0003] The problem posed and solved according to the present
invention is directed toward ensuring that the packaged solution is
protected after opening the bottle and during its period of
use.
[0004] Two alternatives are currently available to assure the user
of this antimicrobial protection.
[0005] The first option consists in offering him liquid solutions
into which have been incorporated antimicrobial or bactericidal
preserving agents. This type of solution has the advantage of being
compatible with prolonged use of the packaged solution over time.
On the other hand, these preserving agents may cause adverse side
effects in the case of certain users.
[0006] The second option consists in formulating the solution in
the form of single-use doses. The solutions thus packaged lack
preserving agents, but, on the other hand, are incompatible with a
prolonged use of more than 3 hours. The major drawback of this
second type of packaging is thus threefold: cost, bulk of the
packaging (for one month of treatment) and difficulty of
installation and impossibility of reuse without the risk of
contamination.
[0007] There is therefore currently a need for a novel packaging
for a sterile liquid solution, which is compatible with prolonged
use of this solution over time, but which does not require the
incorporation into said solution of antimicrobial and/or
bactericidal preserving agents.
[0008] New types of devices have been developed taking these
considerations into account. However, they are not considered to be
entirely satisfactory since they generally involve a new bottling
concept which, for reasons of costs, has not been taken up by
industrialists.
[0009] One object of the present invention is, specifically, to
propose a solution that satisfies all the points discussed
above.
[0010] A first aspect of the invention thus relates to a porous
antimicrobial component based on polymer material grafted at the
surface and in bulk with ammonium units with antimicrobial and/or
bactericidal and/or fungicidal activity, characterized in that it
has a porosity that is, on the one hand, high enough to allow the
passage through its structure of a liquid of compatible viscosity,
and, on the other hand, low enough to ensure that contaminant
microorganisms are trapped within this structure.
[0011] The inventors have thus demonstrated that it is possible
using such a porous component to satisfy all the requirements
presented above.
[0012] The porous component according to the invention has the
first advantage of being entirely compatible with the
already-existing bottling devices. Given its size, it may be
inserted easily into the distribution nozzle of bottles and provide
at this level an effective barrier function between the solution
packaged in the bottle receptacle and the end of the distribution
nozzle exposed to the ambient atmosphere.
[0013] Owing to its chemical structure, which incorporates units
with antimicrobial and/or bactericidal activity at the surface and
in the bulk, it allows, by means of an effect of retention of the
contaminant microorganisms, within its active surface, an effective
isolation of these microorganisms with respect to the liquid
solution, and then, by intimate contact between the material and
the microorganisms, the reduction and elimination over time of such
microorganisms.
[0014] Finally, its porous structure which has a deep-down internal
network of tubules, allows the liquid solution to pass when it is
administered.
[0015] The threefold objective mentioned previously is consequently
achieved using the porous component according to the invention.
[0016] More specifically, the chemical structure of this porous
component is derived from a polymer consisting of units of general
formula I: --[CH.sub.2--CH(Ar)]-- (I) in which Ar represents a
chain of formula:
--Ph--CH.sub.2--N.sup..sym.(CH.sub.3).sub.2R,X.sup..crclbar. (II)
or --Ph--CH.sub.2--X (III) in which: [0017] R represents a
C.sub.2-C.sub.15 alkyl, [0018] Ph is a phenyl unit, and [0019]
X.sup.- is chosen from the anions usually used in the field, which
are pharmaceutically acceptable with chains of formula II being
present in an amount that is sufficient to give the said material
antimicrobial properties.
[0020] Representative of the ions featured by X.sup.-, mention may
be made more particularly of halides, for instance chloride,
bromide or iodide, acetate, benzoate, carbonate, citrate, formate,
gluconate, glycolate, hydroxide, lactate, malate, maleate,
malonate, nitrate, phosphate, propionate, succinate, sulfate,
tartrate and the like. According to one preferred variant of the
invention, it is a chloride anion.
[0021] According to one preferred variant of the invention, the
polymer is derived from a polystyrene, which is preferably
non-crosslinked.
[0022] As regards the benzalkonium units of formula II, they
preferably comprise as quaternary ammonium a
dimethyltetradecylammonium group.
[0023] The content of units of benzalkonium type of formula II
present on the polymer structure is liable to vary as a function
especially of the nature of the polymer skeleton and of that of the
substituents featured on the benzalkonium unit.
[0024] In point of fact, it is adjusted so as to achieve a
compromise between the antimicrobial and/or antibacterial efficacy
and the assurance, as regards the plastic material thus
constituted, of a hydrophobicity which is compatible with the
desired use. Specifically, an excessively high degree of grafting
on the polymer can give it an excessively hydrophilic nature, which
is reflected by the formation of a gel when the material comes into
contact with an aqueous solution, this phenomenon not being
compatible with the desired use.
[0025] When the polymer is made of a polystyrene skeleton, this
compromise is advantageously achieved for a molar percentage of
grafting from about 15% to 30%, and preferably of about 20%, i.e. a
weight percentage of benzalkonium units of formula II of about 30%
to 40%, and preferably of about 36%, of the mass of the grafted
polymer thus obtained. Clearly, it is possible to lower this value
as a function of the desired antimicrobial efficacy.
[0026] The polymer material is preferentially a polystyrene
partially grafted with dimethyltetradecylammonium units and
preferably grafted to a molar percentage of between 18% and
25%.
[0027] The polymer material may be obtained by reacting a polymer
consisting of units ##STR1## such as, preferably, a chloromethyl
polystyrene, with an amine of formula N(CH.sub.3).sub.2(R) with X
and R being as defined above, in a homogeneous medium, i.e. in a
solubilized form, and in a molar ratio adjusted as a function of
the desired degree of grafting.
[0028] According to one preferred preparation method, the polymer
material is purified beforehand by dissolving it in an organic
solvent such as dichloromethane and reprecipitating it by adding an
alcohol such as methanol. The polymer thus recrystallized is
collected by filtration. This step allows the removal from the
polymer of low molecular weight compounds which, after the grafting
reaction, are liable to be released into the aqueous medium.
[0029] The polymer thus purified and the amine defined above are
dissolved in an organic medium such as acetone and kept stirring
constantly for 24 hours at room temperature.
[0030] Preferably, the grafted amine is dimethyltetradecylamine and
the molar percentage of grafting is in the region of 20%.
[0031] The material thus obtained is then isolated, preferably by
precipitation by incorporating a solvent such as hexane into the
reaction medium. This treatment not only allows the material to be
purified, but also allows a powder of uniform particle size to be
obtained. Adjusting the stirring conditions and the volumes of
solvent used produces a product of perfectly controlled purity and
particle size.
[0032] The antimicrobial and/or bactericidal and/or fungicidal
activity of the material thus obtained was tested especially with
respect to Pseudomonas, Staphylococcus, Candida and Aspergillus
strains. This test forms the subject of Example 2 below.
[0033] The antimicrobial activity of the polymer material satisfies
criteria A of the European Pharmacopoeia for 3 reference
microorganisms (Staphylococcus aureus, Pseudomonas aeruginosa and
Candida albicans) and criteria B for the fourth reference
microorganism (Aspergillus niger), which is reputed to be
relatively insensitive to quaternary ammoniums, even solubilized
ones. With an initial contaminant load of 100 000 microorganisms
(in 0.1 ml of microbial suspension) per 100 mg of material, these
results obtained without stirring are entirely satisfactory and
reproducible.
[0034] Similarly, the aqueous insolubility of the material and the
absence of release of its constituent units (quaternary ammonium
oligomers of low molecular weight) were demonstrated after 24 hours
of contact with vigorous stirring between 2 grams of material and
100 ml of distilled water: the integrity of the solutions is thus
ensured in the long term, since the contact between the porous
component and the packaged solution is limited to the passage
through the porous component during delivery.
[0035] The polymer material thus obtained is then fashioned as a
single porous component. This fashioning may be performed according
to various techniques familiar to those skilled in the art, such
as, for example, the technique consisting in compacting the powder
of the material defined above in the form of a sinter. In a mold of
defined dimensions and under parameterized temperature and pressure
conditions, the grains of material are softened to stick together
so as thus to form a rigid plastic component. The interstices left
free between the adhered grains of powder create a multidimensional
network of tubules which give the component deep-down porosity.
[0036] After this fashioning, a material is thus obtained which is
functionalized at the surface and in the bulk with units with
antimicrobial activity, and which has a porosity that is sufficient
to allow a solution of low viscosity to pass through the
structure.
[0037] The deep-down porosity of the component defined above is
conditioned firstly by the particle size homogeneity of the
material and the mean grain size of the material, and secondly by
the resistance of this same material to the temperature and
pressure conditions used.
[0038] The porous component according to the invention is
preferably in the form of a sinter whose deep-down porosity is
between 5 and 30 microns, requiring a mean particle size of the
material of between 30 and 350 microns and preferably between 80
and 125 microns.
[0039] A third aspect of the invention relates to the use of the
porous component claimed in the distribution nozzle of a bottle for
packaging a liquid solution.
[0040] The solutions concerned may be of very diverse nature. They
may especially be solutions for food use (such as fruit juices or
liquid yogurts), for medicinal use (such as drinkable solutions,
syrups, ophthalmic solutions, nasal solutions or auricular
solutions) or for dermatological use (such as bodily fluids or
make-up-removing solutions).
[0041] In point of fact, the only selection criterion of this
solution is linked to its viscosity. It must, of course, be
compatible with the deep-down porosity of the porous component.
[0042] According to one preferred mode of the invention, the
packaged solution is an ophthalmic solution.
[0043] The third aspect of the invention relates more particularly
to a nozzle for distributing a liquid solution, of the type
comprising a tube comprising an inner channel and fitted, at one of
its ends, with an end piece for fitting into a bottle opening, and,
at the other of a said ends, with an orifice for the dropwise
delivery of the liquid solution, characterized in that the tube
comprises in said inner channel a porous component as defined
above.
[0044] As discussed previously, one of the advantages of the porous
component claimed is that of being able to be adapted to any
already-existing bottling system. Specifically, it is possible to
fashion, from the polymer material, porous components whose sizes
are adjusted to the distribution nozzles of the bottles under
consideration.
[0045] The examples and figures are given below for the purpose of
nonlimiting illustration of the present invention.
FIGURES
[0046] FIG. 1 represents a diagrammatic view in exploded
perspective of a bottle equipped with a liquid solution
distribution nozzle, and
[0047] FIG. 2 represents a diagrammatic view in axial cross section
of this nozzle equipped with an antimicrobial porous component in
accordance with the invention.
[0048] Shown in FIG. 1 is a bottle denoted as a whole by reference
1, which comprises a body 2 forming a reservoir intended to contain
the liquid solution. The body 2 comprises at the top a neck 3
equipped with an opening 4 for mounting a nozzle for distributing
said liquid solution contained in the body 2.
[0049] Moreover, the neck 3 is provided on its outer surface with a
thread 5 to screw on a cap, not shown, intended to close the
nozzle.
[0050] The nozzle denoted by the general reference 10 is formed of
a tube 11 comprising an inner channel 12. This tube 11 is fitted,
at one of its ends, with an end piece 13 for fitting into the
opening 4 of the body 2 of the bottle 1 and, at the other of said
ends, with an orifice 14 for dropwise delivery of the liquid
solution contained in said bottle 1.
[0051] The tube 11 is also equipped externally with a groove 15 for
snap-fitting onto a rim made in the orifice 4 of the body 2 and
also with a stop flange ring 16 on the top edge of the neck 3 of
the bottle 1.
[0052] The tube 11 comprises in the inner channel 12 an
antimicrobial porous component 20.
[0053] Preferably, the porous component 20 comprises at one of its
ends a tip 21 for penetrating into the orifice 14 for delivery of
the liquid solution.
[0054] This porous component 20 has a porosity that is on the one
hand high enough to allow the passage through its structure of a
liquid of compatible viscosity, and on the other hand low enough to
ensure that contaminant microorganisms are trapped within this
structure.
[0055] These microorganisms are then, by contact activity, reduced
and eliminated therein.
EXAMPLES
Example 1
Manufacture of an Antimicrobial Material
[0056] The chloromethyl polystyrene corresponds to the Aldrich
reagent ref: 18,253-2/batch 00128 TQ.
[0057] The dimethyltetradecylamine coresponds to the Fluka reagent
ref: 41653/batch 363679/1-22399.
[0058] The chloromethyl polystyrene (21 g) is dispersed in 2000 ml
of methanol for 1 hour, recovered by filtration, dissolved in 130
ml of dichloromethane and then reprecipitated in 2000 ml of
methanol. This step is repeated. The polymer thus purified is
isolated by filtration after stirring for 1 hour 30 minutes, and
then oven-dried at 40.degree. C.
[0059] 20 g of purified polymer are dissolved in 40 ml of acetone
in a 2 liter round-bottomed flask with stirring, and 6.4 g of
dimethyltetradecylamine are then incorporated. The mixture is
stirred for 24 hours.
[0060] The grafted product is isolated by precipitation by
gradually adding to the reaction medium with stirring 1500 ml of
hexane. The mixture is stirred for 4 hours and the product obtained
is then oven-dried at 40.degree. C.
[0061] The product obtained is screened so as to obtain a particle
size of between 80 and 125 microns.
[0062] 25 grams of the product thus obtained are washed in 1000 ml
of distilled water for 1 hour with stirring, and the final product
is isolated by filtration and then oven-dried at 40.degree. C. for
12 hours. 25 grams of the expected material are thus obtained.
[0063] The characterization of the material obtained was performed
by proton Nuclear Magnetic Resonance in deuterated chloroform, Gel
Permeation Chromatography, chloride assay and Differential Thermal
Analysis: the results confirm the expected structure of the
polymer.
[0064] The aqueous insolubility of the material was checked after
24 hours of contact under vigorous stirring between 2 grams of
material and 100 ml of distilled water: no significant weight loss
is detected on the material before and after treatment and the
aqueous solution does not contain any soluble benzalkonium units.
The UV, HPLC and GC monitoring of this same solution make it
possible to conclude that the constituent low molecular weight
compounds of the polymer are not released into the water to a dose
of greater than 0.05 mg/liter, thus confirming that the
antimicrobial activity of the material is a contact activity.
Example 2
Antimicrobial Efficacy of the Porous Component
[0065] In order to check the antimicrobial activity of the material
defined above, the product is subjected to the antimicrobial
conversion efficacy test of the European Pharmacopoeia.
[0066] The test microorganisms are Pseudomonas aeruginosa,
Staphylococcus aureus, Candida albicans and Aspergillus niger.
[0067] For each test microorganism, 4 hemolysis tubes each
containing 100 mg of material are inoculated with 100 000
microorganisms in 0.1 ml; homogenize and leave in contact without
stirring.
[0068] At each prescribed interval (6 hours, 24 hours, 7 days, 14
days and 28 days of contact), the residual viable microorganisms
were counted.
[0069] The results obtained are expressed relative to the initial
count of the inoculum, in the form of a decimal logarithmic
reduction.
[0070] The criteria of the European Pharmacopoeia are given in the
following table:
Parenteral and Ophthalmic Preparations
[0071] TABLE-US-00001 Logarithmic reduction 6 24 7 14 28 hours
hours days days days Bacteria CRITERIA A 2 3 -- -- NF* CRITERIA B
-- 1 3 -- NI** Fungi CRITERIA A -- -- 2 -- NI** CRITERIA B -- -- --
1 NI** *NF: not found **NI: no increase
[0072] The results obtained on the material according to the
invention described above are listed in the following table:
TABLE-US-00002 Pseudomonas Staphylococcus Aspergillus niger Candida
albicans aeruginosa aureus ATCC 16 404 ATCC 10 231 CIP 82 118 CIP 4
83 {Inoculum} in CFU/ml 1.60 .times. 10.sup.6 1.39 .times. 10.sup.6
1.43 .times. 10.sup.6 1.85 .times. 10.sup.6 Amount of CFU
introduced in 160 000 139 000 143 000 185 000 0.1 ml T 6 hours
Amount of CFU -- -- 0 0 counted in the dipping solution Logarithmic
-- -- NF NF reduction R T 24 hours Amount of CFU -- -- 0 0 counted
in the dipping solution Logarithmic -- -- NF NF reduction R T 7
days Amount of CFU 95 000 0 0 0 counted in the dipping solution
Logarithmic 0.23 NF NF NF reduction R T 14 days Amount of CFU 2 576
0 -- -- counted in the dipping solution Logarithmic 1.79 NF -- --
reduction R T 28 days Amount of CFU 0 0 0 0 counted in the dipping
solution Logarithmic NF NF NF NF reduction R Conclusion: criterion
obtained B A A A NF = not found
[0073] The antimicrobial activity of the polymer material satisfies
criteria A of the European Pharmacopoeia for Staphylococcus aureus,
Pseudomonoas aeruginosa and Candida albicans (the microorganisms
being entirely eliminated after 6 hours for the two bacteria and 7
days for the yeast, respectively) and criteria B for Aspergillus
niger (the mold being totally eliminated after 28 days).
* * * * *