U.S. patent application number 11/381252 was filed with the patent office on 2006-08-31 for aqueous polymer dispersion.
Invention is credited to Maximilian Angel, Karl Kolter, Katrin Zeitz.
Application Number | 20060193798 11/381252 |
Document ID | / |
Family ID | 26007249 |
Filed Date | 2006-08-31 |
United States Patent
Application |
20060193798 |
Kind Code |
A1 |
Kolter; Karl ; et
al. |
August 31, 2006 |
Aqueous Polymer Dispersion
Abstract
An aqueous polymer dispersion prepared by free-radical
polymerization of vinyl acetate in the presence of at least one
ionic emulsifier, at least one free-radical initiator and at least
one protective colloid, wherein the polymerization is carried out
in the presence of a polymerization regulator and wherein the ratio
by weight of protective colloid to ionic emulsifier is at least 4:1
and wherein the ratio by weight of vinyl acetate monomer to
protective colloid is between 19:1 and 4:1.
Inventors: |
Kolter; Karl; (Limburgerhof,
DE) ; Angel; Maximilian; (Schifferstadt, DE) ;
Zeitz; Katrin; (Ludwigshafen, DE) |
Correspondence
Address: |
NOVAK DRUCE DELUCA & QUIGG, LLP
1300 EYE STREET NW
SUITE 400 EAST TOWER
WASHINGTON
DC
20005
US
|
Family ID: |
26007249 |
Appl. No.: |
11/381252 |
Filed: |
May 2, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10381372 |
Mar 25, 2003 |
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PCT/EP01/11053 |
Sep 25, 2001 |
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11381252 |
May 2, 2006 |
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Current U.S.
Class: |
424/59 ; 424/486;
424/70.15; 504/361 |
Current CPC
Class: |
A61K 9/284 20130101;
A61K 9/5026 20130101; A61K 8/046 20130101; C08F 271/02 20130101;
C08F 2/26 20130101; A61L 26/0076 20130101; A61K 8/8135 20130101;
C08F 118/08 20130101; A61K 9/7053 20130101; C08F 2/24 20130101;
A61Q 17/04 20130101; A61K 9/7015 20130101 |
Class at
Publication: |
424/059 ;
424/070.15; 424/486; 504/361 |
International
Class: |
A61K 8/81 20060101
A61K008/81; A61K 9/14 20060101 A61K009/14; A01N 25/10 20060101
A01N025/10 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 29, 2000 |
DE |
10048888.9 |
May 10, 2001 |
DE |
10122786.8 |
Claims
1.-37. (canceled)
38. A pharmaceutical dosage form comprising an active ingredient
and, as an auxiliary, an aqueous dispersion of polyvinyl acetate
prepared by free-radical polymerization of vinyl acetate monomer in
the presence of at least one ionic emulsifier, at least one
free-radical initiator and at least one protective colloid, wherein
the polymerization is carried out in the presence of a
polymerization regulator, and wherein the ratio by weight of
protective colloid to ionic emulsifier is at least 4:1, and the
ratio by weight of the vinyl acetate monomer to protective colloid
is between 19:1 and 4:1.
39. A solid pharmaceutical, agrochemical or nutritional dosage form
comprising, as a coating agent, an aqueous dispersion of polyvinyl
acetate prepared by free-radical polymerization of vinyl acetate
monomer in the presence of at least one ionic emulsifier, at least
one free-radical initiator and at least one protective colloid,
wherein the polymerization is carried out in the presence of a
polymerization regulator, and wherein the ratio by weight of
protective colloid to ionic emulsifier is at least 4:1, and the
ratio by weight of the vinyl acetate monomer to protective colloid
is between 19:1 and 4:1.
40. A detergent, dishwashing and cleaning composition of any type
comprising, as an auxiliary, an aqueous dispersion of polyvinyl
acetate prepared by free-radical polymerization of vinyl acetate
monomer in the presence of at least one ionic emulsifier, at least
one free-radical initiator and at least one protective colloid,
wherein the polymerization is carried out in the presence of a
polymerization regulator, and wherein the ratio by weight of
protective colloid to ionic emulsifier is at least 4:1, and the
ratio by weight of the vinyl acetate monomer to protective colloid
is between 19:1 and 4:1, or a powder prepared therefrom.
41. The composition as claimed in claim 40, wherein the detergent,
dishwashing or cleaning composition is in the form of granules.
42. A fragrance or flavoring comprising, as coating or embedding
agent, an aqueous dispersion of polyvinyl acetate prepared by
free-radical polymerization of vinyl acetate monomer in the
presence of at least one ionic emulsifier, at least one
free-radical initiator and at least one protective colloid, wherein
the polymerization is carried out in the presence of a
polymerization regulator, and wherein the ratio by weight of
protective colloid to ionic emulsifier is at least 4:1, and the
ratio by weight of the vinyl acetate monomer to protective colloid
is between 19:1 and 4:1, or a powder prepared therefrom as coating
or embedding agents.
43. A process for coating a surface comprising spraying a
preparation comprising an aqueous dispersion of polyvinyl acetate
prepared by free-radical polymerization of vinyl acetate monomer in
the presence of at least one ionic emulsifier, at least one
free-radical initiator and at least one protective colloid, wherein
the polymerization is carried out in the presence of a
polymerization regulator, and wherein the ratio by weight of
protective colloid to ionic emulsifier is at least 4:1, and the
ratio by weight of the vinyl acetate monomer to protective colloid
is between 19:1 and 4:1, or a powder prepared therefrom onto the
surface.
44. The process as claimed in claim 43, wherein the surface
comprises human or animal skin.
45. The process as claimed in claim 43, wherein the preparation is
a wound dressing spray.
46. A transdermal therapeutic system comprising an aqueous
dispersion of polyvinyl acetate prepared by free-radical
polymerization of vinyl acetate monomer in the presence of at least
one ionic emulsifier, at least one free-radical initiator and at
least one protective colloid, wherein the polymerization is carried
out in the presence of a polymerization regulator, and wherein the
ratio by weight of protective colloid to ionic emulsifier is at
least 4:1, and the ratio by weight of the vinyl acetate monomer to
protective colloid is between 19:1 and 4:1, or a powder prepared
therefrom.
47. A cosmetic preparation comprising an aqueous dispersion of
polyvinyl acetate prepared by free-radical polymerization of vinyl
acetate monomer in the presence of at least one ionic emulsifier,
at least one free-radical initiator and at least one protective
colloid, wherein the polymerization is carried out in the presence
of a polymerization regulator, and wherein the ratio by weight of
protective colloid to ionic emulsifier is at least 4:1, and the
ratio by weight of the vinyl acetate monomer to protective colloid
is between 19:1 and 4:1, or a powder prepared therefrom.
48. A process for protecting skin from sunburn, said process
comprising applying to the skin a preparation comprising an aqueous
dispersion of polyvinyl acetate prepared by free-radical
polymerization of vinyl acetate monomer in the presence of at least
one ionic emulsifier, at least one free-radical initiator and at
least one protective colloid, wherein the polymerization is carried
out in the presence of a polymerization regulator, and wherein the
ratio by weight of protective colloid to ionic emulsifier is at
least 4:1, and the ratio by weight of the vinyl acetate monomer to
protective colloid is between 19:1 and 4:1.
Description
[0001] The invention relates to an aqueous polymer dispersion
prepared by free-radical polymerization of vinyl acetate, to a
process for preparing an aqueous polymer dispersion of this type,
and to the use thereof.
[0002] U.S. Pat. No. 5,252,704 discloses polymer powders which can
be redispersed in water and which are prepared using
polyvinylpyrrolidone (PVP) as dispersant. The polymer powders are
prepared with use inter alia of vinyl esters in a conventional
emulsion polymerization. PVP is added to the emulsion before the
spray drying. The polymer powders are intended in particular as
additives for cement mixtures.
[0003] DE 43 41 156 C1 discloses the use of plastic dispersion
powders which are redispersible in water as pharmaceutical carriers
in drug forms with controlled delivery of active ingredient, the
powders having a core/shell structure with particular values of Tg
for the core polymers and shell polymers.
[0004] DE 197 09 532 A describes the use of redispersible polymer
powders or polymer granules for coating pharmaceutical or
agrochemical dosage forms, the powders or granules consisting of 10
to 95% by weight of polyvinyl acetate and 5 to 90% by weight of an
N-vinylpyrrolidone-containing polymer and, where appropriate, other
additives.
[0005] For producing pharmaceutical dosage forms there are
frequently used, as in DE 197 09 532, polymer powders which must be
redispersed in water to produce these dosage forms. The reasons for
this preparation of redispersible powders is that it is frequently
impossible to stabilize the aqueous preparations appropriately for
them to comply with the great demands made on starting materials
for pharmaceuticals. Thus, for example, there must be no
microbiological attack nor any increase in particle size, to say
nothing of coagulation or sedimentation, because reliable
production of the pharmaceutical is endangered thereby. The aqueous
preparations are often stable only for some weeks. To prolong the
stability, the aqueous preparations are converted into powders from
which it is necessary in turn to prepare an aqueous preparation by
stirring into water before use. This procedure consumes a large
amount of energy and time and the thermal and mechanical stresses
on the product during spray drying and stirring change the original
properties. In addition, the reproducibility of important
properties of the dosage forms, such as, for example, the release
of active ingredient, is often poor because redispersible powders
frequently result in coatings which adhere poorly, do not form
complete films and are inhomogeneous. One reason for this is
certainly that it is never possible to obtain a 100% redispersion
of the powders, and such redispersions therefore always contain
proportions of coarse particles or particle agglomerates (larger
than 1 .mu.m in diameter). A shift in the average particle diameter
to values greater than 300 nm is enough to result in poor use
properties.
[0006] Solid pharmaceutical dosage forms such as tablets, capsules,
pellets, granules, crystals etc. are coated, i.e. provided with a
film coating, for a wide variety of reasons. Thus, for example, it
is possible to mask an unpleasant odor or taste and improve the
swallowability. The stability of the active ingredient may be
increased by the coating since less water vapor and oxygen reaches
the interior of the tablets. The dosage forms have a better
appearance and can be distinguished better by incorporating dyes.
In addition, it is possible in particular to adjust the rate of
release of active ingredient by the film coating. These criteria
also apply in a similar way to agrochemical dosage forms.
[0007] In general, a distinction is made between instant release
forms and sustained or slow release forms.
[0008] The intention with instant release forms is to release the
active ingredient in the shortest possible time. In these cases the
coating must impede release of the active ingredient from the core
only slightly or not at all. In pharmaceutical technology, instant
release forms are preparations from which more than 80% of the
active ingredient are released within one hour.
[0009] By contrast, release from sustained release forms is delayed
in order, for example, to avoid plasma level peaks and thus
possible side effects, or to reduce the frequency of intake. In the
so-called coated sustained release forms, a film coating slows down
the release of the drug substance. Frequently employed for this
purpose are water-insoluble cellulose derivatives such as
ethylcellulose or (meth)acrylate copolymers, in particular
Eudragit.RTM. NE, RS and RL (Rohm Pharma). For Eudragit.RTM. RS and
RL it is recommended to add from 10 to 20% by weight, based on the
film former, of plasticizer. An even higher plasticizer content
(about 30% by weight) is indispensable for ethyl cellulose. Only
Eudragit.RTM. NE requires no plasticizer because it has a very low
glass transition temperature and minimum film-forming temperature.
However, this causes it to be tacky and difficult to process.
[0010] It is an object of the present invention to provide starting
materials for producing in particular pharmaceutical dosage forms,
which are very stable on storage, which can be processed very
easily, which in particular easily result in good, homogeneous film
coatings with very reproducible release and which, where
appropriate, need not be prepared from powders which are initially
dried and then redispersed in H.sub.2O.
[0011] We have found that this object is achieved by an aqueous
polymer dispersion prepared by free-radical polymerization of vinyl
acetate in the presence of at least one ionic emulsifier, at least
one free-radical initiator and at least one protective colloid,
wherein the polymerization is carried out in the presence of a
polymerization regulator and wherein the ratio by weight of
protective colloid to ionic emulsifier is at least 4:1, preferably
at least 8:1, particularly preferably in the range between 8:1 and
12:1, and wherein the ratio by weight of vinyl acetate monomer to
protective colloid is between 19:1 and 4:1, preferably between 15:1
and 6:1.
[0012] A preferred embodiment of the abovementioned aqueous polymer
dispersion is prepared by free-radical polymerization at a pH in
the range from 1 to 7, particularly preferably in the range from 3
to 6.
[0013] It has proved advantageous in this connection for the pH to
be kept constant in the range from pH 1 to pH 7 during the
polymerization by addition of a reagent with a basic action. A pH
kept constant means, both during and after the polymerization, a pH
with variations in the region of +/-1.5, preferably +/-1,
particularly preferably +/-0.5 units.
[0014] The reagents with a basic action used for the purposes of
the invention are preferably alkali metal or alkaline earth metal
hydroxides, particularly preferably aqueous solutions of an alkali
metal or alkaline earth metal hydroxide--especially sodium
hydroxide or potassium hydroxide solution--and aqueous ammonia
solutions.
[0015] It has proved to be particularly advantageous for the pH to
be kept constant during the polymerization by addition of a buffer
system.
[0016] Buffer systems mean conventional buffer and/or polymeric
buffers.
[0017] Examples of suitable buffers are all salts of weak acids and
strong bases or strong acids and weak bases, it being possible for
the salts to be of the same acids or bases or mixtures of different
acids or bases.
[0018] It is preferred in this connection for the buffering range
of the buffer system to be chosen between pH 1 to 7. Suitable
buffers or buffer solutions with a buffering range in acidic medium
between pH 1 to 7 are, for example, buffers such as Walpole buffer
(acetic acid/Na acetate, pH 3.6-5.6), Gomori aconitate buffer
(aconitic acid/NaOH, pH 2.5-5.7), Kolthoff buffer (borax/succinate,
pH 3.0-5.8), Sorensen citrate buffer (disodium citrate/HCl, pH
2.2-4.8), Sorensen glycine I buffer (glycine, NaCl/HCl, pH
1.2-3.6), Clark and Lub phthalate I buffer (potassium
biphthalate/HCl, pH 2.2-3.8), Clark and Lub phthalate II buffer
(potassium-biphthalate/NaOH, pH 4.0-6.2), Smith and Smith
piperazine buffer (piperazine, HCl/NaOH, pH 4.8-7.0), Clark and Lub
potassium chloride/HCl buffer (KCl/HCl, pH 1.0-2.2), Gomori tris
maleate buffer (tris maleate/NaOH, pH 5.2-8.6) or Gomori succinate
buffer (succinate/NaOH, pH 3.8-6.0). Buffers such as MES, ADA,
PIPES or ACES, which are buffers customary in biochemistry, or
amino acid buffers are also suitable buffers.
[0019] Preferred buffers are those which can advantageously be
prepared from weak acids and their salts, such as, for example,
sodium acetate/acetic acid, sodium borate/boric acid, sodium
phosphate/phosphoric acid, bicarbonate/sodium carbonate, sodium
hydroxide/citric acid, sodium hydroxide/tartaric acid. Buffers of
weak bases and their salts are also suitable. It is possible to use
individual buffers or mixtures for adjusting the pH in the
dispersions.
[0020] It is also possible to use buffer systems with a buffer
range between pH 7 to 13. Suitable buffers and buffer solutions
with a buffering range in basic medium between pH 7 to 13 are, for
example, buffers such as Clark and Lub borate buffer (boric acid,
KCl/NaOH, pH 7.8-10.0), Delory and King buffer
(carbonate/bicarbonate, pH 9.2-10.7) or Sorensen glycine II buffer
(glycine, NaCl/HCl, pH 8.4-13). Buffers such as cholamine chloride,
BES, TES, HEPES, acetamidoglycine, glycinamide, tris, bicine,
tricine or glycylglycine, which are buffers customary in
biochemistry, or amino acid buffers are also suitable buffers.
[0021] Buffer systems which can also be used are salts, for example
sodium salts of succinic acid, pyruvic acid, maleic acid, malonic
acid, malic acid, lactic acid and other amino acids. It is also
possible to consider as buffer salts of polyacrylic acid,
polymethacrylic acid, acrylic acid/methacrylic acid copolymers,
carboxymethylcellulose, carboxymethyl starch, hemiesters of
cellulose, hydroxypropylmethylcellulose or polyvinyl alcohol with
polybasic acids such as phthalic acid, succinic acid or trimellitic
acid.
[0022] It is possible with this aqueous polymer dispersion, without
the need for redispersion with the disadvantages associated
therewith, to apply homogeneous film coatings with great
reproducibility in a simple process step, in particular to
pharmaceutical, agrochemical or nutritional dosage forms, which
adhere extremely well, are resistant to external influences and
ensure reproducible release of active ingredient. Compared with
powders which are redispersible in H.sub.2O, the amount which must
be applied to achieve a particular release rate is less, thereby
saving further costs.
[0023] "Nutritional dosage forms" mean tablets, capsules, granules
or similar solid forms which do not contain active pharmaceutical
ingredients but contain food supplements such as vitamins,
carotenoids, minerals, plant extracts or nutraceuticals.
[0024] The preparations of the invention are unexpectedly
insensitive to other auxiliaries normally employed in spray
preparations, such as pigments, fillers, thickeners, suspension
stabilizers, emulsifiers, gloss improvers, release accelerators
etc. and to shear stress and variations in the coating process.
Because the (polymer) films are very elastic, no fissuring occurs
on storage because the coatings comply with the changes in shape of
the core, for example caused by a change in ambient humidity.
Coatings of this type are therefore also stable in regions with
extremes of climate such as cold or high humidity.
[0025] It has surprisingly emerged that the aqueous polymer
dispersions of the invention--although they were prepared with the
aid of a regulator and thus tend to have low molecular weights and
K values--are not at all tacky and can be sprayed distinctly more
quickly onto solid dosage forms than the preparations previously
disclosed, without agglomeration or sticking together of shaped
articles or the coating becoming rough. This increased spraying
rate is associated with a distinct cost advantage on use. The
coating process is speeded up further through an increase in the
inlet air temperature and the solids concentration in the spray
solution. This is not possible with conventional preparations.
[0026] The dosage forms coated with the aqueous polymer dispersions
of the invention show excellent reproducibility of properties such
as, for example, the release, which is due inter alia to the good
film-forming properties.
[0027] Release of active ingredient can be speeded up appropriately
by additions of water-soluble substances, in particular of
water-soluble polymers, so that it is also possible to form
rapid-release coatings or coatings for taste masking.
[0028] Besides the coating of pharmaceutical dosage forms it is
also possible to employ the aqueous polymer dispersions of the
invention, but also the polymer powders produced therefrom in the
conventional way, advantageously for coating detergent or
dishwashing composition granules or tablets.
[0029] The coating of or incorporation into fragrance and flavoring
preparations allows release thereof to be adjusted deliberately
and, in this way, the effect to be prolonged.
[0030] Because of the good spray and film-forming properties, and
the good skin compatibility, of the aqueous polymer dispersions of
the invention or the polymer powders produced therefrom they are
additionally suitable for producing wound dressing sprays which can
be employed with active ingredients (e.g. in the form of
disinfectant pump sprays) or without active ingredients in order to
cover and treat wounds. It is a particular advantage in this
connection that the film is homogeneous, scarcely impedes cutaneous
respiration, adheres very well to the skin, is, owing to its
flexibility, unimpaired even by large movements of the skin, but
can be removed as a whole even after moistening with water, with no
residues remaining on the skin or wound. This is not the case with
the acrylic/methacrylic esters normally employed.
[0031] The aqueous polymer dispersions of the invention or the
polymer powders produced therefrom are generally suitable not only
for producing wound dressing sprays but also for all products which
are to be sprayed onto the skin, parts of the body or articles. For
example, such spray preparations which have been colored can be
sprayed without difficulty onto window panes or automobile windows
and then produce pictures or patterns depending on the template
used, which can be removed again in a simple manner after
moistening with water.
[0032] The aqueous polymer dispersions of the invention or the
polymer powders produced therefrom have a large uptake capacity for
active ingredients and can easily be processed to transdermal
therapeutic systems which are highly compatible with the skin. In
addition, it is possible and advantageous to produce so-called acne
plasters which, applied overnight, heal blackheads, pimples and
pustules.
[0033] The aqueous polymer dispersions of the invention or the
polymer powders produced therefrom are also suitable for producing
cosmetic preparations, in particular sunscreen preparations.
[0034] The aqueous polymer dispersions of the invention are
distinguished in that the polyvinyl acetate present therein
preferably has a K value of from 45 to 95, in particular 65 to 85.
The K value desired in each case can be adjusted to a certain
extent in a manner known per se through the choice of the
polymerization conditions, for example the polymerization time and
the initiator concentration. The K value of the polymers of the
invention is adjusted by the use of a regulator. The K values are
measured as described by Fikentscher, Cellulosechemie, vol. 13, pp.
58-64 and 71-74 (1932) at 25.degree. C. in 0.1% by weight aqueous
solution, but in practice also in other, even nonaqueous solutions
with different polymer concentrations. The measurement in this case
preferably takes place in a tetrahydrofuran solution containing 1%
by weight of polymer.
[0035] The protective colloid present in the aqueous dispersion of
the invention is preferably polyvinylpyrrolidone, in an amount
between 5 and 20% by weight based on vinyl acetate monomer, which
particularly preferably has a K value of from 20 to 40. It is also
possible in addition to employ other water-soluble or
water-swellable protective colloids such as, for example, cellulose
derivatives, preferably hydroxypropylmethylcellulose,
methylcellulose or hydroxyethylcellulose, galactomanan, pectin,
xanthan, polyvinyl alcohol, acrylate/methacrylate copolymers,
sodium carboxymethyl starch, cellulose, degraded starches,
maltodextrins etc. The auxiliaries can moreover be added before,
during and after the polymerization.
[0036] The dispersion has a solids content of from 10 to 45% by
weight, preferably of from 15 to 35% by weight.
[0037] The aqueous polymer dispersion of the invention has the
additional feature that the viscosity of the dispersion with the
abovementioned solids content is in the range from 5 to 500 mPas,
preferably in the range from 10 to 250 mPas, particularly
preferably in the range from 15 to 100 mPas.
[0038] The ionic emulsifier present in the aqueous dispersion of
the invention can be a conventional ionic emulsifier such as, for
example, alkali metal and ammonium salts of alkyl sulfates (alkyl
radical: C.sub.8 to C.sub.16), of alkylsulfonic acids (alkyl
radical: C.sub.8 to C.sub.16), of sulfuric acid monoesters of
ethoxylated alkanols (EO degree: 4 to 100, alkyl radical: C.sub.12
to C.sub.16), and ethoxylated alkylphenols (EO degree 3 to 50,
alkyl radical: C.sub.4 to C.sub.12), and of alkylarylsulfonic acids
(alkyl radical: Cg to C.sub.18). Other anionic emulsifiers which
have proved advantageous are compounds such as Dowfax 2A1 (brand
name of Dow Chemical Company). Sodium lauryl sulfate is preferred.
The ionic emulsifier is employed in concentrations of from 0.2 to
5% by weight based on the total eight of the monomer content.
[0039] It is also possible in addition to employ conventional
nonionic emulsifiers.
[0040] The free-radical initiator employed for the polymerization
is preferably Na-, K- or ammoniumperoxodisulfate, but other
free-radical initiators which are customary per se, such as
hydrogen peroxide, organic peroxides, hydroperoxides or azo
compounds, are also possible--also in conjunction with redox
components such as, for example, ascorbic acid.
[0041] The ratio of free-radical initiator to buffer system is
preferably between 1:3 and 3:1 by weight.
[0042] The aqueous polymer dispersion of the invention is a
so-called "regulated" polymer dispersion, i.e. the dispersion is
carried out in the presence of a polymerization regulator,
particularly suitable regulators being sulfur-containing compounds
such as, for example, thioglycol, t-dodecyl mercaptan, n-dodecyl
mercaptan and ethylhexyl thioglycolate, which result inter alia in
being able to adjust the K values preferred according to the
invention and in the resulting polymers having sulfur-containing
end groups. The total amount of the regulator, normally between
0.05 and 1%, preferably between 0.1 and 0.5%, in each case based on
the total monomer content, is preferably introduced in the emulsion
feed.
[0043] Besides the molecular weight or K value, particularly
important for producing coatings is the size of the dispersion
particles.
[0044] The polymer dispersion of the invention therefore preferably
has dispersion particles having an average size of only 50 to 300
nm, preferably from 100 to 200 nm. The determination takes place in
a conventional way, for example by means of an ultracentrifuge,
photon correlation spectroscopy or by determining the transmittance
of light. The particle size is normally controlled via the
emulsifier concentration. The dispersion particles obtained
according to the invention are very fine although a considerable
amount of a nonionic protective colloid is present in the initial
charge for the polymerization. By contrast, U.S. Pat. No. 5,252,704
discloses that such ratios preferentially result in coarse-particle
dispersions.
[0045] The present invention also relates to a process for
preparing an aqueous polymer dispersion, in which vinyl acetate is
polymerized by free-radical polymerization in the presence of at
least one ionic emulsifier, at least one free-radical initiator and
at least one protective colloid, wherein the polymerization is
carried out in the presence of a polymerization regulator and
wherein the ratio by weight of protective colloid to ionic
emulsifier is at least 4:1, preferably at least 8:1, particularly
preferably in the range between 8:1 and 12:1, and wherein the ratio
by weight of vinyl acetate monomer to protective colloid is between
19:1 and 4:1, preferably between 15:1 and 6:1. The ratio by weight
of free-radical initiator to buffer system is preferably between
1:3 and 3:1.
[0046] The polymerization preferably takes place at a pH in the
range from 1 to 7, particularly preferably in the range from 3 to
6. It is possible, depending on the settings of the polymerization
reactors, for the pH to be adjusted to the desired pH during the
reaction by suitable measuring and control devices.
[0047] For the preferred embodiment of the process of the
invention, the pH is kept constant during the polymerization by
addition of one of the reagents with a basic action which has
already been described at the outset or are particularly
preferably, by the buffer systems already mentioned.
[0048] However, it is also possible to polymerize vinyl acetate
without additional pH control. In this case, after the
polymerization, the pH of the aqueous dispersion is ordinarily
adjusted by addition of one of the buffer systems mentioned at the
outset to a value in the range from 1 to 7, preferably 3 to 6. It
is possible by this subsequent pH control to improve the storage
stability of the aqueous polymer dispersion.
[0049] The emulsion polymerization is carried out in a manner known
per se at temperatures of from 40.degree. C. to 95.degree. C. under
an atmospheric pressure or, preferably at temperatures of from
55.degree. C. to 80.degree. C. under a pressure of from 1.1 to 15
bar, particularly preferably under a pressure of from 1.5 to 6 bar.
The desired pressure can be adjusted in this case by feeding
nitrogen into the reactor before and/or during the polymerization,
preferably before the polymerization.
[0050] This process is preferably carried out as a semicontinuous
feed process with the total amount of the protective colloid being
present in the initial charge. Another preferred procedure
comprises more than 50 of 100 parts of the ionic emulsifier being
present in the initial charge.
[0051] The present invention further relates to the use of the
aqueous polymer dispersions of the invention as auxiliary for
pharmaceutical, agrochemical or nutritional dosage forms, in
particular as coating agent for solid pharmaceutical, agrochemical
or nutritional dosage forms. It additionally relates to the use of
the dispersion of the invention or of the powders produced
therefrom as auxiliary, in particular coating agent, in detergent,
dishwashing and cleaning compositions of any type, especially when
they are in the form of granules.
[0052] The invention further relates to the use of the dispersion
of the invention or of the powders produced therefrom as coating or
embedding agents for fragrances and flavorings.
[0053] The invention further relates to the use of the dispersions
of the invention and of the powders produced therefrom for
producing preparations which are sprayed onto surfaces, in
particular the human or animal skin, especially for wound dressing
sprays or for producing transdermal therapeutic systems or else for
producing cosmetic preparations, especially sunscreen
preparations.
PREPARATION EXAMPLE
[0054] 343.7 g of water, 1.8 g of Na lauryl sulfate (100% pure),
74.7 g of polyvinylpyrrolidone with a K value of 30 (30% strength
in H.sub.2O) and 63.5 g of a portion of feed 1 (see below) were
introduced into a 2 l reaction vessel with anchor stirrer and
heated to 75.degree. C.
[0055] At 65.degree. C., feed 2 (see below) was added within 10
minutes and, at 75.degree. C., feed 1 was metered in over the
course of 2 h and feed 3 (see below) was metered in over the course
of 3 h.
[0056] After completion of the feeds, polymerization was continued
at 75.degree. C. for 2 h. After cooling, the pH was adjusted to
about 5 with 1% strength NaOH.
[0057] A 30% strength dispersion (solids content 30%) with a K
value of 71 (measured as 1% strength solution in tetrahydrofuran)
and a particle size of 121 nm was obtained. The coagulum content of
the dispersion was very small (0.2 g of coagulum on the stirrer and
in the 120 .mu.m filter). The pH remained unchanged over 3 months.
TABLE-US-00001 Feed 1: 298.8 g of VAc 1.2 g of Na lauryl sulfate
100% pure 333.0 g of water 0.9 g of ethylhexyl thioglycolate 0.75 g
of sodium acetate*3H.sub.2O Feed 2: 0.45 g of Na peroxodisulfate
6.0 g of water Feed 3: 0.9 g of Na peroxodisulfate 12.1 g of
water
EXAMPLE 1
Sustained Release Propranolol Pellets
[0058] Propranolol HCl pellets with a particle size of 0.5 to 1.5
mm and an active ingredient content of 20% were coated in a
fluidized bed with the polyvinyl acetate dispersion of the
invention (from the Preparation Example).
[0059] The coating dispersion had the following composition:
TABLE-US-00002 polyvinyl acetate dispersion 30% 50.0% propylene
glycol 1.7% talc 5.0% water 43.3%
[0060] The solids content of the spray suspension was 23.4%.
[0061] The spray dispersion was prepared by respectively dissolving
and suspending propylene glycol and talc in water and then
homogenizing with a corundum disk mill. This suspension was slowly
introduced into the 30% strength polyvinyl acetate dispersion while
stirring. 500.0 g of this spray preparation were sprayed onto 500 g
of propranolol pellets in a fluidized bed in an Aeromatic Strea 1
(from Aeromatic).
[0062] Spraying Conditions: TABLE-US-00003 Nozzle: 0.8 mm Inlet air
temperature: 60.degree. C. Outlet air temperature: 35.degree. C.
Spraying pressure: 0.8 bar Spraying rate: 15 g/min Drying:
50.degree. C./5 min
[0063] The pellet coating was very smooth and uniform. No twins
were formed.
[0064] The release was determined by packing the coated pellets, in
an amount equivalent to 160 mg of propranolol HCl into gelatin
capsules and releasing them over 2 h in simulated gastric fluid
(0.08-N HCl) in a paddle release apparatus (from Pharmatest) at
37.degree. C. and 50 revolutions/min. After 2 h, the buffer was
changed to pH 6.8 by adding a phosphate buffer concentrate.
[0065] The following values were determined for release:
TABLE-US-00004 1 h 2% 2 h 5% 4 h 10% 8 h 35% 12 h 55% 16 h 74% 20 h
91% 24 h 99%
[0066] The release from the uncoated pellets was very rapid at 98%
after 45 min.
EXAMPLE 2
Sustained Release Diclofenac Pellets
[0067] Diclofenac sodium pellets with a particle size of 0.7 to 1.5
mm and an active ingredient content of 30% were coated in a
fluidized bed with the polyvinyl acetate dispersion of the
invention.
[0068] The coating dispersion had the following composition:
TABLE-US-00005 Polyvinyl acetate dispersion 30% 58.0% Propylene
glycol 2.6% Water 39.4%
[0069] The solids content of the spray suspension was 20%.
[0070] The spray dispersion was prepared by dissolving propylene
glycol in water and slowly introducing into the 30% strength
polyvinyl acetate dispersion while stirring. 964.0 g of this spray
preparation were sprayed onto 500 g of diclofenac sodium pellets in
a fluidized bed in an Aeromatic Strea 1 (from Aeromatic).
[0071] Spraying Conditions: TABLE-US-00006 Nozzle: 0.8 mm Inlet air
temperature: 55.degree. C. Outlet air temperature: 34.degree. C.
Spraying pressure: 1.2 bar Spraying rate: 18 g/min Drying:
45.degree. C./5 min
[0072] The pellet coating was very smooth and uniform. No twins
were formed.
[0073] The release was determined by packing the coated pellets, in
an amount equivalent to 100 mg of diclofenac sodium, into gelatin
capsules and releasing them over 2 h in simulated intestinal fluid
(phosphate buffer pH 6.8) in a paddle release apparatus (from
Pharmatest) at 37.degree. C. and 50 revolutions/min.
[0074] The values determined for the release were as follows:
TABLE-US-00007 1 h 6% 2 h 16% 4 h 41% 8 h 89% 12 h 100%
[0075] The values for the release from uncoated pellets were 99%
after 1 h.
EXAMPLE 3
Slow-Release Ascorbic Acid
[0076] Ascorbic acid crystals with a particle size of 0.5 to 1.5 mm
were coated in a fluidized bed in a Huttlin Kugelcoater (from
Huttlin) with the polyvinyl acetate dispersion of the
invention.
[0077] The coating dispersion had the following composition:
TABLE-US-00008 Polyvinyl acetate dispersion 30% 50.0% Propylene
glycol 1.7% Talc 7.0% Sicovit Rot 30 (red iron oxide) 1.0% Water
40.3%
[0078] The solids content of the spray suspension was 26.4%.
[0079] The spray dispersion was prepared by respectively dissolving
and suspending propylene glycol and talc and Sicovit Rot 30 in
water and then homogenizing with a corundum disk mill. This
suspension was slowly introduced into a 30% strength polyvinyl
acetate dispersion with stirring. 4500.0 g of this spray
preparation were sprayed onto 3000 g of ascorbic acid crystals in a
fluidized bed in a Huttlin HKC 5 Kugelcoater (from Huttlin).
[0080] Spraying Conditions: TABLE-US-00009 Nozzle: 0.8 mm Inlet air
temperature: 60.degree. C. Outlet air temperature: 35.degree. C.
Spraying pressure: 1.2 bar Spraying rate: 69 g/min Drying:
50.degree. C./5 min
[0081] The coating was very smooth and uniform. No twins were
formed.
[0082] The release was determined by packing the coated crystals,
in an amount equivalent to 500 mg of ascorbic acid, into gelatin
capsules and releasing these in simulated gastric fluid (0.1-N HCl)
in a paddle release apparatus (from Pharmatest) at 37.degree. C.
and 50 revolutions/min.
[0083] The values determined for the release were as follows:
TABLE-US-00010 1 h 4% 2 h 9% 4 h 28% 8 h 49% 12 h 69% 16 h 85% 20 h
98%
[0084] By contrast, the release from the uncoated crystals was very
rapid (100% after 1 h).
EXAMPLE 4
Wound Dressing Spray
[0085] A propellant gas aerosol which forms a film on the skin or
on wounds is produced by stirring 133.3 g of 30% strength polyvinyl
acetate dispersion of the invention into 366.7 g of ethanol. A 6 oz
aerosol can is charged with 50.0 g of this mixture and closed with
a suitable valve. Then 50.0 g of dimethyl ether are forced into the
aerosol can under pressure.
[0086] After spraying onto the skin, a homogeneous film forms and
adheres very strongly and is very elastic.
EXAMPLE 5
Film-Forming Disinfectant Pump Spray with Cetylpyridinium
Chloride
[0087] 400.0 g of the 30% strength polyvinyl acetate dispersion are
mixed with 50.0 g of a 30% strength solution of
polyvinylpyrrolidone K 30 in water and freeze dried. 30.0 g of this
powder are dissolved in 570.0 g of an ethanol/water mixture (19:1)
and, while stirring, 1.0 g of cetylpyridinium chloride and then
399.0 g of ethyl acetate are added. 100 ml pump spray bottles with
a suitable spray head delivering 0.1 ml are charged with this
preparation.
[0088] After spraying onto the skin, a flexible film forms and
adheres very well.
EXAMPLE 6
Acne Plaster
[0089] 32.0 g of a 25% strength aqueous solution of
polyvinylpyrrolidone with a K value of 90 are added to 120.0 g of
30% strength polyvinyl acetate dispersion while stirring. Then 0.04
g of thimerosal and 0.5 g of dexpanthenol are dissolved in 2.0 g of
water and 8.0 g of propylene glycol and slowly added to a mixture
of polyvinyl acetate dispersion and polyvinylpyrrolidone while
stirring. This preparation is applied by means of an Erichsen
film-drawing apparatus using a 200 .mu.m knife onto a 40 .mu.m
thick polyester sheet (Hostaphan, from Hoechst). After drying at
55.degree. C., the knife-application process is repeated twice in
order to result in a layer thickness of about 200 .mu.m. The dried
film is covered with a siliconized release liner. The individual
plasters with an area of 1 cm.sup.2 are produced by punching.
EXAMPLE 7
Transdermal Therapeutic System with Propranolol
[0090] 40.0 g of N-pyrrolidone, 20.0 g of propranolol HCl and 20.0
g of polyvinylpyrrolidone with a K value of 90 are dissolved in
40.0 g of demineralized water. This solution is incorporated into
333.3 g of 30% strength polyvinyl acetate dispersion of the
invention while stirring. A 200 .mu.m knife is used to spread this
mixture onto a 40 .mu.m-thick polyester sheet, which is then dried
at 60.degree. C. The spreading process is repeated once more to
increase the layer thickness. After covering the polymer layer with
a siliconized released liner it is possible to punch out any
desired shapes.
EXAMPLE 8
Sunscreen Preparation
[0091] 25.0 g of Uvinul MC 80 (2-ethylhexyl p-methoxycinnamate),
20.0 g of tocopheryl acetate, 25.0 g of isopropyl myristate and
15.0 g of Cremophor RH 40 are dissolved in 150.0 g of ethanol at
40.degree. C. while stirring. Then 50.0 g of demineralized water,
150.0 g of propylene glycol, 50.0 g of glycerol and 25.0 g of dried
polyvinyl acetate dispersion are incorporated while stirring. The
preparation is cooled to room temperature and used to fill lotion
bottles or spray bottles.
* * * * *