U.S. patent application number 12/734317 was filed with the patent office on 2010-10-21 for amphiphilic polymeric material.
This patent application is currently assigned to REVOLYMER LIMITED. Invention is credited to Thomas Charles Castle, David Alan Pears, Pennadam Shanmugam Sivanand.
Application Number | 20100266513 12/734317 |
Document ID | / |
Family ID | 40193797 |
Filed Date | 2010-10-21 |
United States Patent
Application |
20100266513 |
Kind Code |
A1 |
Pears; David Alan ; et
al. |
October 21, 2010 |
AMPHIPHILIC POLYMERIC MATERIAL
Abstract
The present invention concerns an amphiphilic polymeric material
which comprises a straight or branched chain carbon-carbon backbone
and a multiplicity of side chains attached to the backbone, wherein
the side chains have formula (I). At least one of R.sup.1 and
R.sup.2 is the group --C(O)Q; wherein Q comprises a hydrophilic
polymeric group terminated with an amine. Chewing gum bases and
chewing gum compositions comprising the amphiphilic polymeric
material are provided. ##STR00001##
Inventors: |
Pears; David Alan; (Poynton,
GB) ; Sivanand; Pennadam Shanmugam; (Chester, GB)
; Castle; Thomas Charles; (Chester, GB) |
Correspondence
Address: |
OLIFF & BERRIDGE, PLC
P.O. BOX 320850
ALEXANDRIA
VA
22320-4850
US
|
Assignee: |
REVOLYMER LIMITED
LONDON
GB
|
Family ID: |
40193797 |
Appl. No.: |
12/734317 |
Filed: |
November 26, 2008 |
PCT Filed: |
November 26, 2008 |
PCT NO: |
PCT/EP2008/066256 |
371 Date: |
April 23, 2010 |
Current U.S.
Class: |
424/48 ; 426/4;
525/333.1 |
Current CPC
Class: |
C08F 291/00 20130101;
C08F 255/02 20130101; C08L 51/003 20130101; C08L 51/04 20130101;
C08L 51/04 20130101; C08F 255/00 20130101; C08L 51/003 20130101;
C08F 279/02 20130101; A23G 4/08 20130101; C08L 2666/02 20130101;
C08F 255/04 20130101; C08F 267/04 20130101; C08F 265/02 20130101;
C08L 2666/02 20130101 |
Class at
Publication: |
424/48 ;
525/333.1; 426/4 |
International
Class: |
A61K 9/68 20060101
A61K009/68; A23G 4/08 20060101 A23G004/08 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 26, 2007 |
EP |
07121564.4 |
Feb 26, 2008 |
WO |
PCTEP2008/052325 |
Feb 26, 2008 |
WO |
PCTEP2008/052326 |
Jun 5, 2008 |
EP |
08157683.7 |
Jun 5, 2008 |
EP |
EPO08157684.5 |
Oct 15, 2008 |
WO |
PCTEP2008/063879 |
Claims
1. A chewing gum base comprising an amphiphilic polymeric material
which comprises a straight or branched chain carbon-carbon backbone
and a multiplicity of side chains attached to the backbone, wherein
the side chains have the formula (I) ##STR00014## wherein R.sup.1
and R.sup.2 are each, independently H, --C(O)WR.sup.4 or --C(O)Q;
provided that at least one of R.sup.1 and R.sup.2 is the group
--C(O)Q; or R.sup.1 and R.sup.2 together form a cyclic structure
together with the carbon atoms to which they are attached, of
formula (II) ##STR00015## R.sup.3-R.sup.5 are each independently, H
or C.sub.1-6 alkyl; W is O or NR.sup.4; Q is a group of formula
--NR.sup.4--Y--X.sup.1P; T is a group of formula
--N--Y--X.sup.1--P; wherein X.sup.1 is O, S, (CH.sub.2).sub.n,
NR.sup.4 or is absent; wherein n is 1-6; P is H or another
backbone; and Y is a hydrophilic polymeric group.
2. A chewing gum base according to claim 1, wherein the hydrophilic
polymeric group Y is a poly(alkylene oxide), polyglycidol,
poly(vinyl alcohol), poly(styrene sulphonate) or poly(acrylic
acid).
3. A chewing gum base according to claim 2, wherein the hydrophilic
polymeric group Y is a polyalkylene oxide.
4. A chewing gum base according to claim 3, wherein the
polyalkylene oxide has general formula (ZO).sub.b wherein Z is an
alkylene group having from 2 to 4 carbon atoms and b is an integer
in the range 1 to 125.
5. A chewing gum base according to claim 2, wherein the
polyalkylene oxide is a random, statistical, alternating or block
copolymer, or a combination of two of these, of two or more monomer
units ZO, wherein each Z is, independently an alkylene group having
from 2 to 4 carbon atoms.
6. A chewing gum base according to claim 1, wherein the backbone of
the said polymeric material is derived from a homopolymer of an
ethylenically unsaturated hydrocarbon monomer or from a copolymer
of two or more ethylenically-unsaturated polymerisable hydrocarbon
monomers, and the side chains are hydrophilic.
7. A chewing gum base according to claim 6, wherein the
carbon-carbon polymer backbone is derived from a homopolymer of an
ethylenically-unsaturated polymerisable hydrocarbon monomer
containing 4 or 5 carbon atoms.
8. A chewing gum base according to claim 7, wherein the
carbon-carbon polymer backbone is derived from a homopolymer of
isobutylene, butadiene or isoprene.
9. A chewing gum composition comprising an amphiphilic polymeric
material which comprises a straight or branched chain carbon-carbon
backbone and a multiplicity of side chains attached to the
backbone, wherein the side chains have the formula (I) ##STR00016##
wherein R.sup.1 and R.sup.2 are each, independently H,
--C(O)WR.sup.4 or --C(O)Q; provided that at least one of R.sup.1
and R.sup.2 is the group --C(O)Q; or R.sup.1 and R.sup.2 together
form a cyclic structure together with the carbon atoms to which
they are attached, of formula (II) ##STR00017## R.sup.3-R.sup.5 are
each independently, H or C.sub.1-6 alkyl; W is O or NR.sup.4; Q is
a group of formula --NR.sup.4--Y--X.sup.1P; T is a group of formula
--N--Y--X.sup.1P; wherein X.sup.1 is O, S, (CH.sub.2).sub.n,
NR.sup.4 or is absent; wherein n is 1-6; P is H or another
backbone; and Y is a hydrophilic polymeric group; and one or more
sweetening or flavouring agents.
10. A chewing gum composition comprising an amphiphilic polymeric
material which comprises a straight or branched chain carbon-carbon
backbone and a multiplicity of side chains attached to the
backbone, wherein the side chains have the formula (I) ##STR00018##
wherein R.sup.1 and R.sup.2 are each, independently H,
--C(O)WR.sup.4 or --C(O)Q; provided that at least one of R.sup.1
and R.sup.2 is the group --C(O)Q; or R.sup.1 and R.sup.2 together
form a cyclic structure together with the carbon atoms to which
they are attached, of formula (II) ##STR00019## R.sup.3-R.sup.5 are
each independently, H or C.sub.1-6 alkyl; W is O or NR.sup.4; Q is
a group of formula --NR.sup.4--Y--X.sup.1P; T is a group of formula
--N--Y--X.sup.1P; wherein X.sup.1 is O, S, (CH.sub.2).sub.n,
NR.sup.4 or is absent; wherein n is 1-6; P is H or another
backbone; and Y is a hydrophilic polymeric group; and one or more
sweetening or flavouring agents; the chewing gum composition
comprises the chewing gum base as defined in claim 1.
11. A chewing gum composition according to claim 9, further
comprising a medicament.
12. An amphiphilic polymeric material as defined in claim 1,
wherein the carbon-carbon backbone is derived from a homopolymer of
isoprene, and in the formula (I) or (II) X.sup.1 is
(CH.sub.2).sub.n or is absent; and P is H.
13. A method for making an amphiphilic polymeric material according
to claim 12, wherein backbone precursors comprising pendant units
of general formula MO ##STR00020## wherein R.sup.3 is H or
C.sub.1-6 alkyl, R.sup.5 is H or C.sub.1-6 alkyl and R.sup.6 and
R.sup.7 are H or an acylating group, provided at least one of
R.sup.6 and R.sup.7 is an acylating group, or R.sup.6 and R.sup.7
are linked to form, together with the carbon atoms to which they
are attached, a group of formula (IV): ##STR00021## are reacted
with side chain precursors of general formula (V) in a reaction
mixture HR.sup.4N--Y--X.sup.1H (V) wherein X.sup.1 is selected from
(CH.sub.2).sub.n or is absent; wherein n is 1-6; and R.sup.4 is H
or C.sub.1-6 alkyl; and Y is a hydrophilic polymeric group; wherein
in the method, the amine group HR.sup.4N in compound of formula (V)
reacts with the units of general formula (III) or (IV) to give the
amphiphilic polymeric material with side chains of general formula
(I) ##STR00022## wherein R.sup.1 is H, --C(O)WR.sup.4 or --C(O)Q;
and R.sup.2 is H, --C(O)WR.sup.4 or --C(O)Q; provided that at least
one of R.sup.1 and R.sup.2 is the group --C(O)Q; or R.sup.1 and
R.sup.2 together form a cyclic structure together with the carbon
atoms to which they are attached, of formula (II) ##STR00023##
wherein W is O or NR.sup.4; Q is a group of formula
--NR.sup.4--Y--X.sup.1P; T is a group of formula
--N--Y--X.sup.1--P; and P is H.
14. A method according to claim 13, wherein no solvent is used.
15. A method according to claim 13, wherein the backbone and side
chain precursors are dissolved in an organic solvent during the
reaction.
16. A method according to claim 13 wherein an acid or base catalyst
is added to the reaction mixture.
17. A method according to claim 13 wherein any acylating groups
which have not reacted with side chain precursors are reacted with
a sodium or potassium salt.
Description
[0001] The present invention relates to a new graft polymeric
material and methods for producing the same.
[0002] Chewing Gum is a consumer good that is regularly enjoyed by
millions of people worldwide. We have disclosed, in our previous
Patent application published as WO2006/016179 that the addition of
an amphiphilic graft copolymer to chewing gum formulations can
result in them having reduced stickiness, combating the problems
associated with pollution resulting from carelessly discarded gum
cuds. In that Patent application, the graft copolymer is formed by
reacting polyisoprene-graft-maleic anhydride (the backbone) with
poly(alkyleneoxy) alcohol side chain precursors in an organic
solvent such as toluene and typically in the presence of an
activator, for instance, triethylamine at elevated temperature.
[0003] As gum is a commodity product it is desirable to ensure that
the synthesis of all of the ingredients is as efficient as possible
to ensure that the cost of the resulting material is competitive.
WO2006/016179 specifically discloses hydroxyl-terminated side chain
precursors only, and we have now found that the use of side chain
precursors terminated with amine groups results in more efficient
production of polymeric material.
[0004] Graft polymeric materials formed by grafting backbones with
amine terminated polymers are known. US2005/0054796, for instance,
discloses the reaction of olefin-maleic anhydride copolymers with
methoxy polyethylene glycol amines. The resultant polymeric
materials are used as concrete additives.
[0005] US2005/0084466 discloses the reaction of JEFFAMINE.RTM.
M-1000 with polyisobutylene succinic anhydride. The resultant
polymeric material is said to be useful in oil-in-water
emulsions.
[0006] Jiang-Jen Lin et al in Polymer 41 (2000) 2405-2417 disclose
the preparation and electrostatic dissipating properties of
poly(oxyalkylene)imide grafted polypropylene copolymers. Jiang-Jen
further goes in to describe, in Ind. Eng. Chem. Res. 2000, 39,
65-71, the synthesis, characterisation and interfacial behaviour of
polystyrene-b-poly(ethylene/butylene)-b-polystyrene grafted with
various poly(oxyalkylene)amines.
[0007] However, none of these references describe use of the graft
polymeric materials in chewing gum bases and chewing gum
compositions.
[0008] Accordingly, there is provided in a first aspect of the
invention a chewing gum base comprising an amphiphilic polymeric
material which comprises a straight or branched chain carbon-carbon
backbone and a multiplicity of side chains attached to the
backbone, wherein the side chains have the formula (I)
##STR00002##
wherein R.sup.1 and R.sup.2 are each, independently, H,
--C(O)WR.sup.4 or --C(O)Q;
[0009] provided that at least one of R.sup.1 and R.sup.2 is the
group --C(O)Q;
[0010] or R.sup.1 and R.sup.2 together form a cyclic structure
together with the carbon atoms to which they are attached, of
formula (II)
##STR00003##
[0011] R.sup.3-R.sup.5 are each independently H or C.sub.1-6
alkyl;
[0012] W is O or NR.sup.4;
[0013] Q is a group of formula --NR.sup.4--Y--X.sup.1P;
[0014] T is a group of formula --N--Y--X.sup.1P;
[0015] X.sup.1 is O, S, (CH.sub.2).sub.n, NR.sup.4 or is absent;
wherein n is 1-6;
[0016] P is H or another backbone; and
[0017] Y is a hydrophilic polymeric group.
[0018] In a second aspect of the invention there is provided a
chewing gum composition comprising the amphiphilic polymeric
material as defined in the first aspect of the invention, and one
or more sweetening or flavouring agents.
[0019] In a third aspect of the invention, there is provided an
amphiphilic polymeric material as defined above in the first aspect
of the invention, wherein the carbon-carbon backbone is derived
from a homopolymer of polyisoprene, and in the formula (I) or (II)
X.sup.1 is (CH.sub.2).sub.n or is absent; and P is H.
[0020] In a fourth aspect of the invention, there is provided a
method for making the amphiphilic polymeric material of the third
aspect of the invention, wherein backbone precursors comprising
pendant units of general formula (III)
##STR00004##
wherein R.sup.3 is H or C.sub.1-6 alkyl, R.sup.5 is H or C.sub.1-6
alkyl and R.sup.6 and R.sup.7 are H or an acylating group, provided
at least one of R.sup.6 and R.sup.7 is an acylating group, or
R.sup.6 and R.sup.7 are linked to form, together with the carbon
atoms to which they are attached, a group of formula (IV):
##STR00005##
are reacted with side chain precursors of general formula (V) in a
reaction mixture
HR.sup.4N--Y--X.sup.1H (V)
wherein X.sup.1 is selected from (CH.sub.2).sub.n or is absent;
wherein n is 1-6;
[0021] and R.sup.4 is H or C.sub.1-6 alkyl; and
[0022] Y is a hydrophilic polymeric group;
[0023] wherein in the method, the amine group HR.sup.4N in compound
of formula (V) reacts with the units of general formula (III) or
(IV) to give the amphiphilic polymeric material with side chains of
general formula (I)
##STR00006##
wherein R.sup.1 and R.sup.2 are each, independently, H,
--C(O)WR.sup.4 or --C(O)Q;
[0024] provided that at least one of R.sup.1 and R.sup.2 is the
group --C(O)Q;
[0025] or R.sup.1 and R.sup.2 together form a cyclic structure
together with the carbon atoms to which they are attached, of
formula (II)
##STR00007##
[0026] wherein
[0027] W is O or NR.sup.4;
[0028] Q is a group of formula --NR.sup.4--Y--X.sup.1P;
[0029] T is a group of formula --N--Y--X.sup.1P; and
[0030] P is H.
[0031] The invention outlined herein involves the strategy of
minimising the use of the materials that were previously required
to create the polymeric material. More specifically, this is
achieved by using side chain precursors terminated with amine
groups, which react more fully with acylating groups than their
hydroxyl-equivalents. The resultant amphiphilic polymeric material
retains all of the qualities associated with material made using
side chain precursors terminated with hydroxyl groups--i.e. the
material is of low tack and can be incorporated into chewing gum
compositions to reduce their adhesive nature.
[0032] Amphiphilic polymeric material having a backbone derived
from polyisoprene and side chains formed from monoamine side chain
precursors is a particularly preferred material for use in the
chewing gum bases and compositions of the invention. The use of
monofunctional side chain precursors ensures that cross-linking
does not occur, which reduces product complexity. This amphiphilic
polymeric material accordingly forms the third aspect of the
invention.
[0033] Methods for making compositions containing anhydride based
graft copolymers are known. EP0945473, for instance, describes a
solvent-free method which involves mixing an
ethylenically-unsaturated monomer, an anhydride monomer, and either
a monofunctional polyglycol having a hydroxyl or amine terminal
group or a polyfunctional polyglycol, and a free radical initiator
to form a mixture. The mixture is heated to form a mixture of graft
copolymeric materials of the polyglycol and the ethylenically
unsaturated monomer including the graft copolymer product, which
may be useful as a soil release agent in detergent
formulations.
[0034] The method used to make the compounds of the present
invention differs from the disclosure in EP0945473, in that the
method in the latter results in a multitude of different products,
most of which comprise units derived from maleic anhydride actually
in the backbone of the copolymer, rather than being present as a
graft on the backbone. The method used in this invention avoids the
problem of such product complexity by reacting a pre-formed
polymeric backbone with side chain precursors. Furthermore, the
present method does not proceed via a free-radical mechanism.
[0035] The backbone of the polymeric material in this invention is
preferably derived from a homopolymer of an ethylenically
unsaturated hydrocarbon monomer or from a copolymer of two or more
ethylenically unsaturated hydrocarbon monomers. The backbone
precursor is typically an elastomeric material. The amphiphilic
polymeric material may also be an elastomeric material.
[0036] The backbone typically comprises a homopolymer of an
ethylenically-unsaturated polymerisable hydrocarbon monomer or a
copolymer of two or more ethylenically-unsaturated polymerisable
hydrocarbon monomers. By the term "ethylenically-unsaturated
polymerisable hydrocarbon monomer" we mean a polymerisable
hydrocarbon containing at least one carbon-carbon double bond which
is capable of undergoing addition (otherwise known as chain-growth
or chain-reaction) polymerisation to form a straight or branched
chain hydrocarbon polymer having a carbon-carbon polymer backbone.
According to one preferred embodiment, the backbone comprises a
homopolymer of an ethylenically-unsaturated polymerisable
hydrocarbon monomer containing 4 or 5 carbon atoms, for example,
isobutylene (2-methylpropene). The carbon-carbon polymer backbone
may also, according to another embodiment, be derived from a
homopolymer of a conjugated diene hydrocarbon monomer, especially
one containing 4 or 5 carbon atoms, such as 1,3-butadiene or
isoprene.
[0037] As mentioned above, the carbon-carbon polymer backbone may
comprise a copolymer of two or more ethylenically-unsaturated
polymerisable hydrocarbon monomers. Preferably, it comprises a
copolymer of two such monomers. For example, it may comprise a
hydrocarbon copolymer of a hydrocarbon monomer having one
carbon-carbon double bond and a hydrocarbon monomer having two
carbon-carbon double bonds. For example, the carbon-carbon polymer
backbone may comprise a copolymer of isobutylene and isoprene.
According to a different embodiment, the carbon-carbon polymer
backbone is derived from a butadiene-styrene block copolymer. The
backbone may comprise a random, alternating or block, e.g. A-B or
AB-A block copolymer.
[0038] The backbone precursors used to form the backbone in the
polymeric materials have pendant units which have acylating groups.
The acylating groups may be, for instance, units derived from
maleic anhydride. The backbone precursor typically has units
derived from maleic anhydride grafted thereon. One suitable
backbone precursor is polyisoprene grafted with maleic anhydride,
PIP-g-MA. Such graft copolymers are commercially available as
further detailed below, or can be synthesised (see Examples).
[0039] The backbone precursor used to form the backbone in the
polymeric material typically has a molecular weight in the range
10,000 to 200,000, preferably 20,000 to 40,000, more preferably
from 25,000 to 45,000. Unless otherwise specified, the unit of
molecular weight used in this specification is g/mol.
[0040] The backbone is typically hydrophobic in nature. In
contrast, the side chains are hydrophilic by virtue of the group Y,
which confers several advantages. The hydrophobic/hydrophilic
balance of the resultant amphiphilic polymeric material has a
comb-like copolymer structure which gives the material its low-tack
properties. The hydrophilic side chains confer surface active
properties on the polymeric material.
[0041] The group Y in this invention is preferably a poly(alkylene
oxide) such as poly(ethylene oxide), polyglycidol, polyvinyl
alcohol), poly(styrene sulphonate) or poly(acrylic acid), most
preferably poly(ethylene oxide). Alternatively, the group Y may be
a polypeptide, for example polylysine. The side chain precursors
used in the method of this invention are preferably polyether
amines.
[0042] In one preferred embodiment of the invention, the group Y is
a polyalkylene oxide of general formula (ZO).sub.b wherein Z is an
alkylene group having from 2 to 4 carbon atoms and b is an integer
in the range 1 to 125.
[0043] In a different embodiment, the polyalkylene oxide is a
random, statistical, alternating or block copolymer (or a mixture
of two of these) of two or more monomer units ZO, wherein each Z
is, independently, an alkylene group having from 2 to 4 carbon
atoms. The total number of monomer units is generally in the range
1 to 125.
[0044] In the side chains of formula (I), typically, W is O.
Preferably, X.sup.1 is O or NR.sup.4. R.sup.4 is preferably H or
CH.sub.3. n is preferably in the range 1-4. R.sup.2 is preferably
--C(O)WR.sup.4 or --C(O)Q.
[0045] Each backbone in the amphiphilic polymeric material may have
a plurality of side chains which may include a mixture of the side
chains listed above, and/or have different chain lengths/molecular
weights. Preferably, however, each side chain has the same chain
length/molecular weight.
[0046] In this invention, the side chain precursors are terminated
with at least one amine group, and the side chains in the
amphiphilic polymeric material are linked to the backbone via amide
linkages.
[0047] In the side chains of formula (I) or (II), preferably,
R.sup.5 is H. In a further preferred embodiment, R.sup.3 is H or
CH.sub.3.
[0048] According to one embodiment of the present invention, the
side chains in the polymeric material have the formula
##STR00008##
wherein R.sup.3, R.sup.4 and Q are as defined above. These groups
are derived from maleic anhydride units or derivatives thereof
grafted onto the backbone.
[0049] Preferably, the polymeric material has pendant carboxylic
acid groups. In the above formula therefore, preferably R.sup.4 is
H.
[0050] According to another embodiment, the side chains may have
formula
##STR00009##
wherein Q is as defined above.
[0051] In another embodiment the side chains have the following
formula
##STR00010##
wherein Q is as defined above. These are derived from
methacrylic-grafted materials.
[0052] According to another embodiment the side chains may have the
formula
--CH.sub.2CH.sub.2C(O)Q
[0053] These are derived from acrylic grafted materials.
[0054] From the above it can be seen that the acylating groups in
the backbone precursors eventually form part of the side chains in
the amphiphilic polymeric material. Suitable acylating groups
include carboxylic acids, carboxylic acid esters, acid amides, acyl
chlorides and acid anhydrides.
[0055] In the method according to this invention, up to 2
equivalents of side chain precursors with respect to each acylating
group can be reacted. Preferably, the acylating group is derived
from a maleic anhydride unit. Suitable side chain precursors which
are polyether amines are available commercially; a range of mono
and difunctionalised amine polymers of ethylene oxide (EO) and
propylene oxide (PO) are sold under the Jeffamine brand name by
Huntsman. Reaction between the amine functionalized polymers with
maleic anhydride derived units, for instance, can generate any of
three different structures:
##STR00011##
[0056] The structure marked C may be formed by an intramolecular
reaction of A, accompanied by the elimination of H.sub.2O, is more
likely to occur with the assistance of catalysis (e.g by the
addition of an acid). Both mono and difunctional amine polymers are
used in the invention. Depending on the reaction conditions, the
use of hydrophilic difunctional amine side chain precursors can
lead to a cross-linked or chain extended amphiphilic polymeric
material. Alternatively mono and difunctional side chain precursors
may be combined to modify the properties of the resulting polymeric
material to that required. The structure and properties of the
polymers sold under the trade names Jeffamine M-1000 and M-2070 are
particularly preferred.
##STR00012##
[0057] [x=6; y.apprxeq.35 where R is a mixture of H for (EO), or
CH.sub.3 for (PO) units]
[0058] Jeffamine M-1000 is a monoamine polyether with a EO:PO ratio
of 19:3 and a molecular weight of approximately 1000, M-2070 is a
monoamine polyether with an EO:PO ratio of 31:10 and a molecular
weight of approximately 2000. Due to the relatively high ratios of
ethylene oxide units in these polymers they are regarded as
hydrophilic materials. Both M-1000 and M-2070 have been found to
react efficiently with PIP-g-MA.
[0059] It is possible to synthesise amphiphilic polymeric material
through the reaction of backbone precursors with a monoester of
maleic anhydride, for instance we have obtained good results with a
PIP-g-MaMme (polyisoprene-graft-monoacid monomethyl ester supplied
by Kuraray Co. Ltd, sold as LIR-410) with the general formula
##STR00013##
and has a functionality (i.e. n) of approximately 10, an average
molecular weight of about 25,000, and a glass transition
temperature of -59.degree. C. Each monomethyl ester may react with
a single amine functionality.
[0060] As stated above, the properties of the polymeric material
depend not only on the character of the side chains grafted onto
the carbon-carbon polymer backbone but also on the number of
grafted side chains. In the invention a multiplicity of side chain
precursors react with each backbone precursor. The term
"multiplicity" is defined herein as meaning one or more grafted
side chains. At least one side chain precursor reacts with each
backbone precursor. In order to achieve a desired degree of
hydrophilicity in the polymeric material, it is preferred that the
ratio of side chains to backbone units in the resultant polymeric
material is in the range 1:400 to 1:5, but more preferably 1:200 to
1:10. The side chains are typically statistically distributed along
the carbon-carbon polymer backbone since the location of attachment
of the side chain on the backbone will depend on the positions of
suitable attachment locations in the backbone of the hydrocarbon
polymer used in the manufacture.
[0061] When the side chains are linked to the polymer backbone via
grafted maleic anhydride units, each maleic anhydride unit in the
polymer backbone may be derivatised with either zero, one or two
side chains.
[0062] In the method of this invention, side chain precursors of
general formula (II) comprise at least one nucleophilic group which
is an amine. In the reaction to form an amphiphilic polymeric
material, the nucleophilic groups react with pendant units on the
polymer backbone which are acylating groups to form a polymeric
material as defined in the first aspect of the invention.
Preferably, the pendant units are derived from maleic
anhydride.
[0063] In one embodiment of the invention, each side chain
precursor has two nucleophilic groups (for instance, X.sup.1 is O
or NR.sup.4) which may react with two acylating groups on two
different backbone precursor molecules, thereby forming a
cross-linked structure. In this case, P, in groups of formulae
--NR.sup.4--Y--X.sup.1P and --N--Y--X.sup.1--P is "another
backbone".
[0064] When the acylating group is derived from maleic anhydride,
in some embodiments of the invention, only one side chain precursor
reacts per maleic anhydride monomer. This leaves the unit derived
from maleic anhydride with a free carboxylic acid group, which may
be derivatised at a later stage in the method. This group may also
be deprotonated to give an ionic pendant group in the polymeric
material.
[0065] The reaction between the backbone precursors (for instance,
PIP-g-MA) and the side chain precursors could be carried out in an
organic solvent (such as toluene, xylene or tetrahydrofuran) and
typically in the presence of an activator, for example,
triethylamine at elevated temperature. The yield may be increased
by removal of the water from the reaction mixture by azeotropic
distillation since toluene and water form azeotropic mixtures which
boil at a lower temperature than any of the components. The side
chain precursor may also be reacted with a monoester derivative of
PIP-g-MA for instance, the PIP-g-MaMme detailed above. The reaction
of this monomethyl ester with the side chain precursor is typically
carried out in an organic solvent such as toluene at an elevated
temperature. The yield of ester may be increased by removing water
from the reaction mixture by azeotropic distillation.
[0066] The synthesis of the amphiphilic polymeric material may
achieved by mixing the intended side chain precursors with the
backbone precursors, in the absence of solvent. This `no-solvent`
process eliminates the costs associated with purchasing and
handling organic solvents, and removing the otherwise harmful
materials from the polymer. It will be appreciated that this
approach is also desirable in eliminating volatile organic
compounds that may be harmful to the environment.
[0067] The side chain and backbone precursors may be either a
solid, in fluid form, a liquid or a gel, provided that they can be
mixed fairly efficiently. More preferably they will be either a
liquid or finely ground solid. Alternatively, the backbone
precursors are in liquid form and the side chain precursors are in
solid form. In one embodiment of the invention, the side chain
precursors are in liquid form and the backbone precursors are a
finely ground solid. Most preferably both side chain and backbone
precursors will be a liquid at the temperature at which the
acylation reaction takes place.
[0068] In one preferred embodiment of the invention, the backbone
precursors are mixed with the side chain precursors by dissolving
or dispersing the backbone precursors in molten side chain
precursors.
[0069] It will be appreciated by those skilled in the art that the
reaction process may be performed using any piece of equipment that
is capable of providing sufficient mixing. These may include
reactors or other any vessels where agitation is provided by an
overhead stirrer, a magnetic stirrer, most preferably mixing is
achieved using an appropriate an extruder, z-blade mixer, batch
mixer, U trough mixer, RT mixer, compounder, internal mixer,
Banbury type mixer, two roll mill, Brabender type mixer, a wide
blade mixer (or hydrofoil blade mixer), horizontal (delta or
helical) blade mixer, kneader-reactor, or a related variation of
one of these mixers such as such as a double z-blade mixer or twin
screw extruder.
[0070] Increasing the temperature of the reaction mixture generally
results in the side chain precursors melting, which allows
efficient mixing, and in turn contributes to an increase in the
rate of reaction. Therefore the temperature of the reaction will
preferably be between 50.degree. C. and 300.degree. C., more
preferably between 100 and 250.degree. C., even more preferably
between 120.degree. C. and 200.degree. C., and most preferably
between 140.degree. C. and 180.degree. C. Preferably the mixing
apparatus is supplied with an inert gas to prevent degradation of
the polymeric materials. Alternatively the reactor may be placed
under vacuum in order to ensure that air is excluded. The reaction
can also be catalysed by addition of acid or base. Optionally water
may be added to the reactor at the end of the reaction to hydrolyse
any unreacted acylating groups. Hydrolysis of unreacted acylating
groups can also advantageously increase the hydrophilicity and thus
water compatibility or solubility of the materials.
[0071] Any remaining acylating groups may be preferably converted
into acid groups by the addition of water to the material, or by an
aging process. An aging process typically involves leaving the
material in atmospheric air to ensure hydrolysis of any residual
maleic anhydride by the atmospheric moisture. Alternatively the
remaining acylating groups may be hydrolysed with the aid of a base
catalyst, or by the addition of an alcohol (hydroxyl) or amine with
or without base. By way of an example, any remaining maleic
anhydride groups are typically converted into diacid groups by
addition of water to the material.
[0072] The reaction mixture, at the end of the reaction, normally
comprises unreacted starting materials which may include free side
chain precursor and backbone precursor. There may be some residual
catalyst, if this has been used in the reaction. The reaction
generally produces no by-products. The amphiphilic polymeric
material need not be purified from the reaction mixture, since it
can be advantageous to have free side chain precursors in the final
composition. The free side chain precursor may interact with the
amphiphilic polymeric material and thereby improve its
properties.
[0073] The amphiphilic polymeric material may be used in a variety
of applications, such as in coatings, personal and household care
formulations. A particularly desirable application is in the
manufacture of a chewing gum base and/or chewing gum composition.
Such compositions form aspects of the present invention. A typical
chewing gum base comprises 2-90% by weight of the amphiphilic
polymeric material, preferably, 2-50%, more preferably 2-25%, most
preferably 3-20% by weight. The amphiphilic polymeric material may
act as a substitute for part or all of the ingredients in the gum
base which contribute to adhesiveness.
[0074] Alternatively, the gum base comprises no amphiphilic
polymeric material. Instead, the amphiphilic polymeric material is
added to a chewing gum composition independently of the chewing gum
base. Most typically, the amphiphilic polymeric material is added
to both the gum base and chewing gum composition.
[0075] The chewing gum base comprises, in addition to the polymeric
material, conventional ingredients known in the art.
[0076] The chewing gum base may comprise 0-6% by weight wax.
Examples of waxes which may be present in the gum base include
microcrystalline wax, natural wax, petroleum wax, paraffin wax and
mixtures thereof. Waxes normally aid in the solidification of gum
bases and improving the shelf-life and texture. Waxes have also
been found to soften the base mixture, improve elasticity during
chewing and affect flavour retention. Preferably, the gum base
comprises substantially no wax, and these properties are provided
by the polymeric material. However, in some embodiments wax is
present and this works with the amphiphilic polymeric material (and
optionally unreacted side chain precursor with it) to control the
release of the active.
[0077] The chewing gum base may comprise an elastomeric material
which provides desirable elasticity and textural properties as well
as bulk. Suitable elastomeric materials include synthetic and
natural rubber. More specifically, the elastomeric material is
selected from butadiene-styrene copolymers, polyisobutylene and
isobutylene-isoprene copolymers. It has been found that if the
total amount of elastomeric material is too low, the gum base lacks
elasticity, chewing texture and cohesiveness, whereas if the
content is too high, the gum base is hard and rubbery. Typical gum
bases contain 10-70% by weight elastomeric material, more typically
10-15% by weight. Typically, the polymeric material will form at
least 1% by weight, preferably at least 10% by weight, more
preferably at least 50% by weight of the elastomeric material in
the chewing gum base. In some embodiments, the polymeric material
completely replaces the elastomeric material in the chewing gum
base.
[0078] Elastomer plasticisers (also known as elastomer solvents)
aid in softening the elastomeric material and include methyl
glycerol or pentaerythritol esters of rosins or modified rosins,
such as hydrogenated, dimerized, or polymerized rosins or mixtures
thereof. Examples of elastomer plasticisers suitable for use in the
chewing gum base include the pentaerythritol ester of partially
hydrogenated wood rosin, pentaerythritol ester of wood rosin,
glycerol ester of partially dimerized rosin, glycerol ester of
polymerised rosin, glycerol ester of tall oil rosin, glycerol ester
of wood rosin and partially hydrogenated wood rosin and partially
hydrogenated methyl ester of rosin; terpene resins including
polyterpene such as d-limonene polymer and polymers of
.alpha.-pinene or .beta.-pinene and mixtures thereof. Elastomer
plasticisers may be used up to 30% by weight of the gum base. The
preferred range of elastomer solvent, however, is 2-18% by weight.
Preferably it is less than 15% by weight. Alternatively, no
elastomer solvent may be used.
[0079] The weight ratio of elastomer plus polymeric material to
elastomer plasticiser is preferably in the range (1 to 50):1
preferably (2 to 10):1.
[0080] The chewing gum base preferably comprises a non-toxic vinyl
polymer. Such polymers may have some affinity for water and include
poly(vinyl acetate), ethylene/vinyl acetate and vinyl laurate/vinyl
acetate copolymers. Preferably, the non-toxic vinyl polymer is
poly(vinyl acetate). Preferably, the non-toxic vinyl polymer is
present at 15-45% by weight of the chewing gum base. The non-toxic
vinyl polymer should have a molecular weight of at least 2000.
[0081] In alternative embodiments, the chewing gum base comprises
no vinyl polymer.
[0082] The chewing gum base preferably also comprises a filler,
preferably a particulate filler. Fillers are used to modify the
texture of the gum base and aid in its processing. Examples of
typical fillers include calcium carbonate, talc, amorphous silica
and tricalcium phosphate. Preferably, the filler is silica, or
calcium carbonate. The size of the filler particle has an effect on
cohesiveness, density and processing characteristics of the gum
base on compounding. Smaller filler particles have been shown to
reduce the adhesiveness of the gum base.
[0083] The amount of filler present in the chewing gum base is
typically 0-40% by weight of the chewing gum base, more typically
5-15% by weight.
[0084] Preferably, the chewing gum base comprises a softener.
Softeners are used to regulate cohesiveness, to modify the texture
and to introduce sharp melting transitions during chewing of a
product. Softeners ensure thorough blending of the gum base.
Typical examples of softeners are hydrogenated vegetable oils,
lanolin, stearic acid, sodium stearate, potassium stearate and
glycerine. Softeners are typically used in amounts of about 15% to
about 40% by weight of the chewing gum base, and preferably in
amounts of from about 20% to about 35% of the chewing gum base.
[0085] A preferred chewing gum base comprises an emulsifier.
Emulsifiers aid in dispersing the immiscible components of the
chewing gum composition into a single stable system. Suitable
examples are lecithin, glycerol, glycerol monooleate, lactylic
esters of fatty acids, lactylated fatty acid esters of glycerol and
propylene glycol, mono-, di-, and tri-stearyl acetates,
monoglyceride citrate, stearic acid, stearyl monoglyceridyl
citrate, stearyl-2-lactylic acid, triacyetyl glycerin, triethyl
citrate and polyethylene glycol. The emulsifier typically comprises
from about 0% to about 15%, and preferably about 4% to about 6% of
the chewing gum base.
[0086] The chewing gum base detailed above may be used to form a
chewing gum composition. The chewing gum composition may comprise a
gum base and one or more sweetening or flavouring agents.
Typically, the chewing gum composition comprises both a sweetening
and a flavouring agent. The chewing gum composition may
additionally comprise other agents, including nutraceutical
actives, herbal extracts, stimulants, fragrances, sensates to
provide cooling, warming or tingling actions, microencapsulates,
abrasives, whitening agents and colouring agents.
[0087] The amount of gum base in the final chewing gum composition
is typically in the range 5-95% by weight of the final composition,
with preferred amounts being in the range 10-50% by weight, more
preferably 15-25% by weight.
[0088] The chewing gum composition may comprise a variety of other
ingredients, for instance a biologically active ingredient such as
a medicament.
[0089] The biologically active ingredient is any substance which
modifies a chemical or physical process in the human or animal
body. Preferably, it is a pharmaceutically active ingredient and
is, for instance, selected from anti-platelet aggregation drugs,
erectile dysfunction drugs, decongestants, anaesthetics, oral
contraceptives, cancer chemotherapeutics, psychotherapeutic agents,
cardiovascular agents, NSAID's, NO Donors for angina, non-opioid
analgesics, antibacterial drugs, antacids, diuretics, anti-emetics,
antihistamines, anti-inflammatories, antitussives, anti-diabetic
agents (for instance, insulin), opioids, hormones and combinations
thereof. Preferably, the active ingredient is a stimulant such as
caffeine or nicotine. Alternatively, the active ingredient is an
analgesic. A further example of an active ingredient is
insulin.
[0090] In one embodiment of the invention, the biologically active
ingredient is a non-steroidal anti-inflammatory drug (NSAID), such
as diclofenac, ketoprofen, ibuprofen or aspirin. Alternatively the
active ingredient is paracetamol (which is generally not classed as
an NSAID).
[0091] In a different embodiment of the invention, the biologically
active ingredient is a vitamin, mineral, or other nutritional
supplement.
[0092] The biologically active ingredient may be an anti-emetic,
for instance Dolasetron. Alternatively the biologically active
ingredient is an erectile dysfunction drug, such as sildenafil
citrate.
[0093] Generally the chewing gum composition comprises 0.01-20% wt
active ingredient, more typically 0.1-5 wt %. The chewing gum
composition may be in unit dosage form suitable for oral
administration. The unit dosage form preferably has a mass in the
range 0.5-4.5 g, for instance around 1 g. Generally, the chewing
gum composition comprises 1-400 mg biologically active ingredient,
more typically 1-10 mg, depending on the active ingredient. When
the active ingredient is nicotine, for instance, the chewing gum
composition typically comprises 1-5 mg nicotine. When the active
ingredient is a non-steroidal anti-inflammatory drug, such as
ibuprofen, the composition typically comprises 10-100 mg active
ingredient.
[0094] In the laboratory, a HAAKE MiniLab Micro Compounder (Thermo
Fisher Corporation) may be used to form both the gum base and the
chewing gum composition.
[0095] In the case of the gum base, the ingredients are typically
mixed together by adding them in stages at a temperature in the
range 80-120.degree. C., typically around 100.degree. C. After the
gum base has formed, the material is extruded out of the
MiniLab.
[0096] It will be noted that the MiniLab Compounder would not be
used to mix large scale batches of chewing gum. An industrial scale
machine, such as a Z-blade mixer would be used in this case.
[0097] The method of forming the chewing gum composition typically
comprises blending the gum base with the sweetening and flavouring
agents. Standard methods of production of chewing gum compositions
are described in Formulation and Production of Chewing and Bubble
Gum. ISBN: 0-904725-10-3, which includes manufacture of gums with
coatings and with liquid centres.
[0098] Typically, chewing gum compositions are made by blending gum
base with sweetening and flavouring agents in molten form, followed
by cooling of the blend. Such a method may be used in the present
invention.
[0099] The chewing gum composition may require heating to a
temperature of around 100.degree. C. (for instance, in the range
80-120.degree. C.) in order to uniformly mix the components.
Amphiphilic polymeric material as made in the first aspect of the
invention is added at either the gum base-forming step, or when the
chewing gum composition is formed. The amphiphilic polymeric
material of this invention, or alternatively, any amphiphilic
polymeric material may be added during both of these steps.
[0100] Preferably the mixture is heated to a temperature in the
range 80-120.degree. C., typically around 100.degree. C. The
mixture is generally cooled to a temperature in the range
40-80.degree. C., preferably 50-70.degree. C. If biologically
active ingredient is to be included in the composition, it is
generally added at this stage.
[0101] The biologically active ingredient may be added in solid,
molten or liquid form. Nicotine is generally added as an oil, for
instance, although use of a solid form (e.g. nicotine on an ion
exchange resin, such as Polacrilex.TM.) is preferred. Before adding
the active ingredient in step (ii) the active ingredient may be
pre-mixed with polymeric material and/or sweetening agent.
Preferably, the sweetening agent is sorbitol.
[0102] After the mixing is complete, the chewing gum composition
may be extruded.
[0103] During any of the steps of the method, the mixture may be
stirred to improve homogeneity.
[0104] The final stage may comprise use of compression to form the
chewing gum composition.
[0105] A unit dosage form of the chewing gum composition may be
formed by extruding the chewing gum and shaping the extrudate to
the desired form. The unit dosage form typically has a mass in the
range 0.5-2.5 g, typically around 1 g. The dosage unit may take the
form of a cylindrical or spherical body, or a tab.
[0106] Typically, the chewing gum composition comprises 5-95% by
weight, preferably 10-50% by weight, more preferably 15-45% of the
chewing gum base. Additional amphiphilic polymeric material may
also be added to form the chewing gum composition, in an amount
such that it comprises 1-15%, more preferably 3-15% of the chewing
gum composition.
[0107] The steps to form the chewing gum composition may be carried
out sequentially in the same apparatus, or may be carried out in
different locations, in which case there may be intermittent
cooling and heating steps.
[0108] The invention will now be illustrated further in the
following Examples, and with reference to the accompanying
drawings, in which:
[0109] FIG. 1 compares the molecular weight distribution of a
number of batches of P1 as determined by GPC;
[0110] FIG. 2 compares the molecular weight distribution of samples
of the graft copolymers P2, P3, and P4 with the LIR-403 backbone
starting material as determined by GPC;
[0111] FIG. 3 compares the molecular weight distribution of samples
of the graft copolymers P6, P7, and P8 with the LIR-403 backbone
starting material as determined by GPC;
[0112] FIG. 4 compares the molecular weight distribution of samples
of the graft copolymers P9, and P10 with the LIR-410 backbone
starting material as determined by GPC;
[0113] FIG. 5 compares the molecular weight distribution of samples
of the graft copolymers P11, and P12 with the Isolene 40-S and
MAGPI polyisoprene backbone starting materials as determined by
GPC; and
[0114] FIG. 6 compares cumulative cinnamaldehyde release in
artificial saliva from gum containing P1, P7, and a control gum
determined using HPLC.
MATERIALS
[0115] Two different forms of PIP-g-MA have been used; the first
supplied under the name LIR-403 by Kuraray and the other is a
PIP-g-MA synthesized by the reaction of maleic anhydride with
polyisoprene (Isolene 40-S) in 1,2-dichlorobenzene (See Example
17). This latter material will subsequently be referred to as
maleic anhydride-grafted-polyisoprene (MAGPI) to avoid confusion
with the generic term PIP-g-MA. The polyisoprene used in the
synthesis of MAGPI, Isolene 40-S manufactured by Royal Elastomers,
is a synthetic polyisoprene with a glass transition temperature of
-65.degree. C., a typical molecular weight of 32,000, and a
relatively broad molecular weight distribution compared with that
of LIR-403. Subsequently the resulting MAGPI synthesized from
Isolene 40-S has a similarly broader molecular weight distribution
compared to LIR-403.
REFERENCE EXAMPLE A
Determination of Molecular Weights of Polymeric Materials and Free
MPEG
[0116] The polymer samples were analyzed using a PL-GPC50 plus GPC
system manufactured by Polymer Labs. The following conditions were
used:
[0117] Eluent: THF stabilised with 250 ppm BHT
[0118] Eluent RI: 1.408
[0119] Flow Rate (mL/min):1
[0120] Temperature: 40.degree. C.
[0121] Column Set Name: 2 Columns 30 mm PL gel 5 um MIXED-D
[0122] Detector Name: DRI
[0123] Detector Calibration Curve: Polystyrene Standards
(538Da-265000Da)
[0124] This apparatus was used to determine the molecular weights
of all of the graft copolymers. In order to determine the amount of
free MPEG present in the samples 10 different solutions of known
concentration of MPEG 2000 in THF (0.05-2 mg/mL) were accurately
prepared and analysed on the apparatus. The relevant intensity of
the samples was then used to generate a calibration curve which was
used to generate the concentration of free MPEG in the samples.
REFERENCE EXAMPLE B
Determination of Degrees of Grafting with Peg Using FT-IR
[0125] The analysis described below is used to calculate the degree
of grafting of side chain precursor to backbone precursor. The
analysis determines the amount of cyclic units derived from maleic
anhydride in the backbone precursor starting material and product
polymeric material. The degree of grafting calculation is based on
the assumption that all units derived from maleic anhydride react
with side chain precursors.
[0126] The analysis was carried out on a PerkinElmer Paragon 2000
Infrared spectrometer. Samples for analysis were dissolved in
spectrometric grade chloroform and placed in a liquid cell (Barium
fluoride plates separated by PTFE spacer) in a mounting
bracket/carriage in an IR beam with known cell path length. A
sample of the batch of PIP-g-MA used to synthesize the graft
copolymer was accurately weighed out, .about.0.1 g (+/-0.05 g) into
the stoppered conical flask and dissolved in 10 g of accurately
weighed out chloroform. The FT-IR of the sample was collected, and
the percentage transmission values measured at 1830 cm.sup.-1 and
at 1790 cm.sup.-1 recorded. The sample of polymer was accurately
weighed out, .about.1.5 g (+/-0.5 g) into the stoppered conical
flask, dissolved in 10 g of accurately weighed out chloroform, and
studied by FT-IR in a similar manner. The Concentration of maleic
anhydride in each sample was then calculated using the following
formula:
.mu. mole / g ( in sample ) = 33600 C .times. Log 10 % T ( at
1830.0 cm - 1 ) % T ( at 1790.0 cm - 1 ) ##EQU00001##
[0127] where C is the concentration in the test solution (quoted in
mg g.sup.-1). The percentage conversion of maleic anhydride can
then be determined by comparing the values from the backbone and
graft copolymer.
[0128] This method can also be used to determine the degrees of
grafting in the other polymeric materials (P2-P8). The method does
not work for P9 and P10, as these are synthesised from LIR-410
which does not comprise cyclic units derived from maleic
anhydride.
REFERENCE EXAMPLE C
Cinnamaldehyde Release Tests on Chewing Gums--Experimental
Method
[0129] Each pre-shaped piece of gum was weighed before chewing, and
the weight recorded to allow estimation of the total quantity of
drug in each piece. A `ERWEKA DRT-1` chewing apparatus from AB FIA
was used, which operates by alternately compressing and twisting
the gum in between two mesh grids. A water jacket, with the water
temperature set to 37.degree. C. was used to regulate the
temperature in the mastication cell to that expected when chewed in
vivo, and the chew rate was set to 40 `chews` per minute. The jaw
gap was set to 1.6 mm.
[0130] 40 mL artificial saliva (composed of an aqueous solution of
various salts, at approx pH 6--see below, Table 1) was added to the
mastication cell, then a plastic mesh placed at its bottom. A piece
of gum of known weight was placed on the centre of the mesh, and a
second piece of mesh put on top.
Artificial Saliva:
TABLE-US-00001 [0131] TABLE 1 Artificial Saliva Formulation
Components Quantity (mmol/L) KH.sub.2PO.sub.4 2.5 Na.sub.2HPO.sub.4
2.4 KHCO.sub.3 15 NaCl 10 MgCl.sub.2 1.5 CaCl.sub.2 1.5 Citric acid
0.15 PH adjusted to 6.7 with HCl
Procedure for Analysing the Release Profiles of Active Ingredients
from Gum
[0132] The parameters in Table 2 were always used in chewing unless
otherwise noted.
TABLE-US-00002 TABLE 2 Chewing Parameters Parameter Value
Temperature 37.degree. C. Gaps between jaws 1.6 mm Twisting angle
20.degree. Chew Frequency 40 strokes/min
[0133] At the start of each run, the cell containing the artificial
saliva and gum was left for 5 minutes so that the system could
equilibrate to 37.degree. C. The gum was then masticated. A sample
volume of 0.5 mL was then withdrawn from the test cell periodically
during a release run (5, 10, 15, 20, 25, 30, 40, 50 and 60
minutes).
[0134] All the samples were then analysed by HPLC using a typical
Perkin Elmer HPLC Series 200 system, equipped with an autosampler,
pump, and diode array detector. Data handling and instrument
control was provided via Totalchrom v 6.2 software. The columns and
mobile phase were adjusted to the active ingredient as follows:
[0135] Cinnamaldehyde details: Column--Varian Polaris 5u C18-A
250.times.4.6 m. Mobile Phase--Acetonitrile/0.05% orthophosphoric
acid (60/40). Flow rate--1 mL/min. Detection--UV 250 nm. Inj vol--5
uL
[0136] Two injections into the HPLC column were used for each
sample, to ensure reproducibility.
EXAMPLE 1
Reaction of Polyisoprene-Graft-Maleic Anhydride with Poly(ethylene
Glycol) Methyl Ether (Preparation of P1.sub.a) in a Reaction Flask
(Comparative)
[0137] PIP-g-MA (300 g, Polyisoprene-graft-maleic anhydride
obtained from Kuraray, LIR-403 grade) having the CAS No.
139948-75-7, an average M.sub.w of approximately 25,000 and a
typical level of grafting of MA of around 1.0 mol %, and
poly(ethylene glycol) methyl ether (PEGME) (212 g, purchased from
Clariant), having an average molecular weight of 2000 were weighed
out and added to a reaction flask with a 1 L capacity, equipped
with an overhead stirrer. The PIP-g-MA was present as a liquid, and
PEGME as a solid. A flow of nitrogen gas was passed through the
vessel, which was then heated to 120.degree. C. using an oil bath.
Stirring of the molten mixture then commenced and the vessel was
then heated to 160.degree. C.
[0138] The reaction mixture was maintained at this temperature for
a total of approximately 24 hours. Following this it was allowed to
cool to below 100.degree. C. and water (400 mL) was then added. The
mixture was allowed to cool to room temperature and the water was
removed by filtration, following which the product was dried under
vacuum at 40-50.degree. C.
[0139] The product was studied using GPC and FTIR. A comparison of
the GPC chromatogram of this and other samples of P1 may be found
in FIG. 1.
EXAMPLE 2
Reaction of Polyisoprene-Graft-Maleic Anhydride with Poly(ethylene
Glycol) Methyl Ether Preparation of P1.sub.b in a Batch Ploughshare
Mixer (Comparative)
[0140] PIP-g-MA (738 g, Polyisoprene-graft-maleic anhydride
obtained from Kuraray, LIR-403 grade) having the CAS No.
139948-75-7, an average M.sub.w, of approximately 25,000 and a
typical level of grafting of MA of around 1.0 mol %, and
poly(ethylene glycol) methyl ether (PEGME) (526 g, purchased from
Clariant), having an average molecular weight of 2000 were weighed
out and added to a Lodige 3 L batch ploughshare mixer, equipped
with an overhead stirrer. A flow of nitrogen gas was passed through
the vessel, which was then heated to 120.degree. C. using an oil
bath. Stirring of the molten mixture then commenced and the vessel
was then heated to 160.degree. C. An essentially homogenous mixture
was formed, with the backbone precursors dissolved in the side
chain precursors.
[0141] The reaction mixture was maintained at this temperature for
a total of approximately 24 hours. Following this it was allowed to
cool to below 100.degree. C. and water (1 L) was then added. The
mixture was allowed to cool to room temperature and the water was
removed by filtration, following which the product was dried under
vacuum at 40-50.degree. C.
[0142] The product was studied using GPC and FTIR. A comparison of
the GPC chromatogram of this and other samples of P1 may be found
in FIG. 1.
EXAMPLE 3
Reaction of Polyisoprene-Graft-Maleic Anhydride with Poly(ethylene
Glycol) Methyl Ether (Preparation of P1.sub.c) in a Z-Blade Mixer
(Comparative)
[0143] PIP-g-MA (385 g, Polyisoprene-graft-maleic anhydride
obtained from Kuraray, LIR-403 grade) having the CAS No.
139948-75-7, an average M.sub.w of approximately 25,000 and a
typical level of grafting of MA of around 1.0 mol %, and
poly(ethylene glycol) methyl ether (PEGME) (293 g, purchased from
Clariant), having an average molecular weight of 2000 were weighed
out and added to a Winkworth z-blade mixer, equipped with an
overhead stirrer. A flow of nitrogen gas was passed through the
vessel, which was then heated to 120.degree. C. using an oil bath.
Stirring of the molten mixture then commenced and the vessel was
then heated to 160.degree. C.
[0144] The reaction mixture was maintained at this temperature for
a total of approximately 24 hours. Following this it was allowed to
cool to below 100.degree. C. and water (0.5 L) was then added. The
mixture was allowed to cool to room temperature and the water was
removed by filtration, following which the product was dried under
vacuum at 40-50.degree. C.
[0145] The product was studied using GPC and FTIR. A comparison of
the GPC chromatogram of this and other samples of P1 may be found
in FIG. 1.
EXAMPLE 4
Reaction of Polyisoprene-Graft-Maleic Anhydride with Poly(ethylene
Glycol) Methyl Ether in Toluene Solvent Preparation of P1.sub.d)
(Comparative)
[0146] PIP-g-MA (5.25 Kg, Polyisoprene-graft-maleic anhydride
obtained from Kuraray, LIR-403 grade) having the CAS No.
139948-75-7, an average M.sub.w of approximately 25,000 and a
typical level of grafting of MA of around 1.0 mol %, and
poly(ethylene glycol) methyl ether (PEGME) (4.00 kg, purchased from
Aldrich), having an average molecular weight of 2000 were weighed
out and added to an air-tight jacketed reactor with a twenty litre
capacity, equipped with an overhead stirrer. Toluene (10.0 Kg) was
added to the reactor to dissolve the starting materials, and a flow
of nitrogen gas passed through the vessel.
[0147] The vessel was then heated to reflux the toluene
(115-116.degree. C.) using an oil bath set to 140.degree. C.
connected to the reactor's jacket. A Dean-Stark trap and condenser
between the vessel and nitrogen outlet were used in order to remove
any water from the poly(ethylene glycol) methyl ether and toluene
by means of azeotropic distillation. Thus water was collected in
the Dean-Stark trap over the course of the reaction.
[0148] The reaction mixture was refluxed for a total of
approximately 24 hours. The reaction can also be catalysed by
addition of acid or base. The product was purified in 2 L batches
by adding the still warm (50.degree. C.) material to 3 L tanks of
deionised water. In the case of each batch the water was removed by
filtration and the process of washing the graft copolymer with
deionised water, and removing the water wash with the aid of
filtration repeated a further five times. The product was dried
under vacuum at 50.degree. C. overnight.
[0149] The product was studied using GPC and FTIR. A comparison of
the GPC chromatogram of this and other samples of P1 may be found
in FIG. 1, and serves as a comparison with the data for the samples
of polyether amine functionalised amphiphilic polymeric material
(FIGS. 2-5).
EXAMPLE 5
Reaction of Polyisoprene-Graft-Maleic Anhydride with an Amine
Functionalised Polyether (Jeffamine M-1000) (Preparation of
P2.sub.a) with a 1:1 Ratio of Graft to Each Maleic Anhydride
Group
[0150] PIP-g-MA (150.0 g, Polyisoprene-graft-maleic anhydride
obtained from Kuraray, LIR-403 grade) having the CAS No.
139948-75-7, an average M.sub.w of approximately 25,000 and a
typical level of grafting of MA of around 1.0 mol %, and an amine
functionalised polyether (Jeffamine M-1000, 21.8 g, obtained from
Huntsman), having an average molecular weight of 1000 were added to
a reaction flask with a 250 mL capacity, equipped with an overhead
stirrer. A flow of nitrogen gas was passed through the vessel,
which was then heated to 120.degree. C. using an oil bath. Stirring
of the molten mixture then commenced and the vessel was then heated
to 160.degree. C.
[0151] The reaction mixture was maintained at this temperature for
a total of approximately 24 hours. Following this it was allowed to
cool to approximately 80.degree. C. and water (200 mL) was then
added. The mixture was allowed to cool to room temperature and the
water was removed by decantation, following which the product was
dried under vacuum at 40-50.degree. C.
[0152] The structure was confirmed using GPC and FTIR.
EXAMPLE 6
Reaction of Polyisoprene-Graft-Maleic Anhydride with an Amine
Functionalised Polyether (Jeffamine M-1000) (Preparation of
P2.sub.b) with a 1:1 Ratio of Graft to Each Maleic Anhydride
Group
[0153] This product was prepared using the same methodology as
Example 5 using LIR-403 (500 g) of an amine functionalised
polyether (Jeffamine M-1000, 72.7 g), and a 1 L reaction flask. It
was not necessary to add water to the product due to the efficiency
of the reaction between the polymeric backbones and this graft
determined from previous experiment. The structure was confirmed
using GPC and FTIR.
EXAMPLE 7
Reaction of polyisoprene-graft-maleic anhydride with an Amine
Functionalised Polyether (Jeffamine M-1000) (Preparation of
P3.sub.a) with a 2:1 Ratio of Graft to Each Maleic Anhydride
Group
[0154] This product was prepared using the same methodology as
Example 5 using 43.6 g of an amine functionalised polyether
(Jeffamine M-1000).
[0155] The structure was confirmed using GPC and FTIR.
EXAMPLE 8
Reaction of Polyisoprene-Graft-Maleic Anhydride with an Amine
Functionalised Polyether (Jeffamine M-1000) (Preparation of
P3.sub.b) with a 2:1 Ratio of Graft to Each Maleic Anhydride Group
Using an Organic Solvent
[0156] This material was prepared using the same methodology as
Example 7 but used toluene as a solvent.
[0157] PIP-g-MA (150.0 g, Polyisoprene-graft-maleic anhydride
obtained from Kuraray, LIR-403 grade) having the CAS No.
139948-75-7, an average M.sub.w of approximately 25,000 and a
typical level of grafting of MA of around 1.0 mol %, and an amine
functionalised polyether (Jeffamine M-1000, 21.8 g, obtained from
Huntsman), having an average molecular weight of 1000 were added to
a reaction flask with a 250 mL capacity, equipped with an overhead
stirrer. A flow of nitrogen gas was passed through the vessel,
which was then heated to 120.degree. C. using an oil bath. Toluene
(195.0 g) was added to the reactor to dissolve the starting
materials, and a flow of nitrogen gas passed through the
vessel.
[0158] The vessel was then heated to reflux the toluene in an oil
bath set to 170.degree. C. connected to the reactor's jacket. A
Dean-Stark trap and condenser between the vessel and nitrogen
outlet were used in order to remove any water from the
poly(ethylene glycol) methyl ether and toluene by means of
azeotropic distillation. This water was collected in the Dean-Stark
trap over the course of the reaction.
[0159] The reaction mixture was maintained at this temperature for
a total of approximately 24 hours. Following this it was allowed to
cool to approximately 80.degree. C. and precipitated in water (2
L). The stirred mixture was allowed to cool for 30 min, after which
the water was removed by decantation, and the product was dried
under vacuum at 40-50.degree. C.
[0160] The structure was confirmed using GPC and FTIR.
EXAMPLE 9
Reaction of Polyisoprene-Graft-Maleic Anhydride with an Amine
Functionalised Polyether (Jeffamine M-1000) (Preparation of
P3.sub.c) with a 2:1 Ratio of Graft to Each Maleic Anhydride
Group
[0161] This product was prepared using the same methodology as
Example 6 using LIR-403 (500 g) and an amine functionalised
polyether (Jeffamine M-1000, 43.6 g), and a 1 L reaction flask. The
structure was confirmed using GPC and FTIR.
EXAMPLE 10
Reaction of Polyisoprene-Graft-Maleic Anhydride with an Amine
Functionalised Polyether (Jeffamine M-1000) (Preparation of P4)
with a 2.8:1 Ratio of Graft to Each Maleic Anhydride Group
[0162] This product was prepared using the same methodology as
Example 6 using LIR-403 (62.3 g) and an amine functionalised
polyether (Jeffamine M-1000, 25.3 g), and a 250 mL reaction flask.
The structure was confirmed using GPC and FTIR.
EXAMPLE 11
Reaction of Polyisoprene-Graft-Maleic Anhydride with an Amine
Functionalised Polyether (Jeffamine M-2070) (Preparation of P5)
with a 0.5:1 Ratio of Graft to Each Maleic Anhydride Group
[0163] This product was prepared using the same methodology as
Example 6 using LIR-403 (500 g) and an amine functionalised
polyether (Jeffamine M-2070, 72.7 g), and a 1 L reaction flask. The
structure was confirmed using GPC and FTIR.
EXAMPLE 12
Reaction of Polyisoprene-Graft-Maleic Anhydride with an Amine
Functionalised Polyether (Jeffamine M-2070) (Preparation of P6)
with a 1:1 Ratio of Graft to Each Maleic Anhydride Group
[0164] This product was prepared using the same methodology as
Example 6 using LIR-403 (500 g) and an amine functionalised
polyether (Jeffamine M-2070, 145.0 g), and a 1 L reaction flask.
The structure was confirmed using GPC and FTIR.
EXAMPLE 13
Reaction of Polyisoprene-Graft-Maleic Anhydride with an Amine
Functionalised Polyether (Jeffamine M-2070) (Preparation of P7)
with a 2:1 Ratio of Graft to Each Maleic Anhydride Group
[0165] This product was prepared using the same methodology as
Example 6 using LIR-403 (500 g) and an amine functionalised
polyether (Jeffamine M-2070, 290.0 g), and a 1 L reaction flask.
The structure was confirmed using GPC and FTIR.
EXAMPLE 14
Reaction of Polyisoprene-Graft-Maleic Anhydride with an Amine
Functionalised Polyether (Jeffamine M-2070) (Preparation of P8)
with a 2.8:1 Ratio of Graft to Each Maleic Anhydride Group
[0166] This product was prepared using the same methodology as
Example 6 using LIR-403 (61.8 g) and an amine functionalised
polyether (Jeffamine M-2070, 50.18 g), and a 250 mL reaction flask.
The structure was confirmed using GPC and FTIR.
EXAMPLE 15
Reaction of Polyisoprene-Graft-Maleic Acid Monomethyl Ester with an
Amine Functionalised Polyether (Jeffamine M-1000) (Preparation of
P9) With a 1:1 Ratio of Graft to Each Maleic Acid Mono Ester
Group
[0167] This product was prepared using the same methodology as
Example 6 using LIR-410 (60 g) and an amine functionalised
polyether (Jeffamine M-1000, 24.5 g), and a 250 mL reaction flask.
The structure was confirmed using GPC and FTIR.
EXAMPLE 16
Reaction of Polyisoprene-Graft-Maleic Acid Monomethyl Ester with an
Amine Functionalised Polyether (Jeffamine M-2070) (Preparation of
P10) with a 1:1 Ratio of Graft to Each Maleic Acid Mono Ester
Group
[0168] This product was prepared using the same methodology as
Example 6 using LIR-410 (60 g) of an amine functionalised polyether
(Jeffamine M-2070, 50.0 g), and a 250 mL reaction flask. The
structure was confirmed using GPC and FTIR.
EXAMPLE 17
Synthesis of Maleic Anhydride Grafted Polyisoprene (MAGPI)
[0169] Polyisoprene (Isolene 40S, supplied by Royal Elastomers, 72
g), maleic anhydride (1.0 g), and 1,2-dichlorobenzene were weighed
out into a 3 neck round bottom flask. The reaction flask was
equipped with an overhead stirrer, and condenser and thoroughly
purged with nitrogen gas. Stirring of the reaction mixture then
commenced, and the reaction mixture was rapidly heated up under a
still nitrogen atmosphere. The reaction mixture was refluxed for
five hours (180.degree. C.). After this period the solvent from the
reaction mixture was distilled off (under vacuum), and the
remaining material allowed to cool to room temperature. This was
then washed with acetone (3.times.100 mL) in-order to remove any
un-reacted MA. The product was then dried under vacuum at
100.degree. C.
[0170] To avoid confusion with the generic term
polyisoprene-graft-maleic anhydride (PIP-g-MA) the products of
these reactions will be referred to as MAGPI.
EXAMPLE 18
Reaction of MAGPI with an Amine Functionalised Polyether (Jeffamine
M-1000) (Preparation of P11) with a 2:1 Ratio of Graft to Each
Maleic Anhydride Group
[0171] This product was prepared using the same methodology as
Example 6 using MAGPI (60 g) and an amine functionalised polyether
(Jeffamine M-1000, 27.9 g), and a 250 mL reaction flask. The
structure was confirmed using GPC and FTIR.
EXAMPLE 19
[0172] Reaction of MAGPI with an amine functionalised polyether
(Jeffamine M-2070) (preparation of P12) with a 2:1 ratio of graft
to each maleic anhydride group This product was prepared using the
same methodology as Example 6 using MAGPI (60 g) and an amine
functionalised polyether (Jeffamine M-2070, 55.8 g), and a 250 mL
reaction flask. The structure was confirmed using GPC and FTIR.
EXAMPLE 20
Preparation of Gum Base and Chewing Gum Chemicals
[0173] Calcium carbonate (CaCO.sub.3), ester gum, hydrogenated
vegetable oil (HVO), polyisobutylene (PIB), polyvinyl acetate)
(PVAc), glyceromonostearate (GMS), microwax, sorbitol liquid,
sorbitol solid, and peppermint oil, were all food grade materials
obtained from the Gum Base Company. Cinnamaldehyde (98+%) was
obtained from Fisher-Scientific UK.
Mixing of the Chewing Gum and Chewing Gum Base
[0174] The chewing gum base had the composition as shown in the
table below:
TABLE-US-00003 TABLE 3 Recipe for the Manufacture of the Gum Bases
Stage Component % Composition Mass/g 1 PIB 13 1.04 PVAc 6 0.48
CaCO.sub.3 6 0.48 Ester Gum 3.6 0.288 2 Ester Gum 5.4 0.432
CaCO.sub.3 9 0.72 3 PVAc 9 0.72 Ester Gum 9 0.72 CaCO.sub.3 15 1.2
4 HVO 12 0.96 GMS 6 0.48 X 6 0.48 Total 100 8 X is either
microcrystalline wax in the case of S3 control, P1 or P7. HVO =
hydrogenated vegetable oil, PVAc = poly(vinyl acetate).
X is either microcrystalline wax in the case of the S3 control, P1
or P7. HVO=hydrogenated vegetable oil, PVAc=poly(vinyl
acetate).
[0175] The gum base materials were mixed on a Haake Minilab micro
compounder manufactured by the Thermo Electron Corporation, which
is a small scale laboratory mixer/extruder. The screws were set to
co-rotate at 80 turns/min.
[0176] The ingredients were mixed together in four steps, the gum
only being extruded after the final step. The gum base was mixed at
100.degree. C.
[0177] The chewing gum was mixed according to the following
table.
TABLE-US-00004 TABLE 4 Ingredients for the Chewing Gum Stage Time
Component Amount 1 15 min 37.5% Gum Base Containing X 3 g 10%
Sorbitol Liquid 0.8 g 17% Sorbitol Powder 1.36 g 2 15 min 25.5%
Sorbitol Powder 2.04 g 6% X 0.48 g 3% Sorbitol Liquid 0.24 g 1%
Cinnamaldehyde Flavour 0.08 mL 30 min TOTAL 8 g X is either P1, or
P7, microcrystalline wax in the case of the S3 control.
X is either P1, or P7, microcrystalline wax in the case of the S3
control.
[0178] The gum was mixed using the same equipment as the base and
extruded after the final step. The gum was mixed at 60.degree. C.
In stage 1 the sorbitol liquid and powder were premixed prior to
adding them to the gum.
[0179] The gums were tested using the method described in Reference
Example C. The fastest and highest release profile was observed for
the formulation containing P1. The release rate from the P7 gum
formulations was comparatively slow compared with those from P1
during the period between the 5.sup.th and 20.sup.th minutes. It
subsequently increased to a level above that of P1, so that the
total percentage amount of cinnamaldehyde released from the P7 and
P1 gums is almost identical by the end of the experiment. The
microwax control by contrast to the formulations containing the two
polymers, has a consistently lower release rate after 5 minutes;
the total amount of cinnamaldehyde released at the end of the
experiment is approximately half that of the other two
formulations.
[0180] A series of gum formulations were made on a laboratory
compounder using either P1, P7 or in the case of the control,
microwax. The P1 was P1.sub.d, i.e. prepared in accordance with
Example 4, but any of P1.sub.a-P1.sub.c would also be suitable. The
finished gum samples were masticated in artificial saliva and the
release of cinnamaldehyde, added as a flavour, monitored via HPLC
(FIG. 1). The slowest release was observed with the microwax
control. The fastest release was observed from the gum containing
P1, with the formulation containing P7 observed to have only a
slightly slower release profile.
Summary of Results
[0181] In these results, the terms "graft" and "side chain
precursor" are used interchangeably. The backbones of each of the
polymers synthesised are derived from polyisoprene to which maleic
anhydride has been grafted. The level of grafting of MA is
typically around 1.0 mol % in the LIR-403 PIP-g-MA used to
demonstrate the concept. In PIP-g-MaMme the same level was 2.7 mol
% of the mono-acid mono-methyl ester of MA. The level of grafting
depends on the degree of functionalisation of the polyisoprene. For
example, in P1 the number of grafts per chain is generally between
1 and 7, whereas in P2 it is between 1 and 10.
[0182] Table 5 lists a number of polymers synthesised from PIP-g-MA
or PIP-g-MaMme and Jeffamine M-1000 and M-2070.
TABLE-US-00005 TABLE 5 Properties of Graft Copolymers Synthesised
from Jeffamines. Ratio of Graft to Functional Polymer Backbone
Graft group M.sub.n (g mol.sup.-1) PDI P2.sub.a LIR-403 M1000 1 to
1 24600 1.18 P3.sub.c LIR-403 M1000 2 to 1 23200 1.16 P4 LIR-403
M1000 2.8 to 1 22400 1.16 P5 LIR-403 M2070 0.5 to 1 21710 1.19 P6
LIR-403 M2070 1 to 1 23850 1.16 P7 LIR-403 M2070 2 to 1 25120 1.15
P8 LIR-403 M2070 2.8 to 1 31340 1.19 P9 LIR-410 M1000 1 to 1 22750
1.20 P10 LIR-410 M2070 1 to 1 25930 1.16 P11 MAGPI M1000 2 to 1
13630 1.77 P12 MAGPI M2070 2 to 1 19530 1.67 M.sub.n = Number
Average Molecular Weight, PDI = Polydispesity Index; both
determined by GPC.
[0183] The ratio of graft to maleic anhydride can easily be varied
to achieve different loadings of the graft on the backbone and thus
different properties in the resulting polymeric material. Polymeric
materials with a higher degree of grafting will tend to be more
hydrophilic and are likely to be easier to disperse or dissolve in
water. The degree of grafting was in all cases confirmed by FT-IR,
here the disappearance of the peaks at 1790 and 1830 cm.sup.-1 from
the maleic anhydride was monitored. GPC was used to determine the
molecular weight distribution of the resulting products and the
amount of free polyether amine graft. For comparison the GPC
chromatograms of samples synthesised using the hydroxyl
functionalised polyether, in particular methoxy poly(ethylene
glycol), are depicted in FIG. 1. Two peaks are observed, one from
that of the graft copolymeric material, and one from free polyether
graft at higher retention time (corresponding with lower molecular
weight). FIGS. 2-5 depict the GPC traces of the samples of polymers
synthesised using the amine functionalised polyethers. As will be
apparent from the data, in contrast to the case with hydroxyl
functionalised polymers, the amines have reacted efficiently with
the maleic anhydride groups leaving very little free graft. This
means a smaller quantity of graft needs be added to the reaction to
achieve the same degree of grafting, and the process is
subsequently more efficient than when MPEG is utilised.
Alternatively it is possible to increase the degree of grafting
with amine functionalised polyether beyond that which is possible
using MPEG. If desired it is still possible to use an excess of
Jeffamine (for instance P4 and P8) to increase the probability that
every maleic anhydride group and/or acid group is consumed. Unless
it is removed by purification this will inevitably lead to a
material with a greater percentage of free graft in its
composition. Therefore using only a small excess of graft is
preferred, using a stoichiometric amount is preferred to a greater
degree. Slightly less free graft was observed in the cases where
the lower molecular weight amine polyether was used. This is due to
the tendency of lower molecular weight polymers to react faster
than the higher molecular weight species, and this trend is also
observed with the hydroxyl functionalised PEGs.
* * * * *