Title of Invention

BIODEGRADABLE GRAFTED COPOLYMERS

Abstract The invention discloses a copolymer comprising a polysaccharide backbone and amphiphilic diblock copolymers grafted on said polysaccharide backbone, each amphiphilic diblock comprising: a) a hydrophobic polymeric segment directly grafted on the polysaccharide backbone and comprising from 5 to 200 repeated units; and b) a hydrophilic polymeric segment covalently bonded to the hydrophobic segment and comprising from 5 to 300 repeated units. The invention is also for a process for preparation of said copolymer and a biodegradable particle comprising said copolymer.
Full Text Technical Field
The present invention relates to the field of biodegradable copolymers. It concerns
more particularly a novel copolymer composition based on a polysaccharide backbone
grafted with amphiphilic diblock copolymers. The compositions of the invention can find
use in various fields of application in particular in pharmaceutical, perfume and flavour
areas, as they adopt, in a particular environment, a core-shell conformation which renders
them suitable to be used as delivery systems for active ingredients. The invention also
concerns a process for the preparation of such copolymer compositions.
Background Art
Biodegradable copolymer compositions as well as their use as carriers for
biologically active materials have been described in the prior art, both in the general
literature and in the patent literature. In fact, many biodegradable copolymers have been
developed for medical applications, and more particularly for the encapsulation of drugs.
In the patent literature, some disclosures in the area of biodegradable copolymer
compositions are directed to the use of diblock, triblock or multiblock copolymers which
consist of sequenced structures, wherein segments of various natures (e.g. hydrophobic
and hydrophilic segments) are covalently linked together. WO 02/39979, US 5,221,534 or
US 5,756,082 provide examples of preparation of such structures and describe their uses
as drug delivery systems, as well as in cosmetic compositions or other applications.
On the other hand, by opposition to sequenced structures, grafted structures based
on biodegradable polymer compositions have also been the object of patents and patent
applications. In particular, systems based on the grafting of single polymers along
polysaccharide chains have been disclosed. WO 01/79315 describes for instance
copolymer compositions consisting of a hydrophobic macromolecule such as a polylactic
acid cross-linked with a water-soluble polymer having multiple hydroxyl functionalities
which may serve as potential reaction sites. The described composition can be used as a
controlled drug delivery system.
More recently, US 2002/0146826 has described a system based on a
polysaccharide chain which has been grafted with an ohgoamrne on the one hand, and by
at least one further group selected from the group consisting of a hydrophobic and an
amphiphilic group. The oligoamines are conjugated with at least one oligomer per five
saccharide units, whereas the hydrophobic and amphiphilic groups are positioned with at
least one group per 50 saccharide units. The document discloses the application of said
systems to gene therapy.
Summary of the Invention
Now, the present invention concerns new biodegradable polymeric systems, based
on the use of a polysaccharide backbone which has been grafted with amphiphilic diblock
copolymers. Such systems have never been described in the prior art and they proved to
constitute very advantageous delivery systems for drugs, flavours, fragrances or other
active ingredients.
A first object of the present invention relates to a copolymer comprising a
polysaccharide backbone and amphiphilic diblock copolymers grafted on said
polysaccharide backbone, each amphiphilic diblock comprising:
a) a hydrophobic polymeric segment directly grafted on the polysaccharide backbone
and comprising from 5 to 200 repeated units; and
b) a hydrophilic polymeric segment covalently bonded to the hydrophobic segment and
comprising from 5 to 300 repeated units.
Said compositions proved to adopt a core-shell structure when put into an aqueous
medium, and thus form particles that can be useful as delivery systems for active
ingredients as varied as drugs, flavours or fragrance ingredients or compositions. These
particles, as well as their use as delivery systems and functional compositions such as
perfumes, foods or pharmaceutical compositions comprising these delivery systems, are
also object of the invention.
Furthermore the present invention concerns a process for the preparation of a
copolymer as defined above, which comprises the major steps of preparing a micro-
initiator by chemical modification of a polysaccharide; using said macro-initiator to
polymerise hydrophobic monomers providing hydrophobic primary segments grafted on
the polysaccharide; using the obtained polymer as a micro-initiator to polymerise
monomers constituting secondary segments covalently linked to the hydrophobic primary
ones ; and optionally chemically modifying the secondary segments.
The present invention thus relates to a copolymer comprising a polysaccharide
backbone and amphiphilic diblock copolymers grafted on said polysaccharide backbone.
In a preferred embodiment, the amphiphilic diblock copolymers are grafted on
said backbone with a degree of substitution via hydroxyl functions comprised between
30% and 80%. Each amphiphilic diblock comprises a hydrophobic polymeric segment
directly grafted on the polysaccharide backbone, comprising from 5 to 200 repeated units,
and a hydrophilic polymeric segment covalently bonded to the hydrophobic segment
comprising from 5 to 300 repeated units. In a preferred embodiment of the invention, the
hydrophobic segments comprises 15-100 repeated units, and the hydrophilic polymeric
segment comprises 15-200 repeated units.
Preferably, each amphiphilic diblock consists of a hydrophobic polymeric
segment and a hydrophilic polymeric segment.
The copolymer of the invention is novel, as no document from the prior art has
ever described the grafting of a polysaccharide with amphiphilic diblock copolymers. The
composition of the invention, besides being novel, proved to form particles which can be
very useful as delivery systems for active ingredients enclosed therein. In fact, in an
aqueous medium, the amphiphilic copolymers of the invention adopt a core-shell
structure, the physico-chemical characteristics of which can be tuned by varying the
degree of polymerisation of each segment, the functionality of the amphiphilic block and
the grafting density. Depending on the latest parameter, the copolymer compositions can
form a stable aqueous dispersion of isolated macromolecules.
More objects, aspects and advantages of the invention will become apparent from
the detailed description hereinafter.
Accompanying
Brief Description of/Drawings
Figure 1 represents isotherm curves obtained at 25 °C for hydroxypropyl-
cellulose/linalool samples on the one hand and HPC-g-PLLA-b-polytrimemylammomum
ethyl methacrylate salt (PTMAEMA)/linalool samples on the other hand.
Figure 2 represents the weight loss of an Eau de toilette (EDT) in the presence (5f, 5g,
Id) or not (Perfume, EtOH/Eau) of grafted polymers of the invention by
thermogravimetric analysis over time. The weight loss at 50°C over 115 minutes forms a
plateau, with samples supplied with the polymer of the invention (5f, 5g, Id) have less
perfume loss than the control.
Detailed Description of the Invention
The biodegradable polymer of the invention is based on a polysaccharide
backbone which has been grafted with amphiphilic diblock copolymers, preferably with a
degree of substitution via hydroxyl functions comprised between 30% and 80%. Any
polysaccharide, preferably biodegradable, can suit the invention. Typical examples of
appropriate polysaccharide chains include those selected from the group consisting of
dextrans, arabinogalactan, pullulan, cellulose, cellobios, inulin, chitosan, alginates,
hyaluronic acid and cyclodextrins. According to a preferred embodiment, the
polysaccharide used in the present invention has a molecular weight higher than
800 g/mol.
Preferably, the copolymer of the invention is a biodegradable copolymer.
Preferably, the copolymer of the invention is present in the form of a copolymer
composition.
The amphiphilic diblock copolymers grafted on the polysaccharide backbone
consist each of a hydrophobic polymeric segment comprising from 5 to 200, preferably
15-100 repeated units, said hydrophobic polymeric segment being directly grafted on the
polysaccharide; and a hydrophilic polymeric segment comprising from 5-300, preferably
15 to 200 repeated units, which is covalently bonded to the hydrophobic segment.
Hydrophobicity and hydrophilicity of the segments constituting the amphiphilic
diblock copolymer entity is defined as follows: A polymer segment is hydrophobic it is
either insoluble in water or less soluble in water than the hydrophilic polymer segment. A
polymer segment is hydrophilic if it can be dissolved at 0.01wt.% or more in water at
room temperature (25°C) following the procedure of US 6,733,787, Example 2, which is
incorporated herein by reference. For example, a diblock-copolymer ([A]n-[B]p) grafted
on a polysaccharide backbone fulfils the hydrophobicity/ -philicity requirements of the
present invention if a polymer [A]n cannot be dissolved at 0.01wt.-% in water and if a
polymer [B]p, in contrast, can be dissolved at 0.01wt.-%. in water.
As a generally good indication, the calculated Van Krevelen solubility parameter,
can be adduced for determining if a segment of the copolymer of the invention is
hydrophobic or hydrophilic: Van Krevelen/Hofzyger "Properties of Polymers", p. 200-
225 by D.W. van Krevelen (Elsevier, 1990). A polymer block or segment is hydrophobic
if the vanKrevelen/Hofzyger solubility parameter and 3-D solubility parameter is The polymer is hydrophilic if the parameter is > 25.
For determining the parameter values for the purpose.of the present invention, a
number of 8 polymerised monomeric units with unrepealed terminal endings replaced by
H- are taken as a reference molecule. For example, for a polymer comprising tert-butyl
acrylate as monomeric moieties the standard-molecule below is used to calculate the
vahKrevelen/Hofzyger solubility parameter. ,

The vanKrevelen/Hofzyger solubility parameter can be approximated by software
tools like Molecular Modeling Pro, version 5.22, commercialized by Norgwyn
Montgomery Software Inc, ©2003. For the polymer above, a value of 29.35 is obtained.
Alternatively, Hydrophobicity and hydrophilicity can be defined using the
Hildebrand solubility parameter, also called Hansen solubility parameter, well known in
the art, which characterises the polarity of chemical ingredients. Ethanol is usually taken
as reference, the latter having a solubility parameter 5 of 25. A segment will thus be
considered as hydrophobic when its Hansen solubility parameter is below or equal to 25
and as hydrophilic when its solubility parameter is above 25. The Hansen solubility
parameter may be approximated, by the above indicated software and standard-molecule.
Hydrophobic polymeric segments susceptible of being grafted directly onto the
polysaccharide backbone are characterised by the number of repeated units which is
comprised between 5 and 200, preferably 15 and 100. They are preferably selected from
the group consisting of polylactides, polycaprolactone, polypropylene glycol and
polyanhydrides.
Hydrophilic polymeric segments susceptible of being covalently bonded to the
hydrophobic polymeric segments are characterised by the number of repeated units which
is comprised between 5 and 300, preferably 15 and 200. They are preferably selected
from the group consisting of poly (meth)acrylic acid, polydimethyl aminoethyl
(meth)acrylate, polytrimethyl ammonium ethyl (meth)acrylate salts, polyhydroxyethyl
(meth)acrylate, polymethylether diethyleneglycol (meth)acrylate, polyethylene oxide,
polyvinylpyrrolidone, polyaminoacids and polyacrylonitriles. The term (meth)acrylate
encompasses the corresponding acrylates and/or methacrylates.
In an aqueous environment the copolymer composition of the invention takes the
organised form of a core-shell. Therefore, another object of the invention concerns a
particle having a core-shell structure, consisting of a biodegradable copolymer
composition as defined above. More particularly, when contacted with an aqueous
medium, the hydrophobic blocks of the composition according to this invention are
grouped so as to constitute the core and the hydrophilic blocks are arranged so as to form
a shell around the hydrophobic block. The system is arranged around the polysaccharide
backbone forming a particle and it can thus be advantageously used as a delivery system
for an active ingredient, in particular for a hydrophobic ingredient that would be, due to
its nature, embedded in the core part, the polymer matrix thus providing a controlled
delivery system for this active ingredient.
The above-mentioned particles are obtainable by a process comprising contacting
the copolymer composition of the invention with an aqueous medium.
They have a mean diameter preferably comprised between 10 and 500 nm.
The particles thus formed are susceptible of entrapping an active ingredient such
as a drug, a flavour or a fragrance ingredient or composition and can be used as delivery
systems for the controlled release of the latter ingredient or composition through its
diffusion from the copolymer composition, prior to copolymer degradation, or by release
from the copolymer matrix as the polymer degrades. The release of encapsulated active
ingredients may be regulated in part by the molecular weight of the various polymers of
the composition and also by the grafting density.
In a particular embodiment, the active material susceptible of being protected is a
perfume or flavour ingredient or composition. The terms " perfume or flavour ingredient
or composition" are deemed to designate a variety of flavour and fragrance materials of
both natural and synthetic origin. They include single compounds and mixtures. Natural
extracts can also be encapsulated within the particles of the invention; these include e.g.
citrus extracts, such as lemon, orange, lime, grapefruit, or mandarin oils, or essential oils
of spices, amongst other. Specific examples of such flavour and perfume components
may be found in the current literature, e.g. in Perfume and Flavour Chemicals, 1969, by
S. Arctander, Montclair NJ. (USA); Fenaroli's Handbook of Flavour Ingredients, CRC
Press or Synthetic Food Adjuncts by M.B. Jacobs, van Nostrand Co., Inc. They are well
known to the skilled person in the art of perfuming, flavouring and/or aromatising
consumer products, i.e. of imparting an odour or taste to a consumer product.
The active ingredient can be loaded into the particles by absorption and, or
diffusion. This loading can be obtained by dispersing a pre-mixed composition of
copolymer and active ingredient into an aqueous medium. More particularly, a process for
the preparation of a delivery system according to the invention comprises the steps of
preparing a copolymer composition as detailed below, drying said composition and
mixing the dried composition with an active ingredient or composition. The latter can be
present in the system in amounts varying between 5 and 70% by weight relative to the
total weight of the delivery system.
When the particles of the invention enclose a perfume ingredient or composition,
they can be advantageously used in many applications in perfumery, both in fine and
functional perfumery. In particular, they can be used, together with other perfuming
ingredients, solvents or adjuvants of current use in the preparation of a perfume
formulation, in applications such as in a perfume, an eau de toilette, or an after-shave
lotion, but also in functional products, together with functional constituents of bases
present in products such as soaps, bath or shower gels, shampoos or other hair-care
products, cosmetic preparations, deodorants or air-fresheners, detergents or fabric
softeners or household products. Functional ingredients present in these bases have
detergent, cleaning, purifying, softening, antibacterial, or stabilising-type of properties.
In all applications, the particles of the invention filled in with perfume may be
used as such or as part of a perfuming formulation comprising other perfuming
ingredients, solvents or adjuvants or current use in the preparation of perfume
formulations.
The terms "perfume formulation" must be understood within the framework of the
art of perfumery. More particularly, they designate in a general manner, a blend of
odoriferous materials, perceived as having its own unique and aesthetically appropriate
identity. It is a carefully balanced blend (specific ingredients in specific proportions) in
which each material plays its part in achieving the overall fragrance. This creative and
original composition is thus structurally characterised by a formulation constituted by the
ingredients themselves and their relative proportions.
A perfume formulation in the field of perfumery is not just a mixture of pleasantly
smelling materials. On the other hand, a chemical reaction involving reactants and
products formed, which constitutes a dynamic system, cannot be assimilated, unless
otherwise specified, to a perfume formulation, even when odoriferous materials are
present among the starting products, the formed products, or even both of them.
Now, apart from having a well defined identity, a perfume or perfume formulation
must meet a number of technical requirements. It must be for instance sufficiently strong,
it must be diffusive, it must be persistent, and it must retain its essential fragrancing
character throughout its period of evaporation.
Besides, a perfume formulation must be adapted as a function of the application
for which it is intended. In particular, a perfume formulation may be designated for fine
fragrance or designed for a functional product (soap, detergent, cosmetics, etc.) which
needs to present a degree of persistence appropriate to the use for which it is intended.
The formulations must also be chemically stable in the end product. The technique by
which this is achieved is an essential part of the perfumer's art, and it is needed many
years of dedicated work to arrive at the level of experience necessary to formulate
perfumes or perfume formulations that are not only original but also well made.
Now, these technical considerations imply that a perfume formulation may
comprise other ingredients than perfuming materials, which are hereby designated as
"solvents or adjuvants of current use in the preparation of a perfume formulation".
First of all, independently of whether the composition is designed for fine
perfumery or for use in a technical product, a solvent system is most of the time part of
the fragrance. Solvents currently used in the preparation of a perfume formulation
include, but are not limited to, dipropylene glycol, diethyl phtalate, isopropyl myristate,
benzyl benzoate, 2-(2-ethoxyethoxy)-l-ethanol or ethyl citrate for the most commonly
used.
On the other hand, the creation of a perfume formulation intended for a functional
product involves considerations both of hedonics (how should the product smell) and of
the technique of adapting the perfume to the product formulation or, as is often said, to
the product base. The perfume formulation may therefore comprise "adjuvants" which can
have many different functions, depending on the base which has to be perfumed. These
adjuvants include for instance stabilisers and antioxidants.
Today, the range of product types and product formulations that are perfumed has
become so extensive and subjected to such frequent changes that an approach based on a
product-by-product basis and on the definition for each case of the adjuvants that can be
used, is impractical. That is why the present application does not comprise an exhaustive
list or detailed approach of the solvents or adjuvants currently used in perfume
formulations. However, a skilled person in the art, i.e. an expert perfumer, is capable of
choosing these ingredients as a function of the product to be perfumed and of the nature
of the perfuming ingredients in the perfume.
On the other hand, when the particles of the invention enclose a flavour ingredient
or composition, they may be added to a flavouring composition or directly to an edible
ready-to-consume product. By "flavouring composition", it is meant here a mixture of
flavouring ingredients, solvents or adjuvants or current use for the preparation of a
i
flavouring formulation, i.e. a particular mixture of ingredients which is intended to be
added to an edible composition to impart, improve or modify its organoleptic properties,
in particular its odour, flavour and/or taste.
Solvents and adjuvants of current use for the preparation of a flavouring
formulation are also well known in the art. They allow flavouring formulations to meet
technical requirements, such as stability or tonality persistence. The solvent is most of the
time part of a flavouring composition. Solvents currently used in this framework include
for instance benzyl alcohol, propylene glycol, triacetine, vegetable oils, ethanol or
limonene. The adjuvants, on the other hand, can have many various functions in a
flavouring composition. They include for instance stabilizers.
On the other hand, the particles of the invention can also be directly added to a
ready-to-consume or end-product. In other words, they can either be initially added to a
flavouring composition as defined above, the resulting composition being then added to
an end-product, or be added independently of a flavouring composition to an edible
product.
In a third embodiment, when the particles of the invention enclose a drug, they
can be added to pharmaceutical compositions.
Other actives may be enclosed in the particles of the invention, such as
nutraceuticals, or sweeteners for instance. The cited actives should thus not be considered
as limiting the invention.
In compositions such as perfume formulations, flavouring compositions or
pharmaceutical compositions, the particles of the invention can be used in a wide range of
concentrations, depending on the application and on the desired effect. A skilled person in
the art is able to choose the right dosage for a particular application.
Another object of the invention is a process for the preparation of a biodegradable
copolymer composition as defined above. The process of the invention comprises the
major steps of preparing a micro-initiator by chemical modification of a polysaccharide ;
using said macro-initiator to polymerise hydrophobic monomers providing hydrophobic
primary segments grafted on the polysaccharide; using the obtained polymer as a micro-
initiator to polymerise monomers constituting secondary segments covalently linked to
the primary segments ; and if necessary chemically modifying the hydrophilic segments.
More particularly, the first step of the process of the invention consists in partially
protecting the hydroxyl groups of a polysaccharide chain by silylation of hydroxyl
functions. The ratio between the polysaccharide hydroxyl functions and the sylilation
agent is comprised between 1 and 3 equivalents so as to provide 20 to 70% of protected
polysaccharide hydroxyl functions. The ratio of protected hydroxyl functions can be
controlled by NMR analysis. Sylilation is well known in the art and a skilled person is
able to choose suitable reaction conditions and a suitable sylilation agent.
Hexamethyldisilazane is commonly used as sylilation agent. A detailed description of this
step will be given in the examples below.
The unprotected hydroxyl functions of the modified polysaccharide are used in the
second step of the process as initiator for the polymerisation of hydrophobic monomers.
In other words, the obtained modified polysaccharide backbone constitutes a macro-
initiator capable of initiating the polymerisation of various monomers, which
polymerisation is carried out in the second step of the process by ring opening
polymerisation. During this second step, hydrophobic segments also referred to as
"primary segments" are thus grafted onto the polysaccharide backbone. Preferably, the
polymerisation is carried out at a temperature comprised between 120 and 150°C and in
the presence of a catalyst. Specific experimental conditions will be given in a more
detailed manner in the examples below.
In a third step, the ending groups of the hydrophobic segments now grafted on the
polyaccharide backbone are esterified by means of an initiator, namely an alkyl bromide,
in order to provide bromide functions. This newly formed macro-initiator is capable of
polymerising monomers, such as (meth-) acrylate monomers, which polymerisation
constitutes the last essential step of the process. In a particular embodiment, this
polymerisation is carried out by Atom Transfer Radical Polymerization (ATPR), which is
a known technique commonly used for the synthesis of well-defined diblock, triblock and
grafted copolymers, as reported in reference articles, such as in Hedrick J.L. et al.,
Macromolecules, 1998, 31, 8691. This article describes that the esterification of hydroxyl
functions of a hydrophobic block can be obtained by an initiator such as an alkyl bromide.
This process allows the polymerisation of a wide range of functional monomers and is not
sensitive to protonic solvents or functions such as hydroxyl. During the fourth step of the
process according to the invention, monomers are polymerised to provide secondary
segments which are covalently bonded to the primary hydrophobic segments. In a first
embodiment, the monomers used in this step are hydrophilic and this step this directly
lead to the desired product, namely amphiphilic polymer diblocks grafted on a
polysaccharide chain. Now, according to a second embodiment, the monomers
polymerised in the fourth step of the process are hydrophobic. In that case, a fifth step is
necessary to modify the secondary segments in order to render them hydrophilic. This is
possible through a chemical modification of the latter segment. Therefore, functions
present on the secondary segments can be chemically modified in a last step of the
process. As example, quaternization can be performed in order to provide a cationic shell
of the comb. Hydrolysis is another possibility of chemical modification. These
modifications can also influence the solubility of the particles in water.
The described process allows to provide a composition which takes a core-shell
structure when contacted with water. The latter has a hydrophilic shell, which can be
anionic (e.g. with polymethacrylic acid), cationic (e.g. with salt of polytrimethyl
ammoniumethyl methacrylate) or non-ionic (e.g. with polyhydroxyethyl methacrylate,
polymethylether diethyleneglycol methacrylate).
The present invention further relates to a perfumed product comprising the
copolymer of the present invention. Preferably, the perfumed product is a liquid product.
For example, the perfumed product is a perfume, an eau de toilette, a shampoo, a
conditioner, a shower gel, a soap (liquid or solid), a cream, a lotion, a liquid detergent, a
solid detergent, or a fabric softener. The polymer of the invention may be directly added
to the product, if it is a liquid. Alternatively, it first be brought in contact with a perfume
in order to absorb or associate fragrance compounds within its hydrophobic block.
Thereafter, the polymer may be added to the product at any stage in the manufacturing of
the product, preferably when perfumes are added.
Figure 1 shows the corresponding average curves showing the evolution of the weight •
loss of linalool with time. One could observe a significant effect of the copolymer on the
fragrance release. The isotherm of the release of linalool seems to be composed of two
regimes : a fast regime at the beginning of the isotherm followed by a slow one. This
effect is not observed for the HPC samples.
Figure 2 shows the corresponding average curves showing the evolution of the weight
. loss of a fragrance with time in EDT, in the presence or not of grafted copolymers. There
are three main phases, the first one corresponding to the loss mainly of water and ethanol,
the second one is a plateau persisting for about 3000 seconds characterized by low loss of
fragrance at 50°C and the last one, the complete loss of fragrance by gradually increasing
the temperature to 150°C.
The invention will now be described in a more detailed manner in the following examples
wherein the temperatures are indicated in degrees Celsius and the abbreviations have the
usual meaning in the art.
Modes of Carrying out the Invention
General comments
a) Chemicals
Solvents and pentamemyldiemylenetriamine (PMEDETA) were distilled on CaH2 and
stored under nitrogen. Methacrylate and acrylate monomers were purified by filtration
on a column of an inhibitor-remover (CAS 9003-70-7 ; origin : Aldrich). The cupper
bromide (CAS 7787-70-4; origin: Aldrich) and the hydroxypropyl-cellulose
(Mw=l 00000 g.mol"1; origin : Aldrich, CAS 9004-64-2) were used as received. The
(3S)-cis-3,6-dimethyl-l,4-dioxane-2,5-dione was recrystallized in ethyl acetate before
used.
b) Size Exclusion Chomatography (SEC)
SEC measurements were carried out with a column Macherey-Nagel Nucluogel GPC
104-5. As a solvent, THF HPLC grade was used. The polymer concentration was
fixed at 4mg/ml. The flow rate was lml/min and the injection volume was 50
microliters.
Example 1
Synthesis of a biodegradable copolymer composition according to the invention-degree
of substitution of 66%
a) Synthesis of functionalised hvdroxypropvlcellulose with trimethylsilvl group (HPC-g-
TMS)
In a three-necked round bottom flask of 100 ml, 4 g of HPC (M=105 g.mol"1, n=4.10"
5mmol, DPn=150, MU=3 50,41 g.mol_1) were solubilized in 60 ml of dried
acetonitrile (distilled and stored on molecular sieve). 2,66M1 of hexamethyldisilazane
(M=161,39 g.mol-1, n=12,77mmol, m=l,89g, d=0,7742, m-2,06 g) were added
dropwise and the media was heated at 90° for 4 h under nitrogen. The polymer was
obtained by precipitation in water (three times) to give a white solid, which was dried
under vacuum for 24 h.
m=4,75 g, yield=80%.
Analytical data:
NMR 2H (400 MHz, 25°, CDC13): 5.00-3.00 (m, 5H, HPC backbone); 1,13 (s broad,
3H, Me HPC); 0.20 (s, 3H, SiMeA
13C (100 MHz, 25°, CDCI3): 102.29(q)-82.82(d)-81.70(d)-75.10(d)-74.73(d)-
73.29(d)-67.79(d)-67.63(d)-68.05 to 64.81(d)- 18.56(q)-17.99(q)-17.41(d)-
17.34(d)-0.27(d).
m(cm-1):3478(s)-2965(m)-2932(m)-2896(m)-2871(m)-1638(s)-1451(s)-1406(s)-
1372(m)-1315(s)-1248(s)-1083(m)-1007(m)-928(s)-889(s)-835(s)-747(m).
GPC (THF. standard PMMA): M„=96000 g.mol"1; Mw=243000 g.mol"1; Ip=2.54.
b) Synthesis of hydroxypropylcellulose grafted with poly-L-lactic acid (HPC-g-PLLA)
In a three-necked round bottom flask of 100 ml with a refrigerator, 200 mg of HPC-g-
TMS (66% OH group, MU=408.60 g.mol"1, n=0.98 mmol) and 7.06 g of L-lactide
(M=144.13 g.mol"1, n=48.98mmol) were dried under vacuum for 1 h. These solids
were solubilized into 25 ml of dried xylene. The media was warmed up to 135° and
one drop of tin octaote was added to initiate the polymerisation. The media was stirred
at 135° for 72 h. Then the polymer was precipitated into cold heptane and filtered to
give a white solid, which was dried under vacuum. Iu order to remove all of the
monomer,.the copolymer was solubilized in acetone and precipitated it in cold water
to obtain a white solid.
m=5.92 g, yield=82%.
Analytical data:
li'H(400MHz,25°, CDC13): 5.16 (q, 60H,OC-CH(CH3)-0); 5.0-3.0 (m, 10H,
HPC backbone); 4.35 (q, 1H, OC-CH(CH3)~0) ; 1.58 (d, 180H, OC-CHfCHO-
O); 1.49 (d, 3H, OC-CHfCHjVO): 1.23 (m, 3H, MeHPC) ; 1.12 (m, 6H, Me
HPQ;0.14(s.3H.SiMeO.
13C (100MHz,25°,CDCl3): 169.62(qu)-69.02(d)-66.71(d)-20.53(q)- 16.66(d).
m(cm-1):3641(w)-3509(w)-2996(w)-2945(w)-2881(w)-1748(s)-1453(m)-1382(m)-
1358(m)-1302(w)-1267(w)-1209(m)-1180(s)-1128(s)-1085(s)-1043(s)-956(w>
918(w)-870(m)-754(m)-694(w).
GPC (THF, standard PS): Mn.=835000g.mor1, Mw=1700000g.mor!, Ip=2.03
c) Synthesis of HPC-g-PLLA-initiator
In a three-necked round bottom flask, 5.80 g of HPC-g-PLLA (MU=3290 g.moi"1;
noH=3.52 mmol) were solubilized into 20 ml of distilled THF. This solution was
cooled down to 0°. Then, 740 uL of 2-bromopropionyl bromide (M=215.88 g-mol"1,
n=7.06 mmol, m=1.52 g) were added, followed by 983 \xL of Et3N
(M=101.19 g.mol"1, n=7.06 mmol, m=713 mg, d=0.7255). The media was stirred at
room temperature for 48 h to give a suspension. The polymer was precipitated two
times into water to give a solid, which was solubilized in acetone and precipitated into
cold heptane. The solid was dried under vacuum for 24 h.
m=5.80 g. yield=92%.
Analytical data :
NMR lR (400 MHz, CDC13): 5.18 (q, 35H, Br-CH(Me)-CO-0-0|CMe)-CO); 4.42
(m, 1H, 0-CH(Me)-CO-0-CH(Me)Br); 5.09-2.60 (m, 5H, HPC backbone); 1.95
(m, 3H, OC-CH(Me)-Br); 1.58 (d, 105H, 0-CH(Me)-0); 1.11 (m, Me HPC).
13C (100 MHz, CDC13): 169.62(qu)-69.02(d)-69.46(d)-21.60(q)-16.66(q).
m(cm"1):3504(w)-2996(w)-2945(w)-2876(w)-2648(w)-1748(s)-1720(w)-1601(w)-
1452(m)-1383(m)-1358(m)-1305(w)-1267(w)-1210(m)-1180(s)-1128(s)-
1082(s)-1042(s)-956(w)-918(w)-870(m)-755(m)-694(m).
GPC: (THF, standard PS): Mn=706000g.mol"1, Mw=1684000g.mol"1, Ip=2.39
d) Synthesis of hydroxvpropylcellulose -g- polv-L-lactic acid-6-polydimetb.vlaniiiio-
ethvl methacrvlate (HPC-g-PLLA-fe-PDMAEMA)
In a two-necked round bottom flask of 50 ml, 0.5 g of HPC-g-PLLA-initiator
(Mu=3560 g.mol"1, n=0.14mmol) were solubilized in 7.85 ml of distilled anisole.
Then, 4.73 ml of 2-(N3N-dimemylaminoethyl)methacrylate (M=157.21 g.mol"1,
d=0.933, n=28.09mmol, DPn=100, m=4.41 g) and 59 jxl of HMTETA
(M=173.30 g-mol"1, d=0.83, n=0.28 mmol) were added and followed by two freeze-
pump-thaw cycles. Then, the cupper bromide was added (M=143.45 g-mol"1,
m=40 mg, n=0.28 mmol) and degassed by one freeze-pump-thaw cycle. The media
was warmed up to 60° and stirred for 3 h. The polymerisation was stopped by freezing
in liquid nitrogen and the media was diluted in THF. The solution was filtered on a
silica gel column and the solvent was removed. The polymer was dissolved in
chloroform and precipitated into cold heptane (0°) to give a yellow solid.
m=2.4 g. yield=48%.
Analytical data:
NMR ]H (400 MHz, 25°, CDC13): 5.15 (q, 1H, Initiator-0-CH(Me)-CO); 5.0-3.0
(HPC backbone); 4.06 (m, 6H, Q-CHrCH?-N): 2.57 (m, 6H, CHrN); 2.30 (s,
18H, NMez); 2.10-1.70 (m, 6H, CHrC- PDMAEMA backbone); 1.59(m, 3H, O-
CH(Me)-CO); 1.15-0.90 (Me-C- PDMAEMA backbone, 3H).
13C (100 MHz, 25°, CDCI3): 178.02(qu)-177.67(qu)-177.31(qu)-176.58(qu)-
169.67(qu)-68.96(q)-63.03(t)-62.87(t)-57.06(t)-56.97(t)-54.04(t)-52.11(t)-
45.82(q)-44.92(qu)-44.56(qu)-18.41(m)-16.61(m).
ffi:(cm-1):2943(s)-2861(w)-2818(m)-2766(s)-1758(s)-1722(s)-1453(s)-1386(m)-
1359(m)-1333(w)-1266(m)-1178(w)-1133(w)-1096(w)-1041(w)-1015(w)-
956(m)-848(m)-778(m)-748(m).
GPC (THF, standard PMMA): No data available. Slightly soluble in THF.
e) Synthesis of HPC-g-PLLA-6-PTMASEMA (25-75)
In a two-necked round bottom flask of 50 ml, washed and dried, 1.0 g of HPC-g-
PLLA-b-PDMAEMA (Mu=36400 g-mol"1, n=0.028 mmol) were solubilized into
10 ml of distilled THF. Then 168 uL of dimethylsulfate (10% in THF) were added
dropwise (M=126.13 g-mol"1, n=1.94mmol, d=1.3322, m=225mg). The media was
stirred 12 h at RT. The product precipitated and was obtained by filtration to give a
white solid.
m=1.2g. yield=96%.
Analytical data:
NMR lH (400 MHz, 25°, MeOD): 5.18 (q, Imtiator-0-CH(Me)-CO); 4.45 (m, O-
CH2-CH7-N*); 4.15 (m, 0-CHrCH2-N); 3.85 (m, Q-CH7-CHz-Nf); 3.71 (m,
MeS04~); 3.31 (m, N^Mgs); 2.51 (m, 6H, CH2-NV, 2.45 (s, 18H, NMeg); 1.94 (m,
CHa-C-PDMAEMATPTMASEMA backbone); 1.55(m, 3H, O-CHfMeVCO);
1.30-0.80 (Me-C- PDMAEMA/PTMASEMA backbone, 3H).
13C (100 MHz, 25°C, MeOD): 179.46(qu)-178.39(qu)-70.35(d)-63.44(t)-57.76(t)-
55.22(d)-54.50(d)-46.05(qu)-45.72(d)-45.56(d)-20.07(q)-18.30(d)-17.10(q). '
m(cm"1):3429(w)-3033(w)-2987(w)-2943(m)-2861(w)-2820(m)-2768(m)-2653(w)-
1756(s)-1721(s>1454(s)-1385(m)-1360(m)-1219(s)-1179(s)-1141(s)-1086(s)-
1057(s)-1006(s)-953(s)-854(w)-740(s).
Example 2
Synthesis of a biodegradable copolymer composition according to the invention-
polvsaccharide backbone with a degree of substitution of 66%
Steps a), b) and c) were carried out as described in Example 1.
d) Synthesis of hydroxvpropvlcellulose-g-poly-L-lactic acid-b-polyterriobutvl-
methacrvlate (HPC-g-PLLA-6-P'BuMA) (66% PLLA-b-P'BuMA (40/601)
In a two-necked round bottom flask of 50 ml, 0.50 g of BDPC-g-PLLA-initiator
(Mu=3560 g.mol"1, n=0.14 mmol) were solubilized in 7.50 ml of distilled THF. Then,
4.60 ml of tertfo-butylmethacrylate (M=142.20 g-mol"1, d=0.875, n=28.09mmol,
DPn=100, m=4.00g) and 59 ul of PMDETA (M=l73.30 g-mol-1, d=0.83,
n=0.28 mmol) were added and followed by two freeze-pump-thaw cycles. Then, the
cupper bromide was added (M=143.45 g-mol"1, m=40.30 mg, n=0.28 mmol) followed
by one freeze-pump-thaw cycle. The media was heated at 60° and stirred for 24 h. The
polymerisation was stopped by freezing in liquid nitrogen and the media was diluted
in THF. The solution was filtered on a silica gel column and the solvent was removed.
The polymer was dissolved in THF, precipitated into cold heptane (0°), then
solubilized in acetone and precipitated into cold water to give a white solid.
m=1.40g. yield=31%.
Analytical data:
NMR ltt (400 MHz, 25°, CDC13): 5.16 (q, 1H, 0-CH(Me)-CO); 2.20-1.70 (m, 3H,
CFJb-C- P'BuMA backbone); 1.58 (d, 3H, 0-CH(Me)-0); 1.42 (m, 6H, CfMeQ);
1.20-0.70 (m, 4H, Me-C- P'BuMA backbone).
13C (100 MHz, 25°, CDC13): 177.42 to 176.70(qu)-169.62(qu)-80.91(qu)-80.78(qu>
80.56(qu)-69.02(d)-46.47(qu)-46.23(qu)-27.78(d)-22.69(q)-18.48(q)-17.82(q)-
16.64(d).
rR(cm"1):2974(m)-2933(m)-2881(w)-1758(s)-1718(s)-1476(m)-1455(m)-1391(s)-
1365(s)-1269(m)-1249(s)-1181(w)-1130(s)-1090(s)-1039(w)-968(w)-941(w>
873(w)-847(s)-752(m).
GPC (THF, standard PS): Mn=1990000 g-mol"1, Mw=4970000 g-mol"1, Ip=2.50
Synthesis of Hvdroxvpropvlcellulose-g-poly-L-lactic acid-b-polymethacrylic acid
fHPC-g-PLLA-6-PMAA) (66% PLLA)
. In a round bottom flask, 900 mg of HPC-g-PLLA-6-P'BuMA were solubilized into
5 ml of dichloromethane. 3 Ml of trifluoroacetic acid were added and the media was
stirred at room temperature for lh and it became orange. The solvent was removed to
give a clear red solid. This one was washed 4 times by diethyl ether to give a red
filtrate and a white solid
m=0.70 g yield=89%
Analytical data:
NMR !H (400 MHz, 25°, CDC13): 3.88 to 3.11 (HPC backbone); 2.00 to 1.89 (m, CH?
PMAA backbone); 1.51 to 1.28 (Me PMAA backbone); 1.14 (m, Me HPC).
13C (100 MHz, 25°, CDCI3): 182.58(qu)-182.32(qu)-18.1.38(qu)-171.04(qu)-70.48(d)-
58.36(t)-55.91(t)-55.79(t)-46.34(qu)-45.97(qu)-31.18(qu)-28.23(q)-27.77(q)-
19.26(q)-17.34(q)-17.08(q)
IR (cm"1): 3696 to 2152 (COOH) (m)-2994(m)-2942(m)-2886(w)-1735 (ester) (s)-
1696(COOH)(s)-1479(w>14501(m)-1383(m)-1368(m)-1264(m)-1157(s)-
1132(s)-1084(s)-1042(s)-958(w)-933(w)-865(w)-829(w)-777(w)-756(w)-
687(m).
' Example 3
Synthesis of a biodegradable copolymer composition according to the invention -degree
of substitution of 50%
a)' Synthesis of functionalised HPC with trimethylsilyl group
A procedure similar to Example la) was carried out with the following ingredients :
3.3 g of HPC (M=105 g.mol"1, n=3.3.10"5 mmol, DPn=150, MU=350.41 g.mol"1)
3.97 ml of hexamethyldisilazane (M=161.39 g.mol"1, n=18.84mmol, m=3.04 g,
d=0.7742)
50 ml of dried acetonitrile (distilled and stored on molecular sieve)
90°, 5h
m=4.2g, yield=74%
Analytical data:
NMR lH (400 MHz, 25°, CDC13): 5.00-3.00 (m, 5H, HPC backbone); 1,13 (s broad,
3H, Me HPC); 0.20 (s, 4.5H, SiMeV).
13C (100 MHz, 25°, CDCI3): 102.43(q)-82.90(d)-78.67(q)-74.97(d)-74.74(d)-
67.74(d)-67.57(d)-67.63(d)-20.94(d)-17.41(d)-1.36(q)-0.24(d).
. R (cm"1): 3470(s)-2965(m)-2927(m)-2891(m)-2871(m)-1676(s)-1453(s)-1411(s)-
1373(m)-1315(s)-1248(s)-1082(m)-1007(m)-888(s)-835(s)-747(m)-680(m).
GPC (THF. standard PMMA): Mn=44000g.mol"1; Mw^SOOOOg.mol"1; Ip=6.34.
b) Synthesis of HPC-g-PLLA (Degree of substitution : 50% PLLA'I
A procedure similar to Example lb) was carried out with the following ingredients :
500 mg of HPC-g-TMS (50% OH group, MU=917.45g.mor1, n=0.545mmol)
5.89 g of L-lactide (M=l44.13 g.mol"1, n=40.87 mmol)
28 ml of dried xylene
m=4.72 g, yield=74%.
Analytical data:
NMR liL (400 MHz, 25°, CDC13): 5.16 (q, 17H, OC-CH(CH3)-0); 5.0-3.0 (m, 5H,
HPC backbone); 4.35 (q, 1H, OC-CH(CH3)-0) ; 1.58 (d, 51H, OC-CHfCHjVO):
1.49 (d, 3H, OC-CH(CHi)-0); 1.22 (m, 4.5H, Me HPC) ; 1.12 (m, 4.5H, Me
HPC); 0.14 (s, 4.5H, SiMe^.
13C (100 MHz, 25°, CDCI3): 169.62(qu)-69.02(d)-66.71(d)-20.52(q)-16.66(q)-
16.64(q)-0.15(q).
ffi:(cm"1):3518(w)-2996(w)-2946(w)-2881(w)-1755(s)-1748(s)-1454(m)-1383(m)-
1359(m)-1264(w)-1210(m)-1183(s)-1130(s)-1087(s)-1043(s)-956(w)-920(w)-
871(m)-755(m)-695(w).
GPC (THF, standard PS): Mn= 371000 g.mol"1, Mw=831000 g.mol"1, Ip=2.24
c) Synthesis of HPC-g-PLLA-initiator
In a two-necked round bottom flask, 1.30 g of HPC-g-PLLA (MU=7835 g.mol"1;
noH=0-5 mmol) were solubilized into 10 ml of distilled THF. This solution was cooled
down to 0°. Then, 350 p.L of Et3N (M=101.19 g-mol"1, n=2.49mmol, m=252mg,
d=0.7255) were added, followed by 261 uL of 2-bromopropionyl bromide
(M=215.88 g.mol"1, n=2.49 mmol, m=540 mg). The media was stirred at 60° for 72 h
to give a suspension. The polymer was obtained by precipitation into water to give a
solid, which was solubilized in acetone and precipitated into cold heptane. The solid
was dried under vacuum for 24 h.
m=1.27 g. yield=97%.
Analytical data:
NMR 'H (400 MHz, CDC13): 5.18 (q, 10H, Br-CH(Me)-CO-0-CH(Me)-CO); 4.42 (q,
1H, 0-CH(Me)-CO-0-CH(Me)Br); 5.09-2.60 (m, 5H, HPC backbone); 1.95 (m,
3H, OC-CH(Me)-Br); 1.58 (d, 30H, 0-CH(Me)-0); 1.11 (m, MeHPC>
13C (100 MHz, CDCI3): 169.62(qu)-69.57(d)-69.02(d)-46.10(t)-39.38(d)-39.29(d)-
30.71(q)-21.60(q)-16.66(q)-8.67(qu).
m (cm"1): 3651(w)-3499(w)-2995(w)-2944(w)-2876(w)-2684(w)-1747(s)-1716(w>
1452(m)-1382(m)-1358(m)-1305(w)-1267(w)-1210(m)-1181(s)-1128(s)-
1082(s)-1042(s)-921(w)-870(m)-755(m)-686(w).
GPC: (THF, standard PS): Mn=165000 g.mor1, Mw=357000 g.mor1, Ip=2.17
d) Svrithesis of poly-L-lactic acid-b-poly-terrio-buthvlmethacrvlic acid (50% PLLA-b-
PfBuMA)
In a two-necked round bottom flask of 25 mL, 0.311 g of HPC-g-PLLA-initiator
(Mu=3110 g.mor1, n=0.10mmol) were solubilized in 5.70 ml of distilled anisole.
Then, 2.75 ml of ferrio-ButylMethacrylate (M=l42.20 g.mol"1, d=0.875,
n=15.00mmol, DPn=100, m=2.13 g) and 31.3 \xl of PMDETA (M=173.30 g.mol"1,
d=0.83, n=0.15 mmol) were added and followed by two freeze-pump-thaw cycles.
Then, the cupper bromide was added (M=143.45 g.mol"1, m=21.50 mg, n=0.15 mmol)
followed by one freeze-pump-thaw cycle. The media was heated at 60° and stirred for
24 h. The polymerisation was stopped by freezing in liquid nitrogen and the media
was diluted in chloroform. The cupper bromide was removed by extraction in water.
The polymer was dried on Na2S04 with a small amount of silica, filtered and then
precipitated into cold heptanes (0°) and filtered to give a solid. This one was
solubilized in acetone and precipitated into cold water to give a white solid.
m=0.52 g. yield=29%.
Analytical data :
NMR XB. (400 MHz, 25°, CDCI3): 5.16 (q, 1H, 0-CH(Me)-CO); 2.24-1.71 (m, 3H,
CHrC- P'BuMAbackbone): 1.58 (d, 3.1H, Q-CH(Me)-Q); 1.43 (m, 13H,
C(MeV>): 1.20-0.70 (m, 4.2H, Me-C- P'BuMA backbone).
m, (cm-1): 2974(m)-2931(m)-2881(w)-2658(w)-1756(s)-1718(s)-1474(m)-1455(m)-
1390(m)-1365(s>1267(m)-1247(s)-1211(m)-1183(s)-1129(s)-1088(s)-1044(s)-
968(w)-873(w)-846(s)-752(m)-692(w).
GPC (THF, standard PS): Mn=500000 g.mol"\ Mw=1750000 g.mol"1, Ip=3.50
e) Synthesis of Polv-L-lactic acid-b- polvmethacrvlic acid (50% PLLA-b-PMAA")
la a round bottom flask, 0.45 g of HPC-g-PLLA-6-P'BuMA were solubilized into
5 ml of dichloromethane. 3 Ml of trifluoroacetic acid were added and the media was
stirred at room temperature for 1 h. The polymer was obtained by precipitation into
cold heptane and filtered to give a white solid.
m=0.30 g; yield=85%
Analytical data :
NMR rH (400 MHz, 25°, CDC13): 5.20 (m, 1H, 0-CH(Me)-CO); 3.88 to 3.11 (HPC
backbone); 2.21 to 1.75 (m, 5H, CH2PMAAbackbone); 1.56 (m, 3.23H, O-
CH(Me)-CO); 1.27 to 0.99 (m, 8.1H, Me PMAA backbone).
W, (cm"1): 3696 to 2146 (COOH) (m)-2991(m)-2942(m)-2884(w)-1734 (ester) (s)-
1696 (COOH) (s)-1481(m)-1450(s)-1384(s)-1366(s)-1263(s)-1159(s)-1131(s)-
1085(s)-1044(s)-961(m)-933(m)~798(w)-754(w)-690(m).
Example 4
Synthesis of a biodegradable copolymer composition according to the invention -degree
of substitution of 33%
a) Synthesis of functionalised HPC with trimethylsilvl group
A procedure similar to Example la) was carried out with the following ingredients :
2 g of HPC (M=105g.mor1, n=2.10"5 mmol, DPn=150, MU=350.41 g.mol'1)
3.61ml of hexamethyldisilazane (M=161.39 g-mol"1, n=17.13 mmol, m=2.76 g,
d=0.7742)
30 ml of dried acetonitrile (distilled and stored on molecular sieve)
90°, 24 h
m=2.4 g, yield=85%
Analytical data:
NMR 3H (400 MHz, 25°, CDC13): 5.00-3.00 (m, 5H, HPC backbone); 1,13 (s broad,
3H, Me HPC); 0.20 (s, 6H, SiMeg).
13C (100 MHz, 25°, CDCI3): 102.43(q)-84.07(d)-83.09(d)-78.62(q)-75.07(d)-
67.81(d)-67.63(d)-67.40(d)-20.99(d)-17.47(q)-1.36(q)-0.29(d).
m (cm"1): 3494(s)-2964(m)-2932(m)-2896(m)-2870(m)- 1451(w)-1401(w)-1373(m)-
1315(w)-1248(s)-1084(s)-1006(s)-923(s)-888(m)-835(s)-747(s)-684(w).
GPC (THF. standardPMMA): M„=47000g.mol"1; Mw=152000g.mor1; Ip=3.23
b) Synthesis of HPC-g-PLLA (33% PLLA)
A procedure similar to Example lb) was carried out with the following ingredients :
370 mg of HPC-g-TMS (33% OH group, MU=480.80 g-mol"1, n=0.77 mmol).
5.55 g of L-lactide (M=l44.13 g-moi"1, n=38.50 mmol).
28 ml of dried xylene.
m=5.06 g, yield=86%.
Analytical data:
NMR lH (400 MHz, 25°, CDCI3): 5.16 (q, 27H, OC-CH(CH3)-0); 5.0-3.0 (m, 5H,
HPC backbone); 4.35 (q, 1H, OC-CH(CH3)-0) ; 1.58 (d, 81H, OC-CHCCThVO);
1.49 (d, 3H, OC-CH(CH^)-0); 1.22 (m, 3H, Me HPC); 1.12 (m, 6H, Me HPC) ;
0.14 (s, 3H, SiMea).
13C (100 MHz, 25°, CDCI3): 175.16(qu)-169.62(qu)-69.02(d)-66.71(d)-20.53(q)-
16.66(q).
rR(cm"1):3632(w)-3484(w)-2995(w)-2944(w)-2876(w)-1754(s)-1454(m)-1383(m)-
1359(m)-1305(w)-1267(w)-1210(m>1182(s)-1129(s)-1082(s)-1043(s)-955(w)-
920(w)-871(m)-755(m)-693(w).
GPC (THF, standard PS): Mn=536000 g.mol'1, Mw=l 140000 g-mor1, Ip=2.12
c) Synthesis of HPC-g-PLLA-initiator
In a two-necked round bottom flask, 700 mg of HPC-g-PLLA (MU=1922 g.mol"1;
noH=0.54 mmol) were solubilized into 7 ml of distilled THF. This solution was cooled
down to 0°. Then, 381 ^L of Et3N (M=101.19 g-mol"1, n=2.73 mmol, m=276mg,
d=0.7255) were added, followed by 286 |j,L of 2-bromopropionyl bromide
(M=215.88 g-mol"1, n=2.73 mmol, m=589 mg). The media was stirred at 60° for 72 h
to give a suspension. The polymer was obtained by precipitation into water to give a
solid, which was solubilized in acetone and precipitated into cold heptane. The solid
was dried under vacuum for 24 h.
m=0.65 g. yield=87%.
Analytical data :
NMR !H (400 MHz, CDC13): 5.18 (q, 25H, Br-CH(Me)-CO-0-CH(Me)-CO); 4.42
(m, 1H, 0-CH(Me)-CO-0-CH(Me)Br); 5.09-2.60 (m, HPC backbone); 1.95 (m,
3H, OC-CH(Me)-Br); 1.58 (d, 75H, 0-CH(Me)-0); 1.11 (m, Me HPC).
13C (100 MHz, CDC13): 169.62(qu)-69.57(d)-69.44(d)-69.02(d)-39.29(q)-30.33(q>
29.71(q)-21.60(q)-16.66(q).
ffi(cm"1):3504(w)-2993(w)-2944(w)-2876(w)-2643(w)-1747(w)-1451(m)-1381(m)-
1358(m)-1305(w)-1264(m)-1209(m)-1181(s)-1128(s)-1085(s)-1042(s)-955(w)-
915(w)-867(m)~754(m)-690(w).
GPC: (THF, standard PS): Mn=296000 g.mor1, Mw=889000 g-mol"1, Ip=3.00
d) Synthesis of polv-L-lactic acid-b-poly-fertzo-butvl methacrvlate (33% PLLA-b-
P'BuMA)
In a two-necked round bottom flask of 25 mL, 0.60 g of HPC-g-PLLA-initiator
(Mu=3000 g-mol"1, n=0.20 mmol) were solubilized in 7.50 ml of distilled THF. Then,
3.40 ml of tertfo-ButylMethacrylate (M=142.20 g-mol"1, d=0.875, n=20.00mmol,
DPn=1003 m=2.84g) and 42 jal of PMDETA (M=173.30 g.mol"1, d=0.83,
n=0.20mmol, m=34.6mg) were added and followed by two freeze-pump-thaw
cycles. Then, the cupper bromide was added (M=143.45 g-mol"1, m=28.7mg,
n=0.20 mmol) followed by three freeze-pump-thaw cycles. The media was heated at
60° and stirred for 24 h. The polymerization was stopped by freezing in liquid
nitrogen and me media was diluted in chloroform. The cupper bromide was removed
by extraction in water. The polymer was dried on Na2S04 with a small amount of
silica, filtered and then precipitated into cold heptane (0°) and filtered to give a solid.
This one was solubilized in acetone and precipitated into cold water to give a white
solid.
m=1.20g.yield=35%.
Analytical data:
NMR 1H (400 MHz, 25°, CDC13): 5.16 (q, 1H, 0-CH(Me)-CO); 2.26-1.74 (m, 1.5H,
CHrC- P'BuMA backbone); 1.58 (d, 3.2H, 0-CH(Me)-0); 1.43 (m, 7.30H,
C(Me3); 1.33-0.94 (m, 2.2H, Me-C- PtBuMA backbone).
IR (cm-1): 2975(m)-2934(m)-2876(w)-2648(w)-1754(s)-1718(s)-1601(w)-1475(m)-
1454(s)-1390(s)-1365(s)-1247(s)-1182(s)-1128(s)-1085(s)-1042(s)-968(m)
939(w)-921(w)-872(m)-846(s)-753(s)-693(w).
GPC (THF, standard PS): Mn=l000000 ginol-1, Mw=l680000 g.mol-1, Ip=1.68
e) Synthesis of Poly-L-lactic acid-b-polymethacrylic acid (33% PLLA-b-PMAA)
In a round bottom flask, 1.00 g of HPC-g-PLLA-b-PtBuMA were solubilized into
4 ml of dichloromethane. 4 Ml of trifiuoroacetic acid were added and the media was
stirred at room temperature for 1 h. The polymer was obtained by precipitation into
cold heptane and filtered to give a white solid.
m=0.80 g yield=91%
Analytical data:
NMR lH (400 MHz, 25°, CDCl3): 3.88 to 3.11 (HPC backbone); 2.00 to 1.89 (m, CH2
PMAA backbone); 1.51 to 1.28 (Me PMAA backbone); 1.14 (m, Me HPC).
13C (100 MHz, 25°C, CDCI3): 182.58(qu)-182.32(qu)-181.38(qu)-171.04(qu)-
70.48(d)-58.36(t)-55.91(t)-55.79(t)-46.34(qu)-45.97(qu)-31.18(qu)-28.23(q)-
27.77(q)-19.26(q)-17.34(q)-17.08(q)
m (cm4): 3701 to 2162 (COOH) (m)-2991(m)-2943(m)-2886(w)-1744 (ester) (s)-
1698(COOH)(s)-1484(m)-1451(s)-1383(s)-1367(s)-1265(m)-1180(s)-1129(s)-
1084(s)-1044(s)-959(m)-928(m)-867(w)-829(w)-799(w)-781 (w)-752(w)-
688(m).
Example 5
Synthesis of grafted HPC by poly L-lactic acid-b-polvacrylate (HPC-g-PLLA-b-PAA)
In a round bottom flask, acrylate monomers (tertio-butyl acrylate (5d-e), 2-(N,N-
dimemylamino)ethyl acrylate (5f), 2-hydroxyethyl acrylate (5g) and diethyleneglycol
methyl ether) acrylate (5h) are polymerised as well as in bulk or in dioxane (50% v/v).
Polymers, described in examples lc, 3c and 4c, are used as initiators. HMTETA,
bipyridine and tris(dimethylamino ethyl)amine are used as ligands and CuBr as catalyst.
Polymerisations have been carried out at temperature comprised between 50°C and
110°C, under nitrogen. Further chemical modifications have been carried out on the poly
(tert-butyl acrylate) and the poly (2-(N,N-dimethylamino)ethyl acrylate), corresponding
to examples 2e, 3e, 4e and le, respectively, to provide HPC-g-PLLA-b-PAA.
Example 6
Preparation of a fragrance delivery system with a copolymer composition of the invention
A copolymer HPC-g-PLLA-PTMASEMA prepared as described in Example 1 was dried
and mixed directly with linalool at the mixing ratio of 50/50% (w/w). The same
preparation was done with HPC. The two samples were kept at room temperature for at
least one day. Then, an amount of 10 mg of each sample was analysed with
Thermogravimetry Analyser by recording the isotherms at 25° under a constant flow of
nitrogen gas (20 ml/min). The analysis was repeated three times with HPC-PLLA-
PTMASEMA/linalool sample (masse : 8.99, 9.57 and 8.85 mg) and two times with
HPC/linalool sample (masse : 9.76 and 9.77 mg). The time of the isotherm was fixed at
200 min.
Example 7
Preparation of a Eau de Toilette (EDT) comprising the copolymers of the invention to
control release of fragrances
Different copolymers (Examples Id, 5f and 5g) (0.5wt.%) have been solubilised in an
EDT, containing 80% of ethanol, 10% of water and 10% of a fragrance (benzyle
salycilate 35g, habanolide (1-OXA-12-CYCLOHEXADECEN-2-ONE) 2g, cetalox 2g, hedione
((+-VMETHYL 3-OXO-2-PENTYL-1-CYCLOPENTANEACETATE) 35g, bacdanol (2-ETHYL-4-
(2,2,3-TRIMETHYL-3-CYCLOPENTEN-l-YL)-2-BUTEN-l-OL) lg, lilial (3-(4-TERT-
BUTYLPHENYL)-2-METHYLPROPANAL) lOg, coumarine lg, vanillin 2g, anthranilate (pas
dans chemisis en tant quetel)lg, neoflorol ((+-)-TETRAHYDRO-2-ISOBUTYL-4-METHYL-
4(2H)-PYRANOL ) 1.5g, styrallyl acetate (l-PHENYLETHYL ACETATE) 1.5g, benzyle acetate
6g, zestover (2,4-DMETHYL-3-CYCLOHEXENE-l-CARBALDEHYDE) 2g).
Then, 10 fiL of these solutions are put in an alumina crucible. The weight loss of
fragrance has been measured by thermogravimetric analyses (two times each sample)
under a constant flow of nitrogen (20mVrnin). The measurements (figure 2) start at 25°C
to 50°C (5°C/min), stay at 50°C for 115 minutes and then until 150°C (10°C/min).
The results are shown in Figure 2. It can be seen that weight loss during 115 minutes at
50°C is highest with the EDT devoid of the copolymer of the invention (lowest line,
"Perfume, EtOH/Eau), while samples provided with the copolymer of Examples Id, 5g
and 5f of the invention show clearly less loss (upper 3 lines), with small differences
between the various polymers.
We Claim:
1. A copolymer comprising a polysaccharide backbone and amphiphilic
diblock copolymers grafted on said polysaccharide backbone, each amphiphilic diblock
comprising:
a) a hydrophobic polymeric segment directly grafted on the polysaccharide backbone
and comprising from 5 to 200 repeated units; and
b) a hydrophilic polymeric segment covalently bonded to the hydrophobic segment and
comprising from 5 to 300 repeated units.
2. The co-polymer as claimed in claim 1, wherein the amphiphilic diblock
copolymers are grafted on the polysaccharide backbone with a degree of substitution via
hydroxyl functions comprised between 30% and 80%.
3. The co-polymer as claimed in claim 1, wherein the polysaccharide
backbone is selected from the group consisting of dextrans, arabinogalactan, pullulan,
cellulose, cellobios, inulin, chitosan, alginates, hyaluronic acid and cyclodextrins.
4. The co-polymer as claimed in claim 1, wherein the hydrophobic polymeric
segment is selected from the group consisting of polylactides, polycaprolactone,
polypropylene glycol and polyanhydrides.
5. The co-polymer as claimed in claim 1, wherein the hydrophilic polymeric
segment is selected from the group consisting of poly (meth)acrylic acid, polydimethyl
aminoethyl (meth)acrylate, polytrimethyl ammonium ethyl (meth)acrylate salts,
polyhydroxyethyl (meth)acrylate, polymethylether diethyleneglycol (meth)acrylate,
polyethylene oxide, polyvinylpyrrolidone, polyaminoacids and polyacrylonitriles.
6. A process for the preparation of a copolymer as claimed in claim 1,
comprising the steps of
a) partially sylilating the hydroxyl functions of a polysaccharide chain with a sylilation
agent, the ratio between the polysaccharide hydroxyl functions and the sylilation agent
being comprised between 1 and 3 equivalents, to provide a modified polysaccharide ;
b) using the modified polysaccharide obtained under a) to polymerise biodegradable
hydrophobic monomers by ring opening polymerisation, at a temperature comprised
between 120°C and 150°C in the presence of a catalyst, to provide a polysaccharide
backbone grafted with primary hydrophobic segments ;
c) preparing a macro-initiator that is capable of polymerising monomers, such as (meth-)
acrylate monomers by esterification of ending groups of the primary hydrophobic
segments with an alkyl bromide used in excess ;
d) using the macro-initiator obtained under c) to polymerise monomers to covalently link
secondary segments to the primary segments, thus producing a copolymer diblock
composition.
7. A process as claimed in claim 6, wherein the monomers used in step d) are
hydrophilic.
8. A process as claimed in claim 6, wherein the monomers used in step d) are
hydrophobic.
9. A process as claimed in claim 6, wherein polymerisation in step d) is
carried out by atom transfer radical polymerisation.

The invention discloses a copolymer comprising a polysaccharide backbone and
amphiphilic diblock copolymers grafted on said polysaccharide backbone, each
amphiphilic diblock comprising: a) a hydrophobic polymeric segment directly grafted
on the polysaccharide backbone and comprising from 5 to 200 repeated units; and b) a
hydrophilic polymeric segment covalently bonded to the hydrophobic segment and
comprising from 5 to 300 repeated units.
The invention is also for a process for preparation of said copolymer and a biodegradable
particle comprising said copolymer.

Documents:

02970-kolnp-2006-abstract.pdf

02970-kolnp-2006-assignment-1.1.pdf

02970-kolnp-2006-assignment.pdf

02970-kolnp-2006-claims.pdf

02970-kolnp-2006-correspondence others-1.1.pdf

02970-kolnp-2006-correspondence others.pdf

02970-kolnp-2006-description(complete).pdf

02970-kolnp-2006-drawings.pdf

02970-kolnp-2006-form-1.pdf

02970-kolnp-2006-form-3.pdf

02970-kolnp-2006-form-5.pdf

02970-kolnp-2006-international publication.pdf

2970-KOLNP-2006-ABSTRACT 1.1.pdf

2970-KOLNP-2006-ABSTRACT.pdf

2970-KOLNP-2006-AMANDED CLAIMS 1.1.pdf

2970-KOLNP-2006-AMANDED CLAIMS.pdf

2970-KOLNP-2006-AMANDED PAGES OF SPECIFICATION 1.1.pdf

2970-KOLNP-2006-AMANDED PAGES OF SPECIFICATION.pdf

2970-kolnp-2006-assignment.pdf

2970-KOLNP-2006-CORRESPONDENCE 1.1.pdf

2970-KOLNP-2006-CORRESPONDENCE 1.2.pdf

2970-kolnp-2006-correspondence.pdf

2970-KOLNP-2006-DESCRIPTION (COMPLETE) 1.1.pdf

2970-KOLNP-2006-DESCRIPTION (COMPLETE).pdf

2970-KOLNP-2006-DRAWINGS.pdf

2970-KOLNP-2006-EXAMINATION REPORT REPLY RECIEVED.pdf

2970-kolnp-2006-examination report.pdf

2970-KOLNP-2006-FORM 1 1.1.pdf

2970-KOLNP-2006-FORM 1.pdf

2970-kolnp-2006-form 13-1.1.pdf

2970-KOLNP-2006-FORM 13.pdf

2970-kolnp-2006-form 18.pdf

2970-KOLNP-2006-FORM 2 1.1.pdf

2970-KOLNP-2006-FORM 2.pdf

2970-kolnp-2006-form 3-1.1.pdf

2970-KOLNP-2006-FORM 3.pdf

2970-kolnp-2006-form 5-1.1.pdf

2970-KOLNP-2006-FORM 5.pdf

2970-kolnp-2006-gpa.pdf

2970-kolnp-2006-granted-abstract.pdf

2970-kolnp-2006-granted-claims.pdf

2970-kolnp-2006-granted-description (complete).pdf

2970-kolnp-2006-granted-drawings.pdf

2970-kolnp-2006-granted-form 1.pdf

2970-kolnp-2006-granted-form 2.pdf

2970-kolnp-2006-granted-specification.pdf

2970-KOLNP-2006-OTHERS 1.1.pdf

2970-KOLNP-2006-OTHERS 1.2.pdf

2970-kolnp-2006-others-1.3.pdf

2970-KOLNP-2006-OTHERS.pdf

2970-KOLNP-2006-PETITION UNDER RULE 137.pdf

2970-kolnp-2006-reply to examination report.pdf


Patent Number 251834
Indian Patent Application Number 2970/KOLNP/2006
PG Journal Number 15/2012
Publication Date 13-Apr-2012
Grant Date 11-Apr-2012
Date of Filing 13-Oct-2006
Name of Patentee FIRMENICH SA
Applicant Address 1, ROUTE DES JEUNES, P.O. BOX 239, CH-1211 GENEVA 8
Inventors:
# Inventor's Name Inventor's Address
1 BERTHIER DAMIEN CHEMIN DES CRETS-DE-CHAMPEL, 25, 1206 GENEVA
2 OUALI LAHOUSSINE 40, ROUTE DE MONTHOUX, F-74100 VETRAZ-MONTHOUX
PCT International Classification Number C08G 83/00
PCT International Application Number PCT/IB2005/001179
PCT International Filing date 2005-05-02
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 04101930.8 2004-05-05 EUROPEAN UNION