U.S. patent application number 15/121746 was filed with the patent office on 2017-03-16 for sustained release composition using biobased biodegradable hyperbranched polyesters.
The applicant listed for this patent is CENTRAL MICHIGAN UNIVERSITY, MICHIGAN MOLECULAR INSTITUTE. Invention is credited to Bobby A. Howell, Patrick B. Smith, Cuiwei Zhang.
Application Number | 20170073465 15/121746 |
Document ID | / |
Family ID | 54009766 |
Filed Date | 2017-03-16 |
United States Patent
Application |
20170073465 |
Kind Code |
A1 |
Smith; Patrick B. ; et
al. |
March 16, 2017 |
SUSTAINED RELEASE COMPOSITION USING BIOBASED BIODEGRADABLE
HYPERBRANCHED POLYESTERS
Abstract
The present invention provides a sustained release composition
having hyperbranched polymers that are polyesters that are biobased
and biodegradable, and that have at least one active ingredient,
which composition delivers the active ingredient over time. These
active ingredients can be a wide variety of compounds so long as
they can covalently bind to the polymer or be encapsulated in the
polymer in a manner that is released at the point of delivery,
usually by acid hydrolysis or enzymatic bond scission.
Inventors: |
Smith; Patrick B.; (Midland,
MI) ; Howell; Bobby A.; (Mt. Pleasant, MI) ;
Zhang; Cuiwei; (Midland, MI) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MICHIGAN MOLECULAR INSTITUTE
CENTRAL MICHIGAN UNIVERSITY |
Midland
Mt. Pleasant |
MI
MI |
US
US |
|
|
Family ID: |
54009766 |
Appl. No.: |
15/121746 |
Filed: |
February 23, 2015 |
PCT Filed: |
February 23, 2015 |
PCT NO: |
PCT/US15/17069 |
371 Date: |
August 25, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61946599 |
Feb 28, 2014 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C08G 2310/00 20130101;
C08L 101/16 20130101; C08G 2220/00 20130101; A01N 37/10 20130101;
A61K 31/192 20130101; A61K 31/165 20130101; A01N 25/18 20130101;
A01N 35/02 20130101; A01N 25/10 20130101; C08L 101/005 20130101;
A01N 37/10 20130101; A01N 37/04 20130101; A01N 37/40 20130101; A01N
25/10 20130101; C08G 63/914 20130101; A01N 31/16 20130101; A01N
35/02 20130101; A01N 35/02 20130101; A01N 25/18 20130101; A01N
31/14 20130101; A61K 31/198 20130101; C08G 63/12 20130101; A61K
47/34 20130101; A61K 31/573 20130101; A61K 9/0014 20130101; A61K
31/60 20130101; A61K 9/7007 20130101 |
International
Class: |
C08G 63/91 20060101
C08G063/91; A01N 35/02 20060101 A01N035/02; A61K 9/00 20060101
A61K009/00; A61K 31/573 20060101 A61K031/573; A01N 37/10 20060101
A01N037/10; A61K 47/34 20060101 A61K047/34; A01N 25/10 20060101
A01N025/10; A61K 31/192 20060101 A61K031/192; A61K 31/198 20060101
A61K031/198; A01N 31/14 20060101 A01N031/14; A61K 47/48 20060101
A61K047/48 |
Claims
1. A composition comprising a synthetic or natural biobased,
biodegradable hyperbranched polyester that has at least one active
ingredient either covalently bonded to or encapsulated in the
hyperbranched polyester.
2. The composition of claim 1, wherein the polyester linkage
degrades into its starting monomers or other environmentally benign
degradation products and the active ingredient is released and is
effective.
3. The composition of claim 1, wherein the active ingredient has a
carboxylate, hydroxy, amino, ketone, aldehyde, double- or
triple-bond, or triazole groups to covalently bond to the
hyperbranched polyester.
4. The composition of claim 1, wherein the polyester is synthetic
and formed from glycerol and adipic acid and/or succinic acid and
is prepared using bimolecular non-linear polymerization (BMNLP)
methodology.
5. The composition of claim 1, wherein the hyperbranched polyester
is formed from a multifunctional biobased alcohol and a
multifunctional biobased carboxylic acid using bimolecular
non-linear polymerization (BMNLP) methodology.
6. The composition of claim 5, wherein the multifunctional biobased
alcohol glycerol, pentaerythritol, sugars, sugar alcohols, or
multifunctional biobased acids.
7. The composition of claim 1, wherein a ketal is formed by the
hyperbranched polyester and the active ingredient.
8. The composition of claim 7, wherein the ketal is a dioxane,
dioxolane, inter- or intra-molecular ketal or mixtures thereof.
9. The composition of claim 2, wherein the active ingredient is
released from the hyperbranched polyester either by hydrolysis or
enzymatic bond scission.
10. The composition of claim 9, wherein the hydrolysis is catalyzed
by a biobased acid having a pKa of from about -8 to about 2.2.
11. The composition of claim 10, wherein the biobased acid is HCl,
p-toluenesulfonic acid, or phytic acid.
12. The composition of claim 9, wherein the rate of release is
adjusted by one or more of the following: 1) the level of acid
catalyst present in the formulation or in situ; 2) the pKa of the
acid catalyst; 3) the MW of the BBB-HB-PE; 4) the composition of
the BBB-HB-PE; 5) the amount of water in the formulation; or 6) the
temperature of the formulation.
13. The composition of claim 9, wherein the enzyme used for
enzymatic bond scission is an esterase, lipase or ketalase.
14. The composition of claim 1, wherein the active ingredient is
encapsulated and held by secondary forces within the hyperbranched
polyester.
15. The composition of claim 14, wherein the active ingredient is
released by diffusion.
16. The composition of claim 1, wherein the active ingredient is
released from the hyperbranched polyester over time from about 1
day to several months.
17. The composition of claim 1, wherein the hyperbranched polyester
has been formed into a network.
18. The composition of claim 17, wherein the network is formed into
films, sheets or coatings.
19. The composition of claim 1, wherein the active ingredient is an
agent for wound healing.
20. The composition of claim 1, wherein the active ingredient is a
transdermal drug.
21. The composition of claim 1, wherein the active ingredient is a
topical drug.
22. The composition of claim 21, wherein the topical drug is for
dermatological disorders, venereal disease, an analgesic, or an
anti-inflammatory.
23. The composition of claim 22, wherein the topical drug for an
analgesic is capsaicin, salicylic acid, ketoprofen, or ferulic
acid.
24. The composition of claim 22, wherein the topical drug for an
anti-inflammatory is a hydrocortisone derivative.
25. The composition of claim 1, wherein the active ingredient is an
antibiotic.
26. The composition of claim 1, wherein the active ingredient is an
antitumor agent.
27. The composition of claim 26, wherein the antitumor agent is
organo-platinum.
28. The composition of claim 1, wherein the active ingredient is an
herbicide.
29. The composition of claim 28, wherein the herbicide is atrazine,
2,4-D esters, or glyphosate.
30. The composition of claim 1, wherein the active ingredient is a
miticide
31. The composition of claim 30, wherein the miticide is oxalic
acid.
32. The composition of claim 1, wherein the active ingredient is a
veterinary drug.
33. The composition of claim 1, wherein the active ingredient is a
plant growth regulator.
34. The composition of claim 33, wherein the plant growth regulator
is auxin, cytokinin, gibberellic acid, or naphthalene acetic
acid.
35. The composition of claim 1, wherein the active ingredient is
disinfectant or sanitizer.
36. The composition of claim 35, wherein the disinfectant or
sanitizer is triclosan, benzalkonium chloride, cetylpyridinium
chloride, or chlorhexidine gluconate.
37. The composition of claim 36, wherein the disinfectant or
sanitizer is triclosan.
38. The composition of claim 1, wherein the active ingredient is an
insect repellant.
39. The composition of claim 38, wherein the insect repellant is
2-undecanone.
40. A BMNLP process for preparing the compound as defined in claim
1, which comprises the reaction of: a monomer of the form A.sub.x,
where A is either an OH or O(O)CR group for the polyfunctional
acids, or is C(O)OH, C(O)OR, or C(O)Cl group for the polyfunctional
alcohols; with another monomer of the form B.sub.y, where B is
either a C(O)OH, C(O)OR or C(O)Cl group for the polyfunctional
acids, or OH or O(O)CR group for the polyfunctional alcohols; under
conditions at which neither A nor B groups can react with
themselves but only with each other; and where x and y are integers
where one integer is equal to or larger than 2 and the other is
equal or larger than 3; and the molar ratio of the reacting A
groups and B groups (r=A/B) and the extent of the reaction must be
selected to avoid gelation; and an active ingredient having
carboxylate, hydroxyl, carbonyl or amine groups is covalently
bonded to the alcohol or acid end groups of the polyester.
41. The process of claim 40, wherein the polyester forms
networks.
42. The process of claim 40, wherein the process is in the bulk
system wherein the extent of the reaction of the minor component
(either p.sub.A or p.sub.B) is about unity, and the value of r is
outside of the "gelation window" defined by the following equation:
1[(x-1)(y-1)].ltoreq.r.ltoreq.(x-1)(y-1).
43. A dioxane, dioxolane, inter- or intra-molecular ketal or
mixtures thereof formed by reacting a hydroxyl terminated HBPE with
a H.sub.3C--C(O)--R wherein: R is a C.sub.4 to C.sub.20 straight-
or branched-chain alkyl.
44. The ketal of claim 43 wherein R is C.sub.7 to C.sub.13.
45. The ketal of claim 44 wherein R is R is C.sub.9 (UD;
2-undecanone) or C.sub.13 (2-tridecanone).
Description
FIELD OF THE INVENTION
[0001] This invention concerns the controlled delivery of active
ingredients, over time, using biobased, biodegradable hyperbranched
polyesters.
BACKGROUND OF THE INVENTION
[0002] Today with the concerns about recycling of plastics many
manufactures would like a plastic to be biobased and biodegradable.
Various approaches have been tried with varying degrees of success
for recycling, efficacy and customer acceptance.
[0003] Polyesters can be synthesized from readily renewable hydroxy
acid building blocks such as lactic acid and 3-hydroxybutyric acid
or via poly-condensation reactions between dicarboxylic acids with
diols, transesterification of diesters with diols, and ring opening
polymerization of lactones. Polyesters from renewable feedstocks
are very often also biodegradable, through either hydrolytic or
enzymatic depolymerization to fragments which are microbially
consumed. Polyesters with functional groups along their chains or
in pendant groups are attracting increased interest since these
groups can be used to regulate polymer material properties. Thus
using polyesters from renewable sources is a desired goal for
delivery systems.
Delivery Systems
[0004] Traditionally, active ingredients that are drugs have
primarily consisted of small molecules that are dispensed orally
(as solid pills and liquids) or as injectables. Over the past three
decades, however, sustained release formulations (i.e.,
compositions that control the rate of drug delivery and allow
delivery of the therapeutic agent at the site where it is needed)
have become increasingly common and complex. Nevertheless, many
questions and challenges regarding the development of new
treatments as well as the mechanisms with which to administer them
remain to be addressed.
[0005] Although considerable research efforts in this area have led
to significant advances, drug delivery methods/systems that have
been developed over the years and are currently used still exhibit
specific problems that require some investigating. For example,
many drugs exhibit limited or otherwise reduced potencies and
therapeutic effects because they are generally subject to partial
degradation before they reach a desired target in the body. Some
drugs presently used in sustained delivery systems are naproxen and
ibuprofen, but there are many others.
[0006] Once administered, sustained release medications deliver
treatment continuously, e.g. for days or weeks, rather than for a
short period of time (hours or minutes). Furthermore, orally
administered therapeutics are generally preferable over injectable
medications, which are often more expensive and more challenging to
administer, and thus it would be highly desirable if injectable
medications could simply be dosed orally. However, this goal cannot
be achieved until methods are developed to safely shepherd drugs
through tissue barriers, such as epithelial or dermal barriers, or
specific areas of the body, such as the stomach, where low pH can
degrade or destroy a medication, or through an area where healthy
tissue might be adversely affected.
[0007] One objective in the field of drug delivery systems,
therefore, is to deliver medications intact to specifically
targeted areas of the body through a system that can control the
rate and time of administration of the therapeutic agent by means
of either a physiological or chemical trigger. Over the past
decade, materials such as polymeric microspheres, polymer micelles,
soluble polymers and hydrogel-type materials have been shown to be
effective in enhancing drug targeting specificity, lowering
systemic drug toxicity, improving treatment absorption rates, and
providing protection for pharmaceuticals against biochemical
degradation, and thus have shown potential for use in biomedical
applications, particularly as components of drug delivery
devices.
[0008] There is considerable published literature on the
time-release delivery of medications using synthetic polymers to
which medications are covalently bonded. Polymers such as acrylics
(Mizrahi, B.; Domb, A., AAPS PharmSciTech, 2009, 10, 453-458),
methacrylics (Gallardo, A.; et al., J. Controlled Release, 2001,
71, 127-140) and poly(vinylalcohol) (Borovac, T., et al., J.
Controlled Release, 2006, 115, 266-274) have been investigated.
There are several drawbacks to this approach, including the fact:
that the synthetic polymers are not readily bioresorbable or
biodegradable potentially causing adverse effects, that it is
difficult to covalently bond high concentrations of actives to
them, and that they often require difficult chemical syntheses.
Uhrich, et al. took a different approach, synthesizing "prodrugs"
where the medication itself is a part of the polymer backbone
(Wada, K., et al., J. Controlled Release, 2013, 171, 33-37). One
example of such a formulation is polyaspirin where salicylic acid
was polymerized with sebacic acid to obtain a polyanhydride ester.
The polymer would degrade, through hydrolysis in the stomach,
releasing aspirin and sebacic acid in a time-release manner.
Advantages of this approach include the ability to bind higher
levels of the medication, e.g. 50 to 60% by weight, and the ability
to completely degrade within the body, releasing the medication and
benign co-products. There are also major limitations to this
approach which include the fact that the synthetic chemistry is
often complex with expensive reagents, and, more importantly, a
multi-functional medication is necessary for polymerization. Most
actives do not possess multifunctional structures capable of this
type of polymerization.
[0009] Biodegradable Polymers
[0010] The design and engineering of biomedical polymers (e.g.,
polymers for use under physiological conditions) are generally
subject to specific and stringent requirements. In particular, such
polymeric materials must be compatible with the biological milieu
in which they will be used, which often means that they show
certain characteristics of hydrophilicity. They also have to
demonstrate adequate biodegradability (i.e., they degrade to low
molecular weight species). The polymer fragments are in turn
metabolized in the body or excreted, leaving no trace.
[0011] Biodegradability is typically accomplished by synthesizing
or using polymers that have hydrolytically unstable linkages in
their backbone. The most common chemical functional groups with
this characteristic are esters, anhydrides, orthoesters, and
amides. Chemical hydrolysis of the hydrolytically unstable backbone
is the prevailing mechanism for the polymer's degradation.
Biodegradable polymers can be either natural or synthetic.
[0012] Synthetic polymers commonly used in medical applications and
biomedical research include polyethyleneglycol (pharmacokinetics
and immune response modifier), polyvinyl alcohol (drug carrier),
and poly(hydroxypropylmethacrylamide) (drug carrier).
[0013] In addition, natural polymers are also used in biomedical
applications. For instance, dextran, hydroxyethylstarch, albumin
and partially hydrolyzed proteins find use in applications ranging
from a plasma substitute, to radiopharmaceuticals and parenteral
nutrition.
[0014] In general, synthetic polymers may offer greater advantages
than natural materials because they can be tailored to give a wider
range of properties and more predictable lot-to-lot uniformity than
can be obtained from materials from natural sources. Synthetic
polymers also represent a more reliable source of raw materials,
having fewer concerns of infection or immunogenicity.
[0015] Methods of preparing polymeric materials are well known in
the art. However, synthetic methods that successfully lead to the
preparation of polymeric materials that exhibit adequate
biocompatibility, biodegradability, hydrophilicity and minimal
toxicity for biomedical use are scarce. The restricted number and
variety of biopolymers currently available attest to this
difficulty.
[0016] One class of synthetic polymers is the hyperbranched
polymers that show promise for use in this area and, in particular,
hyperbranched polyesters have shown promise for these applications.
Their synthesis using bimolecular non-linear polymerization (BMNLP)
is economically advantaged over other methods to prepare HBPs since
the synthesis can be carried out using a simple, one-pot synthesis
strategy while at the same time controlling important parameters
such as end group functionality and molecular weight. The synthesis
of hyperbranched polyesters is taught in U.S. Pat. Nos. 6,534,600
and 6,812,298, which processes are hereby incorporated by
reference, but they have not been used in medical or biodegradable
applications. Hyperbranched polyesters can be synthesized from a
limited number of biobased, biodegradable monomers. These monomers
must consist of alcohol and acid functionality and be
multifunctional in nature, in order to create the hyperbranched
architecture (see Dvornic, P. R.; Meier, D. J., Hyperbranched
Silicon-Containing Polymers by Bimolecular Non-linear
Polymerization, pp. 401-420 in Silicon-Containing Dendritic
Polymers, Dvornic, P. R.; Owen, M. J., Eds., Springer, 2009). One
embodiment is to use a trifunctional alcohol (such as glycerol) or
tetrafunctional alcohol (such as pentaerythritol) and a
difunctional acid (such as succinic, adipic, fumaric or sebacic
acid). Each of these acids is biobased and biodegradable and has
the added advantage that they are FDA approved.
Hyperbranched Polyesters (HB-PE)
[0017] Hyperbranched polyesters of glycerol and succinic or adipic
acid have been reported in the literature. Stumbe and Bruchmann
synthesized a glycerol, adipic acid HB-PE neat at 100.degree. C.
using dibutyltin oxide catalyst under reduced pressure (Stumbe,
J.-F.; Bruchmann, B.; Macromol. Rapid Commun., 2004, 25, 921-924).
These authors varied the stoichiometry of the monomers and
determined the molecular weight of the resulting polymer, but it
was determined from end group titration that these polymers only
went to about 85% degrees of polymerization. Average molecular
weights above 20,000 were obtained, but gelation was also observed
with some stoichiometries. The molecular weight of these polymers
was controlled by viscosity. Since viscosity is a function of
molecular weight, and the molecular weight in these systems is
determined by both the stoichiometry of the reacting groups and the
degree of polymerization, then viscosity is not a viable control
parameter. It is possible to produce polymers with the same
viscosity from these monomers which have very different end groups
and therefore, different properties. It is also difficult to stop
the polymerization at a given viscosity to attain a targeted
molecular weight.
[0018] Wyatt and Strahan synthesized glycerol HB-PEs from succinic
acid, from glutaric acid, and from sebacic acid (Wyatt, V. T.,
Strahan, G. D., Polymers, 2012, 4, 396-407). They used dibutyltin
oxide as catalyst. They performed a complete structural analysis
using NMR spectroscopy, but did not determine the molecular weight
of the polymers. In a separate publication, Wyatt also ran the
polymerizations as a function of stoichiometry and found that the
molecular weight was a function of reaction temperature and time
for the same initial monomer stoichiometry (Wyatt, V. T., J. Am.
Oil Chem. Soc., 2012, 89, 313-319). In fact, he found that the
molecular weight of the polymer varied from 10,600 to 445,000 for a
glycerol to glutaric acid molar ratio of 2:1 and suggested its
origin was due to side reactions. Molecular weight control was
difficult with this synthetic strategy.
[0019] Kulshrestha, et al. synthesized glycerol, adipic acid HB-PEs
by enzyme catalysis using Novozyme 435 (Kulshrestha, A. S. et al.,
Biomacromolecules, 2007, 8, 1794-1801). A molecular weight of 3,700
was obtained by this method and alternate stoichiometries of
glycerol to adipic acid were not investigated. Glycerol sebacic
acid HB-PEs were synthesized by Kafouris, et al. in Macromolecules,
2013, 46, 622-630 and Li, et al. in Polym. Int., 2013, 62,
534-547). No attempt to control the molecular weight of these
polymers was made.
[0020] Clearly, it would be desired to find a biobased,
biodegradable polymer that is synthetic, has controlled physical
properties (e.g. molecular weight), can carry an active biological
material, provide a mechanism for sustained release, and the
residual materials could be recycled.
BRIEF SUMMARY OF THE INVENTION
[0021] This invention relates to a sustained release composition
having a synthetic or natural polymer of hyperbranched polyesters
that are biobased and biodegradable, which composition delivers at
least one active ingredient over time. The active ingredient can be
one or more of such active ingredients selected from a wide variety
of compounds so long as they can covalently bind to the
hyperbranched polyester or be encapsulated in the hyperbranched
polyester in a manner that the active ingredient is released at the
point of delivery, usually by hydrolysis or enzymatic action.
[0022] Specifically, this invention concerns a composition
comprising a biobased, biodegradable hyperbranched polyester that
has at least one active ingredient, either covalently bonded to or
encapsulated in the hyperbranched polyester. Preferably the active
ingredient has carboxylate, hydroxyl, amino, ketone, aldehyde,
double- or triple-bond, or triazole groups to covalently bond to
the hyperbranched polyester. More preferably the active ingredient
has either carboxylate or hydroxyl groups to bond to the polyester.
Additionally, some active ingredients form ketals with the
hyperbranched polyester. The polyester can form networks.
[0023] The process to make these hyperbranched polyesters involves
bimolecular non-linear polymerization (BMNLP) methodology. The
process to form the composition (hyperbranched polyester and active
ingredient) is provided later herein. Some preferred monomers used
to prepare the synthetic hyperbranched polyester are glycerol and
adipic acid and/or succinic acid. The composition may be formulated
using known and customary inert components selected for the
particular active ingredient's utility.
[0024] The active ingredient is released from the polyester or
network either by hydrolysis or enzymatic bond scission when the
active ingredient is covalently bound to the polyester or is
released by diffusion, hydrolysis or enzymatic bond scission when
the active ingredient is encapsulated in the polyester or network.
The polyester linkage degrades into the starting monomers or other
environmentally benign degradation products and the active
ingredient is released and is effective. All monomers and polymeric
components and biodegradation catalysts used for this sustained
release system are biodegradable.
DETAILED DESCRIPTION OF THE INVENTION
Glossary
[0025] It is understood that the terminology used herein is for the
purpose of describing particular embodiments only and is not
intended to be limiting. As used in this specification, the
singular forms "a", "an", and "the" include plural referents unless
the content clearly indicates otherwise. The following terms in the
Glossary as used in this application are to be defined as stated
below and for these terms, the singular includes the plural.
[0026] Various headings are present to aid the reader, but are not
the exclusive location of all aspects of that referenced subject
matter and are not to be construed as limiting the location of such
discussion.
[0027] Also, certain US patents and PCT published applications have
been incorporated by reference. The U.S. Provisional Appln.
61/946,599 from which this application claims priority is hereby
incorporated by reference. However, the text of such patents is
only incorporated by reference to the extent that no conflict
exists between such text and other statements set forth herein. In
the event of such conflict, then any such conflicting text in such
incorporated by reference US patent or PCT application is
specifically not so incorporated in this patent. [0028] "adipic
acid" or "AA" means 1,4-butanedicarboxylic acid [0029] "AI" means
active ingredient [0030] "Brookfield" is a brand name of a
well-known line of rotating spindle viscometers which are routinely
referred to in applied rheology as Brookfield viscometers
(www.brookfieldengineering.com). [0031] "BBB" means biobased
biodegradable [0032] "BMNLP" means bimolecular non-linear
polymerization [0033] "bulk" polymerization means a neat reaction
system devoid of solvent [0034] "composition" means the amount of
each component present in a sample, e.g., the ratio of monomers
comprising the HBP, HB-PE or BBB-HB-PE as well as that of AIs
associated with the polymer as further defined herein [0035]
"2,4-D" means 2,4-dichlorophenoxyacetic acid [0036] "DI water"
means distilled water [0037] "DMSO" means dimethylsulfoxide [0038]
"excess" means that the level of one monomer's functional group
composition is greater than that of the other monomer in the
BB-HB-PE or HB-PE [0039] "formulation" means a composition that has
suitable known inert ingredients, and acid or enzyme, as needed as
defined herein, to aid administration of the composition for the
AI's intended use [0040] "g" means grams [0041] "glycerol" means
1,2,3-propanetriol [0042] "HBP" means hyperbranched polymer(s)
[0043] "HB-PE" means hyperbranched polyester polymers; this is a
specific class of dendritic polymer and excludes dendrimers,
dendrons, and dendrigrafts [0044] "GRAS" means generally recognized
as safe by the US FDA under C.F.R. 21, Part 182 [0045] "hr" means
hour(s) [0046] "L" means liter [0047] "min" means minute(s) [0048]
"mL" means milliliter [0049] "M.sub.n" means number average
molecular weight [0050] "M.sub.w" means weight average molecular
weight [0051] "M.sub.t" means z average molecular weight [0052]
"NAA" means 1-naphthylene acetic acid [0053] "NMR" means Nuclear
Magnetic Resonance using either a Varian Mercury 500 or Bruker
Avance 300 spectrometer using trimethylsilane as the internal
reference and measured for proton (.sup.1H) and carbon (.sup.13C)
[0054] "overnight" means from about 12 to about 14 hrs [0055] "PDI"
means polydispersity index; PDI=M.sub.w/M.sub.n [0056] "SEC" means
Size Exclusion Chromatography [0057] Molecular weights measured by
SEC were performed using a Waters 1525 liquid chromatography
instrument equipped with two Agilent PLgel 3 .mu.m MIXED-E columns
in series and a Waters 410 refractive index detector in series with
a Wyatt Technologies DAWN Heleos-II light scattering detector. The
solvent was THF at a flow rate of 1 mL min.sup.-1 The sample
concentration was 5 mg mL.sup.-1. [0058] "succinic acid" or "SA"
means butanedioic acid [0059] "THF" means tetrahydrofuran [0060]
"TMP" means trimethylolpropane [0061] "p-TSA" means
p-toluenesulfonic acid [0062] "UD" means 2-undecanone or methyl
nonyl ketone [0063] "wt %" means percent by weight
[0064] The hyperbranched polyester approach described herein uses
simple synthesis procedures with inexpensive, GRAS-listed reagents
and is capable of achieving active ingredient loadings of 35 to 40%
by weight. These materials degrade hydrolytically either through
enzymatic methods or through acid-catalysis to release the active
ingredient, in its active form, leaving benign co-products. Use of
BMNLP technology allows targeting of a given molecular weight by
choice of monomer stoichiometry for a polymerization which is taken
to high degree of polymerization. This approach is much easier to
control the desired molecular weight and thus the properties of the
HB-PE.
[0065] This invention relates to hyperbranched polyester (HB-PE)
compounds, prepared as described in U.S. Pat. No. 6,812,298,
incorporated herein by reference, that are prepared from biobased
monomers. The HB-PE polymers of this invention are biobased and
biodegradable (BBB) and referred to as BBB-HB-PE polymers. These
BBB-HB-PE polymers use hyperbranched polyesters that are taught in
U.S. Pat. Nos. 6,534,600 and 6,812,298, incorporated herein by
reference.
[0066] The monomers for BBB-HB-PEs are selected from FDA approved
materials and the BBB-HB-PE polymers are of nanoscopic sizes. These
polymers can be crosslinked to form networks, films, sheets or
coatings (as described on pp. 408-410 in Dvornic, P. R.; Meier, D.
J., Hyperbranched Silicon-Containing Polymers by Bimolecular
Non-linear Polymerization; and pp. 401-420 in Silicon-Containing
Dendritic Polymers, Dvornic, P. R.; Owen, M. J., Eds., Springer,
2009). The AI is either encapsulated (with diffusion of the AI) or
covalently bonded to the HB-PE scaffold so that the rate of
diffusion or the rate of this bond scission coincides well with the
time desired for the AI delivery.
[0067] The covalent bond can be broken upon use, such as by
hydrolysis or enzymatic degradation, to release the AI. These
BBB-HB-PE polymers have diverse chemistry to bind with AI, have
very high end group functionality that can be used for targeted
delivery, can bind or encapsulate high loadings of AI with either
rapid or time-release features, and the BBB-HB-PE polymers
biodegrade after use. These types of HBPEs have been shown to
effectively encapsulate actives [Irfan, M., Seiler, M., Ind. Eng.
Chem. Res., 2010, 49, 1169-1196.]
[0068] The BBB-HB-PE polymers of the present invention are
hyperbranched polyesters, which possess the inherent capability of
linear polyesters to degrade into the starting monomers either by
hydrolysis or enzymatic degradation.
[0069] The monomers for the BBB-HB-PE polymers are from renewable
resources and the polymers biodegrade in a controlled fashion to
benign products. Examples of such monomers are multi-functional
alcohols such as glycerol or pentaerythritol and difunctional acids
such as furandicarboxylic, succinic, adipic or sebacic acid. All
these monomers are obtained from biobased feedstocks and degrade by
hydrolysis or enzymatically into environmentally benign
products.
[0070] The HB-PEs from glycerol and succinic or adipic acid degrade
both hydrolytically and enzymatically in a matter of hours to days,
typically from about 1 to about 7 days, depending on the polymer
composition, polymer molecular weight, and the type of AI.
[0071] These HB-PEs can be produced from a number of different
biobased multifunctional alcohols and acids. The alcohols include
glycerol, pentaerythritol, sugars such as sucrose, glucose, and
xylose, sugar alcohols such as sorbitol and xylitol,
1,3-propanediol, 1,4-butanediol, resorcinol and isosorbide. The
chemical structures of glucose, sorbitol and glycerol are provided
below to illustrate their multifunctional nature.
##STR00001##
The multifunctional biobased acids include succinic, oxalic,
adipic, glutaric, gluconic, sebacic, maleic, fumaric and
2,5-furandicarboxylic acid. Multifunctional biobased molecules such
as tartaric acid, glucaric acid could also be used.
[0072] It has been shown that the chain length of the dicarboxylic
acid monomer controls the polymer hydrophilicity and thereby the
rate of degradation, providing a degree of control over the release
rate of the AI and the HB-PE degradation process (see Coneski, P.
N., et al., Biomacromolecules, 2010, 11, 3208-3215). These monomers
were chosen as they have FDA approval and have been shown to slowly
degrade under physiological conditions in a time frame of days.
When the AI is an insect repellant, such as UD, this release rate
is preferred for dermal uses to minimize skin irritation.
[0073] The BMNLP process for the preparation of BBB-HB-PE polymers
involves the reaction between polyfunctional acids and alcohols.
More specifically, it involves a monomer of the form A.sub.x (where
A is either an OH or O(O)CR group for the polyfunctional acids; or
C(O)OH, C(O)OR or C(O)Cl group for the polyfunctional alcohols),
which reacts with another monomer of the form B.sub.y (where B is
either a C(O)OH, C(O)OR or C(O)Cl group for the polyfunctional
acids; or OH or O(O)CR group for the polyfunctional alcohols),
under conditions at which neither A nor B groups can react with
themselves but only with each other, and where x and y are integers
where one integer is equal or larger than 2 and the other is equal
or larger than 3. Additional reaction requirements are that the
molar ratio of the reacting A groups and B groups (r=A/B) and the
extent of the reaction must be selected so as to avoid gelation.
This is accomplished in the bulk system if the extent of the
reaction of the minor component (either p.sub.A or p.sub.B) is
equal to unity (i.e., complete conversion of the minor reagent is
achieved) and the value of r is outside of the "gelation window"
defined by the following equation:
1[(x-1)(y-1)].ltoreq.r.ltoreq.(x-1)(y-1).
[0074] The process to prepare these BBB-HB-PE polymers from
biobased alcohols, such as excess glycerol, is shown in Scheme 1
below. In this general reaction Scheme 1, a diacid, such as adipic
or succinic acid, is reacted with a multifunctional alcohol, such
as glycerol. This reaction may be performed in solution or in the
bulk and an acid catalyst, such as sulfuric acid or
p-toluenesulfonic acid, or a polyesterification catalyst such as
dibutyltin oxide or tin octoate is often used. An excess of
glycerol is used in Scheme 1 which results in the HBP end groups
primarily being alcohol end groups. In Scheme 1, n is 2 or 4.
##STR00002##
[0075] The process to prepare these BBB-HB-PE polymers from
biobased acids using excess acid is shown in Scheme 2 below. The
characteristics of the polymerization are similar to those
described for Scheme 1 above except that the diacid is in excess
resulting in a HBP possessing primarily acid end groups. In Scheme
2, n is 2 or 4.
##STR00003##
HB-PE Distribution
[0076] There is a distribution of glycerol structures in the
polymer, mono-, di- and tri-ol of glycerol itself (triol) that
remains in the HB-PE after the above reactions as described in
Scheme 1 or 2 above. The molecular weight of the HB-PE is
controlled by the BMNLP process.
[0077] One preferred BBB-HB-PE polymer is made from glycerol and
(adipic acid and/or succinic acid), especially where alcohol is in
excess. Other BBB-HB-PE polymers are also of interest. Various AI
can be reacted as discussed below.
[0078] In some cases a ketal is formed where the ketone used is of
the structure:
H.sub.3C--C(O)--R
wherein: R is a C.sub.4 to C.sub.20 straight- or branched-chain
alkyl, preferably C.sub.7 to C.sub.13.
[0079] Of special interest are the ketones where R is C.sub.9 (UD;
2-undecanone) or C.sub.13 (2-tridecanone). UD is an approved insect
repellant.
[0080] Since there is a distribution of hydroxyl structures on the
HB-PE, there is a distribution of ketal structures formed as shown
below. The R-group is an adipate ester connecting the terminal
glycerol unit to the HB-PE. Dioxane and dioxolane structures form
as well as inter- and intra-molecular ketals. These latter ketals
can be between primary alcohol groups as shown or between secondary
and primary alcohols or secondary and secondary alcohols. Evidence
from NMR and SEC suggests that they all form. There is also a
distribution of molecular weights for the HB-PE so the resulting
product is a distribution of species that can be defined
statistically (molecular weight distribution) and with an average
composition.
##STR00004##
Bonding of BBB-HB-PE with AI
[0081] The present BBB-HB-PE compounds serve as delivery systems
for the AI. The AI is either bonded to the BBB-HB-PE polymer
through end groups by a readily cleavable bond at the site of use
or is encapsulated in a host-guest complex within the BBB-HB-PE
polymer. As used herein "associated with" means that the active
ingredient (AI) can be physically encapsulated within the HB-PE,
dispersed partially or fully throughout the HB-PE, or attached or
linked to the HB-PE or any combination thereof, whereby the
attachment or linkage is by means of covalent bonding, hydrogen
bonding, adsorption, absorption, metallic bonding, van der Walls
forces or ionic bonding, or any combination thereof. When the AI is
encapsulated in the HB-PE, it can be "associated with" the HB-PE by
covalent, coulombic, hydrophobic, or chelation type association
between the AI and moieties located within in the HB-PE such as
--OH or C(O)OH moieties.
[0082] HB-PE (a class of dendritic polymers) does not possess a
defined void volume, in contrast to dendrimers which have a defined
void volume (another class of dendritic polymers). BBB-HB-PE can
therefore release an encapsulated AI more easily. A preferred
bonding between the AI and BBB-HB-PE is an ester linkage, which can
be hydrolyzed by an esterase to release the AI. These ester
linkages are formed from acids and alcohols such as found as end
groups in the BBB-HB-PE described in Schemes 1 and 2 above.
[0083] Carbonyls such as ketones and aldehydes can be bound with
glycols such as glycerol through terminal groups on the BBB-HB-PE
to form dioxolanes. The double and triple bonds of an AI can be
bound by several techniques: reversible Diels Alder reaction with
furan end groups on the BBB-HB-PE; click chemistry with triazole
end groups on the BBB-HB-PE; or Michael addition with amine end
groups on the BBB-HB-PE. Especially preferred are those AIs that
have carboxylate, hydroxyl or amine groups to covalently bond to
the BBB-HB-PE. As will be appreciated, many such AI exist. Some AIs
that are possible include insect repellants such as 2-undecanone,
and 2-tridecanone; plant hormones such as 1-naphthalene acetic acid
and auxin; herbicides such as glyphosate (Roundup.RTM., trademark
of Monsanto) and 2, 4-D; NSAIDs such as naproxen and ibuprofen; the
anti-acne drug salicylic acid; antibiotics such as the penicillin
and related antibiotics, gentamycin, and neomycin;
anti-inflammatories such as hydrocortisone; antifungals such as
fluconazole; disinfectants such as ticlosan; analgesics such as
capsaicin; transdermal drugs such as testosterone; vitamins such as
vitamin A and vitamin D; veterinary drugs such as diclofenac,
nystatin, surolan, and liothyronine; and many others. The chemical
structures of several of these compounds are given below showing
their amine, carboxylic acid and hydroxyl reactive functional
groups through which they can be covalently bonded to the
BBBV-HB-PE for controlled delivery.
##STR00005## ##STR00006##
BBB-HB-PE Release of AI
[0084] For the AI to release from the BBB-HB-PE polymer, the
covalent bonds with the BBB-HB-PE are broken by hydrolysis or
enzymatic bond scission. If the AI is encapsulated in the
BBB-HB-PE, it can be released over time by diffusion or by
hydrolysis or enzymatic bond scission.
[0085] When hydrolysis is by an acid to cause the release of the AI
from the BBB-HB-PE polymer, the pK.sub.a of the acid in the
formulation or available in the environment (such as soil) is
important. If a strong acid, such as HCl (pK.sub.a=-8) or p-TSA
(pK.sub.a=-2.8) is used, the AI is released rapidly. Phytic is also
a strong acid (pK.sub.a=1.8) and has 6 phosphate groups where each
first proton of each ester group has that pK.sub.a of 1.8. Other
suitable acids are: oxalic (pK.sub.a=1.2), taurine (pK.sub.a=1.5),
pyruvic (2.4), alanine (pK.sub.a=2.3), methylglycine
(pK.sub.a=2.2), cysteic (pK.sub.a=1.3), maleic (pK.sub.a=1.8),
aspartic (pK.sub.a=2.0), threonine (pK.sub.a=2.1), proline
(pK.sub.a=2.0), trans-4-hydroxyproline (pK.sub.a=1.8), glutamic
(pK.sub.a=2.1), betaine (pK.sub.a=1.8), picolinic acid
(pK.sub.a=1.0), nicotinic (pK.sub.a=2.2), cis-aconitic
(pK.sub.a=2.0), lysine (pK.sub.a=2.2), arginine (pK.sub.a=1.8),
phenylglycine (pK.sub.a=1.8), and homocystine (pK.sub.a=1.6). These
acids are also biodegradable for their use as a catalyst to release
AI. Thus strong acids with a pK.sub.a of from about -8 to about 2.2
will cause the release of the AI from the BBB-HB-PE. These strong
acids catalyze the hydrolysis, including hydrolysis of the ketal,
thereby releasing the AI.
[0086] To control the rate of release of AI, the following
parameters can be adjusted in the formulation: 1) the level of acid
catalyst present--increasing the level will increase the rate of
release; 2) the pK.sub.a of the acid catalyst--the lower pK.sub.a
gives faster rates; 3) the MW of the BBB-HB-PE--the lower MW will
release faster; 4) the composition of the polymer--more hydrophobic
monomers give slower rates; 5) the amount of water in the
formulation; or 6) the temperature of the formulation. Typically,
the AI is released over about 1 to about 7 days.
Formulations
[0087] Because these compositions of BBB-HB-PE compounds with AI
are delivery systems, the possible uses are broad so long as the AI
can be covalently bound to or encapsulated in the BBB-HB-PE. The
release of the AI will depend on the application and formulation as
it requires an acid or enzyme or time if by diffusion. As will be
known by one skilled in the art of sustained release delivery
systems, the formulations may be aqueous-based or non-aqueous or a
combination and may be used as foams, gels, suspensions, emulsions,
microemulsions, emulsifiable concentrates, ointments, sprays,
granules, powders, and the like. These formulations may include
various rheological agents, surfactants, dispersants, excipients,
buffers, and other inert ingredients for the intended application
and utility. The concentration of the AI in the BBB-HB-PE can be
controlled by the process used to make the composition and the
concentration can be measured. Thus the amount of AI for the
various uses can be tuned by the polymer. If the formulation is
applied to a skin surface of an animal or human, such as an insect
repellant, the acid on the skin may be sufficient to begin the
release of the AI from the BBB-HB-PE. Strong acid, as discussed
above, can serve to catalyze the release of the AI. Such acid, as
phytic acid, may be present in the soil if the formulation is used
as a pesticide, fungicide or herbicide. Thus an enzyme or acid can
be present in the formulation or in situ at the place of
application of the formulation to promote the release of AI from
the BBB-HB-PE polymer.
[0088] The formulations are applied in the usual manner for the
intended utility.
Utility
[0089] Some examples of such uses are numerous and varied,
including but not limited to sustained release agents for insect
repellants, various agents for dermal application, for pesticides
for animals and humans, and other uses and AI mentioned herein.
[0090] Wound healing often involves antibiotics and/or
anti-inflammatory agents as AI, which can be delivered by the
present BBB-HB-PE. The formulation is mostly oil based emollients
or ointments with such AIs as gentamycin, neomycin, polymyxin B, or
cortisone derivatives; preferred as a general antibiotic for wound
healing are gentamycin and neomycin.
[0091] Transdermal drugs are designed to deliver therapeutic agents
across the skin and may have a penetration accelerator such as DMSO
used to enhance delivery. Some examples of AIs with the BBB-HB-PE
for this use are scopolamine, clonidine, estradiol,
estradiol/norelgestromin, ethynyl-estradiol/norelgestromin,
nicotin, testosterone, lidocaine, oxybutyrin, methylphenidate,
selegiline, rotigotine, and rivastigmine.
[0092] Topical drugs for dermatological or venereal diseases are
formulated as tinctures, creams, or ointments. Some AIs with the
BBB-HB-PE for dermatological disorders are hydrocortisone,
fulconazole, capsaicin, vitamin A, and vitamin D. For venereal
diseases some AIs with the BBB-HB-PE are metronidazole, nystatin,
podofilox, and imiquimod. Preferred topical analgesics are
capsaicin and salicylic acid; topical NSAIDs are ketoprofen and
ferulic acid. A topical anti-inflammatory drug is hydrocortisone
derivatives.
[0093] Antibiotics are often desired to be released over time,
sometimes after an initial dose as a starting treatment. Suitable
as such AI with a BBB-HB-PE is, for example, penicillin,
ampicillin, amoxicillin, or bacampicillin.
[0094] Antitumor agents can be released over time to treat tumors.
Such agents are organo-platinum and other organo-metals known for
this purpose.
[0095] Cosmetics are able to be delivered using BBB-HB-PE where the
AI is used for various treatments such as oil removal or acne
control where AI is aspirin, anti-inflammatory or antibiotics used
as discussed for topical drugs. All these AIs can be formulated as
for topical drugs discussed before.
[0096] Insecticides and herbicides that are mixed with the soil and
where the AI would be withdrawn from the soil (no carryover to the
next crop) contain organo-phosphates and organo-carbamates mixed
with water or organic solvents to deliver to plants. If these AIs
have a hydroxyl or carboxylic acid group that can form esters, they
could link to the BBB-HB-PE matrix. Some AIs for insecticides are
nicotine derivatives. Insect repellants are also included. Such
insects are ticks, fleas, cockroaches, biting flies, mosquitoes,
horse flies, deer flies, black flies, gnats, no-seeums and
chiggars. UD, 2-undecanone, is approved as a mosquito repellant.
This present 2-undecanone as the AI in a BBB-HB-PE degrades by
hydrolysis in the presence of low levels of acid such as p-TSA,
phosphoric acid, or phytic acid. Some AIs for herbicides are
atrazine, 2,4-D esters, and glyphosate. A miticide AI is formic or
oxalic acid.
[0097] Plant growth regulators are usually inorganic compounds or
very unique structures that work at low concentrations. Some AIs
for plant growth regulation are auxin, cytokinin, gibberellic acid,
and naphthalene acetic acid. For example, the naphthalene acetic
acid polymer degrades effectively using one of several enzymes,
releasing the active, naphthalene acetic acid.
[0098] Veterinary drugs are usually special formulations of
combined ingredients, often as ointments or pour-ons. Some AIs for
veterinary use are Derma-Vet cream, diclofenac cream, vetropolycin,
nystatin, neomycin sulfate, thiostrepton, triamcinolone acetonide,
surolan drops, ivermectin pour-on, dectomax pour-on, hibitane
ointment, liothyronine, and various transdermal drugs.
[0099] Disinfectants and sanitizers are used as wipes, liquids,
gels, and sprays to rid a surface of microbes. Some AIs for
disinfectants and sanitizers are triclosan and chlorhexidine
gluconate; preferred is triclosan.
[0100] Thus this invention provides BBB-HB-PE polymers preferably
made from glycerol and (adipic acid and/or succinic acid). These
polymers are then reacted to covalently attach an AI that can react
with either the alcohol end group or an acid end group (depending
on whether the glycerol or the acid was used in excess) or the AI
is encapsulated within the polymer. To release the AI over time
from the polymer, various strong acids can be used, some of which
are found naturally in the site for use of the BBB-HB-PE-AI, such
as phytic acid in soil, or can be added to the formulation when
used, or various enzymes can be present or added to the
formulation. The rate of time release of the AI can be controlled
by, for example, varying the level of hydrolysis catalyst in the
formulation. Lower levels release the AI more slowly. Since release
occurs by hydrolysis, the level of water in the formulation impacts
the rate, lower levels of water causing slower release. Decreased
temperature would also cause slower release. These compositions can
be designed to achieve complete release of the AI in times as short
as one day to times as long as several months.
[0101] The invention will be further clarified by a consideration
of the following examples, which are intended to be purely
exemplary of the present invention. The numbered examples are
within the scope of this invention. The lettered examples are
comparative.
Materials and Methods:
[0102] The Following General Methods were Used in the Following
Examples.
[0103] .sup.13C NMR spectroscopy of the samples was done as
follows: The sample was dissolved in DMSO-d6 using a Varian Inova
500 NMR spectrometer operating at 125.7 MHz.
[0104] Size Exclusion Chromatograms (SEC) were obtained using a
Waters 1525 chromatograph equipped with dRI and a Wyatt Dawn Helios
II multiangle light scattering detector. The mobile phase was THF
at 1 mL/min.
[0105] Two PLgel mixed E columns from Agilent were used for the
separation
EXAMPLES
Example A (Comparative)
Preparation of HB-PE from Trimethylolpropane (TMP) and Adipic Acid
(AA)
##STR00007##
[0107] Into a dry 100 mL, three-necked, round-bottomed flask fitted
with a magnetic stirring bar and a condenser bearing a gas-inlet
tube, was placed 5.02 g (37.4 mmol) of trimethylolpropane (TMP),
4.08 g (27.7 mmol) of adipic acid, and 0.24 g (1.39 mmol, 2.5 mol %
of the reactive carboxyl groups present) of p-TSA. The flask was
mounted in an oil bath maintained at 140.degree. C. and the mixture
was stirred. The reaction was driven to completion by purging the
reaction vessel with a continuous stream of nitrogen to remove
water. A FIB-PE of M.sub.w of 7,000-8,000 was obtained after three
hrs reaction time. The product was characterized by IR, .sup.1H,
.sup.13C NMR and SEC, provides the following spectra:
[0108] .sup.1H NMR (500 MHz, THF-d8) .delta.(ppm) monomers: TMP
3.46 (s, --OCH.sub.2), 1.31 (q, --CH.sub.2), 0.83 (t, --CH.sub.3);
adipic acid (AA) 1.58 (mult., --CH.sub.2), 2.22 (mult.,
--CH.sub.2).
[0109] .sup.13C NMR (75.5 MHz, THF-d8) .delta.(ppm) monomers: TMP
8.0 (--CH.sub.3), 23.2 (--CH.sub.2), 42.0 (--C--), 65.1
(--OCH.sub.2); AA 174.5 (--C.dbd.O), 34.1 (--CH.sub.2), 24.7
(--CH.sub.2).
[0110] The reaction product showed expected distribution of mono-
(M), di- (D) and tri- (T) functionalized molecules, the NMR
assignments of which are as follows.
[0111] .sup.1H NMR (500 MHz, THF-d8), .delta.(ppm): 4.00 (M,
--OCH.sub.2 ester), 3.92 (D, --OCH.sub.2 ester), 3.58 (free TMP,
--OCH.sub.2 alcohol), 3.49 (M, --OCH.sub.2 alcohol), 3.35 (D,
--OCH.sub.2 alcohol), 1.34 (q, --CH.sub.2 free TMP), 1.23 (q,
--CH.sub.2 M), 1.18 (q, --CH.sub.2 D), 0.78 (mult., --CH.sub.3),
adipate ester 2.27 (mult., --CH.sub.2), 1.57 (mult.,
--CH.sub.2).
[0112] .sup.13C NMR (75.5 MHz, CDCl.sub.3), .delta.(Ppm): 7.6
(--CH.sub.3), 22.6 (--CH.sub.2), 43.0 (free TMP, --C--), 42.8 (M,
--C--), 42.4 (D, --C--), 40.8 (T, --C--), 62 to 66 (--OCH.sub.2),
adipate ester, 174.2 (free acid, --C.dbd.O), 174.1 (M, --C.dbd.O
ester), 173.7 (D, --C.dbd.O ester), 173.2 (T, --C.dbd.O ester),
34.0 (--CH.sub.2), 24.6 (--CH.sub.2).
[0113] SEC (in THF): M.sub.n=1068, M.sub.w=8600, PDI=8.1;
Refer to Example E below that provides the degradation
information.
Example B (Comparative)
Preparation of HB-PE from Glycerol and Adipic Acid Using p-TSA as
Catalyst
[0114] Synthesis of a HB-PE from glycerol and AA with p-TSA
catalyst was performed by the following procedure: 5 g of glycerol,
5.95 g of AA and 0.05 g of p-TSA (0.5 wt %) were added to a 100 mL
three-necked, round-bottomed flask and heated to 150.degree. C. for
about 12 hrs. The reaction mixture was blanketed with nitrogen. A
clear semi-solid gel was obtained which was not soluble in any of
the usual solvents for this type of polyester. This result led to
the conclusion that side reactions occurred causing the HB-PE to
gel.
Example 1
Preparation of BBB-HB-PE from Glycerol and Adipic Acid Using
Dibutyltin Oxide as Catalyst
##STR00008##
[0116] The polyester was generated by melt polymerization at
150.degree. C. with dibutyltin oxide as catalyst and driven to
completion by purging the reaction vessel with a continuous stream
of nitrogen to remove water. An HB-PE of stoichiometry
[--OH]/[--COOH] equal to 2.0 was achieved by using 23.8 g of AA, 20
g of glycerol and 0.219 g of dibutyltin oxide (0.5 wt %) that were
added to a 250 mL three-necked, round-bottomed flask and heated to
150.degree. C. for about 12 hrs. The reaction mixture was blanketed
with nitrogen. Samples of the reaction mixture were removed
periodically and analyzed according to the general procedure
above.
[0117] The resulting polymer was a viscous clear colorless liquid
with a degree of branching (determined from .sup.13C NMR) of
15%-20%. The conversion was about 80% by weight. The HB-PE
structure was characterized using FT-IR, NMR and SEC;
[0118] M.sub.w=2,600;
[0119] .sup.1H NMR (.delta., DMSO-d6) 1.54 (OCOCH.sub.2CH.sub.2),
2.24 (OCOCH.sub.2CH.sub.2), 3.33-5.21 (all glycerol resonances
including those of the glycerol esters and unsubstituted
alcohols);
[0120] .sup.13C NMR (.delta., DMSO-d6) 23.92 (OCOCH.sub.2), 33.17
(OCOCH.sub.2CH.sub.2), 59.69-65.67 (methylene carbon), 68.94-75.69
(methine carbon), 172.27-172.95 (carbonyl ester group);
[0121] IR (ATR, cm.sup.-1) 3424 (O--H stretch), 2950, 2876 (C--H
saturated), 1734 (C.dbd.O ester), 1175 (C--O stretch).
Example 2
Preparation of BBB-HB-PE from Glycerol and Succinic Acid (SA) Using
Dibutyltin Oxide Catalyst
##STR00009##
[0123] An HB-PE of stoichiometry [--OH]/[--COOH] equal to 2.0 was
achieved by using 10 g of glycerol, 9.62 g of SA, and 0.098 g
dibutyltin oxide (0.5 wt %) that was added to a 100 mL
three-necked, round-bottomed flask and heated to 150.degree. C. for
about 12 hrs. The reaction mixture was blanketed with nitrogen. An
opaque white colored semi-solid was obtained. The conversion was
about 75% by weight. The HB-PE structure was characterized by
FT-IR, NMR and SEC:
[0124] M.sub.w=2,200;
[0125] .sup.1H NMR (.delta., DMSO-d6) 2.57 (OCOCH.sub.2), 3.34-5.24
(all glycerol resonances including those of the glycerol esters and
unsubstituted alcohols);
[0126] .sup.13C NMR (.delta., DMSO-d6) 28.51 (OCOCH.sub.2),
59.37-65.82 (methylene carbon), 68.94-75.82 (methine carbon),
171.82 (carbonyl ester group);
[0127] IR (ATR, cm.sup.-1) 3462 (O--H stretch), 2952, 2873 (C--H
saturated), 1736 (C.dbd.O ester), 1175 (C--O stretch).
Example 3
Preparation of BBB-HB-PE from Glycerol and Adipic Acid (AA) Using
Dibutyltin Oxide Catalyst
##STR00010##
[0129] An HB-PE of stoichiometry [--COOH]/[--OH] equal to 2.0 was
achieved by using 12.9 g of AA, 2.5 g of glycerol and 0.075 g of
dibutyltin oxide (0.5 wt. %) that was added to a 100 mL
three-necked, round-bottomed flask and heated to 150.degree. C. for
about 12 hrs. The reaction mixture was blanketed with nitrogen. The
crude product was a white, opaque, waxy solid. The final product,
as a solution in the minimum amount of methanol, was purified by
precipitation from DI water. After purification a clear viscous
liquid was obtained. The HB-PE structure was characterized using
FT-IR, NMR and SEC:
[0130] M.sub.w=4,000;
[0131] .sup.1H NMR (.delta., DMSO-d6) 1.50-1.49
(OCOCH.sub.2CH.sub.2), 2.17-2.21 (OCOCH.sub.2CH.sub.2), 2.29
(OCOCH.sub.2CH.sub.2), 4.08-4.26 (all glycerol ester
resonances);
[0132] .sup.13C NMR (.delta., DMSO-d6) 23.73-24.11
(OCOCH.sub.2CH.sub.2), 32.92-33.43 (OCOCH.sub.2CH.sub.2 and
HOOCCH.sub.2CH.sub.2), 61.88 (methylene carbon from glycerol after
forming ester), 68.84 (methine carbon from glycerol after forming
ester), 172.12-172.47 (carbonyl ester group), 174.45 (carbonyl acid
group);
[0133] IR (ATR, cm.sup.-1) 3225 (O--H stretch), 2953, 2873 (C--H
saturated), 1739 (C.dbd.O ester), 1708 (C.dbd.O acid) 1171 (C--O
stretch).
Example 4
Binding of the UD, as AI, to the BBB-HB-PE
[0134] When the alcohol end groups of the BBB-HB-PE polymer of
Example 1 were reacted with UD, a ketal was formed. A majority of
the hydroxyl functionality on the HB-PE polymer was converted to
ketals. Because of the distribution of the hydroxyl structures on
the HB-PE, there was a distribution of ketal structures formed as
described above.
[0135] Part A: Ketalization of UD to HB-PE (Glycerol-AA)
[0136] Into a dry 100 mL two-necked, round-bottomed flask fitted
with a magnetic stirring bar and vacuum adapter was placed 10.46 g
of glycerol-AA (89.85 mmol 011; prepared in Example 1), 7.65 g
(89.85 mmol) of UD and 2 mg of p-TSA. The flask was mounted in an
oil bath maintained at 120.degree. C. and the mixture was stirred
for 30 mins, after which vacuum was applied to the reaction
apparatus. The reaction was continued with stirring; under vacuum
for 4 hrs. A viscous, clear, light yellow liquid was obtained. The
conversion was about 77%. The molecular weight of the polymer
increased dramatically from 2,600 of the starting HB-PE to 5,400
for the ketalized HB-PE. The .sup.13C NMR spectrum showed a
resonance from the ketal structure at about 110 ppm.
[0137] Free UD remained after the reaction for which excess of UD
was used. This excess UD is beneficial in that it is potentially
encapsulated by the HB-PE, providing an initial burst of protection
followed by a slower time-release of UD from the HB-PE. The level
of UD that can be bound to the HB-PE as a function of molecular
weight (MW) is shown in Table 1 below.
TABLE-US-00001 TABLE 1 MW of MW of Structure Polymer UD/Molecule
Polymer + UD Wt % UD G-UD 92 1 244 63 G2A 290 2 596 51 G3A2 491 2.5
873.5 44 G4A3 692 3 1151 40 G5A4 893 3.5 1428.5 37 G6A5 1094 4 1706
36 G7A6 1295 4.5 1983.5 35 G8A7 1496 5 2261 34 G9A8 1697 5.5 2538.5
33 G10A9 1898 6 2816 33 G11A10 2099 6.5 3093.5 32 G12A11 2300 7
3371 32
In Table 1, column 1 for Structure means the following: [0138]
G-UD=glycerol ketal; G2A=(glycerol).sub.2-AA;
G3A2=(glycerol).sub.3-(AA).sub.2 oligomer;
G4A3=(glycerol).sub.4-(AA).sub.3 oligomer;
G5A4=(glycerol).sub.5-(AA).sub.4 oligomer;
G6A5=(glycerol).sub.6-(AA).sub.5 oligomer;
G7A6=(glycerol).sub.7-(AA).sub.6 oligomer;
G8A7=(glycerol).sub.8-(AA).sub.7 oligomer;
G9A8=(glycerol).sub.9-(AA).sub.8 oligomer;
G10A9=(glycerol).sub.10-(AA).sub.9 oligomer;
G11A10=(glycerol).sub.11-(AA).sub.10 oligomer;
G12A11=(glycerol).sub.12-(AA).sub.11 oligomer.
[0139] These results indicate that the lower MW HB-PE polymer,
about 800 to about 1,000, attach the most UD. This means G5A4 and
G6A5 oligomers have a UD loading of about 36 wt %.
[0140] Part B: Ketalization of UD to HB-PE (Glycerol-SA)
[0141] The synthesis of the glycerol-SA HB-PE in the neat condition
produced a very viscous polymer to which UD could not be mixed even
at 120.degree. C. Therefore, the synthesis was done in solution.
The HB-PE (glycerol-SA) (2 g, 19.52 mmol --OH end group) and UD
(1.08 g, 9.76 mmol) with 2 mg of p-TSA in 20 mL dioxane solution
were added into a 100 mL 2-necked, round-bottomed flask fitted with
a magnetic stirring bar, N.sub.2 inlet and outlet, a small Soxhlet
extractor containing anhydrous 4 .ANG. molecular sieves, and a
condenser. The gas flow was started. The reaction mixture was
heated to 120.degree. C. and the refluxed dioxane was allowed to
return to the flask through molecular sieves to remove the water
by-product. The reaction mixture was stirred with heating for 5
hrs. Final product was precipitated from DI water. After drying, a
viscous clear yellow liquid was obtained. The product was
characterized by NMR, SEC and IR. The molecular weight of the
polymer increased dramatically from 3,300 of the starting HB-PE to
5,400 for the ketalized HB-PE. The .sup.13C NMR spectrum showed a
resonance at 110 ppm consistent with a ketal structure.
Example C (Comparative)
Binding of UD to the HB-PE Using Only the Residual Dibutyltin Oxide
Catalyst
[0142] 5.85 g (34.36 mmol) of UD and 8 g (68.72 mmol --OH) of
glycerol-AA were added into a 100 mL two-necked, round-bottomed
flask. The flask was mounted in an oil bath maintained at
140.degree. C. After 5 hrs of reaction, a white viscous material
was obtained. SEC chromatograms showed no evidence for the
formation of any ketal, and also .sup.13C NMR showed no ketal
resonance at 110 pm.
Example 5
Binding of NAA, as AI, to the Glycerol-AA HB-PE
[0143] NAA was covalently bonded to a HB-PE with alcohol end groups
using an esterification procedure similar to that with glycerol-AA
of Example 1. The reaction was driven to completion by purging the
reaction vessel with a continuous stream of nitrogen to remove
water. The HB-PE (glycerol-AA) (2.7 g, 23.19 mmol --OH end group)
and NAA (5.18 g, 27.83 mmol) with 2 mg of p-TSA were added into a
100 mL two-necked, round-bottomed flask fitted with a magnetic
stirring bar. The flask was mounted in an oil bath maintained at
140.degree. C. and the mixture was stirred for 12 hrs. The excess
of NAA was removed by precipitation from mixture of ethyl acetate
and hexane in 1.5:8.5 (v). A very viscous brown colored liquid was
obtained. .sup.13C NMR resonances of the carbonyl carbon of NAA at
170 to 174 ppm were consistent with the NAA ester. The NAA acid
carbonyl resonance at about 177 ppm was not present after
purification.
Example 6
Binding of Salicylic Acid, as AI, to BBB-HB-PE
[0144] The carboxylic acid functionality of salicylic acid was
esterified with an HB-PE possessing --OH end groups. HB-PE
(glycerol-AA) (10 g, 85.9 mmol --OH end group; prepared in Example
1) and salicylic acid (11.86 g, 85.9 mmol) with 20 mg of p-TSA in
140 mL triglyme solution were added into a 250 mL three-necked,
round-bottomed flask fitted with a magnetic stirring bar, N.sub.2
purge, a Soxhlet extractor containing 40 g of anhydrous 4 .ANG.
molecular sieves, and a condenser. The gas flow was started. The
reaction mixture was heated to 150.degree. C. and the refluxed
triglyme was allowed to return to the flask through molecular
sieves to remove the water by-product. The reaction mixture was
stirred with heating for 12 hrs. After the reaction was complete,
hexane was used to remove the triglyme solvent; the excess
salicylic acid was removed by precipitation from diethyl ether. A
viscous, clear yellow liquid was obtained. The product was
characterized by NMR, SEC and IR. The molecular weight of the
polymer increased dramatically from 1,500 of the starting HB-PE to
3,200 for the HB-PE attached to salicylic acid.
[0145] .sup.13C NMR resonances of the carbonyl carbon of salicylic
acid at 169 ppm showed that the salicylic acid ester was formed.
The acid peak, around 175 ppm, was gone after purification.
Example 7
Binding of Ferulic Acid, as AI, to the BBB-HB-PE
[0146] Ferulic acid is covalently bonded to the BBB-HB-PE by
esterification using the methodology of Example 5. The BBB-HB-PE of
Example 1 and ferulic acid are melt esterified using p-TSA as
catalyst by adding the reactants to a 100 mL two-necked,
round-bottomed flask fitted with a magnetic stirring bar. The flask
is mounted in an oil bath maintained at 140.degree. C. and the
mixture is stirred for 12 hrs. The reaction is driven to completion
by purging the reaction vessel with a continuous stream of nitrogen
to remove water. Excess ferulic acid is removed by precipitation
using a solvent-non-solvent mixture, for example ethyl
acetate/hexane.
Example 8
Binding of Liothyronine, as AI, to the BBB-HB-PE
[0147] Liothyronine, a transdermal veterinary drug, has carboxylic
acid functionality, and is an AI. This AI can be attached to the
BBB-HB-PE with acid end groups (prepared in Example 1) in a fashion
similar to that done in Example 5. It is covalently bonded to the
HBP by, for example, by melt esterification using p-TSA as
catalyst. The reactants are added to a 100 mL two-necked,
round-bottomed flask fitted with a magnetic stirring bar. The flask
is mounted in an oil bath maintained at 140.degree. C. and the
mixture is stirred for 12 hrs. The reaction is driven to completion
by purging the reaction vessel with a continuous stream of nitrogen
to remove water. Excess liothyronine is removed by precipitation
using a solvent/non-solvent mixture, for example ethyl
acetate/hexane.
Example D (Comparative)
[0148] The products of Example 1, combined with UD by the method of
Example 4, were evaluated for their degradation. Lipase enzymes
were ineffective in hydrolyzing the ketal and releasing UD as
determined by SEC analysis.
[0149] Chemical hydrolysis with a weak acid like acetic acid
(pK.sub.a=4.8) was also ineffective. For example, a mixture of 1 mL
of THF:glacial acetic acid in a 9:1 ratio with 0.1 mL DI water was
combined with about 20 mg of HB-PE-UD. The cloudy suspension was
stirred at 37.degree. C. in a water bath for 4 days. SEC analysis
of the starting materials and the degradation solution showed no
change in the chromatograms indicating negligible molecular weight
loss or release of 2-undecanone.
[0150] This experiment was repeated with a mixture of 1 mL buffer
solution of either pH=3, 4, or 5 with a few drops of THF solvent
which was combined with about 20 mg of HB-PE-UD. The cloudy
suspension was stirred at 37.degree. C. in a water bath for 4 days.
SEC analysis of starting materials and degradation solution showed
no discernable change in the chromatograms indicating negligible
molecular weight loss or release of 2-undecanone.
Example 9
Release of AI, UD, from HB-PE
[0151] When strong acids, such as HCl (pK.sub.a=-8); p-TSA
(pK.sub.a=-2.8) and phytic acid (pK.sub.a=1.8) were used, they were
very effective in releasing UD. The release rate can be varied from
hours to weeks by varying the level of strong acid in the
formulation. For example, when no acid is present in the
formulation, UD is released over a period of months. NMR and GC-MS
verified that UD was released.
[0152] Degradation experiments were conducted with a mixture of
glycerol-AA-UD (from Example 4A) with glycerol in a 1:1 mole ratio,
and either a 50% aqueous phytic acid solution or solid phytic acid
was added. The degradation solutions were analyzed by NMR, GC-MS
and SEC. The following table shows degradation data from NMR and
molecular weight changes from SEC at 15% and 2% phytic acid vs.
time. Release of UD was complete after 12 hrs in 15% phytic acid
solution at physiological temperature (37.degree. C.).
[0153] These data show that both temperature and the level of acid
affect the degradation rate. Degradation was much faster at
physiological temperature than at room temperature (about
21.degree. C.). Degradation in 15% phytic acid was much faster than
3% phytic acid. In Table 2 the degradation conditions were about
100 mg of a composition of UD in HB-PE was mixed with glycerol in
1:1 wt ratio and phytic acid (50% water solution) was added.
TABLE-US-00002 TABLE 2 .sup.13C NMR data % wt of Degradation Time
M.sub.w Weight Weight Free Composition phytic acid temp (.degree.
C.) (hrs) (kDa) Bound UD % UD % Glycerol- 0 37 0 4.7 11.1 0.0 AA-UD
15 2 3.9 9.6 2.9 4 3.9 8.5 3.8 6 2.3 7.4 5.3 24 2.1 0.0 12.2 48 1.4
0.0 11.3 21 24 3.3 8 3 2 37 2 4.1 7 1.2 4 4 6.5 1.6 6 2.7 N/A N/A
24 2.4 3.6 4.5 48 2.1 1.8 5.4 21 24 3.7 N/A N/A
Example 10
Release of NAA, as AI, from HB-PE from Glycerol and AA
[0154] The products of Example 5 were evaluated for their
degradation. NAA was released both enzymatically and also with the
acid catalysts of Example 9. Enzymatic degradation was much faster
than acid catalyzed degradation. GC-MS and SEC verified those
conclusions.
[0155] Enzymatic degradation experiments were conducted with
mixture of a composition of glycerol-AA-NAA or glycerol-SA-NAA,
enzymes and buffer solution (pH=5 and 7.4). Esterase from porcine
liver, Lipase from Aspergillus niger, and Candida antarctica lipase
B (CALB) were used in enzymatic degradation. The degradation
significantly reduced the M.sub.w of the polymer and released NAA
within a matter of one to two days.
Example E (Comparative)
Release of NAA from a TMP-AA HB-PE
[0156] NAA was covalently bonded to the HB-PE polymer from Example
A. The synthesis procedure was the same as that for binding NAA to
HB-PE of glycerol-AA in Example 5. The HB-PE (TMP-AA) (3.23 g, 22.3
mmol --OH end group) and NAA (6.23 g, 33.45 mmol) were added into a
100 mL two-necked, round-bottomed flask fitted with a magnetic
stirring bar. The flask was mounted in an oil bath maintained at
140.degree. C. and the mixture was stirred for 12 hrs. The excess
NAA was removed by precipitation from mixture of methanol. A very
viscous, light yellow colored liquid was obtained. .sup.13C NMR
resonances of the carbonyl carbon of NAA at 170-173 ppm showed that
NAA ester was formed, and also peaks from phenyl group at 123-134
ppm were present. The acid peak at 177 ppm was gone after
purification. This material did not degrade under enzymatic
conditions (enzymes used were esterase, lipase and CALB in buffer
solution with pH=6.5, 7.4 and 9). SEC chromatography showed
negligible molecular weight loss, and NMR confirmed insignificant
release of NAA under enzymatic degradation conditions. The
following table is comparative data showing the rate of polymer
degradation for HB-PEs of TMP-AA and glycerol-AA. The release of
NAA was confirmed by NMR and GC-MS.
[0157] Degradation conditions used in Table 3 were 2 mL of 50 mM
pH=7.4 phosphate buffer solution added to about 25 mg of the
composition and 2.5 mg of CALB, and stirred at physiological
temperature (37.degree. C.).
TABLE-US-00003 TABLE 3 Material composition Time(days) Mw (kDa)
TMP-AA-NAA 0 7.7 (813-49) 7 7.5 28 7.2 Glycerol-AA-NAA 0 7.3
(856-85E) 3 4.5 16 2.1
[0158] These results show that TMP-AA-NAA does not degrade and
release the NAA as desired whereas glycerol-AA-NAA does release
NAA.
Example 11
Production of HBPE Networks
[0159] There are a number of methods whereby HBPEs can be formed
into a network such that they can be fabricated into films, sheets
or coatings. For example, networks are formed when the
stoichiometry of the reactants are within the gel window as taught
by the BMNLP methodology. In one case, a network HBPE polymer was
formed using trimethylolpropane (TMP) and adipic acid with
functional group stoichiometry [--OH]/[--COOH]=1.5. BMNLP
methodology teaches that this is within the gel window. Typical
synthesis conditions are the following:
[0160] Into a 250-mL three-necked, round-bottomed flask equipped
with a mechanical stirrer and a Soxhlet extractor filled with 40 g
of 4 .ANG. molecular sieves and fitted with a condenser bearing a
gas-inlet tube, was placed a solution of 10 g (74.5 mmol TMP, 223.6
mmol of --OH) of trimethylolpropane, 10.89 g (74.5 mmol AA, 149
mmol of --COOH) of adipic acid and 0.5 g of p-TSA catalyst in 90 mL
of anhydrous THF. The solution was stirred at solvent reflux with
the distillate being cycled through the sieves to remove water
formed as the esterification proceeded. After 20 hrs of stirring,
the polymer gelled. It was a transparent, soft and rubber-like gel
which was not soluble in any of the usual solvents.
Example 12
HBPE of Glycerol and Oxalic Acid
[0161] Oxalic acid was copolymerized with glycerol to yield a HBPE
by the following method: 4 g of glycerol was added to a stirred
three-necked, round-bottomed 100 mL flask placed in a warm water
bath and 8 mL dioxane was added to dissolve the glycerol. The flask
was then immersed in an ice water bath and 4.98 g of oxalyl
chloxide was added dropwise into the cold glycerol/dioxane
solution. A nitrogen gas stream was used to purge the evolved HCl
from the headspace of the vessel. The reaction was stopped after 3
hrs, the dioxane and residual HCl were roto-evaporated at
50.degree. C. using a warm water bath. A clear viscous liquid was
obtained. NMR and GPC confirmed the formation of a glycerol-oxalic
acid HBPE.
[0162] The glycerol-oxalic acid HBPE was degraded in water using
the following procedure: 1 mL of DI water was combined with 40 mg
glycerol-oxalic acid HBPE. The cloudy suspension was stirred
overnight at ambient temperature. GPC and NMR analysis showed that
the HBPE degradation was complete after 20 hrs, releasing oxalic
acid and glycerol.
Example 13
Binding of Triclosan, as AI, to the BBB-HB-PE
[0163] Triclosan was covalently bonded to a BBB-HB-PE with
carboxylic acid endgroups using the following procedure: A solution
of dicyclohexyl carbodiimide (DCC) (2.6 g, 12.6 mmol) and
1-dimethylaminopyridine (DMAP) (0.077 g, 0.63 mmol) in 100 mL of
THF was cooled to 0-5.degree. C. in an ice-water bath and the
hyperbranched polyester of glycerol and adipic acid with --COOH end
groups (2 g, 12.6 meq COOH) in about 20 mL of THF was added
dropwise. The reaction mixture was stirred at room temperature for
12 hrs and a white precipitate formed. Triclosan (3.65 g, 12.6
mmol) in 10 mL of THF was added at room temperature with stirring
and blanketed with a stream of nitrogen. The reaction mixture was
then refluxed for 12 hrs. The progress of the reaction was
monitored by taking aliquots at different intervals of time and
analyzing them by SEC. The crude reaction mixture was purified by
filtration to remove the dicyclohexylurea formed in the process,
then ultrafiltration was followed to remove excess triclosan and
other starting materials. The solvent in the ultrafiltration was a
mixture of methylene chloride and methanol in about 1:1 ratio with
the molecular weight cutoff for membrane of 1,000 Da. Purification
was accomplished after 3 ultrafiltration runs, followed by solvent
evaporation. The viscous product was analyzed by SEC, NMR and IR.
The SEC chromatogram of the resulting polymer showed that the
molecular weight of the polymer was not reduced through the
reaction chemistry. The .sup.13C NMR spectrum of the resulting
polymer indicated that triclosan was esterified to the HB-PE as
revealed by the O-aromatic resonances of free triclosan at 142.2,
147.5 and 150.5 ppm shifting to 142.2, 149.6 and 152.3 ppm,
consistent with the triclosan ester. The acid carbonyl resonances
of adipic acid also shifted upfield consistent with esterification.
Side reactions involving the DCC coupling agent were also observed.
This reaction was not optimized but demonstrated that it is
possible to bind triclosan with this chemistry.
[0164] Although the invention has been described with reference to
its preferred embodiments, those of ordinary skill in the art may,
upon reading and understanding this disclosure, appreciate changes
and modifications which may be made which do not depart from the
scope and spirit of the invention as described above or claimed
hereafter. Accordingly, this description is to be construed as
illustrative only and is for the purpose of teaching those skilled
in the art the general manner of carrying out the invention.
* * * * *