U.S. patent application number 14/975156 was filed with the patent office on 2016-04-14 for fiber comprising a biodegradable polymer.
The applicant listed for this patent is DSM IP Assets B.V.. Invention is credited to Astrid FRANKEN, George MIHOV, Jens Christoph THIES.
Application Number | 20160102176 14/975156 |
Document ID | / |
Family ID | 44343199 |
Filed Date | 2016-04-14 |
United States Patent
Application |
20160102176 |
Kind Code |
A1 |
FRANKEN; Astrid ; et
al. |
April 14, 2016 |
FIBER COMPRISING A BIODEGRADABLE POLYMER
Abstract
The present invention relates to a fiber comprising a
biodegradable polymer which undergoes dimensional change upon
injection in the human or animal body wherein the dimensional
change is a reduction of the surface area to volume ratio of a
factor 2 to 10. The fiber is sized for injection via a
pharmaceutical syringe needle having a bore of at least 25 Gauge.
The biodegradable polymer is an amorphous biodegradable polymer
selected from the group of poly-hex am ethylene carbonates or
polyesteramides. The amorphous biodegradable polymer is a
preferably a polyesteramide comprising alpha-amino acids, diols and
dicarboxylic acids as building blocks. The invention further
relates to the use of the fiber for the manufacturing of a
medicament for the treatment of ophthalmic diseases. The invention
also relates to a process for the manufacturing of the fiber
comprising the following process steps; a. extruding a
biodegradable polymer into a fiber fitting in a needle of at least
25 Gauge b. which while under tension is cooled below its glass
transition temperature such that the resultant fiber is
amorphous.
Inventors: |
FRANKEN; Astrid; (Echt,
NL) ; MIHOV; George; (Echt, NL) ; THIES; Jens
Christoph; (Echt, NL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
DSM IP Assets B.V. |
Heerlen |
NL |
US |
|
|
Family ID: |
44343199 |
Appl. No.: |
14/975156 |
Filed: |
December 18, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14115146 |
Feb 18, 2014 |
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PCT/EP2012/058036 |
May 2, 2012 |
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14975156 |
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Current U.S.
Class: |
514/772.3 ;
528/288 |
Current CPC
Class: |
D10B 2331/041 20130101;
D01F 6/82 20130101; D01F 1/10 20130101; A61K 9/0051 20130101; C08G
69/44 20130101; D10B 2401/12 20130101; A61K 47/34 20130101; D01F
6/625 20130101; A61K 9/70 20130101; A61P 27/02 20180101; D10B
2331/02 20130101; A61K 9/0019 20130101 |
International
Class: |
C08G 69/44 20060101
C08G069/44; A61K 47/34 20060101 A61K047/34 |
Foreign Application Data
Date |
Code |
Application Number |
May 2, 2011 |
EP |
11164501.6 |
Claims
1. A fiber comprising a biodegradable polymer which undergoes
dimensional change upon injection in the human or animal body
wherein the dimensional change is a reduction of the surface area
to volume ratio of a factor 1.05-10.
2. A fiber according to claim 1 wherein the dimensional change is a
reduction of the surface area to volume ratio of a factor
1.25-5.
3. A fiber according to claim 1, wherein the fiber is sized for
injection via a pharmaceutical syringe needle having a bore of at
least 25 Gauge.
4. A fiber according to claim 1, wherein the biodegradable polymer
has a wet Tg below 37 C.
5. A fiber according to claim 1, wherein the biodegradable polymer
is an amorphous biodegradable polymer.
6. A fiber according to claim 1, wherein the amorphous
biodegradable polymer is a polyesteramide, comprising alpha-amino
acids, diols and dicarboxylic acids as building blocks.
7. A fiber according to claim 6 wherein the polyesteramide is a
polyesteramide of formula I ##STR00005## wherein m is about 0.01 to
about 0.99; p is about 0.99 to about 0.01; and q is about 0.99 to
0.01; and wherein n is about 5 to about 350; and wherein R.sub.1 is
independently selected from the group consisting of
(C.sub.2-C.sub.20)alkylene, (C.sub.2-C.sub.20)alkenylene,
--(R.sub.9--CO--O--R.sub.10--O--CO--R.sub.9)--,
--CHR.sub.11--O--CO--R.sub.12--COOCR.sub.11-- and combinations
thereof; R.sub.3 and R.sub.4 in a single co-monomer m or p,
respectively, are independently selected from the group consisting
of hydrogen, ##STR00006## R.sub.5 is selected from the group
consisting of (C.sub.2-C.sub.20)alkylene,
(C.sub.2-C.sub.20)alkenylene, alkyloxy or oligoethyleneglycol;
R.sub.6 is a bicyclic-fragments of 1,4:3,6-dianhydrohexitols
R.sub.7 is hydrogen, (C.sub.6-C.sub.10) aryl, (C.sub.1-C.sub.6)
alkyl or a protecting group; R.sub.8 is independently
(C.sub.1-C.sub.20) alkyl or (C.sub.2-C.sub.20)alkenyl; R.sub.9 or
R.sub.10 are independently selected from C.sub.2-C.sub.12 alkylene
or C.sub.2-C.sub.12 alkenylene. R.sub.11 or R.sub.12 are
independently selected from H, methyl, C.sub.2-C.sub.12 alkylene or
C.sub.2-C.sub.12 alkenylene.
8. A fiber according to claim 7 wherein m is about 0.3, p is about
0.45 and q is about 0.25 and wherein n is about 5-100 and R.sub.1
is (CH.sub.2).sub.8 or (CH.sub.2).sub.4 R.sub.3 and R.sub.4 are
selected from (CH.sub.3).sub.2--CH--CH.sub.2--; R.sub.5 is selected
from (CH.sub.2).sub.6, R.sub.6 is 1,4:3,6-dianhydrosorbitol (DAS);
R.sub.7 is a benzyl protecting group; R.sub.8 is (CH.sub.2).sub.4
.sub.
9. A fiber according to claim 1, comprising at least a bioactive
agent.
10. A fiber according to claim 1, used as a drug eluting
vehicle.
11. Use of a fiber according to claim 1, for the manufacturing of a
medicament for the treatment of ophthalmic diseases.
12. Process for the manufacturing of a fiber according to claim 1,
comprising the following process steps; a. extruding the
biodegradable polymer into a fiber fitting in a syringe needle of
at least 25 Gauge b. which fiber while under tension, is cooled
below its dry glass transition temperature.
Description
[0001] The present invention relates to a fiber comprising a
biodegradable polymer which undergoes dimensional change. The
present invention further relates to the use of the fiber as a drug
delivery vehicle for the treatment of ophthalmic diseases.
[0002] The present invention also relates to a process for the
manufacturing of a fiber via melt extrusion.
[0003] The present invention is based on the premise that the
fibers can be formulated as drug delivery vehicles that may
incorporate a bioactive agent for delivery to the anterior and/or
posterior segment of the eye in a consistent and reliable manner.
Release will depend on diffusion of bioactive agent through the
polymer matrix and biodegradation of the polymer.
[0004] Intraocular delivery of drugs is a particular problem. The
eye is divided into two chambers; the anterior segment which is the
front of the eye, and the posterior segment which is the back of
the eye. Diseases of the anterior segment are easier to treat with
formulations such as eye drops because they can be applied
topically. For example, glaucoma can be treated from the front of
the eye. Diseases of the retina, such as diabetic retinopathy and
macular degeneration, are located in the posterior segment and are
difficult to treat because drugs applied topically, such as eye
drops, typically do not penetrate to the back of the eye. Drugs for
these diseases have customarily been delivered by injection
directly into the back of the eye. These injections often have to
be repeated to provide therapeutic doses of said drugs for the
required duration of the therapy, but this is very uncomfortable
for the patient. There is thus a need for drug delivery vehicles
which allow an easy, safe and more comfortable injection, while
providing an increase duration of sustained drug delivery.
[0005] Moreover there is a need in the art for new and better
controlled delivery of a variety of different types of bioactive
agents to target specific body sites, such as the exterior and
interior tissues of the eye. In particular, there is a need in the
art for more efficacious delivery vehicles for continuous delivery
of ophthalmologic agents to the anterior or posterior segment of
the eye over a sustained period of time, for example in treatment
of chronic diseases of the front and back of the eye.
[0006] Surprisingly it has been found that the above disadvantages
can be overcome providing a fiber comprising a biodegradable
polymer which undergoes dimensional change upon injection in the
human or animal body wherein the dimensional change is a reduction
of the surface area to volume ratio of a factor ranging from
1.05-10, preferably ranging from 1.25-5, more preferably ranging
from 1.5-4, most preferably ranging from 2 to 10.
[0007] The fiber of the present invention thus has the ability to
physically reshape or remodel after being injected into the human
or animal body. The dimensional change leads to an improved
sustained release of bioactive agents due to the change of the
surface to volume ratio, as diffusion of the bioactive agent from
the bulk through the surface will be slowed by a relative reduction
of the surface area. It moreover will decrease the number of
injections needed to release the required amount of bioactive
agents. A further advantage is that a fibers can be injected that
may even remodel into a drug delivery depot, which drug delivery
depot as such would never be injectable.
[0008] The fiber according to the present invention is sized for
injection via a pharmaceutical syringe needle having a bore of at
least 25 Gauge. In general the fibers may have a size ranging from
100-250 .mu.m.
[0009] The fiber according to the present invention comprises a
biodegradable polymer, preferably a biodegradable polymer which is
an amorphous biodegradable polymer. By amorphous is meant that the
molecules are oriented randomly and are intertwined, much like
cooked spaghetti in which the polymer has a glasslike, transparent
appearance. Whether or not polymers are amorphous can easily be
determined by a man skilled in the art and may be measured using
DSC or X-ray diffraction as is known in the art.
[0010] The biodegradable polymer preferably has a dry Tg ranging
from 45 to 60 C. Further the biodegradable polymer preferably has a
wet Tg below 37 C. Dry and wet Tg can be measured according to ASTM
test method NO. D3418.
[0011] Examples of biodegradable polymers are polyesteramides or
polyhydroxyacids (for example PLGA or poly L, D lactic acid).
[0012] An example of an amorphous biodegradable polymer is a
polyesteramide comprising alpha-amino acids, dials and dicarboxylic
acids building blocks.
[0013] Preferably the fiber comprises a polyesteramide comprising
alpha-amino acids, dials and dicarboxylic acids building
blocks.
[0014] More preferred the fibers comprise a polyesteramide
according to formula I
##STR00001##
wherein
[0015] m is about 0.01 to about 0.99; p is about 0.99 to about
0.01; and q is about 0.99 to 0.01; and wherein n is about 5 to
about 350; and wherein
[0016] R.sub.1 is independently selected from the group consisting
of (C.sub.2-C.sub.20)alkylene, (C.sub.2-C.sub.20)alkenylene,
--(R.sub.9--CO--O--R.sub.10--O--CO--R.sub.9)--,
--CHR.sub.11--O--CO--R.sub.12--COOCR.sub.11-- and combinations
thereof;
[0017] R.sub.3 and R.sub.4 in a single co-monomer m or p,
respectively, are independently selected from the group consisting
of hydrogen, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl,
(C.sub.2-C.sub.6)alkynyl, (C.sub.6-C.sub.10)aryl,
(C.sub.1-C.sub.6)alkyl, --(CH.sub.2)SH,
--(CH.sub.2).sub.2S(CH.sub.3), --CH.sub.2OH, --CH(OH)CH.sub.3,
--(CH.sub.2).sub.4NH.sub.3+,
--(CH.sub.2).sub.3NHC(.dbd.NH.sub.2+)NH.sub.2, --CH.sub.2COOH,
--(CH.sub.2)COOH, --CH.sub.2--CO--NH.sub.2,
--CH.sub.2CH.sub.2--CO--NH.sub.2, --CH.sub.2CH.sub.2COOH,
CH.sub.3--CH.sub.2--CH(CH.sub.3)--,
(CH.sub.3).sub.2--CH--CH.sub.2--, CH.sub.2N--(CH.sub.2).sub.4--,
Ph-CH.sub.2--, CH.dbd.C--CH.sub.2--, HO-p-Ph-CH.sub.2--,
(CH.sub.3).sub.2--CH--, Ph-NH--, NH--(CH.sub.2).sub.3--O--,
NH--CH.dbd.N--CH.dbd.C--CH.sub.2--.
[0018] R.sub.5 is selected from the group consisting of
(C.sub.2-C.sub.20)alkylene, (C.sub.2-C.sub.20)alkenylene, alkyloxy
or oligoethyleneglycol;
[0019] R.sub.6 is a bicyclic-fragments of
1,4:3.6-dianhydrohexitols
[0020] R.sub.7 is hydrogen, (C.sub.6-C.sub.10) aryl,
(C.sub.1-C.sub.6) alkyl or a protecting group;
[0021] R.sub.8 is independently (C.sub.1-C.sub.20) alkyl or
(C.sub.2-C.sub.20)alkenyl;
[0022] R.sub.9 or R.sub.10 are independently selected from
C.sub.2-C.sub.12 alkylene or C.sub.2-C.sub.12 alkenylene.
[0023] R.sub.11 or R.sub.12 are independently selected from H,
methyl, C.sub.2-C.sub.12 alkylene or C.sub.2-C.sub.12
alkenylene.
[0024] Even more preferred the fiber comprises a polyesteramide of
Formula III, further disclosed as PEA-III-Ac Bz wherein m is about
0.3, p is about 0.45, q is about 0.25, n is about 5-100 and
wherein
[0025] R.sub.1 is (CH.sub.2).sub.8;
[0026] R.sub.3 and Re, are selected from
(CH.sub.3).sub.2--CH--CH.sub.2--;
[0027] R.sub.5 is selected from (CH.sub.2).sub.6;
[0028] R.sub.6 is 1,4:3,6-dianhydrosorbitol (DAS);
[0029] R.sub.7 is a benzyl protecting group;
[0030] R.sub.8 is (CH.sub.2).sub.4.
A more extended description of PEA-III-Ac Bz is
poly-8-[(L-Leu-DAS).sub.0.45(L-Leu-6).sub.0.3-[L-Lys(Bz)].sub.0.25.
The fractions indicate overall fractions of the monomers in the
synthesis.
##STR00002##
[0031] As used herein, the term "alkyl", refers to a straight or
branched chain hydrocarbon group including methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, and the
like.
[0032] As used herein, "alkenyl" or "alkenylene", refers to
structural formulas herein to mean a divalent branched or
unbranched hydrocarbon chain containing at least one unsaturated
bond in the main chain or in a side chain.
[0033] As used herein, "alkynyl", refers to straight or branched
chain hydrocarbon groups having at least one carbon-carbon triple
bond.
[0034] The term "aryl" is used with reference to structural
formulas herein to denote a phenyl radical or an ortho-fused
bicyclic carbocyclic radical having about nine to ten ring atoms in
which at least one ring is aromatic. Examples of aryl include, but
are not limited to, phenyl, naphthyl, and nitrophenyl.
[0035] At least one of the alpha-amino acids used in the
co-polymers is a natural alpha-amino acid. For example, when the
R.sub.3s or R.sub.4s are CH.sub.2Ph, the natural alpha-amino acid
used in synthesis is L-phenylalanine. In alternatives wherein the
R.sub.3s or R.sub.4s are CH.sub.2--CH(CH.sub.3).sub.2, the
co-polymer contains the natural amino acid, leucine. By
independently varying the R.sub.3s and R.sub.4s within variations
of the two co-monomers as described herein, other natural
alpha-amino acids can also be used, e.g., glycine (when the
R.sub.3s or R.sub.4s are H), alanine (when the R.sub.3s or R.sub.4s
are CH.sub.3), valine (when the R.sub.3s or R.sub.4s are
CH(CH.sub.3).sub.2), isoleucine (when the R.sub.3s or R.sub.4s are
CH(CH.sub.3)--CH.sub.2--CH.sub.3), phenylalanine (when the R.sub.3s
or R.sub.4s are CH.sub.2--C.sub.6H.sub.5), lysine (when the
R.sub.3s or R.sub.4s (CH.sub.2).sub.4--NH.sub.2); or methionine
(when the R.sub.3s or R.sub.4s are --(CH.sub.2).sub.2S(CH.sub.3),
and mixtures thereof.
[0036] The PEA co-polymers preferably have an average number
molecular weight (Mn) ranging from 15,000 to 200,000 Daltons. The
PEA co-polymers described herein can be fabricated in a variety of
molecular weights and a variety of relative proportions of the two
bis-(alpha amino acid)-containing units and optional Lysine-based
monomer of the co-polymer. The appropriate molecular weight for a
particular use is readily determined by one of skill in the art. A
suitable Mn will be in the order of about 15,000 to about 150,000
Daltons, for example from about 30,000 to about 80,000 or from
about 35,000 to about 75,000. Mn is measured via GPO in THF with
polystyrene as standard.
[0037] Other examples of a biodegradable polymers include, but are
not limited to, polyester amides, polyhydroxyalkanoates (PHA),
poly(3-hydroxyalkanoates) such as poly(3-hydroxypropanoate),
poly(3-hydroxybutyrate), poly(3-hydroxyvalerate),
poly(3-hydroxyhexanoate), poly(3-hydroxyheptanoate) and
poly(3-hydroxyoctanoate), poly(4-hydroxyalkanaote) such as
poly(4-hydroxybutyrate), poly(4-hydroxyvalerate),
poly(4-hydroxyhexanote), poly(4-hydroxyheptanoate),
poly(4-hydroxyoctanoate) and copolymers including any of the
3-hydroxyalkanoate or 4-hydroxyalkanoate monomers described herein
or blends thereof, poly(D,L-lactide), poly(L-lactide),
polyglycolide, poly(D,L-lactide-co-glycolide),
poly(L-lactide-co-glycolide), polycaprolactone,
poly(lactide-co-caprolactone), poly(glycolide-co-caprolactone),
poly(dioxanone), poly(ortho esters), poly(trimethylene carbonate),
polyphosphazenes, poly(anhydrides), poly(tyrosine carbonates) and
derivatives thereof, poly(tyrosine ester) and derivatives thereof,
poly(imino carbonates), poly(glycolic acid-co-trimethylene
carbonate), polyphosphoester, polyphosphoester urethane, poly(amino
acids), poly(ethylene glycol) (PEG), copoly(ether-esters) (e.g.
PEO/PLA), polyalkylene oxides such as poly(ethylene oxide),
poly(propylene oxide), poly(ether ester), polyalkylene oxalates,
poly(aspirin), biomolecules such as collagen, chitosan, alginate,
fibrin, fibrinogen, cellulose, starch, collagen, dextran, dextrin,
fragments and derivatives of hyaluronic acid, heparin, fragments
and derivatives of heparin, glycosamino glycan (GAG), GAG
derivatives, polysaccharide, elastin, chitosan, alginate, or
combinations thereof.
[0038] The fiber according to the present invention may further
comprise at least a bioactive agent. The bioactive agent can be any
agent which is a therapeutic, prophylactic, or diagnostic agent.
Such bioactive agent may include without any limitation small
molecule drugs, peptides, proteins, DNA, cDNA, RNA, sugars, lipids
and whole cells. The bioactive agents can have antiproliferative or
anti-inflammatory properties or can have other properties such as
antineoplastic, antiplatelet, anti-coagulant, anti-fibrin,
antithrombotic, antimitotic, antibiotic, antiallergic, or
antioxidant properties. Examples of antiproliferative agents
include rapamycin and its functional or structural derivatives,
40-O-(2-hydroxy)ethyl-rapamycin (everolimus), and its functional or
structural derivatives, paclitaxel and its functional and
structural derivatives. Examples of rapamycin derivatives include
ABT-578, 40-0-(3-hydroxy)propyl-rapamycin,
40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and
40-0-tetrazole-rapamycin. Examples of paclitaxel derivatives
include docetaxel. Examples of antineoplastics and/or antimitotics
include methotrexate, azathioprine, vincristine, vinblastine,
fluorouracil, doxorubicin hydrochloride (e.g. Adriamycin.RTM. from
Pharmacia AND Upjohn, Peapack N.J.), and mitomycin (e.g.
Mutamycin.RTM. from Bristol-Myers Squibb Co., Stamford, Conn.).
Examples of such antiplatelets, anticoagulants, antifibrin, and
antithrombins include sodium heparin, low molecular weight
heparins, heparinoids, hirudin, argatroban, forskolin, vapiprost,
prostacyclin and prostacyclin analogues, dextran,
D-phe-pro-arg-chloromethylketone (synthetic antithrombin),
dipyridamole, glycoprotein Hb/nia platelet membrane receptor
antagonist antibody, recombinant hirudin, thrombin inhibitors such
as Angiomax (Biogen. Inc., Cambridge, Mass.), calcium channel
blockers (such as nifedipine), colchicine, fibroblast growth factor
(FGF) antagonists, fish oil (omega 3-fatty acid), histamine
antagonists, lovastatin (an inhibitor of HMG-CoA reductase, a
cholesterol lowering drug, brand name Mevacor.RTM. from Merck AND
Co., Inc., Whitehouse Station, N.J.), monoclonal antibodies (such
as those specific for Platelet-Derived Growth Factor (PDGF)
receptors), nitroprusside, phosphodiesterase inhibitors,
prostaglandin inhibitors, suramin, serotonin blockers, steroids,
thioprotease inhibitors, triazolopyrimidine (a PDGF antagonist),
super oxide dismutases, super oxide dismutase mimetic,
4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),
estradiol, anticancer agents, dietary supplements such as various
vitamins, and a combination thereof. Examples of anti-inflammatory
agents including steroidal and nonsteroidal anti-inflammatory
agents include biolimus, tacrolimus, dexamethasone, clobetasol,
corticosteroids or combinations thereof. Examples of such
cytostatic substances include angiopeptin, angiotensin converting
enzyme inhibitors such as captopril (e.g. Capoten.RTM. and
Capozide.RTM. from Bristol-Myers Squibb Co., Stamford, Conn.),
cilazapril or lisinopril (e.g. Prinivil.RTM. and Prinzide.RTM. from
Merck AND Co., Inc., Whitehouse Station, N.J.). An example of an
antiallergic agent is permirolast potassium. Other therapeutic
substances or agents which may be appropriate include
alpha-interferon, pimecrolimus, imatinib mesylate, midostaurin, and
genetically engineered epithelial cells. The foregoing substances
can also be used in the form of prodrugs or co-drugs thereof. The
foregoing substances also include metabolites thereof and/or
prodrugs of the metabolites. The foregoing substances are listed by
way of example and are not meant to be limiting.
[0039] The fiber according to the present invention can be used as
a drug eluting vehicle especially for the treatment of disease in
ophthalmology.
[0040] The invention further relates to the process for the
manufacturing of the fiber according to the present invention
comprising the following process steps: [0041] a. extruding the
biodegradable polymer into a fiber fitting in a syringe needle of
at least 25 Gauge [0042] b. which fiber while under tension is
cooled below its dry glass transition temperature The fiber is
preferably manufactured via an extrusion process for example melt
extrusion in which the biodegradable polymer and eventual
additional compounds are homogenised using a Retsch cryomill. The
resulting powder is then filled into a pre-heated DSM Xplore
micro-extruder with 5 cc barrel size and twin-screws which is
connected to a micro fiber spin device. The biodegradable polymer
preferably has a residence time of 5-10 min at 120 C-140.degree. C.
before it is to be stretched into a fiber with diameter in the
range of 100-250 .mu.m. The extrusion is normally performed under
inert atmosphere in order to minimize the oxidative degradation of
the polymer during the process. Under tension it is subsequently
cooled at room temperature. The obtained fiber is then preferably
cut into pieces from for example 4 mm and may be sterilized via
gamma radiation under cooling conditions.
[0043] In FIG. 1 the dimensional change of the injected fiber
according to the present invention is shown.
[0044] FIG. 1 relates to a PEA III fiber dry (A, 25.times. magn.),
in rabbit vitreous after 1 day (B, 50.times. magn.) and after 14
days (C, 50.times. magn.) It showed a decrease of the surface area
to volume ratio of the fiber i.e., increase in fiber diameter from
150 .mu.m to about 300 .mu.m, with associated decrease in fiber
length while maintaining a relatively constant volume.
[0045] FIG. 2 relates to the release of active pharmaceutical
ingredients (API) from PEA-III Ac Bz fibers.
[0046] FIG. 3 shows the evolution of the length, thickness and
volume of a PEA-III AS Bz fiber containing 30 wt % API.
[0047] FIG. 4. relates to a DSM Pharma extruder Xcelera for
twin-screw micro extrusion with a speed of 1-250 rpm, a temperature
range of 20-400.degree. C., a marximal torque of 9000N and a barrel
capacity of 2 or 5 cm.sup.3 equipped with DSM micro fiber spin
device for thin fiber spinning.
[0048] FIG. 5 shows pictures of the fibers at 0, 0.5, 1 and 6 days
taken using optic microscopy. On the optical light microscopy
pictures is represented the size evolution of a PEA fiber
containing 30 wt % of API, after immersion in PBS.
[0049] The invention will now be further and specifically described
by the following examples.
Materials
[0050] PEA-III-Ac Bz polymers are used in the following examples. A
more extended description of PEA-III-Ac Bz is
poly-8-[(L-Leu-DAS).sub.0.45(L-Leu-6).sub.0.3-[L-Lys(Bz)].sub.0.25.
Structure is given in Formula III. The fractions indicate overall
fractions of the monomers in the synthesis.
##STR00003##
Synthesis of PEA III Ac Bz
[0051] Trietylamine (30.9 mL, 0.222 mole, 2.2 eq) and
N,N-dimethylformamide (53.07 mL, 0.689 mole) were added to a
mixture of Di-OSu-sebacinate (39.940 g, 0.1008 mole, 1.0 eq),
L-leucine(6)-2TosOH (20.823 g, 0.0302 mole, 0.30 eq),
L-leucine-(DAS)-2TosOH (32.503 g, 0.0453 mole, 0.45 eq) and
L-lysine(Bz)-2TosOH (14.628 g, 0.0252 mole, 0.25 eq) in a nitrogen
flushed 500 mL round bottomed flask equipped with a overhead
stirrer at room temperature. The subsequent mixture was heated to
60.degree. C. to allow the reaction to proceed and monitored by GPC
analysis in THF. After 36 hours a stable molecular weight was
obtained, subsequently a portion of L-leucine(6)-2TosOH (4.338 g,
0.0063 mole) along with triethylamine (1.76 mL, 0.0126 mole) and
N,N-dimethylformamide (4.54 mL, 0.0590 mole) was added to terminate
the polymerization reaction. The mixture was heated additionally
for 24 hours after which the viscous solution was further diluted
with N,N-dimethylformamide (407.85 g, 5.301 mole) and allowed to
cool to room temperature. At room temperature acetic anhydride
(1.89 mL, 0.0199 mole) was added to acylate the amino functional
end groups of the polymer. The mixture was stirred at room
temperature for 24 hours. In scheme 1 the general reaction is
shown.
##STR00004##
[0052] The obtained crude polymer mixture was precipitated in water
in a 10:1 ratio (water:reaction mixture). The polymer was collected
and dissolved in ethanol (500 mL, 8.57 mole) and the procedure was
repeated a second time. The polymer was again dissolved in ethanol
(500 mL, 8.57 mole) and precipitated in ethylacetate (5000 mL,
50.91 mole) by drop wise addition to a stirring solution. The
precipitated polymer was washed with two portions ethylacetate (100
mL, 1.00 mole), dried and dissolved in ethanol (500 mL, 8.57 mole)
and filtered over a 0.2 .mu.m PTFE membrane filter. The filtered
polymer solution was dried under reduced pressure at 65.degree.
C.
[0053] Yield 75%, Mn=50 kda (Gel Permeation Chromatography (GPC) in
THF relative to polystyrene standards. Glass transition
temperatures were determined by Differential Scanning calorimetry
(DSC). Measurements were taken from second heating, with a heating
rate of 10.degree. C./min., Tg=48.degree. C.
EXAMPLE 1
[0054] 0.52 g of API (Active Pharmaceutical Ingredient) and 4.31 g
of PEA III Ac Bz were co-dissolved in ethanol, film-casted and
allowed to dry. Films were subsequently cryo-milled. The uniformed
cryomilled formulation was processed into a fiber at a Pharma
mini-extruder shown on FIG. 3. The cryo-milled powder was
melt-extruded at a temperature of 125.degree. C., using a
twin-screw extruder. The extruder dye was of 0.75 mm. Extruded
polymer was spin at a speed of 5 m/min to 15 m/min and thereafter
cooled at room temperature, under nitrogen.
[0055] The resulting fibers of a diameter of .about.300 .mu.m were
cut with a length of 10 mm and individually weight. The release was
performed at 37.degree. C. in PBS. PBS was refreshed at each time
point and quantity of API was measured in triplicate, by HPLC. Upon
immersion in PBS at 37.degree. C. these fibers undergo remodeling
(Process 1) Resulting release is presented in the FIG. 2
COMPARATIVE EXAMPLE A
[0056] 0.03 g of API and 0.25 g of polymer were co-dissolved in 2.5
ml of methanol, film-casted and allowed to dry. Resulting films
were cut into fibers of a length of 5-6 mm and a thickness of 250
.mu.m. Release of API was performed on individually weighted
fibers, releasing in PBS at 37.degree. C. PBS was refreshed at each
time point and quantity of API was measured in triplicate by
HPLC.
[0057] Upon immersion in PBS at 37.degree. C., these fibers do not
remodel (Process 2)
[0058] Resulting release is presented in the FIG. 2.
Results
[0059] Approximately 50% of API is released in 15 days from fibers
without remodeling while only 20% of API is released, at the same
time point, from fibers with remodeling.
[0060] This example shows that a fiber remodeling inducing a
decrease of the surface to volume ratio will influence and slow
down the release of API from the fiber.
EXAMPLE 2
[0061] 2.13 g of API and 5.00 g of PEA III Ac Bz were co-dissolved
in ethanol, film-casted and allowed to dry. Films were subsequently
cryo-milled. The cryo-milled powder was melt-extruded at a
temperature of 115.degree. C., using a twin-screws extruder. The
extruder dye was of 0.75 mm. Extruded polymer was spin at a speed
of 5 m/min to 15 m/min and thereafter cooled at room temperature,
under nitrogen.
[0062] The resulting fibers were cut and placed into PBS at
37.degree. C. Length and thickness were monitored by optical light
microscopy.
[0063] FIG. 3 represents the evolution of length, thickness, and
volume of a PEA III Ac Bz fiber, containing 30 wt % API processed
as described in example 1.
[0064] This figure shows that fibers' length decrease, thickness
increase but the volume stays constant. There is not any swelling
of the fiber but a remodeling that result on a different surface to
volume ratio than initially.
* * * * *