Note: Descriptions are shown in the official language in which they were submitted.
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gyp gg/p~~3 PCTNS98116418
INJECTABLE BIODEGRADABLE BLOCK COPOLYMER GELS
FOR USE IN DRUG DELIVERY
TO THE COMMISSIONER OF PATENTS AND TRADEMARKS:
Your petitioners, Byeongmoon Jeong, a citizen of the United States and
resident of Utah, whose post office address is 714 S. Arapeen Drive, SLC, UT
84108; You Han Bae, a citizen of the republic of Korea, whose post office
address
is 103-103, Hundai Apt., Yongbong-dong, Kwanziu 506-303, Korea; Doo Sung
Lee, a citizen of the republic of Korea, whose post office address is #300
Yung-
Chung Dong Chang An-Ku, Suwon City, Korea 440-746; and Sung Wan Kim a
citizen of the United States and a resident of Utah, whose post office address
is
1711 Devonshire Drive, SLC, UT 84100, pray that letters patent be granted to
them as inventors of INJECTABLE BIODEGRADABLE BLOCK COPOLYMER
GELS FOR USE IN DRUG DELIVERY as set forth in the following specification.
The present invention relates to the preparation of thermosensitive
biodegradable block copolymers and their use for parenteral or subcutaneous
administration of bioactive molecules such as peptide and protein drugs. More
particularly, this invention relates to thermosensitive biodegradable polymers
containing bioactive molecules having a gel/sol transition temperature that is
dependent upon the block length and concentration of the block copolymers.
This
invention is made possible by the use of thermosensitive biodegradable
polymers
based on poly(ether-ester) block copolymers, which are described in detail
hereinafter. The system is based the discovery that poly(ether-ester) block
copolymers having certain molecular weight and composition ranges exist as
aqueous solutions at elevated temperatures, e.g, above the gellsol transition
temperature but, when the temperature is lowered below the transition
temperature,
e.g. to about body temperature, interact to form a semi-solid gel.
There has been a great deal of research focusing on physicochemical
response of stimuli sensitive polymers to changes in temperature, pH, electric
field, and chemical substances. Langer, Science, 249, 1527-1533 (I990);
Ishihara,
et al., J. Appl. Polym. Sci., 29, 211-217, (1995); Thomas, et al., J. Am. Chew
Soc., 117, 2949-2959, (1995) and Kwon et al., Nature, 354, 291-293 (1991).
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Thermosensitive polymers have widely been investigated as drug carriers.
Homopolymers or copolymers of N-isopropylacrylamide (NIPAAm) as disclosed
by Bae et al., Makromol. Chem. Rapid Commun., 8, 481-485 (1987) and Chen,
et al., Nature, 373, 49-52 (1995) are one type. Another type is triblock
copolymers
consisting of hydrophobic polypropylene oxide) as the center block and
hydrophilic polyethylene oxide) as the side blocks, e.g. Poloxamer brand, as
disclosed by Malston, et al., Macromolecules, 25, 5440-5445 (1992). These
polymers are generally nonbiodegradable and their toxicities are of concern.
For
example, following intraperitoneal injections, Poloxamer type copolymers have
been shown to enhance plasma cholesterol and triglycerol in rats. Wout et al.,
J.
Parenteral Sc. & Tech. , 46(6), 192-200 ( 1992).
Much work on polymeric drug delivery systems has focused on injectable
microspheres or biodegradable implant systems that require organic solvents
during fabrication. Youxin, et al., J. Controlled Release, 27, 247-257 (1993).
Because the implant systems possess distinct solid form, they require surgical
insertion. Churchill et al., U.S. Patents 4,526,938 and 4,745,160. Surgical
implants can result in tissue irritation and damage.
A.S. Sawhney and J.A. Hubbell, J. Biomed. Mat. Res., 24, 1197-1411
(1990), synthesized terpolymers of d,l-lactide, glycolide and E-caprolactone
which
degrade rapidly in vitro. The hydrophilicity of the material was increased by
copolymerization with a polyether surfactant prepolymer (Pluronic F-68). This
prepolymer is a block copolymer comprising about 80 % w. of a hydrophobic
polypropylene oxide) block and 20% w. of a hydrophilic polyethylene oxide)
block. It is known that Pluronic type of polymeric surfactants, particularly
the
polypropylene oxide) block portions, are not biodegradable.
Other implantable delivery systems, such as shown in Dunn et al, U.S.
Patents 4,938,763 and 5,278,202, have also been known for some time. These
polymers are either thermoplastic or thermosetting. The thermoplastic solution
requires the use of an organic solvent such as N-methyl-2-pyrrolidone, methyl
ethyl ketone, dimethylformamide, propylene glycol, THF, DMSO,
dodecylazacycloheptan-2-one (Azone) and the like. The thermosetting system
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comprises the synthesis of crosslinkabie polymers which can be formed and
cured
in-situ through the use of a curing agent. However, the major drawback of the
thermoplastic formulations is the use of organic solvents which can be toxic
or
irritating to the body tissues. The thermosetting system requires that the
drug be
admixed with the prepolymer solution prior to additions of the catalysts
because
the curing reaction is quite rapid and injection must take place almost
immediately
following the addition of the curing agent.
A.S. Sawhney et al., Macromolecules, Vol 26, No. 4, 581-589 (1993)
synthesized macromers having a polyethylene glycol) central block, extended
with
oligomers of a-hydroxy acids such as oligo(d,l-lactic acid) or oligo(glycolic
acid)
and terminated with acrylate groups. Using non-toxic photoinitiators, the
macromers can be rapidly polymerized with visible light. Due to the
rnultifunctionality of the macromers, polymerization results in the formation
of
crosslinked gels. The gels degrade upon hydrolysis of the oligo(a-hydroxy
acid)
regions into polyethylene glycol), the a-hydroxy acid, and oligo(acrylic acid)
and
their degradation rates can be tailored by appropriate choice of the oligo(a-
hydroxy
acid) from less than 1 day to up to 4 months. However, in this system, a
photoinitiator, an additional component, is employed as well as an additional
process such as photocrosslinking. This concept is further exemplified in U.S.
Patent 5,567,435.
Cha et al., PCT Publication WO 97115287 published 1 May 1997, discloses
certain block copolymers made up of (i) a hydrophobic A polymer block
comprising a member selected from the group consisting of poly(a-hydroxy
acids)
and polyethylene carbonates) and (ii) a hydrophilic B polymer block comprising
a polyethylene glycol. These copolymers possess thermal reverse gelation
properties in that they form aqueous solutions below the body temperature of
the
animal to which they are to be administered and gel when the temperature is
raised
to body temperature.
An optimum material for use as an injectable or implantable polymeric drug
delivery device should be biodegradable, be compatible with hydrophilic or
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hydrophobic drugs, and allow fabrication with simple, safe solvents, such as
water,
and not require additional polymerization or reaction following
administration.
It is an object of the present invention to provide block copolymer drug
delivery systems that are biodegradable, exhibit thermal gelation behavior and
possess good drug release characteristics.
It is also an object of this invention to provide methods to fabricate
copolymeric biodegradable thermosensitive drug delivery devices wherein the
polymeric matrix can be stored at or below room temperature as a dry, solid
dosage form prior to being formed as a solution for administration.
A still further object of this invention is to provide a drug delivery system
for the parenteral administration of bioactive agents where there is no
requirement
for any surgical procedure for implantation.
Yet another object of this invention is to provide a method for the
parenteral administration of drugs in a biodegradable polymeric matrix
resulting
in the formation of a gel depot within the body from which the drugs are
released
at a controlled rate with the corresponding biodegradation of the polymeric
matrix.
These and other objects may be accomplished by a hydrogel drug delivery
system utilizing a polyethylene oxide) B block and biodegradable poly(a-
hydroxide) A block copolymer having both thermosensitivity and biodegradabilty
properties. The hydrogel contains an appropriate balance of hydrophilicity (B
block) and hydrophobicity (A block) enabling the hydrogel to have
thermoreversibility. Furthermore, organic solvents are not used to load such
polymer systems with bioactive agents. Therefore, the need to remove any
organic
solvent is eliminated.
As used herein the following terms shall have the assigned meanings:
"Parenteral" shall mean any route of administration other than the
alimentary canal and shall specifically include intramuscular,
intraperitoneal, intra-
abdominal, subcutaneous, and, to the extent feasible, intravenous.
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"Solution, " "aqueous solution" and the like, when used in reference to a
combination of drug and biodegradable block copolymer contained in such
solution, shall mean a water based solution having such druglpolymer
combination
dissolved or uniformly suspended therein at a functional concentration and
5 maintained at a temperature above the geI/sol transition temperature of the
block
copolymer.
"Drug delivery liquid" or "drug delivery liquid having thermal gelation
properties" shall means a "solution" suitable for injection into a warm-
blooded
animal which forms a depot upon having the temperature lowered to the body
temperature of the subject into which it is administered.
"Depot" means a drug delivery liquid following injection into a warm-
blooded animal which has formed a gel upon the temperature being lowered to
body temperature.
"Gel," when used, shall mean a semi-solid hydrogel combination of
biodegradable block copolymer and water at a temperature below the gel/sol
transition temperature which is preferably at or below body temperature.
"Gellsol transition temperature," "gel/sol transition" or "gelation
temperature" or any other similar term shall mean the temperature at which an
aqueous combination of the block copolymer undergoes a phase transition
between
a gel and a solution. Above the gellsol transition temperature the aqueous
combination is a solution and below the gellsol transition temperature the
aqueous
combination is a semi-solid hydrogel. The drug will be homogeneously contained
in the solution or gel. While it is possible to formulate the block copolymers
to
have a wide range of gel/sol transition temperatures, it is desirable to have
a
gel/sol transition temperature that is just above the body temperature of the
subject
to which an aqueous solution of the block copolymer and drug is to be
administered. Since normal body temperature in human beings is about
37°C, a
functional range of gel/sol transition temperatures is considered to be
between
about 30 to 60°C.
"Biodegradable" meaning that the block polymer can break down or
degrade within the body to non-toxic components after all drug has been
released.
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"Drug" shall mean any organic compound or substance having bioactivity
and adapted or used for a therapeutic purpose.
"Poly(«-hydroxy acid)" shall mean a poly(«-hydroxy acid) polymer per se
or a poly{«-hydroxy acid) polymer or copolymer derived from the ring opening
polymerization of an «-hydroxy acid precursor, such as a corresponding
lactide,
glycolide or lactone.
"Poly(ethylene oxide)" or "PEO" and "poly(ethylene glycol)" or "PEG" or
"polyoxyethylene" may be used interchangeably and shall mean a polymer of
ethylene glycol or hydrated ethylene oxide.
Basic to the present invention is the utilization of a block copolymer having
hydrophobic or "A" block segments and hydrophilic or "B" block segments.
Generally the block copolymer will be a triblock BAB type block copolymer.
However, the block copolymer could also be a diblock BA type copolymer.
The biodegradable hydrophobic, or A block, segment is preferably a
poly(a-hydroxy acid} member derived or selected from the group consisting of
poly(d,l-lactide), poly(1-lactide), poly(d,l-lactide-co-glycolide),
poly(1-lactide-co-glycolide), poly(E-caprolactone), poly(y-butyrolactone),
poly(8-
valerolactone), poly(E-caprolactone-co-lactic acid), poly(e-caprolactone-co-
glycolic
acid-co-lactic acid), hydroxybutyric acid, malic acid and bi- or terpolymers
thereof. The above listing is not intended to be all inclusive or necessarily
self
limiting as combinations or mixtures of the various a-hydroxy acids that can
be
used to form homopolymeric or copolymeric hydrophobic block segments and still
be within the scope of the invention. Generally, any water insoluble
biodegradable
copolymers can be utilized as the hydrophobic A block including
semicrystalline
polymers and amorphous polymers. The average molecular weight of such a-
hydroxy acid polymeric blocks is between about 500 and 20,000. When formed
into diblock copolymers the average molecular weight of the A block is between
about 500 and 15,000 and is more preferably between about 700 and 10,000.
When formed into triblock copolymers the average molecular weight of the A
block is between about 500 and 20,000 and is more preferably between about 700
and 15,000.
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The hydrophilic B block segment is polyethylene oxide) (PEO) which is
also referred to as (polyoxyethylene) or polyethylene glycol) (PEG) having an
average molecular weight of between about 500 to 25,000 and is more preferably
between about 1,000 and 10,000. The same average molecular weight range is
applicable to both diblock and triblock type copolymers.
The copolymers of this invention are amphiphilic diblock or triblock
copolymers of the structure BA or BAB where B is a hydrophilic block and A is
a hydrophobic bidodgradable block.
The diblock copolymers are synthesized by various methods.
The diblock copolymers may be synthesized by the ring opening
polymerization of a cyclic monomer for the biodegradable hydrophobic A block,
e.g. L-lactide from one end of a PEO block with or without the use of a
catalyst.
IS The PEO is preferably a mono functional PEO of the formula:
X-(CHzCH20)-Y-Z
where X is a lower alkoxy group such as methoxy, ethoxy, etc.; Y is a lower
alkylene group such as methylene, ethylene, propylene, etc.; and Z is a
functional
group selected from the group consisting of hydroxyl (OH), amino (NIA),
carboxyl (COOH), thiol (SH) and the like.
Typical are a-methoxy c.~-hydroxy PEO (X=CH30,Y=CHZCH2,Z=OH)
and a-methoxy w-amino PEO (X=CH30,Y=CHZCH2,Z=NH2).
As mentioned above the cyclic monomer can be D,L-lactide, L-lactide),
glycolide, D,L-lactide-co-glycolide), L-lactide-co-glycolide, E-caprolactone,
y-
butyrolactone, b-valerolactone, E-caprolactone-co-lactic acid,
E-caprolactone-co-glycolic acid-co-lactic acid and the like.
When catalyzed, typical catalysts include stannous octoate, antimony oxide,
tin chloride, aluminum isopropoxide, yttrium isopropoxide, sodium, potassium,
potassium t-butoxide, sodium t-butoxide and the like.
Typically stannous octoate will be used as the catalyst.
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The diblock copolymers can also be synthesized by condensation
polymerization of an a-hydroxy acid monomer at one end of a PEO block. A
monomer such as L-lactic acid, D,L-lactic acid, glycolic acid and the like is
used.
A PEO such as a-methoxy w-hydroxy PEO (X=CH30,Y=CHZCH2,Z=OH) or
a-methoxy w-carboxy PEO (X=CH30,Y=CHZCHZ,Z=COOH) is used as the
PEO source.
Direct coupling of monofiunctional PEO with monofunctional biodegradable
hydrophobic blocks in the presence of coupling agents is another method in
which
the coupling agent may be present as a linkage in the copolymer. Coupling
agents
such as a diisocyanate, e.g. hexamethylene diisocyanate (HMDI); 2,6-toluene
diisocyanate; 1,6-toluene diisocyanate; 2,4-toluene diisocyanate; diphenyl
methane-
4,4' diisocyanate; 3,3'-dimethyl diphenyl methane 4,4'-diisocyanate; (ortho,
meta,
para)phenylene diisocyanate and the like.
Also, coupling after activation of the functional group with activating
agents such as carbonyl diimidazole, succinic anhydride, N-hydroxy
succinimide,
and p-nitrophenyl chloroformate may be utilized.
The triblock copolymers may be prepared by various means.
CouRling of a-h~~r acid A block yith PEO block
A difunctional biodegradable hydrophobic A block may be coupled with
monofunctional PEO to form a BAB copolymer utilizing the coupling techniques
mentioned above for the coupling of B and A blocks to form a diblock, e.g. by
the
use of diisocyanate (DIICN) coupling agents.
In the alternative, dibIock copolymers can be coupled using the end
functional group of biodegradable hydrophobic B (i.e. poly(a-hydroxy acid),
blocks according to the following schematic:
BA + AB + DIICN = BA-DIICN-AB
Triblock copolymers can also be prepared by ring opening polymerization
of ethylene oxide at both ends of a biodegradable hydrophobic A block, e.g.
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poly(a-hydroxy acid), or by sequential ring opening polymerization of cyclic
monomers for the biodegradable hydrophobic block, e.g. L-lactide, followed by
ethylene oxide (another cyclic monomer for PEO).
Both diblock BA and triblock BAB type hydrophiliclhydrophobic block
copolymers synthesized as disclosed herein possess thermal gelation properties
and
are biodegradable. BAB type block copolymers possess some similarities to the
Poloxamer or Pluronic systems described above, but are quite different in that
the
hydrophobic poly(a-hydroxy acid) A block is biodegradable and more
biocompatible than the hydrophobic PPO block of the Poloxamer Pluronic system.
As noted, the B block is formed from appropriate molecular weights of
hydrophilic polyethylene oxide) (PEO). PEO was chosen as the hydrophilic
water-soluble block domain because of its unique biocompatibility,
nontoxicity,
micelle forming properties, and rapid clearance from the body.
The hydrophobic A blocks are synthesized and utilized because of their
biodegradable and biocompatible properties. The in vitro and in vivo
degradation
of these hydrophobic polymer blocks is well understood and the degradation
products are natural metabolites that are readily eliminated by the body.
The molecular weight of the hydrophobic poly(a-hydroxy acid) A blocks,
relative to that of the water-soluble B PEG block, is regulated to retain
desirable
water-solubility and gelling properties. Also, the proportionate weight ratios
of
hydrophilic B block to the hydrophobic A block must also be sufficient to
enable
the block copolymer to possess good water solubility at the required
concentrations
at temperatures above body temperature. Generally, biodegradable block
copolymers possessing desired thermal gelation properties are prepared wherein
the hydrophilic B block makes up about 20 to 90 % by weight of the copolymer
and
the hydrophobic A blocks makes up about 10 to 80% by weight of the copolymer.
Preferably the hydrophilic B block will make up between about 25 to 75 % by
weight of the copolymer, and the hydrophobic biodegradable A block will also
make up between about 25 to 75 °~ by weight.
All resulting diblock and triblock copolymers should be soluble in aqueous
solutions at functional concentrations. There is a minimum concentration for
each
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W0 99107343 PCTNS98116418
copolymer for gelation, i.e. the gel/sol transition temperature, by lowering
the
temperature. Also, if concentrations are too high, aqueous solutions will be
too
viscous to inject parenterally. The only concentration parameter that is
critical is
that under which the polymer is functional.
S Therefore, the concentration at which the block copolymers are soluble at
temperatures to be utilized for parenteral administration may be considered as
the
functional concentration. Generally speaking, block copolymer concentrations
in
the range of about 5 to 60 % are in the functional range and concentrations in
the
range of between about 10 to 50% by weight are preferred. In order to obtain a
I0 viable phase transition of the polymer, a certain minimum concentration is
required.
The mixture of the biodegradable polymer and bioactive agents or drugs
may be prepared as an aqueous solution at a higher temperature than the
gelation
temperature of the polymeric material. Once injected into the body via
intramuscular, subcutaneous or intraperitoneal route as a liquid, the
drug/polymer
formulation will undergo a phase change and will preferably form a highly
swollen
gel, since body temperature will be below the gelation temperature of the
material.
This system will cause minimal toxicity and mechanical irritation to the
surrounding tissue due to the biocompatibility of the materials and will be
completely biodegradable within a specific predetermined time interval. Once
gelled, the drug release from the polymeric matrix can be controlled by proper
formulation of the various copolymer blocks.
The only limitation as to how much drug can be loaded onto the copolymer
is one of functionality. Generally speaking, the drug can make up between
about
1 to 60 % by weight of the drug polymer combination with ranges of between
about 5 to 30 % being preferred:
This invention is applicable to the delivery of any drug that is stable in the
solution as prepared and that will release from the hydrogel matrix following
administration. It would serve no useful purpose to attempt to catalog drugs
as it
will be readily apparent to those skilled in the art the type of drugs that
can be used
*rB
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and minimal experimentation will be required to prove the viability of the
invention as to any particular drug or class of drugs.
The invention may be particularly useful in the delivery of peptide or
protein based drugs. However, in general, the invention may be useful in the
delivery of a broad category of bioactive agents or drugs such as therapeutic
agents
in all of the major therapeutic areas including, but not limited to, anti-
infectives
such as antibiotics and antiviral agents, analgesics and analgesic
combinations,
anorexics, antidiarrheal, antihistamines, anti-inflammatory agents,
antimigraine
preparations, antimotion sickness agents, antinauseants, antineoplastic,
antiparkinsonism drugs, antipruritic, antipsychotic, antipyretics,
antispasmodics
including gastrointestinal and urinary, anticholinergic, sympathomimetic,
xanthine
derivatives, cardiovascular preparations including calcium channel blockers,
beta-
blockers, antiarrythmics, antihypertensives, diuretics, vasodilator including
general
coronary, peripheral and cerebral, central nervous system stimulants including
cough and cold preparations, decongestants, diagnostics, hormones,
immunosupressives, muscle relaxants, parasympatholytic, parasympathomimetic,
psychostimulants, sedatives and tranquilizers.
Within the guidelines stated herein, one skilled in the art can determine,
without undue experimentation, the appropriate drug loading, polymer
composition
and concentration, degradation rates, degree of gelation/emulsion formation,
etc.
DETAILED DESCIZTPTION OF PRFF RFD Eh~BODIh~ NTS
In order to illustrate prefen~ed embodiments of this invention, both diblock
BA copolymers and triblock BAB copolymers were synthesized. The diblock BA
copolymers consisting of PEO/PLLA were synthesized by ring opening
polymerization of L-lactide (LLA) on monomethoxy polyethylene oxide) (PEO)
according to the reaction scheme shown in Formula I:
CH30(CH2CH20)xH + LLA ------- > CH30(CHZCH20),~COCH(CH3)O]YH
B ~ A
. Formula I
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where x and y are integers suitable for the preparation of copolymers having
the
block molecular weights as shown above.
The triblock BAB copolymers were synthesized by coupling the diblock BA
copolymer of Formula I using hexamethylene diisocyanate (HMDI) as a coupling
agent according to the reaction scheme shown in Formula II:
BA + HMDI ------- >
fiCHZO)"~COCH(CHI)O]~OCNH(CH~6NHC0~[OCH(CH~)CO]y~OCHZCHz)xOCH3
B ~ A ; urethane link ; A ; B
Formula II
In both reaction schemes depicted in Formulas 1 and 2 the hydrophilic B
block can be prepared using various molecular weights of poly(L-lactic acid)
PLLA) and polyethylene oxide) (PEO).
Following the reaction scheme of Formula I, methoxy polyethylene
oxide)(PEO)(MW: 5000) (8 g) was dissolved in 80 ml of dried toluene. Residual
water was removed by azeotropic distillation to a final volume of 30 ml. Then,
polymerization of L-lactide (LLA) (4.4 g) and stannous octoate (8.7 mg) onto
PEO
was carried out in this solution and refluxed under a dry nitrogen atmosphere
for
24 hours. The solution was precipitated in diethyl ether and the residual
solvent
was eliminated by vacuum after filtering. The conversion was over 90 % .
Diblock
BA copolymers were prepared wherein the A block had molecular weights of 720,
1000, 1730 and 1960.
Other diblock copolymers including polyethylene oxide-DL-lactic
acid)(PEO-PDLLA; polyethylene oxide-(DIrlactic acid-co-glycolic acid)), (PEO-
P(DLLA/GA)), and polyethylene oxide-(DL-lactic acid-co-E-caprolactone)),
(PEO-P(DLLAICL)) were also synthesized.
Svnthesis of Diblock opQlv,LS,r~(PEO-P(DLLA/CA))
Monomethoxy PEO (10 g) was added in 200 ml of dried toluene. Residual
water was removed by azeotropic distillation and in this case, all of the
toluene was
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13
removed by distillation. DL-lactide (2.5 g) and glycolide (3 g) and stannous
octoate
(10.87 mg) were added to PEO/toluene and heated at 160°C in an oil bath
under
dry nitrogen atmosphere for 24 hours. The reaction mixture was dissolved in
methylene chloride, precipitated in diethyl ether, and the residual solvent
was
eliminated by vacuum after filtering. The conversion was over 90% .
A BA Di-block ((PEO-PLLA-OH), MW: 5000-2560) was added to 200 ml
of dried toluene. Residual water was removed by azeotropic distillation to a
final
volume of 70 ml. HMDI (55.59 mg) and stannous octoate (5.356 mg) were added
to the solution, stirred at b0°C for 12 hours and then gently refluxed
for 6 hours
under a dry nitrogen atmosphere. The resulting triblock copolymers were
purified
by fractional precipitation of the copolymers out of methylene chloride using
diethyl ether. The coupling reaction was monitored by GPC. The yield of
triblock
copolymer after fractional precipitation was 50 % . The copolymers were stored
in
a refrigerator under nitrogen gas. Other triblock copolymers were synthesized
by
the same method.
The resulting triblock copolymer's consisted of two B (PEO) blocks having
a molecular weight of 5000 each and a central A (PLLA) block having molecular
weights of 2040, 3000 and 5000 respectively.
All block copolymers shown in Table 1 were soluble in water at the stated
concentrations above the geUsol transition temperature shown. Initially, the
polymers were dissolved in distilled water at an elevated temperature at the
stated
concentrations and placed in a tightly sealed 4 ml vial. The vials were cooled
below the gelation temperature and stored at 4°C for 12 hours. The
gel/sol
transition temperature was defined by the get melting temperature. The gels
were
equilibrated for 20 minutes at a given temperature in a water bath. Gel mehing
was
measured by increasing the temperature 2°C/step. A gel was defined as
having no
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14
flow in one minute after rotating 90° in the bath. All gels showed
thermosensitivity
and the gel/sol phase transition occurred within a narrow temperature range.
Transition temperatures and concentrations shown in Table 1 are approximations
extrapolated from graphs showing gellsol transition curves plotting
temperature vs.
concentration but are sufficient to demonstrate the influence of molecular
weight
of A and B blocks, relative amount of A vs.B block content and concentration
of
copolymers on the gellsol transition temperature.
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Table 1
Copolymer MW of Copolymer Transition Conc.
Type Blocks (BA or BAB~) Temp(°C) (wt/wt)
5
BA 5000:720 25 30
BA 5000:720 35 35
BA 5000:720 47 40
BA 5000:720 55 45
10 BA 5000:720 57 50
BA 5000:720 65 60
BA 5000:1000 45 35
BA 5000:1000 55 40
BA 5000:1000 60 45
15 BA 5000:1000 65 50
BA 5000:1730 20 20
BA 5000:1730 45 25
BA 5000:1730 75 30
BA 5000:1730 95 35
BA 5000:1960 20 15
BA 5000:1960 45 20
BA 5000:1960 85 25
BA 5000:1960 90 30
B~ 5000:2040:5000 20 18
BAB 5000:2040:5000 30 20
BAB 5000:2040:5000 40 22
BAB 5000:2040:5000 60 25
BAB 5000:2040:5000 75 30
BAB 5000:3000:5000 20 17
BAB 5000:3000:5000 40 20
BAB 5000:3000:5000 . 55 23
B~ 5000:3000:5000 60 25
B~ 5000:3000:5000 75 30
B~ 5000:5000:5000 0 11
BAB 5000:5000:5000 25 13
B~ 5000:5000:5000 40 16
B~ 5000:5000:5000 65 23
B=PEO A=PLAA
Aqueous solutions of diblock BA (PEO-PLAA) and triblock (PEO-PLLA-
PEO) copolymers formed micelles at low concentrations and became gels above
a certain concentration. The micelle packing is thought to be the mechanism of
gelation for these block copolymers. Contrary to the Poloxamer or Pluronic
type
of copolymers, the above described copolymers foam a gel at lower temperatures
CA 02299393 2000-02-07
WO gg/p~~3 PCTIUS98/16418
16
and become a sol at higher temperatures. In other words, they do not exhibit
reverse thermal gelation but follow a more traditional route in that they form
solutions at higher temperature and solidify or gel as the temperature is
lowered.
By changing the biodegradable block length, the sol/gel transition temperature
can
be easily manipulated as shown in Table 1. By decreasing the PLLA block
length,
the gel/soI transition can be shifted toward higher concentrations. Selected
block
copolymers, i.e. 25% aqueous solution of PEO-PLLA (5000:1730) or 22%
aqueous solution of PEO-PLLA-PEO (5000:2040:5000), form gels at body
temperature (37°C) and become a sol above body temperature at a given
concentration.
These polymers combined with appropriate amounts of bioactive agents can
be dissolved in water above body temperature (i.e. 45°C). Due to the
temperature
dependent phase transition, the sol becomes a gel after subcutaneous injection
into
the body. As a gel within the body, it acts as a sustained release matrix.
Based on the thermosensitivity and biodegradability of these block
copolymers, a solvent-free (i.e. no organic solvent) injectable system can be
designed as a controlled drug carrier. This system has numerous advantages
over
common drug delivery systems. First, the formulation is simple and requires no
organic solvent. In addition, the designed matrix, if desired, can be stored
at or
below room temperature as a dry, solid dosage form before administration.
Also,
there is no requirement for a surgical procedure for implantation. The system
is
biodegradable and possesses the typical advantages of hydrogels, e.g.,
little'or no
tissue irritation and improved biocompatability.
The above description will enable one skilled in the art to make and use
drug loaded block copolymers based on thermal gelation properties. The
description is not intended to be an exhaustive statement of specific drugs
which
can be utilized and loaded onto the biodegradable block copolymers. Neither
are
all block copolymers which may be prepared specifically shown. It will be
apparent to one skilled in the art that various modifications may be made
without
departing from the scope of the inventions which is limited only by the
following
claims and their functional equivalents.
