Title of Invention

BIOERODIBLE SUSTAINED RELEASE DRUG DELIVERY SYSTEMS

Abstract The present invention relates to sustained release drug delivery systems, medical devices incorporating said systems, and methods of use and manufacture thereof. The inventive systems feature bioerodible drug delivery devices that include biocompatible solid and biocompatible fluid compositions to achieve desired sustained release drug delivery.
Full Text BIOERODIBLE SUSTAINED RELEASE DRUG DELIVERY SYSTEMS
Background of the Invention
Numerous techniques and systems have been developed to enhance drug delivery. A principal objective is to provide the sustained release of a drug under conditions that allow sufficient control over the drug's delivery rate. Some systems employ a polymer drug delivery device in search of such control, while others achieve sustained release by temporarily altering the chemical properties of the agent or packaging the agent with excipients or other agents. Nevertheless, systems are needed that allow for improved control of drug delivery.
Summary of the Invention
The present invention relates to bioerodible sustained release drug delivery systems featuring polymer drug delivery devices that include biocompatible fluid and biocompatible solid core components, where the biocompatible solid is less soluble in physiological fluid than in the biocompatible fluid. The present invention relates to a bioerodible sustained release drug delivery system comprising:an inner core, comprising:(i) a biocompatible fluid component, wherein the biocompatible fluid is a hydrophilic, hydrophobic or amphiphilic fluid, or a biocompatible oil ,(ii) a biocompatible solid component dispersed, suspended, or dissolved in the biocompatible fluid component, wherein the biocompatible solid component is a bioerodible polymer and is more soluble in the biocompatible fluid component than in physiological fluid, and wherein the bioerodible polymer component precipitates or undergoes a phase transition upon contact with a physiological fluid and (iii) at least one agent dispersed, suspended, or dissolved within the inner core, and a first polymer layer that covers at least part of but less than 100% of said inner core. The systems allow desired sustained release drug delivery. The invention also contemplates medical devices employing such systems, and methods of use thereof.
Detailed Description of the Invention
The invention provides a polymer drug delivery system ("polymer system") comprising an inner core or reservoir that contains a therapeutically effective amount of an agent, a first coating layer that is impermeable, negligibly or partially permeable to the agent and, optionally, a second coating layer that is permeable or semi-permeable to the agent. Additional layers may also optionally be used.
The inner core has biocompatible fluid and biocompatible solid components, where the biocompatible solid is less soluble in physiological fluid than in the biocompatible fluid. The biocompatible fluid may be hydrophilic, hydrophobic or amphiphilic ; and may be polymeric or nonpolymeric. Such fluid may also be a biocompatible oil (such as sesame oil, miglyol, or the like). In certain embodiments, a biocompatible solid (e. g. , a bioerodible polymer) is dissolved, suspended, or

dispersed in the biocompatible fluid (to form a "biocompatible core component").
In certain embodiments, at least one agent is also dispersed, suspended, or dissolved
in the biocompatible core component In certain embodiments, an agent is dissolved
in the biocompatible fluid. In certain embodiments, the biocompatible fluid is a
liquid agent that, when combined with a biocompatible solid, is in a form suitable
for injection.
In certain embodiments, the inner core has biocompatible fluid and
biocompatible solid components, wherein the biocompatible fluid component is a
liquid drug or includes a liquid with a drug dissolved therein, and the biocompatible
solid component is dissolved, suspended, or dispersed in the liquid drug to form a
biocompatible core component Other drugs or agents may, but need not, be
dispersed, suspended, or dissolved in the biocompatible core component.
The first coaling layer surrounds the inner core, is an impermeable,
negligibly or partially permeable polymer, and may feature one or more diffusion
ports or pores ("pores") that further allow the drug to diffuse from the core out of the
system. The rate of drug release from such systems may be controlled by the
permeability of the agent in the core, the solubility of the agent in the biocompatible
core component, the thermodynamic activity of the agent in the biocompatible core
component, the potential gradient of the agent from the core to surrounding
physiological fluid, the size of the diffusion pore(s), and/or the permeability of the
first or additional coating layer(s). In certain embodiments, the coating layer(s) is
bioerodible, while in other embodiments it is non-bioerodible.
U.S. Pat. Nos. 5,378,475, 5,773,019, 5,902,598, 6,001,386, and 6,375,972, as
well as co-pending U.S. Patent Applications 10/428,214 and 60/501947 disclose
various embodiments of sustained release drug delivery systems with one or more
polymer coating layers. By way of illustration and not limitation, such devices may
be usefully employed with the systems described herein, and the entire disclosures
of those references are incorporated herein by reference.
In preferred embodiments, the first coating layer includes at least one
polymer (and may, optionally, include more than one polymer), and is preferably
bioerodible, but may alternatively be non-bioerodible. The first coating layer covers
at least part but preferably not all of the surface of the inner core, leaving at least one
diffusion pore through which the agent can pass from the inner core. In certain
embodiments, particularly where impermeable, the membrane may have one or
more pores. If a second layer is used, it may partially cover or cover essentially all
of the first coating layer and inner core, and its permeability to the agent permits the
agent to diffuse into the surrounding fluid.
A variety of polymers may be suitable to form the coating layer(s) of the
present invention. Preferable polymers are largely insoluble in physiological fluids.
Suitable polymers may include naturally occurring or synthetic polymers. Certain
exemplary polymers include, but are not limited to, polyvinyl acetate, cross-linked
polyvinyl alcohol, cross-linked polyvinyl butyrate, ethylene ethylacrylate
copolymer, polyethyl hexylacrylate, polyvinyl chloride, polyvinyl acetals,
plasticized ethylene vinylacetate copolymer, polyvinyl alcohol, ethylene
vinylchloride copolymer, polyvinyl esters, polyvinylbutyrate, polyvinylformal,
polyamides, polymethylmethacrylate, polybutylmethacrylate, plasticized polyvinyl
chloride, plasticized nylon, plasticized soft nylon, plasticized polyethylene
terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene,
polyethylene, polytetrafluoroethylene, polyvinylidene chloride, polyacrylonitrile,
cross-linked polyvinylpyrrolidone, polytrifluorochloroethylene chlorinated
polyethylene, poly(l,4-isopropylidenedipehenylene carbonate), vinylidene chloride,
acrylonitrile copolymer, vinyl-chloride-diethyl fumerale copolymer, silicone
rubbers, medical grade polydimethylsiloxanes, ethylene-propylene rubber, siliconecarbonate
copolymers, vinylidene chloride-vinyl chloride copolymer, vinyl chlorideacrylonitrile
copolymer, vinylidene chloride-acrylonitride copolymer, etc.
The biocompatible core component includes at least one biocompatible solid
(e.g., a bioerodible polymer) that is at least partially dissolved, suspended, or
dispersed in a biocompatible polymeric or nonpolymeric fluid or a biocompatible
oil. Further, the biocompatible solid is more soluble in the biocompatible fluid or oil
than in immediately surrounding physiological fluid such that, when the device is
placed in contact with physiological fluid, the biocompatible core component
precipitates or undergoes a phase transition. The inner core may be delivered as a
gel. It may preferably be delivered as a particulate or a liquid that converts to a gel
upon contact with water or physiological fluid. In some embodiments, the
biocompatible (e.g., nonpolymeric) fluid may include a drug in free base form.
In certain embodiments, the biocompatible fluid of the biocompatible core
component is hydrophilic (e.g., PEG, cremophor, polypropylene glycol, glycerol
monooleate, and the like), hydrophobic, or amphiphilic. In certain embodiments,
said fluid may be a monomer, polymer or a mixture of the same. If used, the
biocompatible oil may be sesame oil, miglyol, or the like.
In certain embodiments, injectable liquids may be used that, upon injection,
undergo a phase transition and are transformed in situ into gel delivery vehicles. In
certain embodiments, at least one polymer in the inner core may convert from a
drug-containing liquid phase to a drug-infused gel phase upon exposure to a
physiological fluid. Technologies based on in situ gelling compositions are
described in U.S. Patent Nos. 4,938,763, 5,077,049, 5,278,202, 5,324,519, and
5,780,044, all of which may be adapted to the present invention, and the disclosure
of each is incorporated herein by reference.
In certain embodiments, the agent may be covalently linked to a
polyoxyethylene ether, wherein the covalent bonds are cleavable in vivo so as to
release the agent. In certain embodiments, the agent is released in a sustained
manner. Methods shown for forming and applying conjugate prodrugs (e.g., PEG -
drug conjugates) are shown in US Patent No. 5,681, 964 and in US Provisional
Application No. 60/539306, the specifications of which are incorporated by
reference in their entirety herein.
In certain embodiments, the agent is a pegylated prodrug of another agent.
In certain embodiments the agent may be included in compounds having
structure 1 below:
A(-L— )mSn
wherein A is a residue of a pharmaceutically active agent A', L represents a covalent
bond or a linker moiety, and S is a polyoxyethylene ether group having the formula
-(OCILCHypOR, where p is 2-12 and R is a Cj-C4 alkyl group. The biocompatible
fluid may comprise a mixture of compounds having a range of values of p; but in
preferred embodiments p has a single value and the composition comprises only one
compound of structure 1. The bond or linkfcr-L-is-eleavable in vivo so as to release
the active agent A'. The agent A' will typically feature one or more functional
groups to which linkers L can be readily attached. Examples of such functional
groups include but are not limited to -CO2H, -CONH2, -CHO, =O, -OH, -NH2, and
-SH groups.
Examples of bonds and linkages which are cleavable in vivo, either by
hydrolysis or by enzyme catalysis, include but are not limited to esters, amides,
carbamates, carbonates, orthoesters, cyclic ketals, thioesters, thioamides,
thiocarbamates, thiocarbonates, xanthates, disulfides, and phosphate esters. Ester
linkages, carbonate linkers, and/or amino acid linker moieties are preferred.
Enzymatically cleavable linkers for polyoxyethylene derivatives have been
described, for example, in US Patent No. 6,127,355, Ulbrich et al., Makromol.
Chem. 1986; 187:1131-1144, Conover et al., m& Anti-Cancer Drug Design 1999;
14:499-506, and in many of the references cited therein, and the use of such linkers
is specifically contemplated. Ester linkages may also be used (see R. Bronaugh et
al., Percutaneous Absorption 3rd Ed., p.58-63, R.L. Bronaugh and H.I. Maibach,
eds., Marcel Dekker, New York, 1999).
The values of m and n will typically range from 1 to 4, although larger
values are within the scope of the invention. Typically, the linker is divalent and m
and n will have the same value, but multiple links to a single moiety S, as for
example in a ketal or orthoester linkage, may be employed. Alternatively, multiple
moieties S may be appended via a single linker L, for example by esterification of
the agent A with a moiety such as -C(=O)CH[(OCH2CH2)pOR]2 or -
P(=0)[(OCH2CH2)pOR]2. Where m > 1 and/or n > 1, each incidence of L and S
may be the same or different.
The residue represented by A may be derived from any agent, including but
not limited to steroids (preferably corticosteroids), retinoids, NSAIDs, vitamin D3
and vitamin D3 analogs, antibiotics, and antiviral agents. Other suitable agents
include enzymes, peptides and other large molecules. In certain embodiments of this
invention, all-trans retinoic acid is excluded from the residues represented by A,
while in other embodiments retinoids are excluded from the residues represented by
A.
Suitable steroids include but are not limited to androgenic and estrogenic
steroid hormones, androgen receptor antagonists and 5-oreductase inhibitors, and
corticosteroids. Specific examples include but are not limited to alclometasone,
clobetasol, fluocinolone, fluocortolone, diflucortolone, fluticasone, halcinonide,
mometasone, prednisone, prednisolone, methylprednisolone, triamcinolone,
betamethasone, and dexamethasone, and various esters and acetonides thereof.
Suitable retinoids include but are not limited to retinol, retinal, isotretinoin,
acitretin, adapalene, tazarotene, and bexarotene.
Suitable NSAIDs include but are not limited to naproxen, suprofen,
ketoprofen, ibuprofen, flurbiprofen, diclofenac, indomethacin, celecoxib, and
rofecoxib.
Suitable vitamin D3 analogues include but are not limited to doxercalciferol,
seocalcitol, calcipotriene, tacalcitol, calcitriol, ergocalciferol, and calcifediol.
Suitable antiviral agents include but are not limited to trifluridine, cidofovir,
acyclovir, penciclovir, famciclovir, valcyclovir, gancyclovir, and docosanol.
Suitable antibacterial agents include but are not limited to metronidazole,
clindamycin, erythromycin, vancomycin, ciprofloxacin, ofloxacin, lomefloxacin,
bacitracin, neomycin, mupirocin, and polymyxin B. The antiviral and antibacterial
prodrugs of the invention may be used to treat appropriately responsive systemic
infections.
The linker L is cleavable in vivo, meaning that the compound of the
invention is hydrolyzed or otherwise cleaved, with or without enzymatic catalysis,
so as to generate in situ the active agent.
Examples of suitable linkers include, but are not limited to, -CI^O-,
-OCH20-, -C(=0)-0-s -OC(=0)-0-, -C(=OHCH2)M-0-,and-C(=0)-(CH2)w-,
-C(=O)-NH-, and -C(=S)-NH-. Descriptions of suitable linkers may be found in
Prodrugs: Topical and Ocular Drug Delivery, 1992, K.B. Sloan (Ed.), Drugs and
the Pharmaceutical Sciences, Vol 53 (Marcel Dekker). It will be appreciated that the
rate of cleavage will vary depending on the precise structures of the active agent and
the polyoxyethylene ether, and on the nature of the linker or bond L and the point(s)
of attachment. The efficiency of prodrug cleavage of linkers for any specific
embodiment can be readily determined by those of skill in the art; for a review of
methods see A. Stichcomb, 2003, Phann Res. 20:1113-1118.
The linker or bond L may be attached to any suitable heteroatom present in
the topically active agent that carries an exchangeable hydrogen, such as -OH, SH,
NHi, and COOH groups. By way of example, the free hydroxyl group of
triamcinolone acetonide may be acylated with the moiety -C(=O)(OCH2CH2)pOR.
In one embodiment, the active agent comprises a carboxylic acid group, and
the carboxylic acid group is esterified with a polyoxyethylene ether of formula
HO(CH2CH2O)pR. Examples include but are not limited to structures I, II, and III
shown below:
(OCH2CH2)pOCH3 (OCH2CH2)POCH3
In an alternative embodiment, the active agent comprises a hydroxyl group,
and the hydroxyl group is acylated with a polyoxyethylene ether carbonyl moiety of
formula -CO(OCH2CH2)pOR. Examples include but are not limited to structures IV
and V shown below:
In certain embodiments, the biocompatible fluid includes a prodrug
comprising a pharmaceutical compound linked to a polyoxyethylene ether moiety of
the formula: -(OCI^CHypOR, wherein p = 2-12 and R is a Ci-C4 alkyl group. In
certain embodiments, n is an integer from 2 to 6 inclusive. The identities of the
group R may be methyl, ethyl, or any other organic moiety.
In certain embodiments, the use of prodrug linkages in connection with an
agent may improve the solubility of an agent in water or in polymer. For example,
the use of a pegylated prodrug may improve the solubility of an agent in the
biocompatible fluid, and thereby improve the injectability of the invention. The use
of prodrug linkages may also lower the melting point of a solid agent, or increase the
solubility of an agent in physiological fluids, thereby improving the injectability of
the agent.
The agent may be dissolved, dispersed or suspended in the biocompatible
core, whereupon it may leach out of the core and into surrounding fluid. In certain
embodiments, the agent may rapidly escape from an injection mixture after injection
into a physiological system.
In certain embodiments, the biocompatible solid component may be, for
example but without limitation, poly(lactic co-glycolic) acid (PLGA).
In certain embodiments the inner core is a viscous paste containing at least
10% agent, or preferably over 50% agent or, more preferably, over 75% agent.
In certain embodiments, the polymer system is injected or inserted into a
physiological system (e.g., a patient). Upon injection or insertion, the delivery
system will contact water or other immediately surrounding physiological fluid that
will enter the polymer system and contact the inner core. In certain embodiments,
the core materials may be selected so as to create a matrix that reduces (and thereby
allows control of) the rate of release of the agent from the delivery system.
In preferred embodiments, the agent's rate of release from the system is
limited primarily by the permeability or solubility of the agent in the matrix.
However, the release rate may be controlled by various other properties or factors.
For example, but without limitation, the release rate may be controlled by the size of
the diffusion pore(s), the permeability of the second layer of the polymer system, the
physical properties of the core (e.g., the permeability or solubility of an agent in the
biocompatible solid as opposed to the permeability or solubility of the agent in the
biocompatible fluid of the biocompatible core component), the dissolution rate of
the core or components of the core, or the solubility of the agent in the physiological
fluid immediately surrounding the polymer system.
In certain embodiments, the rate of release of the agent may be limited
primarily by any of the foregoing properties. For example, in certain embodiments,
the rate of release of the agent may be controlled, or even limited primarily by, the
size of the diffusion pore(s). Depending on the desired delivery rate of the agent, the
first layer may coat only a small portion of the surface area of the inner core for
faster release rates of the agent (i.e., the diffusion pore(s) is relatively large), or may
coat large portions of the surface area of the inner core for slower release rates of the
agent (i.e., the diffusion pore(s) is relatively small).
For faster release rates, the first layer may coat up to about 10% of the
surface area of the inner core. In certain embodiments, approximately 5-10% of the
surface area of the inner core is coated with the first layer for faster release rates.
Certain embodiments may achieve desirable sustained release if the first
layer covers at least 25% of the surface area of the inner core, preferably at least
50% of the surface area, more preferably at least 75%, or even greater than 85% or
95% of the surface area. In certain embodiments, particularly where the agent is
readily soluble in both the polymer core and the biological fluid, optimal sustained
release may be achieved if the first layer covers at least 95% or 99% of the inner
t core. Thus, any portion of the surface area of the inner core, up to but not including
100%, may be coated with a first coating layer to achieve the desired rate of release
of the agent.
The first coating may be positioned anywhere on the inner core, including
but not limited to the top, bottom or any side of the inner core. In addition, it could
be on the top and a side, or the bottom and a side, or the top and the bottom, or on
opposite sides or on any combination of the top, bottom or sides.
The composition of the first coating layer is selected so as to allow the
above-described controlled release. The preferred composition of the first layer may
vary depending on such factors as the active agent, the desired rate of release of the
agent and the mode of administration. The identity of the active agent is important
because its molecular size determines, at least in part, its rate of release into the
second layer.
In certain embodiments, the release rate of the agent from the inner core may
be reduced by the permeability of the second coating layer. In certain embodiments,
the second layer is freely permeable to the agent. In certain embodiments, the
second layer is semi-permeable to the agent. In certain embodiments, the agent has
a permeability coefficient in the second coating layer of less than about IxlO"10
cm/s. In other embodiments the permeability coefficient in the second coating layer
is greater than IxlO"10 cm/s, or even greater than IxlO"7 cm/s. In certain
embodiments the permeability coefficient is at least IxlO"5 cm/s, or even at least
IxlO"3 cm/s, or at least IxlO"2 cm/s in the second layer.
In certain embodiments, the agent has a permeability coefficient in the first
coating layer of less than about IxlO"10 cm/s. In other embodiments the
permeability coefficient in the first coating layer is greater than IxlO"10 cm/s, or
even greater than IxlO"7 cm/s. In certain embodiments the permeability coefficient
is at least IxlO"5 cm/s, or even at least IxlO"3 cm/s, or at least 1x10"2 cm/s in the first
coating layer.
In certain embodiments, the inner core undergoes a phase change (i.e. the
biocompatible solid precipitates) and converts to a gel upon implant or insertion of
the polymer system in a physiological system. The phase change may reduce the
rate of release of the agent from the inner core. For example, where at least part of
the core is provided first as a liquid and converts to a gel, the gel phase of the
polymer core may be less permeable to the agent than is the liquid phase of the
polymer core prior to the conversion to the gel. In certain embodiments, the
polymer core in gel phase is at least 10% or even at least 25% less permeable to the
agent than is the liquid phase. In other embodiments, the precipitated biocompatible
solid is at least 50% or even at least 75% less permeable to the agent than is the
biocompatible fluid alone.
In certain embodiments, interaction of the core with the physiological fluid
may alter the solubility of the agent in the core, and thereby reduce the release rate
of the agent. For example, the core may be at least 10% or even at least 25% less
solubilizing to the agent than before interaction with physiological fluid; in other
embodiments, where a gel phase occurs, the gel phase is at least 50% or even at least
75% less solubilizing to die agent..
In certain embodiments, the biocompatible solid and/or biocompatible fluid
components of the core may dissolve when in contact with physiological fluid. The
rate at which such components dissolve may impact the rate of release of the agent.
In certain embodiments, as the core component(s) erode or dissolve, the rate of
release of the agent may increase. For example, in certain embodiments less than
about 10% of the core component(s) may erode or dissolve over a period of about 6
hours. This may increase the rate of release of the agent by less than about 10%
over that time. In certain embodiments, the biocompatible core component(s) may
erode or dissolve more slowly (e.g. less than about 10% over a period of about 24
hours, or even over a period of multiple days, weeks, or even months). In certain
embodiments, such erosion or dissolution may occur more rapidly (e.g. greater than
about 10% over a period of about 6 hours, in certain embodiments even greater than
25% over a period of about 6 hours).
In certain embodiments, the solubility of the agent in the core impacts the
rate of release of the agent from the polymer system. In certain embodiments, the
agent is soluble, moderately soluble, or even slightly soluble or very slightly soluble
in the core. The agent's release rate from the polymer core where an agent is soluble
in the core exceeds the rate of release where the agent is only slightly or very
slightly soluble in the polymer core.
In certain embodiments, the release rate of the agent from the inner core may
be controlled by the ratio of the agent to the biocomparible solid component of the
core (also referred to as the "drug loading"). By changing the drug loading,
different release rate profiles can be obtained. Increasing the drug loading may
increase the release rate. For a slower release profile, drug loading may be less than
10%, and preferably less than 5%. For a faster release profile, drug loading may be
more than 10%, and preferably more than 20%, or even greater than 50%.
In certain embodiments, the agent may have low solubility in the
physiological fluid immediately surrounding the implanted/inserted polymer system.
In such embodiments, the rate of release of the agent from the polymer system may
be controlled by the solubility of the agent in such surrounding fluid (i.e., the lower
the solubility of the agent in the immediately surrounding fluid the lower its rate of
release from the polymer system). In certain embodiments, the solubility of the
agent in the surrounding physiological fluid is moderate or less.
In certain embodiments, the agent is a codrug, or a prodrug thereof, wherein
the codrug or prodrug thereof is at least 5% less soluble in the surrounding
physiological fluid than are its constituent components. In such embodiments, the
rate of release of the agent may be at least 5% less than the rate of release of the
unlinked constituents from the polymer system. In certain embodiments, the codrug
or prodrug thereof is at least 10%, even at least 25%, at least 50%, or at least 75%
less soluble in the surrounding fluid than are its unlinked constituents. The rate of
release of the constituents may be reduced accordingly when provided in codrug (or
prodrug thereof) form as compared to their unlinked forms. In certain embodiments
using a codrug, the codrug disassociates upon contact with physiological fluid to
generate and release one or more therapeutically active agents from the core.
Thus, the rate of release of the agent according to the invention may be
limited primarily by any of the above properties or any other factor. For example,
but without limitation, the release rate may be controlled by the size and/or location
of the diffusion pore(s), the permeability or other properties of the first or a second
layer in the polymer system, the physical properties of the core (e.g., a gel after a
phase transition), the dissolution rate of one or more of the core components, the
solubility of the agent within the core, the solubility of the agent in the physiological
fluid immediately surrounding the polymer system, etc. In certain preferred
embodiments, the release of the agent may be limited primarily by any one factor,
such that the rate of release is lower as a result of that one factor. In certain
embodiments, the rate of release of the agent is at least 10% slower as a result of one
factor than as a result of any other factor. In certain embodiments, the rate of release
of the agent is at least 25%, or even at least 50% or at least 75% slower as a result of
one factor than as a result of any other factor.
The foregoing factors are illustrative only. The skilled artisan will readily
appreciate that any other property of the inventive system may be the limiting factor
in the agent's release rate from the system.
In another aspect, the inventive system is provided in a drug delivery device
capable of delivering one drug or even two or more synergistic drugs over a
prolonged period. In certain embodiments, the inventive system provides sustained
release of a therapeutically effective amount of an agent to a patient in need thereof.
In preferred embodiments, the device allows delivery of the compounds over a
period of at least 3 hours, preferably at least 12 hours, or even 1 day, at least 2 days,
or even at least 1 week, at least 1 month, or at least 1 year. In some embodiments,
the inventive system may be deployed on a stent or other device. Such devices
include, but are not limited to surgical screws, prosthetic joints, artificial valves,
plates, pacemakers, sutures, etc.
Definitions
The term "active" as used herein means biologically, therapeutically or
pharmacologically active.
The term "agent" as used herein is synonymous with "at least one agent,"
"compound," or "at least one compound," and means at least one drug or codrug, or
a prodrug thereof. In certain embodiments, the agent may be at least one lowsolubility
codrug, or a prodrug thereof. In certain embodiments the codrug, or
prodrug thereof, is designed to have low solubility in either the core, the biological
fluid or both. In certain embodiments, the agent may be a protein, peptide, or a
pegylated agent. In still other embodiments, the term "agent" refers to a plurality of
drugs, proteins, peptides, etc. In certain embodiments the agent may be in granular
form. In certain embodiments, the agent may be combined with a pharmaceutically
acceptable carrier. In certain embodiments, the agent is in liquid form.
An "effective amount" of an agent, with respect to methods of treatment,
refers to an amount of the agent in a preparation which, when administered as part of
a desired dosage regimen (to a mammal, preferably a human) alleviates a symptom,
ameliorates a condition, or slows the onset of disease conditions according to
clinically acceptable standards for the disorder or condition to be treated or the
cosmetic purpose.
The term "ED50" means the dose of a drug that produces 50% of its
maximum response or effect.
The terms "granule," "particle," or "particulate" as used herein are used
interchangeably and refer to any particle. In certain exemplary embodiments, the
particles have a diameter in the range of about 0.01 mm to about 3 mm, preferably in
the range of about 0.1 mm to about 2 mm, or even more preferably in the range of
about 0.3 mm to about 1.5 mm.
As used herein, the term "£€50" means the concentration of a drug that
produces 50% of its maximum response or effect. The term "ICso" means the dose of
a drug that inhibits a biological activity by 50%.
The term "LDso" means the dose of a drug that is lethal in 50% of test
subjects.
The term "therapeutic index" refers to the therapeutic index of a drug defined
as LD50/ED5Q.
A "patient" or "subject" to be treated by the inventive system refers to either
a human or non-human animal.
"Physiological conditions" describe the conditions inside an organism, i.e.,
in vivo. Physiological conditions include the acidic and basic environments of body
cavities and organs, enzymatic cleavage, metabolism, and other biological processes,
and preferably refer to physiological conditions in a vertebrate, such as a mammal.
In general, "low solubility" means that the agent is only very slightly soluble
in a medium (e.g., aqueous solutions having pH in the range of about 5 to about 8,
and in particular to physiologic solutions, such as blood, blood plasma, etc., other
relevant mediums include gels and other materials in the polymer core). Some
agents, e.g., low-solubility agents, will have solubilities of less than about 1 mg/ml
in the medium, less than about 100 fig/ml, preferably less than about 20 /ig/ml, more
preferably less than about 15 £ig/ml, and even more preferably less than about 10
|ig/ml. Solubility in water is measured at a temperature of 25° C as measured by the
procedures set forth in the 1995 USP, unless otherwise stated. According to the
invention, compounds which are soluble (greater than about 100 mg/ml), moderately
soluble (about 100 mg/ml to about 10 mg/ml), slightly soluble (about 10 mg/ml to
about 1 mg/ml), very slightly soluble (about 1 mg/ml to about 0.1 mg/ml) and
practically insoluble or insoluble compounds (less than about 0.1 mg/ml, preferably
less than about 0.01 mg/ml) are contemplated.
As used herein, an agent's "LogP" refers to the logarithm of P (Partition
Coefficient), where P is a measure of how the agent partitions between octanol and
water. P itself is a constant, defined as the ratio of concentration of compound in
aqueous phase to the concentration of compound in octanol according to the
following:
Partition Coefficient, P = [Organic] / [Aqueous], where [] = concentration
LogP = logio (Partition Coefficient) = logioP
A LogP value of 1 means that the concentration of the compound is ten times
greater in the organic phase than in the aqueous phase. The increase in a LogP value
of 1 indicates a ten-fold increase in the concentration of the compound in the organic
phase as compared to the aqueous phase.
The term "residue" when applied to an agent means a part of an agent that is
substantially identical to the agent from which it is derived, with minor differences
arising by virtue of having one or more atoms removed to provide points of
attachment for the linker(s) L. Typically, at least one functional group of the residue
will be altered (relative to the parent pharmaceutically active agent) to accommodate
the covalent linker. This will typically involve removal of an exchangeable
hydrogen and/or a single heteroatom, leaving a free valence for attachment of the
linkage L. For instance, where the agent includes a carboxylate functional group,
the residue of the agent formed by removal of a hydroxyl group may form an ester
bond with a hydroxyl group on a polyoxyethylene ether residue, which itself is
formed by removal of a hydrogen atom from a hydroxyl group from the
polyoxyethylene ether. In this sense, the term "residue" as used herein is analogous
to the sense of the word as it is used in peptide and protein chemistry to refer to a
residue of an amino acid in a peptide.
. The terms "linker" and "linkage," which are used interchangeably herein,
refer to a direct bond or to a multivalent group of atoms incorporating and
connecting the functional groups of the active agent and a polyoxyethylene ether,
which is metabolized under physiological conditions to release the active agent A'.
In certain embodiments, the linker is a substantially linear moiety having no more
than 25 atoms, more preferably less than 10 atoms. Preferred linkers are ones
which, upon release of the topically active agent, and when further metabolized,
generate byproducts that are non-toxic and inert at the effective dosing
concentration. Direct bonds between the residue A and the polyoxyethylene moiety
S are particularly preferred.
The term "codrug" as used herein means a compound comprising a first
molecule residue associated with a second molecule residue, wherein each residue,
in its separate form (e.g., in the absence of the association), is an active agent or a
prodrug of an active agent. In preferred embodiments, either one or both of the first
and second molecule residues are small molecules. The association between said
residues can be either ionic or covalent and, in the case of covalent associations,
either direct or indirect through a linker. The first molecule can be the same or
different from the second. Exemplary formulae for codrugs can be seen in formulae
I, la, II, Ha, HI, Hla, and IV:
A, (-L-A2)n (I)
A, (-A2)n (la)
A,-L-A2 (H)
A, -A2 (Ha)
A2-L-A, -L-A2 ail)
A2-Ai-A2 (ffla)
A,::A2 (IV)
wherein each of AI, A2, and L are defined as follows:
AI is a residue of a first biologically active compound, AI;
A2 is a residue of a second biologically active compound, A2, which may be
the same as or different from AI;
L is a linking group selected from a direct bond and a divalent organic
linking group; and
n is an integer having a value of from 1 to 4, preferably 1;
and :: is an ionic bond.
The term "prodrug" as used herein means a first residue associated with a
second residue, wherein one of the residues is biologically active. In preferred
embodiments, either one or both of the first and second residues ar small
molecules. In some embodiments, one of the residues is not biologically active; in
some embodiments the prodrug may be biologically inactive in its prodrug form.
The association between said residues is covalent and can be either direct or indirect
through a linker. Prodrugs of biologically active compounds include esters, as well
as anhydrides, amides, and carbamates that are hydrolyzed in biological fluids to
produce the parent compounds. Those skilled in the art will realize that a "prodrug"
is a moiety that is generally not pharmacologically active. However, when activated,
typically vivo by enzymatic or hydrolytic cleavage to convert the prodrug to an
active biological moiety, the administration of the prodrug to the individual will
have had the intended medical effect. Prodrugs are typically formed by chemical
modification of a biologically active moiety. Conventional procedures for the
selection and preparation of suitable prodrug derivatives are described, for example,
in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985."
The term "physiological pH," as used herein, refers to a pH that is about 7.4
at the standard physiological temperature of 37.4° C. The term "non-physiological
pH," as used herein, refers to a pH that is less than or greater than "physiological
pH," preferably between about 4 and 7.3, or greater than 7.5 and less than about 12.
The term "neutral pH," as used herein, refers to a pH of about 7. In preferred
embodiments, physiological pH refers to pH 7.4, and non-physiological pH refers to
pH between about 6 and 7. The term "acidic pH" refers to a pH that is below pH 7,
preferably below about pH 6, or even below about pH 4.
The term "bioerodible" is synonymous with "biodegradable" and is artrecognized.
It includes polymers, compositions and formulations, such as those
described herein, that degrade during use. Biodegradable polymers typically differ
from non-biodegradable polymers in that the former may be degraded during use. In
certain embodiments, such use involves in vivo use, such as in vivo therapy, and in
other certain embodiments, such use involves in vitro use. In general, degradation
attributable to biodegradability involves the degradation of a biodegradable polymer
into its component subunits, or digestion, e.g., by a biochemical process, of the
polymer into smaller, non-polymeric subunits. In certain embodiments,
biodegradation may occur by enzymatic mediation, degradation in the presence of
Wulx.1 uuvl/ur other chemical species in the body, or both.
The terms "biocompatible" and "biocompatibility" when used herein are artrecognized
and mean that the referent is neither itself toxic to a host (e.g., an animal
or human), nor degrades (if it degrades) at a rate that produces byproducts (e.g.,
monomeric or oligomeric subunits or other byproducts) at toxic concentrations,
causes inflammation or irritation, or induces an immune reaction, in the host. It is
not necessary that any subject composition have a purity of 100% to be deemed
biocompatible. Hence, a subject composition may comprise 99%, 98%, 97%, 96%,
95%, 90% 85%, 80%, 75% or even less of biocompatible agents, e.g., including
polymers and other materials and excipients described herein, and still be
biocompatible.
The phrase "pharmaceuticaUy acceptable carrier" as used herein means a
pharmaceutically acceptable material, composition or vehicle, such as a liquid or
solid filter, diluent, excipient, solvent or encapsulating material, involved in carrying
or transporting a subject drug from one organ, or portion of the body, to another
organ, or portion of the body. Each carrier must be "acceptable" in the sense of
being compatible with other ingredients of the fonnulation and not injurious to the
patient.
Some examples of materials which can serve as pharmaceutically acceptable
carriers include (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as
corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered
tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and
suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame
oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11)
polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters
such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as
magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free
water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate
buffer solutions; and (21) other non-toxic compatible substances employed in
pharmaceutical formulations. ,
The phrase "protecting group" or "protective group" as used herein means a
temporary substituent that protects a potentially reactive functional group from
undesired chemical transformations. Examples of such protecting groups include
esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of
aldehydes and ketones, respectively. The field of protecting group chemistry has
been reviewed (Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic
Synthesis, 2nd ed.; Wiley: New York, 1991).
The term "residue" refers to that part of a compound that remains after the
compound is linked, either directly to another compound by a direct bond or to a
divalent linking moiety. For instance, where a residue A\ comprises a carboxylic
acid group that forms a linkage to a second residue AI through an amino group to
form the compound Ai-Ai, including an amide linkage, the first residue AI is the
residue of the parent compound that includes all of the parent except for the -OH
that forms part of the amide group, while the other includes all of the parent except
an H- from the amino group. A person having skill in the art will recognize that this
is analogous to "residues" of amino acids in polypeptides and proteins, or to
"residues" of ribonucleotides and deoxyribonucleotides in RNA and DNA,
respectively.
According to the present invention, the phrase "limited primarily by" refers
to the factor(s) associated with the rate-determining step in the release rate of an
agent from the inventive system. For example, but without limitation, an agent's
release rate is limited primarily by the rate of the agent's dissolution in the polymer
where said rate of dissolution is the rate determining step in the release of the agent
(e.g., said dissolution is slower than the rate of dispersion of the agent in the
surrounding physiological fluid). Similarly, where the rate of release (e.g., the ratedetermining
step) is a result of the properties of the matrix (e.g., molecular weight,
permeability in gel state to passage of the agent, size of the diffusion pore), the rate
of release is also said to be "limited primarily by" such properties, such matrix, etc.
Exemplary Embodiments
In one embodiment, poly(lactic-co-glycolic acid) (PLGA) is dissolved in
polyethylene glycol (PEG); the solution is kept in a 37° C water bath. Equal amount
of the PLGA-PEG solution and bovine albumin are mixed and form a semi-solid gel.
This gel is filled into a silicone cup (1.5 mm ID) with a small hole in the bottom, and
the top of the cup is then sealed with silicone adhesive. The hole in the bottom can
be left open or coated with a polymer membrane to control the release. The finished
assembly (silicone cup filled with Albumin-PGA-PEG gel) is placed in 0.1 m
phosphate buffer (pH 7.4) at 37° C, and the release amount of albumin is analyzed
using HPLC. The albumin release rates are as follows:
The foregoing embodiment is presented for illustrative purposes only, and is
not intended to be limiting. The person skilled in the art will recognize that
additional embodiments according to the invention are contemplated as being within
the scope of the foregoing generic disclosure, and no disclaimer is in any way
intended by the foregoing, non-limiting examples.
All patents, publications, and references cited in the foregoing disclosure are
expressly incorporated herein by reference.








We Claim:
1. A bioerodible sustained release drug delivery system comprising:
an inner core, comprising:
(i) a biocompatible fluid component, wherein the biocompatible fluid is a hydrophilic,
hydrophobic or amphiphilic fluid, or a biocompatible oil,
(ii) a biocompatible solid component dispersed, suspended, or dissolved in the
biocompatible fluid component, wherein the biocompatible solid component is a
bioerodible polymer and is more soluble in the biocompatible fluid component than in
physiological fluid, and wherein the bioerodible polymer component precipitates or
undergoes a phase transition upon contact with a physiological fluid and
(iii) at least one agent dispersed, suspended, or dissolved within the inner core, and
a first polymer layer that covers at least part of but less than 100% of said inner
core.
2. The drug delivery system as claimed in claim 1, preferably comprising a second
polymer layer that is permeable to the at least one agent.
3. The drug delivery system as claimed in claim 1, wherein, when in contact with physiological fluid, the biocompatible solid component precipitates or undergoes a phase transition.
4. The drug delivery system as claimed in claim 1, wherein the hydrophilic fluid is
polyethylene glycol (PEG).
5. The drug delivery system as claimed in claim 1, wherein the first polymer layer is
impermeable to the at least one agent.
6. The drug delivery system as claimed in claim 1, wherein the biocompatible solid
component is a bioerodible polymer.


7. The drug delivery system as claimed in claim 6, wherein the bioerodible polymer is
poly(dl-lactide-co-glycolide)(PLGA).
8. The drug delivery system as claimed in claim 1, wherein the first polymer layer covers
at least 50% of the inner core.
9. The drug delivery system as claimed in claim 1, wherein the biocompatible fluid and
biocompatible solid components form a gel upon contact with physiological fluid.
10. The drug delivery system as claimed in claim 9, wherein the at least one agent is at least 10% more soluble in the inner core in gel form than in the inner core prior to conversion to said gel.
11. The drug delivery system as claimed in claim 1, wherein the at least one agent is capable of moderately soluble or less in surrounding physiological fluid.
12. The drug delivery system as claimed in claim 1, wherein, after contact with
physiological fluid, the inner core is at least 10% less permeable to the agent than is the inner core prior to interaction with said fluid.
13. The drug delivery system as claimed in claim 1, wherein the agent is less than soluble
in the biocompatible fluid component, but wherein the agent, upon solubilizing in said biocompatible fluid component, can permeate the inner core.
14. The drug delivery system as claimed in claim 2, wherein the at least one agent has a
permeability coefficient in the second layer at least lxlO"5 cm/s but less than lxlO"2 cm/s.
15 . The drug delivery system as claimed in any of claims 1-14, wherein the at least one agent has a release rate from the system that is limited primarily by the permeability of the at least one agent in the inner core.


16. The drug delivery system as claimed in any of claims 1-14, wherein the first polymer
layer is substantially impermeable to biological enzymes and proteins present in physiological fluid.
17. The drug delivery system as claimed in any of claims 1-14, wherein the drug delivery
system is water-permeable.
18. The drug delivery system as claimed in claims 1-14, wherein the inner core comprises
a codrug or prodrug that is cleaved by water that permeates into the inner core.
19. The drug delivery system as claimed in any of claims 1-14, wherein the at least one
agent is a prodrug.
20. The drug delivery system as claimed in claim 19, wherein the at least one agent is
covalently linked to a polyoxyethylene ether.
21. The drug delivery system as claimed in claim 1 to 14, wherein said drug delivery
system containing an effective amount of suitable agent is used for treating a patient.
22. A bioerodible sustained release drug delivery system substantially as herein described
with reference to the accompanying specification and examples.


Documents:

157-delnp-2006-correspondence-others 1.pdf

157-delnp-2006-form-18.pdf

165-DELNP-2006-Abstract-(01-10-2008).pdf

165-DELNP-2006-Abstract-(04-12-2008).pdf

165-delnp-2006-abstract.pdf

165-delnp-2006-assignments.pdf

165-DELNP-2006-Claims-(01-10-2008).pdf

165-DELNP-2006-Claims-(04-12-2008).pdf

165-delnp-2006-claims-(10-12-2008).pdf

165-delnp-2006-claims.pdf

165-delnp-2006-correspondence-others 1.pdf

165-DELNP-2006-Correspondence-Others-(01-10-2008).pdf

165-DELNP-2006-Correspondence-Others-(04-12-2008).pdf

165-delnp-2006-correspondence-others.pdf

165-delnp-2006-corrspondence-others-(10-12-2008).pdf

165-DELNP-2006-Description (Complete)-(01-10-2008).pdf

165-DELNP-2006-Description (Complete)-(04-12-2008).pdf

165-delnp-2006-description(complete).pdf

165-DELNP-2006-Form-1-(04-12-2008).pdf

165-delnp-2006-form-1.pdf

165-delnp-2006-form-18.pdf

165-DELNP-2006-Form-2-(01-10-2008).pdf

165-DELNP-2006-Form-2-(04-12-2008).pdf

165-delnp-2006-form-2.pdf

165-delnp-2006-form-3.pdf

165-delnp-2006-form-5.pdf

165-DELNP-2006-GPA-(01-10-2008).pdf

165-delnp-2006-pct-210.pdf

165-delnp-2006-pct-220.pdf

165-delnp-2006-pct-237.pdf

165-delnp-2006-pct-304.pdf

165-delnp-2006-pct-311.pdf


Patent Number 234497
Indian Patent Application Number 165/DELNP/2006
PG Journal Number 26/2009
Publication Date 26-Jun-2009
Grant Date 02-Jun-2009
Date of Filing 10-Jan-2006
Name of Patentee pSivida, Inc.
Applicant Address 400 PLEASANT STREET, WATERTOWN, MA 02472, USA
Inventors:
# Inventor's Name Inventor's Address
1 CHEN, JIANBING 50 SANDRICK ROAD, BELMONT, MA 02478-4628, USA
2 ASHTON, PAUL 19 BRIMMER STREET, BOSTON, MA 02108-1025, USA
3 GUO, HONG 50 SANDRICK ROAD, BELMONT, MA 02478, USA
4 SU, DONGLING 3 SHERBORN LANE, FRANKLIN, MA 02038, USA
PCT International Classification Number A61K 9/00
PCT International Application Number PCT/US2004/020547
PCT International Filing date 2004-06-25
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/575,307 2004-05-28 U.S.A.
2 60/483,316 2003-06-26 U.S.A.
3 60/501,947 2003-09-11 U.S.A.