U.S. patent application number 12/100562 was filed with the patent office on 2009-07-16 for low viscosity liquid polymeric delivery system.
Invention is credited to Richard L. Dunn.
Application Number | 20090181068 12/100562 |
Document ID | / |
Family ID | 40459715 |
Filed Date | 2009-07-16 |
United States Patent
Application |
20090181068 |
Kind Code |
A1 |
Dunn; Richard L. |
July 16, 2009 |
Low Viscosity Liquid Polymeric Delivery System
Abstract
Low viscosity biodegradable polymer solutions of a liquid
biodegradable polymer and biocompatible solvent and methods of
using the compositions to form a liquid polymer implant are
provided.
Inventors: |
Dunn; Richard L.; (Fort
Collins, CO) |
Correspondence
Address: |
WHYTE HIRSCHBOECK DUDEK S C;INTELLECTUAL PROPERTY DEPARTMENT
555 EAST WELLS STREET, SUITE 1900
MILWAUKEE
WI
53202
US
|
Family ID: |
40459715 |
Appl. No.: |
12/100562 |
Filed: |
April 10, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12013912 |
Jan 14, 2008 |
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12100562 |
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Current U.S.
Class: |
424/426 ;
523/113 |
Current CPC
Class: |
A61L 27/34 20130101;
A61L 27/54 20130101; A61L 29/06 20130101; A61L 2400/06 20130101;
A61L 2300/43 20130101; A61P 31/00 20180101; A61L 2300/604 20130101;
A61L 27/50 20130101; A61P 25/18 20180101; A61L 29/16 20130101; A61L
31/16 20130101; A61L 31/06 20130101; A61L 29/085 20130101; A61L
31/14 20130101; A61K 9/0024 20130101; A61K 31/445 20130101; A61K
31/485 20130101; A61P 35/00 20180101; A61L 27/18 20130101; A61L
31/10 20130101; A61L 27/58 20130101; A61P 29/00 20180101; A61L
31/148 20130101; A61K 33/24 20130101; A61K 31/65 20130101; A61L
29/148 20130101; A61L 2300/416 20130101; A61L 2300/406 20130101;
A61L 29/14 20130101; A61L 27/18 20130101; C08L 67/04 20130101; A61L
27/34 20130101; C08L 67/04 20130101; A61L 29/06 20130101; C08L
67/04 20130101; A61L 29/085 20130101; C08L 67/04 20130101; A61L
31/06 20130101; C08L 67/04 20130101; A61L 31/10 20130101; C08L
67/04 20130101 |
Class at
Publication: |
424/426 ;
523/113 |
International
Class: |
A61L 27/54 20060101
A61L027/54; A61L 27/14 20060101 A61L027/14 |
Claims
1. A liquid polymer composition, comprising: a biodegradable liquid
polymer; and a biocompatible organic solvent; wherein the
composition, when placed in contact with an aqueous medium or body
fluid remains in a liquid form and does not form a solid in
situ.
2. The composition of claim 1, wherein the polymer is selected from
the group consisting of polylactic acid, polyglycolic acid,
polylactide, polyglycolide, polycaprolactones, polyanhydrides,
polyamides, polyurethanes, polyesteramides, polyorthoesters,
polydioxanones, polyacetals, polyketals, polycarbonates,
polyphosphazenes, polyhydroxybutyrates, polyhydroxvalerates,
polyalkylene oxalates, polyalkylene succinates, poly(malic acid),
polyethylene glycol, hyaluronic acid, chitin, chitosan, and
copolymers, terpolymers, and combinations or mixtures thereof.
3. The composition of claim 1, wherein the polymer is a copolymer
or terpolymer of any combination of lactide, glycolide,
caprolactone, p-dioxanone, trimethylene carbonate,
1,5-dioxepan-2-one, 1,4-dioxepan-2-one, ethylene oxide, propylene
oxide, sebacic anhydride, diketene acetals/diols, and lactic
acid.
4. The composition of claim 1, wherein the solvent is a hydrophilic
organic solvent having a water solubility greater than 10% by
weight of said solvent in water.
5. The composition of claim 4, wherein the organic solvent is
selected from the group consisting of N-methyl-2-pyrrolidone,
2-pyrrolidone, N-ethyl-2-pyrrolidone, N-cyclohexyl-2-pyrrolidone,
N-hydroethyl-2-pyrrolidone, dimethyl acetamide, dimethyl formamide,
acetic acid, lactic acid, ethanol, propanol, methyl lactate, ethyl
lactate, methyl acetate, diethylene glycol monomethyl ether,
glycofurol, glycerol formal, isopropylidene glycerol, dimethyl
sulfoxide, .epsilon.-caprolactone, butyrolactone, propylene glycol,
polyethylene glycol, glycerol, 1,3-butyleneglycol,
methoxypolyethylene glycol, methoxypropylene glycol, acetone,
methyl ethyl ketone, tetrahydrofuran, and combinations thereof.
6. The composition of claim 4, wherein the solvent is selected from
the group consisting of N-methyl-2-pyrrolidone, 2-pyrrolidone,
dimethyl acetamide, dimethyl sulfoxide, ethyl lactate, glycofurol,
glycerol formal, isopropylidene glycerol, propylene glycol,
polyethylene glycol, methoxypolyethylene glycol, methoxypropylene
glycol, and combinations thereof.
7. The composition of claim 1, wherein the solvent is a lipophilic
organic solvent having a water solubility less than 10% by weight
of the solvent in water.
8. The composition of claim 7, wherein the solvent is selected from
the group consisting of ethyl acetate, ethyl butyrate, ethyl
oleate, isopropyl palmitate, ethyl palmitate, methyl palmitate,
isopropyl myristate, diethyl malonate, diethyl succinate, dimethyl
adipate, dimethyl succinate, dibutyl sebacate, triacetin, triethyl
citrate, tributyrin, acetyl triethyl citrate, acetyl tributyl
citrate, acetyl trihexyl citrate, butyryl trihexyl citrate,
tributyl citrate, caprylic/capric triglycerides,
caprylic/capric/linoleic triglyceride, caprylic/capric/succinic
triglyceride, propylene glycol dicaprylate/caprate, benzyl alcohol,
ethyl benzoate, benzyl benzoate, propylene carbonate, dimethyl
carbonate, N,N-diethyl-toluamide, N-dodecyl-2-pyrrolidone,
N-octyl-2-pyrrolidone, N-methyl-2-caprolactam,
N-dodecyl-caprolactam, heptanoic acid, oleic acid, sesame oil,
peanut oil, castor oil, and combinations thereof.
9. The composition of claim 7, wherein the solvent is selected from
the group consisting of ethyl acetate, ethyl oleate, isopropyl
myristate, triacetin, triethyl citrate, acetyl tributyl citrate,
ethyl benzoate, benzyl benzoate, sesame oil, and combinations
thereof.
10. The composition of claim 1, wherein the solvent is a
combination of a hydrophilic solvent and a lipophilic solvent.
11. A composition, comprising: a pharmaceutically acceptable,
biodegradable liquid polymer; and a biocompatible organic solvent
that is dissolvable or dispersible in situ in a body fluid; wherein
the composition when placed in a body forms a polymeric material
having a liquid consistency which does not form into a solid in
situ.
12. The composition of claim 11, further comprising a
therapeutically effective amount of a biologically active
agent.
13. The composition of claim 12 wherein the biologically active
agent is selected from the group consisting of cisplatin,
carboplatin, anastozole, fulvestrant, exemestane, estradiol,
testosterone, misoprostol, follicle-stimulating hormone,
dustasteride, doxycycline, ciprofloxacin, quinolone, ivermectin,
haloperidol, diazepam, risperidone, olanzapine, naltrexone,
fentanyl, buprenorphine, butorphanol, loperamide, nafarelin,
buserelin, histrelin, deslorelin, leuprolide, goserelin,
triptorelin, ganirelix, abarelix, cetrorelix, teverelix,
octreotide, lanreotide, human growth hormone, interferon-alpha,
interferon-beta, interferon-gamma, interleukin, calcitonin, growth
hormone releasing peptides, glucagon-like peptides,
granulocyte-colony stimulating factor, nerve growth factor,
platelet-derived growth factor, insulin-like growth factor,
vascular endothelial growth factor, fibroblast growth factor, bone
morphogenic protein, erythropoietin, and salts, complexes,
prodrugs, and analogs thereof.
14. The composition of claim 11, wherein the polymer is a liquid at
25.degree. C. up to 37.degree. C.
15-23. (canceled)
24. A kit comprising in association: a container of a
pharmaceutically acceptable, biodegradable liquid polymer; and a
container of a biocompatible organic solvent that is dissolvable or
dispersible in situ in a body fluid; wherein the liquid polymer and
the organic solvent when combined, will form a liquid composition
which, when placed in contact with a body fluid, will form a
polymeric implant having a liquid consistency which does not form
into a solid in situ; and directions for preparation and
administration of the liquid composition to form the polymeric
implant.
25. The kit of claim 24, further comprising a container of a
therapeutically effective amount of a biologically active agent;
wherein the biologically active agent, when combined in the liquid
composition and placed in contact with the body fluid will be
released into the body as the polymeric implant biodegrades within
the body.
26. The kit of claim 24, further comprising a container of a
therapeutically effective amount of a biologically active agent in
a pharmaceutically acceptable carrier or diluent; wherein the
biologically active agent, when combined in the liquid composition
and placed in contact with body fluid will be released into the
body as the polymeric implant biodegrades within the body.
27. A kit comprising in association: a container of a liquid
composition comprising a pharmaceutically acceptable, biodegradable
liquid polymer dissolved in a biocompatible organic solvent that is
dissolvable or dispersible in situ in a body fluid; wherein the
liquid composition, when placed in contact with body fluid, will
form a polymeric implant having a liquid consistency which does not
form into a solid in situ; and directions for administration of the
liquid composition to form the polymeric implant.
28. The kit of claim 27, further comprising a container of a
therapeutically effective amount of a biologically active agent;
wherein the biologically active agent, when combined in the liquid
composition and placed in contact with body fluid will be released
as the polymeric implant biodegrades within the body.
29. A kit comprising in association: a container of a liquid
composition comprising a pharmaceutically acceptable, biodegradable
liquid polymer dissolved in a biocompatible organic solvent that is
dissolvable or dispersible in situ in a body fluid, and a
biologically active agent; wherein the liquid composition, when
placed in contact with body fluid, will form a polymeric implant
having a liquid consistency which does not form into a solid in
situ; and the biologically active agent will be released into the
body as the polymeric implant biodegrades within the body; and
directions for administration of the liquid composition to form the
polymeric implant.
30. The composition of claim 12, wherein the biologically active
agent is released from the polymeric material as the polymeric
material biodegrades.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] The present application is a continuation-in-part of U.S.
patent application Ser. No. 12/013,912, filed Jan. 14, 2008.
FIELD OF THE INVENTION
[0002] Embodiments of the present invention relate to methods and
compositions for producing low viscosity biodegradable polymer
solutions comprising liquid biodegradable polymers and
biocompatible solvent that can be easily administered to the body
where the biocompatible solvent dissipates in body fluid leaving a
liquid polymer implant. The biodegradable liquid polymer implants
are suitable for the delivery of biologically active agents and for
use as medical or surgical devices.
BACKGROUND OF THE INVENTION
[0003] Biodegradable polymers are well known for their use in
biomedical applications such as sutures, surgical clips, staples,
implants, and drug delivery systems. These polymers include the
polyglycolides, polylactides, polycaprolactones, polyanhydrides,
polyorthoesters, polydioxanones, polyacetals, polyesteramides,
polyamides, polyurethanes, polycarbonates, poly(amino acids),
polyphosphazenes, polyketals, polyhydroxybutyrates,
polyhydroxyalerates, and polyalkylene oxalates. Examples of their
uses are described in U.S. Pat. No. 3,297,033 to Schmitt, U.S. Pat.
No. 3,636,956 to Schneider, U.S. Pat. No. 4,523,591 to Kaplan, U.S.
Pat. No. 3,773,919 to Boswell, U.S. Pat. No. 3,887,699 to Yolles,
U.S. Pat. No. 4,155,992 to Schmitt, U.S. Pat. No. 4,379,138 to Pitt
et al., U.S. Pat. No. 4,186,189 to Shalaby et al., U.S. Pat. No.
4,767,628 to Hutchinson, U.S. Pat. No. 4,530,840 to Tice, et al.,
and U.S. Pat. No. 4,891,225 and U.S. Pat. No. 4,906,474 to
Langer.
[0004] All of the biodegradable polymers described in the foregoing
patents are solid materials used to form solid articles such as
sutures, staples, surgical clips, implants or microcapsules and
microparticles. Because these polymers are solids, all of their
applications in the biomedical field require that the polymeric
structures be formed outside the body, and then inserted into the
body for their use. Sutures, clips, and staples are normally placed
in the body during a surgical procedure. Solid implants for drug
delivery are either surgically placed or inserted into the body
using large diameter trochars. Only the microparticles including
microcapsules and microspheres can be injected using standard
syringes and needles. However, the manufacture of microparticles
and nanoparticles is a difficult process with many variables that
have to be controlled to obtain reproducible drug delivery systems.
These include solvent selection, polymer and drug concentration,
temperature, stirring speed, drug loading, particle size, coating
uniformity, and porosity. Because the drug is in contact with the
polymer during the manufacturing steps and on storage, sterility
and stability issues are normally encountered. In addition, a great
deal of the drug is lost if the encapsulation efficiency is not
high during the manufacturing process.
[0005] Dunn et al., in U.S. Pat. Nos. 4,938,763 and 5,278,201 have
overcome the administration problems with the solid implants by
dissolving the solid biodegradable polymers in a biocompatible
solvent and injecting the solution into the body using standard
syringes and needles where the polymer in the solution precipitates
or coagulates upon contact with aqueous body fluid to form a solid
implant matrix. The delivery system described in these patents
offer a number of advantages including the ease of manufacture of
the polymer solution, the incorporation of the drug into the
polymer solution just prior to administration leading to increased
drug and polymer stability as well as no loss of drug during the
manufacturing process, and the ability to terminally sterilize the
polymer solution as well as the drug. However, there are some
disadvantages with this in-situ forming polymer system. Because the
polymers used are solids with relative high molecular weights, the
polymer solutions formed from the combination of the solid polymers
and the biocompatible solvents are quite viscous. With the high
solution viscosities, 18-21 gauge needles are required for
administration and considerable injection force is needed. In
addition, the viscous solutions are not easily injected into muscle
tissue and the solid implants formed from these polymer solutions
tend to cause local irritation of the muscular tissue. For this
reason, the foregoing polymer solutions are normally injected
subcutaneously where the material forms quite distinct and
noticeable bumps.
[0006] Bezwada et al. in U.S. Pat. No. 5,442,033 have attempted to
overcome the use of solvents in the Dunn delivery system and the
formation of solid implant bumps by using liquid biodegradable
polymers of caprolactone and lactide. In later patents including
U.S. Pat. No. 5,631,015; U.S. Pat. No. 5,653,992; U.S. Pat. No.
5,599,852; U.S. Pat. No. 5,728,752; and U.S. Pat. No. 6,335,383,
both Bezwada and Scopelianos et al. have extended this concept by
using a variety of caprolactone, trimethylene carbonate, and ether
lactone copolymers or terpolymers with glycolide, lactide, or
p-dioxanone to form liquid biodegradable polymers which are
injected into the body without the use of solvents to form liquid
implants used as medical devices. Both Bezwada and Scopelianos
indicate that the use of solvents with the Dunn delivery system is
a major disadvantage which they have overcome with their liquid
polymers. However, these liquid polymers are very viscous materials
with viscosities normally much greater than 5,000 cP at 37.degree.
C., and they require large 16-18 gauge needles with special
syringes for administration into the body. The high viscosities of
the liquid polymers and the need for special syringes and large
needles are major disadvantages of the Bezwada and Scopelianos
systems.
[0007] Tipton et al. in U.S. Pat. No. 5,747,058 and Gibson et al.
in U.S. Pat. No. 7,053,209 have found that highly viscous,
nonpolymeric, non-water soluble liquid materials with viscosities
of at least 5,000 cP at 37.degree. C., can also be used as liquid
implants for drug delivery. They further describe the use of
biocompatible solvents to reduce the viscosity of the high
viscosity nonpolymeric liquids to levels less than 1,000 cP so as
to enable administration of the material into the body with smaller
gauge needles. All of these materials are nonpolymeric and would be
expected to show low viscosities when dissolved in a biocompatible
solvent. Even solid nonpolymeric materials as described by Dunn et
al. in U.S. Pat. No. 5,736,152, when dissolved in biocompatible
solvents, form non-viscous solutions which can be injected into the
body with standard syringes and needles to form nonpolymeric
implants having a solid matrix that has a firm consistency ranging
from gelatinous to impressionable and moldable, to a hard, dense
solid. However, the problem with nonpolymeric materials is that
their degradation times in the body cannot be varied, as they are
nonpolymeric with only one molecular weight. In addition, their
release characteristics cannot be modified by changing the
molecular composition as can be achieved with polymeric
materials.
[0008] Therefore, there exists a need for a method and composition
for providing liquid polymeric implants with low viscosities for
easy administration into the body using standard syringes and
needles.
[0009] There also exists a further need for a method and
composition for providing more syringeable liquid implants which
are biodegradable and can be used as medical or surgical devices
and/or controlled delivery systems.
[0010] In addition, there is the need for such liquid implants in
which the polymer biodegradation and drug release characteristics
can be varied over a wide range of time and rates.
SUMMARY OF THE INVENTION
[0011] The present invention relates to compositions composed of
liquid biodegradable polymers combined with biocompatible organic
solvents and the use of the polymer compositions, for example, as
drug delivery systems or medical or surgical devices. In
embodiments of the invention, liquid biodegradable polymers are
dissolved in nontoxic biocompatible organic solvents to form low
viscosity solutions that can be easily injected into the body with
standard syringes and small gauge needles. Once the liquid polymer
solution is placed within the body, the solvent dissipates or
diffuses away from the polymer leaving a more viscous liquid
polymer implant suitable, for example, for delivery of a
biologically active agent or for use as a medical or surgical
device. Because the polymer composition is a low viscosity liquid,
it can be injected into muscle or subcutaneous tissue without
damage to the surrounding tissue and without the noticeable bump
observed with solid implants.
[0012] In some embodiments, the liquid polymer/solvent composition
can be used to form a medical or surgical implant by injection
directly into a tissue site where the material will form a polymer
film or coating, plug or other structure that remains in a liquid
form or consistency after the solvent has dissipated. The liquid
polymer in the form of a film can be used, for example, to separate
tissues to prevent the formation of surgical adhesions. The liquid
polymer/solvent composition can also be used to coat or cover an
in-dwelling catheter or other device. The liquid polymer/solvent
composition can also be applied to form a plug or other liquid mass
that can be used, for example, to temporarily seal tissue tears or
holes.
[0013] In other embodiments, the liquid polymer/solvent composition
can be used as a system for delivery of a biologically active agent
(e.g., drug), which can be dissolved or dispersed into the liquid
polymer/biocompatible solvent solution. When the liquid
polymer/solvent composition with the dissolved or dispersed active
agent is injected into the body, the organic solvent upon exposure
to an aqueous medium (e.g., body fluids) will dissolve or diffuse
away from the liquid polymer component leaving a viscous liquid
polymer implant with the active agent entrapped or encapsulated
therein. The hydrophilic or hydrophobic characteristic of the
liquid polymer combined with its rate of degradation within the
body can be used to control the release of the active agent over a
desired time period.
[0014] An embodiment of a method according to the invention
includes administering to a subject (e.g., patient) in need of a
treatment or prevention, for example, an effective amount of the
liquid polymer/solvent composition of the present invention,
optionally with a bioactive agent. Another embodiment of a method
of the invention includes applying the liquid polymer/solvent
composition, optionally with a bioactive agent, to a device such as
a catheter, and inserting the coated device into the body of a
subject for a desired treatment or procedure.
[0015] The present liquid polymer/solvent compositions provide the
advantages of liquid application to form medical or surgical
devices and/or delivery systems for active agents (e.g., drugs).
The present liquid polymer/solvent compositions also allow the use
of smaller gauge needles compared to other liquid polymer systems
made without a solvent. The solvents used in the present
compositions allow an active agent to also be administered as a
solution in contrast to liquid polymer systems made without
solvents. The use of liquid biodegradable polymers in the present
system also allows the rate of release of an active agent and
degradation of the liquid implant to be varied over a wide range in
contrast to the nonpolymeric liquid implant systems.
DETAILED DESCRIPTION OF THE INVENTION
[0016] The compositions of the present invention relate to
solutions of a biodegradable liquid polymer(s) combined with a
biocompatible organic solvent(s) that dissolves or dissipates when
the liquid polymer/solvent compositions are placed in a body to
form a viscous liquid polymer material in the form of a film, a
coating, a plug or other mass. The implanted polymer compositions
can be used, for example, as a medical or surgical device and/or a
delivery system for a biologically active agent (e.g., drug).
[0017] As used herein, the term "liquid" refers to the ability of
the composition and/or the liquid polymer materials to undergo
continuous deformation under a shearing stress. As a liquid, the
liquid polymer materials have a definite volume, but no definite
shape. The term "polymer" refers generally to polymers, copolymers
and/or terpolymers that can be linear, branched, grafted and/or
star-shaped.
[0018] Conventional belief has been that the use of liquid polymers
combined with biocompatible organic solvents to form implants would
release a drug or other active agent too fast to provide any
sustained activity because of the rapid diffusion of the active
agent through a liquid matrix rather than a solid matrix when
placed into the body. Contrary to this belief, it was surprisingly
found that the present liquid polymer/solvent solutions form
implants that do not solidify and remain as a viscous liquid form
upon injection into the body while providing comparable initial
burst and sustained release of drugs and other active agents as
implants formed from solid polymer/solvent solutions. The present
combination of liquid biodegradable polymers with biocompatible
solvents provides readily injected and sterile filterable
formulations. The liquid implant material is biocompatible and
allows the formulation to be injected into body tissue without
tissue irritation and noticeable bumps associated with solid
implants.
[0019] The compositions are prepared by mixing or blending together
the liquid polymer(s) and the organic solvent(s), which can be
performed by any method at a temperature ranging from about
10-50.degree. C. (e.g., at about 25.degree. C.) using a suitable
device to achieve a homogeneous, flowable liquid at room
temperature. Examples of such devices include a mechanical stirrer,
a mixer, or a roller mill. Because both the polymer and solvents
are liquids, they are readily mixed to form a homogeneous
solution.
[0020] The liquid polymers that can be used according to the
present invention are biodegradable and/or bioabsorbable, remain in
a liquid (flowable) form at room temperature (i.e., at 25.degree.
C.) up to body temperature (i.e., at 37.degree. C.), and have an
intrinsic viscosity that allows the composition to be easily
administered, and in some embodiments effective to provide a
desired controlled release profile of a biologically active agent.
Because the liquid polymer materials are already liquids at room
temperature, they allow the use of lower concentrations of the
biocompatible solvent to be used in the composition to provide a
syringeable formulation than polymer/solvent compositions prepared
with solid polymers.
[0021] Examples of suitable polymers which can be used in this
application include polylactic acid, polyglycolic acid, polylactide
(dl-lactide, d-lactide, l-lactide), polyglycolide,
polycaprolactones, polyanhydrides, polyamides, polyurethanes,
polyesteramides, polyorthoesters, polydioxanones, polyacetals,
polyketals, polycarbonates, polyphosphazenes, polyhydroxybutyrates,
polyhydroxyalerates, polyalkylene oxalates, polyalkylene
succinates, poly(malic acid), polyethylene glycol, hyaluronic acid,
chitin and chitosan, and copolymers, terpolymers, and combinations
or mixtures of the above materials. Preferred materials include
those polymers, copolymer or terpolymers made with lactide,
glycolide, caprolactone, p-dioxanone, trimethylene carbonate,
1,5-dioxepan-2-one, 1,4-dioxepan-2-one, ethylene oxide, propylene
oxide, sebacic anhydride, diketene acetals/diols, and lactic acid
with lower molecular weights and amorphous regions to limit
crystallinity and subsequent solidification.
[0022] Solvents that can be used according to the invention are
non-toxic and can be either hydrophilic or lipophilic depending
upon the desired release profile and the solubility of the polymer
and/or biologically active agent in the polymer/solvent
composition. A hydrophilic organic solvent will quickly dissolve in
body fluids leaving the liquid polymer material as an implant, for
example, in the form of a film, coating or plug. If a drug or other
active agent is dissolved in a liquid polymer/hydrophilic solvent
composition, the active agent will become encapsulated or entrapped
in the liquid polymer material as the hydrophilic solvent dissolves
or dissipates into the body fluid. If a lipophilic solvent is used,
the dissolution or diffusion of the lipophilic solvent into
surrounding aqueous tissue fluid will be relatively slow with a
resultant slower increase in viscosity of the administered
polymer/solvent composition. However, a lipophilic solvent, by its
own nature, will slow the release of a biological active agent
incorporated into the composition until the solvent has dissipated,
leaving the liquid polymer implant with the entrapped active agent.
By adjusting the hydrophilicity/lipophilicity character of the
polymer and/or the solvent, the release of the biologically active
agent can be controlled to provide a low initial burst and
sustained release of both hydrophilic and lipophilic drugs (or
other active agent). In addition, the solubility of a hydrophilic
or lipophilic biologically active agent can be controlled to
provide either solutions or dispersions of the active agent in the
liquid polymer/solvent compositions.
[0023] Suitable hydrophilic biocompatible organic solvents that can
be used according to the present invention have a water solubility
greater than 10% by weight of the solvent in water. Examples of
hydrophilic biocompatible organic solvents include amides such as
N-methyl-2-pyrrolidone (NMP), 2-pyrrolidone, N-ethyl-2-pyrrolidone,
N-cycylohexyl-2-pyrrolidone, N-hydroxyethyl-2-pyrrolidone, dimethyl
acetamide, and dimethyl formamide; acids such as acetic acid and
lactic acid; alcohols such as ethanol and propanol; esters of
monobasic acids such as methyl lactate, ethyl lactate, and methyl
acetate; ether alcohols such as diethylene glycol monomethyl ether,
glycofurol, glycerol formal, and isopropylidene glycerol
(Solketal); sulfoxides such as dimethyl sulfoxide; lactones such as
e-caprolactone and butyrolactone; polyhydroxy alcohols such as
propylene glycol, polyethylene glycol, glycerol, and
1,3-butyleneglycol; esters of polyhydroxy alcohols such as
methoxypolyethylene glycol and methoxypropylene glycol; ketones
such as acetone and methyl ethyl ketone; and ethers such as
tetrahydrofuran. Preferred hydrophilic solvents include
N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethyl acetamide, dimethyl
sulfoxide, ethyl lactate, glycofurol, glycerol formal,
isopropylidene glycerol, propylene glycol, polyethylene glycol,
methoxypolyethylene glycol and methoxypropylene glycol due to their
solvating ability and tissue compatibility.
[0024] Suitable lipophilic biocompatible organic solvents that can
be used according to the invention have a water solubility less
than 10% by weight of the solvent in water. Examples of lipophilic
biocompatible organic solvents include esters of mono-, di-, and
tricarboxylic acids such as ethyl acetate, ethyl butyrate, ethyl
oleate, isopropyl palmitate, ethyl palmitate, methyl palmitate,
isopropyl myristate, diethyl malonate, diethyl succinate, dimethyl
adipate, dimethyl succinate, dibutyl sebacate, triacetin, triethyl
citrate, tributyrin, acetyl triethyl citrate, acetyl tributyl
citrate, acetyl trihexyl citrate, butyryl trihexyl citrate, and
tributyl citrate; esters of caprylic and/or capric acids with
glycerol or alkylene glycols such as MIGLYOL 810 or 812
(caprylic/capric triglycerides), MIGLYOL 818
(caprylic/capric/linoleic triglyceride), MIGLYOL 829
(caprylic/capric/succinic triglyceride), and MIGLYOL 840 (propylene
glycol dicaprylate/caprate); aromatic alcohols such as benzyl
alcohol; esters of aromatic acids such as ethyl benzoate and benzyl
benzoate; esters of carbonic acid such as propylene carbonate and
dimethyl carbonate; amides such as N,N-diethyl-toluamide,
N-dodecyl-2-pyrrolidone, N-octyl-2-pyrrolidone,
N-methyl-2-caprolactam, and N-dodecyl-caprolactam; fatty acids such
as heptanoic acid and oleic acid; and oils such as sesame oil,
peanut oil, and castor oil. Preferred lipophilic solvents include
ethyl acetate, ethyl oleate, isopropyl myristate, triacetin,
triethyl citrate, acetyl tributyl citrate, ethyl benzoate, benzyl
benzoate, and sesame oil.
[0025] Combinations of different hydrophilic solvents can be used
to obtain higher or lower levels of solubility of the liquid
polymer and bioactive agent in the resultant solution. A
combination of organic solvents can also be used to control the
rate of release of an active agent by controlling the rate at which
the solvent dissolves or dissipates when the liquid
polymer/solvent/active agent composition is placed in the body.
Similarly, combinations of different lipophilic solvents can also
be used to control the solubility of the liquid polymer and active
agent in the solvent and the release of the active agent in the
body. In other embodiments, combinations of hydrophilic and
lipophilic solvents can be used to obtain the optimum solvent
characteristics for a delivery system. Examples include a
combination of N-methylpyrrolidone and triacetin which provides a
more hydrophobic solvent than N-methylpyrrolidone alone, and a
combination of N-methylpyrrolidone and ethanol which provides a
more hydrophilic solvent than N-methylpyrrolidone alone.
[0026] The organic solvent is typically added to the compositions
in an amount ranging from about 10 percent to about 70 percent by
weight, relative to the total weight of the composition.
Preferably, the solvent is present in the composition in an amount
ranging from about 30 percent to about 50 percent by weight. The
concentration of solvent allows for the level of liquid polymer in
the composition to range from about 30 percent to about 90 percent
by weight, and preferably from about 50 percent to about 70 percent
by weight relative to the overall composition. The liquid
polymer/solvent concentrations permit the liquid polymer/solvent
compositions to be easily injected with standard syringes and small
gauge needles (e.g., about 18-26 gauge) unlike liquid polymer
formulations previously described, for example, by Bezwada and
Scopelianos. The compositions can be administered into the body of
a human subject or animal such as a dog, cat, horse, etc.
[0027] The composition can be applied or injected into the body of
a subject or onto an object (e.g., mesh, catheter, a screw, plate,
tack, pin, staple, sponge, etc.) using a device such as a syringe
or needle. A device with the composition thereon can be placed into
the body of the subject. The liquid polymer component of the
implanted polymer/solvent compositions of the invention will flow
and fill the voids left by the organic solvent as it dissipates
from the implanted material. The implanted liquid polymer material
remains as a liquid or fluid (flowable) consistency but not a
gelatinous or solid consistency nor a microporous solid or
gelatinous matrix. The liquid polymer implant gradually biodegrades
in the subject's body over time.
[0028] The liquid polymer/solvent compositions can be used, for
example, for a variety of medical and surgical applications. For
example, the liquid polymer/solvent compositions can be injected
into or applied to soft tissue or surgical meshes to form a
protective coating or film to prevent or minimize the formation of
tissue adhesions. The compositions can also be applied as films,
for example, to coat vascular grafts to prevent the formation of
blood clots, as liquid plugs, for example, to seal fluid or air
leaks, or as an injected material, for example, to repair or
augment a body tissue. Because of the low solution viscosity, the
liquid polymer/solvent compositions can be injected, for example,
into facial tissues using small gauge needles to camouflage scars,
fill depressions, and smooth out irregularities. The compositions
can also be applied to restore or improve sphincter function, and
as general purpose fillers in the body.
[0029] In other embodiments, the liquid polymer/solvent
compositions can be used as controlled release implants to provide
a delivery system in which a drug or other biologically active
agent is added to the liquid polymer/solvent composition prior to
injection in the body. Upon exposure to body fluid, the organic
solvent dissolves or dissipates in the aqueous tissue fluid to
leave the more viscous liquid polymer for release of the
encapsulated or entrapped active agent. Surprisingly based upon the
use of only solid polymers to form solid implants by Dunn et al.
and the use of liquid polymers without any solvents described by
Bezwada and Scopelianos, the liquid polymer implant formed from
compositions of the present invention by the dissolution or
dissipation of the solvent can be used to control the release of
biologically active agents.
[0030] The rate of release of the active agent (e.g., drug) can be
controlled by the composition of the biodegradable polymer and/or
by the hydrophilicity or lipophilicity of the organic solvent that
is used. The composition of the liquid polymer (i.e., the type of
monomer used or the ratio of monomers for copolymers or
terpolymers, the end groups on the polymer chains, and the
molecular weight of the polymer) will determine the hydrophilicity
or lipophilicity of the liquid polymer material as well as the
degradation time of the liquid polymer implant. More hydrophilic
liquid polymers (e.g., polylactic acid) and/or more hydrophilic
solvents (e.g., N-methyl-2-pyrrolidone) can be used for active
agents in applications where faster release rates and shorter
durations of release (e.g., about 1-3 days) are needed. For slower
releasing active agents and where longer durations of release for
prolonged delivery (e.g., about 7-90 days) are desired, more
hydrophobic and slower degrading liquid polymers (e.g.,
polycaprolactone) and/or more lipophilic solvents (e.g., triacetin)
can be used to advantage. For even slower rates and longer
durations of release of an active agent, the active agent itself
can be made more water-insoluble by utilizing active agents, for
example, in the form of lipophilic salts, drug complexes, and/or
prodrug esters, amides or ethers. Thus, various forms of the drug
or other biologically active agent can be used as needed. The
liquid polymer implant releases an effective amount of the
bioactive agent by diffusion or dissolution from the liquid implant
as it biodegrades in the body.
[0031] The terms biologically active agent, bioactive agent or
active agent as used herein, refer to a drug or other substance
that provides a biological effect and acts locally or systemically
in the treatment, therapy, cure and/or prevention of a disease,
disorder or other ailment. Representative biologically active
agents include, without limitation, antibiotics, antimicrobials,
anti-infectives, antigens, anti-allergenics, steroidal
anti-inflammatory agents, non-steroidal anti-inflammatory agents,
anti-tumor agents, anticancer drugs, decongestants, miotics,
anti-cholinergics, sympathomimetics, sedatives, hypnotics, psychic
energizers, tranquilizers, androgenic steroids, estrogens,
progestational agents, LHRH agonists and antagonists,
somatotropins, narcotic antagonists, humoral agents,
prostaglandins, analgesics, antispasmodics, antimalarials,
antihistamines, cardioactive agents, antiparkinsonian agents,
antihypertensive agents, vaccines, antigens, anti-virals,
antipsychotics, immunosuppressants, anesthetics, antifungals,
antiproliferatives, anticoagulants, antipyretics, antispasmodics,
growth factors, cell adhesion factors, cytokines, biological
response modifiers, and nutritional agents. Examples of
biologically-active agents include cisplatin, carboplatin,
anastozole, fulvestrant, exemestane, estradiol, testosterone,
misoprostol, follicle-stimulating hormone, dustasteride,
doxycycline, ciprofloxacin, quinolone, ivermectin, haloperidol,
diazepam, risperidone, olanzapine, naltrexone, fentanyl,
buprenorphine, butorphanol, loperamide, nafarelin, buserelin,
histrelin, deslorelin, leuprolide, goserelin, triptorelin,
ganirelix, abarelix, cetrorelix, teverelix, octreotide, lanreotide,
human growth hormone, interferon-alpha, interferon-beta,
interferon-gamma, interleukin, calcitonin, growth hormone releasing
peptides, glucagon-like peptides, granulocyte-colony stimulating
factor, nerve growth factor, platelet-derived growth factor,
insulin-like growth factor, vascular endothelial growth factor,
fibroblast growth factor, bone morphogenic protein, erythropoietin,
and salts, complexes, prodrugs, and analogs thereof.
[0032] The biologically active agent can be, for example, a simple
organic compound, peptide, protein, DNA, or RNA material. The
biologically active agent can be in the form of a liquid or a
finely divided solid that is either dissolved or dispersed in the
liquid polymer/solvent composition. The active agent is
incorporated into the composition in an amount sufficient to
achieve the desired therapeutic effect, the desired release
profile, and the desired period of release of the active agent.
There is no critical upper limit on the amount of the active agent
that is dispersed or dissolved in the liquid polymer/solvent
solution as long as the solution has a fluid viscosity acceptable
for injection through a small gauge syringe needle (e.g., gauge of
18-26). The lower limit of the biologically active agent
incorporated into the liquid polymer/solvent solution is dependent
upon the activity of the active agent, the release rate needed to
achieve the desired therapeutic level, and the length of time for
treatment. The biologically active agent is typically present in
the composition at a range from about 0.2 percent to about 40
percent by weight relative to the total weight of the composition,
and more preferably, at a range from about 1 percent to 15 percent
by weight. Both soluble and insoluble biologically active agents
can be incorporated into the liquid polymer/solvent system.
[0033] The compositions can optionally include one or more
adjuvants or additives, for example, biocompatible and nontoxic
colorants, diluents, odorants, carriers, excipients, stabilizers,
release rate modifiers, or the like.
[0034] The components for forming the compositions of the invention
can be separate packaged and combined within a packaging as a kit.
For example, an embodiment of a kit can include a container of a
pharmaceutically-acceptable biodegradable liquid polymer, copolymer
or terpolymer, a container of a biocompatible organic solvent that
is dissolvable or dispersible in situ in a body fluid, and
optionally at least one of a container of a therapeutically
effective amount of a biologically active agent in a
pharmaceutically-acceptable carrier or diluent, a syringe or other
device for administering the liquid composition, and instructions
or directions for preparation and administration of the
compositions to form a polymeric implant. Alternatively, an
embodiment of a kit can contain a syringe of the liquid
polymer/solvent composition and a separate syringe with the
biologically active agent which can be coupled together for mixing
the biologically agent within the liquid polymer/solvent
composition prior to injection in the body. Another embodiment of a
kit can include a container or syringe of the liquid
polymer/solvent/biologically active agent if the agent is stable in
the liquid polymer solution.
EXAMPLES
[0035] The following examples are set forth as representative of
the present invention. These examples are not to be construed as
limiting the scope of the invention as these and other equivalent
embodiments will be apparent in view of the present disclosure and
accompanying claims.
Example 1
Preparation of a 50/50 Caprolactone/DL-Lactide (PLC) Liquid Polymer
with Higher Molecular Weight and Higher Fluid Viscosity
[0036] A 250 mL, round-bottom single neck flask was dried with a
blow dryer and flushed with nitrogen for several minutes. Then a
glass T-joint was placed in the top of the flask, a nitrogen inlet
was connected to the side of the T-joint, and the top of the
T-joint was connected to rubber tubing which led to a glass pipette
immersed in water. The nitrogen flow was set so as to provide a
steady bubbling of nitrogen in the water.
[0037] The catalyst system was prepared by dissolving 0.2710 grams
of Tin(II) 2-ethylhexanoate in 2 mL of toluene in a small vial. The
vial was flushed with nitrogen and capped.
[0038] Next, 72.3 grams of DL-lactide (Purac) was weighed and
placed into the round-bottom flask. Then 57.1 grams of
.epsilon.-caprolactone (Fluka) was weighed and placed in the flask.
To this mixture was added 5.6 mL of dodecanol and 0.1 mL of the Tin
catalyst. The round-bottom flask was placed in an oil bath and
heated at 160.degree. C. for 18 hours with stirring by a magnetic
stirring bar. The flask was cooled to 110.degree. C. and a vacuum
was pulled for 12 hours to remove any residual monomer. The flask
was then cooled to room temperature, the vacuum released, and the
thick viscous liquid polymer transferred to a sealed glass
container. A total of 96.7 grams of the viscous liquid polymer was
obtained.
Example 2
Preparation of a 50/50 Caprolactone/DL-Lactide (PLC) Liquid Polymer
with a Lower Molecular Weight and Lower Fluid Viscosity
[0039] The procedure in Example 1 was substantially repeated except
that 13.6 mL of dodecanol and 0.1 mL of Tin catalyst were added to
72.1 grams of DL-lactide and 57.2 grams of caprolactone. The
mixture was heated at 160.degree. C. for 20 hours and the residual
monomer removed under vacuum at 110.degree. C. for 12 hours. A
total of 123.1 grams of the viscous polymer was obtained after
transfer to a sealed glass container. The fluid viscosity of this
copolymer was lower than that of the copolymer obtained in Example
1 as evidenced by the amount of polymer that could be poured from
the round-bottom flask into the sealed glass container. The color
of this copolymer was also a little more yellow than that of the
copolymer prepared in Example 1.
Example 3
Preparation of an 80/20 Solution of the Higher Viscosity Liquid
Polymer in N-Methyl-2-Pyrrolidone
[0040] The higher molecular weight and higher fluid viscosity
copolymer obtained in Example 1 (23.1 grams) was weighed into a
glass contained and 5.8 grams of N-methyl-2-pyrrolidone (NMP) was
added to the liquid polymer. The mixture was heated with a blow
dryer in efforts to completely dissolve the copolymer; however, the
complete dissolution required stirring the contents with a spatula
for about 15 minutes to obtain a solution with 80% w/w copolymer
and 20% w/w NMP. The solution was still viscous, but definitely
more flowable.
Example 4
Preparation of a 60/40 Solution of the Higher Viscosity Liquid
Polymer in N-Methyl-2-Pyrrolidone
[0041] 14.6 grams of the higher molecular and higher fluid
viscosity copolymer obtained in Example 1 was weighed into a glass
container and 9.6 grams of NMP were added to the liquid polymer.
The mixture was then stirred with a spatula for several minutes to
fully dissolve the polymer. The resultant solution with 60% w/w
copolymer and 40% NMP was much less viscous than the solution
obtained in Example 3.
Example 5
Preparation of an 80/20 Solution of the Lower Viscosity Liquid
Polymer in N-Methyl-2-Pyrrolidone
[0042] The lower molecular weight and lower fluid viscosity
copolymer obtained in Example 2 (23.1 grams) was weighed into a
glass container and 5.8 grams of NMP were added to the liquid
copolymer. The mixture was then stirred with a spatula until the
polymer was completely dissolved. The resultant solution with 80%
w/w liquid copolymer and 20% w/w NMP had about the same flow
viscosity as the 60/40 solution of the higher molecular weight
copolymer described in Example 4.
Example 6
Preparation of a Cisplatin/Liquid Polymer Formulation
[0043] The lower molecular weight copolymer obtained in Example 2
(29.2 grams) was weighed into a glass container and 19.5 grams of
NMP were added to the copolymer. The mixture was then stirred
vigorously with a spatula until all of the copolymer had dissolved
to give a solution with 60% w/w copolymer and 40% w/w NMP. This
polymer solution was drawn up into a large plastic syringe and the
desired amount of polymer solution was transferred to 1.2 mL male
luer-lok gamma resistant polypropylene syringes using a stainless
steel female coupler. After the filling operation, each syringe was
capped with a female luer-lok polypropylene cap, and the syringes
were placed in a bag for sterilization by exposure to gamma
irradiation at 25 kGy.
[0044] Cisplatin powder was then weighed out in plastic trays at
the desired amounts and the drug was transferred to female luer-lok
polypropylene syringes with the plungers removed. After placing the
cisplatin in the syringes from the top of the syringe with the caps
in place, the plungers were re-inserted into the syringes, the
syringes were held with the tips up, the caps were loosened, and
the plunger tips with the cisplatin contents were moved up toward
the tips until there was only a slight space between the drug and
the tip of the syringe. The caps were then tightened, and the
syringes were set aside for labeling. The doses and fill weights
that were prepared are listed in Table 1.
TABLE-US-00001 TABLE 1 Doses and Fill Weights of Cisplatin/Liquid
Polymer Formulations Cisplatin Dose Fill Weights of Syringes 50 mg
dose 760 mg liquid polymer solution 66 mg cisplatin 30 mg dose 529
mg liquid polymer solution 46 mg cisplatin 20 mg dose 414 mg liquid
polymer solution 36 mg cisplatin 10 mg dose 299 mg liquid polymer
solution 26 mg cisplatin
Example 7
Evaluation of the Cisplatin/Liquid Polymer Formulations in Dogs
[0045] The cisplatin/liquid polymer formulations described in
Example 6 were evaluated in dogs with various forms of cancer. The
specific dose of cisplatin administered in the liquid polymer
formulation was determined by the weight of the dog being
treated.
[0046] Prior to administration, a syringe filled with the liquid
polymer solution was coupled to the cisplatin dry powder syringe
using the luer-lok system. The contents of the liquid polymer
solution were then passed into the cisplatin powder syringe by
pressing on the plunger. The mixture of cisplatin powder and liquid
polymer solution was then moved back into the liquid polymer
syringe, and this step was completed for about 50 back and forth
times to complete the mixing of the cisplatin with the liquid
polymer solution. The homogenous mixture was then pulled back into
the liquid polymer syringe, the two syringes decoupled, and a
syringe needle attached to the liquid polymer syringe with the
cisplatin/liquid polymer formulation. The formulation was next
injected intramuscularly into the animal at the desired dosage
using a 20 gauge needle. Samples of blood from the treated animals
were taken at baseline and after 1, 2, 3, and 4 weeks and analyzed
for neutrophil levels as an indication of the release and activity
of the cisplatin. Cisplatin is an anti-cancer drug known to reduce
neutrophil counts in dogs when administered intravenously as an
aqueous solution.
[0047] With each animal, the neutrophil counts started to drop
immediately after administration of the formulation indicating that
active cisplatin was being released. The neutrophil counts
continued to decrease with minimum values being reached at about
two weeks, after which the values slowly increased. These data
showed that the cisplatin was being released from the liquid
polymer formulation in a sustained release manner. A comparison of
the neutrophil levels obtained with the liquid polymer formulation
to that obtained with a similar formulation using a solid 50:50
poly(DL-lactide-co-glycolide) (PLG) polymer dissolved in NMP is
given in Table 2.
TABLE-US-00002 TABLE 2 Comparison of Neutrophil Counts with
Cisplatin Formulations Neutrophil Count Polymer Initial Week 1 Week
2 Week 3 Week 4 Solid PLG 12.32 8.46 7.11 7.36 12.36 Liquid PLC
11.16 6.72 5.30 9.02 12.08
[0048] These data show that the liquid polymer formulation resulted
in lower levels of neutrophils than the solid polymer formulation,
indicating a more active release of cisplatin, and surprisingly,
the reduction in neutrophils levels were sustained for about the
same length of time with the two formulations.
Example 8
Preparation of a Buprenorphine HCL/Liquid Polymer Formulation
[0049] 6.0 grams of the lower molecular weight copolymer described
in Example 2 was dissolved in 6.0 grams of NMP to give a solution
with 50% w/w copolymer and 50% w/w NMP. This solution was
non-viscous and could be easily pulled up into a syringe using a 20
gauge needle. 5.0 grams of this liquid polymer solution was placed
in a glass ampule and 50 milligrams of buprenorphine HCL powder
from a weigh cup was placed in the ampule with the polymer solution
to provide a formulation with approximately 1% w/w drug.
Buprenorphine is an opioid agonist-antagonist analgesic. The
mixture was stirred vigorously with a spatula until it appeared
that the buprenorphine HCL powder had fully dissolved. The polymer
solution with the dissolved drug was then drawn up into a plastic
syringe with a male luer-lok tip. The plastic syringe with the
polymer/drug solution was attached to the female luer-lok tip of a
sterile filter from Advantec Mfgs., Inc. The filter casing was
polypropylene and the filter itself was hydrophobic Teflon with a
pore size of 0.25 .mu.m and a diameter of 25 mm. The liquid
polymer/drug solution was easily forced through the 0.25 .mu.m
filter to provide a clear and sterile liquid
polymer/solvent/buprenorphine HCL formulation which was placed in
an ampule with a rubber cap and stored. Analysis of the formulation
by ultraviolet (UV) visible spectroscopy showed that the drug was
present at a concentration of 0.98% w/w.
Example 9
Evaluation of the Efficacy of a Buprenorphine HCL/Liquid Polymer
Formulation in a Rat Pain Model
[0050] Male Sprague Dawley rats were selected for the study
involving the hot water tail flick procedure to determine the
efficacy of the buprenorphine/liquid polymer formulation in
reducing pain. Prior to administration of the formulations, each
rat had its tail placed in a heated water bath to observe whether
the animal felt the momentary discomfort from the heat and moved
its tail in response to the heat stimulus. The length of time in
seconds required for the rat to move its tail was recorded. If the
animal did not move its tail within 10 seconds, the tail was
removed from the water bath.
[0051] Three rats were used for each test group. The three groups
consisted of the liquid polymer/NMP solution without drug (vehicle
control), the liquid polymer/NMP/buprenorphine HCL formulation at
0.6 mg dose of drug, and the liquid polymer/NMP/buprenorphine HCL
formulation at 1.8 mg dose of drug. Each of the vehicle control
animals was injected in the scapular region with 180 .mu.l of the
liquid polymer/NMP solution using a 20 gauge needle. The rats with
a dose of 0.6 mg of drug were injected with 60 .mu.L of the liquid
polymer/drug solution, and the animals with a dose of 1.8 mg of
drug were injected with 180 .mu.L of the polymer/drug solution. All
of the injections went well with no administration problems, no
apparent implant bumps, and no apparent local tissue irritation
effects. Each animal was then tested for its response to the hot
water stimulus at 4, 8, 24, 32, 40, 52, 60, and 72 hours. The
results are given Table 3.
TABLE-US-00003 TABLE 3 Hot Water Tail Flick Results with Liquid
Polymer/Buprenorphine Formulation Response Time (seconds) Time
point Vehicle 0.6 mg Dose 1.8 mg Dose Initial 1.00 1.00 1.66 4
hours 2.00 5.66 5.00 8 hours 2.00 6.00 4.66 24 hours 2.00 3.66 3.33
32 hours 1.33 3.00 3.33 40 hours 2.00 2.33 4.33 52 hours 1.33 2.00
3.33 60 hours 1.66 2.66 2.66 72 hours 1.33 2.00 2.33
[0052] The data show that at all time points the response times
were longer with the buprenorphine liquid polymer formulations than
with the vehicle control. This indicates that the drug was being
released in an active form up to 72 hours. Normally, buprenorphine
HCL given in an aqueous solution provides efficacy in the rat tail
flick test for only about 5 hours, therefore, extended release of
the active drug was provided by the liquid polymer formulation.
Example 10
Preparation of a Buprenorphine Base/Liquid Polymer Formulation
[0053] 10 grams of the lower molecular weight copolymer described
in Example 2 was dissolved in 10.1 grams of NMP to give a solution
with 50% w/w copolymer and 50% w/w NMP. To this solution was added
0.2085 grams of buprenorphine base. The white powdered base was
thoroughly mixed and particles crushed until a clear solution was
obtained. Then 0.4170 grams of palmitic acid was added to the
polymer/drug/NMP solution to complex with the buprenorphine base to
form buprenorphine palmitate. The white flaky palmitic acid was
crushed and thoroughly mixed until a clear solution was obtained.
The resultant solution was then filtered through a 0.25 .mu.m
Teflon filter as described in Example 8 to produce a sterile
solution with 1% w/w buprenorphine and 2% w/w palmitic acid. The
sterile solution was stored in a glass ampule with a rubber cap
until needed.
Example 11
Pharmacokinetic Evaluation of Buprenorphine/Liquid Polymer
Formulations
[0054] Samples of the buprenorphine HCL/liquid polymer formulation
described in Example 8 and the buprenorphine base/liquid polymer
formulation described in Example 11 were evaluated in dogs for in
vivo release of the drug. A commercially available aqueous solution
of buprenorphine HCL (Buprenex.RTM.) was used as the control. The
Buprenex.RTM. control formulation was administered to the dogs
subcutaneously every 8 hours at a dose of 0.03 mg/kg for 64 hours
(nine administrations) to give a total dose of 0.27 mg/kg. The two
liquid polymer formulations were administered only once at a total
dose of 0.27 mg/kg to match the dose given with the Buprenex.RTM.
control. Samples of blood were collected from the dogs at 0
(pre-dose administration), and 1, 4, 8, 12, 24, 48, 72, and 90
hours post-administration and separated into plasma for analysis of
buprenorphine concentration by liquid chromatography/mass
spectroscopy (LC/MS/MS). A total of three dogs were used with each
dog receiving one of the three test articles at the initiation of
the study and a different test article 10 days later until each dog
had received all three formulations. The results are presented in
Table 4.
TABLE-US-00004 TABLE 4 Pharmacokinetics of Buprenorphine/Liquid
Polymer Formulations Buprenorphine Plasma Concentration, ng/mL
Time, hrs Buprenex .RTM. Polymer/HCL Polymer/Base 0 0 0 0 1 5.46
2.14 0 4 1.86 1.88 0.25 8 0.99 1.57 0.83 12 2.84 1.58 0.97 24 1.72
1.69 1.26 48 2.30 1.30 1.38 72 2.24 1.21 1.24 90 0.57 0.57 0.63
[0055] The data show that the liquid polymer formulations gave
lower initial plasma levels of drug in the dogs than the
Buprenex.RTM. control formulation even though nine times the amount
of buprenorphine were administered initially as the control. These
data indicate that the liquid polymer delivery system was able to
suppress the initial burst of drug to safe levels. The data also
show that the liquid polymer/base formulation with the addition of
palmitic acid to form the palmitate salt completely suppressed the
initial burst of drug with a resultant delay in drug release. The
almost constant levels of buprenorphine obtained with the liquid
polymer formulations over the 72 hours of the study are a good
indication of the controlled release of the drug from the liquid
polymer delivery system. In contrast, the plasma levels with the
Buprenex.RTM. control formulation were more erratic due to the
administration every 8 hours. Based upon the plasma levels obtained
with the liquid polymer formulations, it appears that they will
provide with only one administration the same degree of pain
control as the Buprenex.RTM. control with eight administrations,
and they will do this without any burst effects from the polymer
system.
Example 12
Evaluation of Doxycycline Hyclate/Liquid Polymer Formulations for
In Vitro Release of Drug
[0056] The 60/40 liquid polymer solution described in Example 4 was
used to fill a 1.2 cc polypropylene syringe with male luer-lok
fittings to about 0.5 cc of polymer solution. Also, a small amount
of the nonpolymeric material, palmitic acid, was added to a
container with some of the 60/40 liquid polymer solution to give a
solution containing by weight 54% liquid polymer, 36% NMP, and 10%
palmitic acid. About 0.5 cc of this solution was filled into a 1.2
cc polypropylene syringe with a male luer-lok fitting. Next, a
small amount of the higher viscosity liquid polymer described in
Example 1 was dissolved in triacetin, a more lipophilic solvent, at
50% w/w polymer and 50% w/w triacetin. About 0.5 cc of this liquid
polymer solution was also filled into a polypropylene syringe. Each
of the syringes with the liquid polymer solutions were connected to
a female luer-lok polypropylene syringe containing 50 mg of
doxycycline hyclate powder, and the contents of the syringe moved
back and forth between the two syringes 50 times. Doxycycline is a
broad-spectrum tetracycline antibiotic. Similarly, a control sample
of the solid polymer, poly(DL-lactide) dissolved in NMP at a ratio
of 37% w/w polymer to 63% w/w NMP was also mixed with 50 mg of
doxycycline hyclate for 50 times. The thoroughly mixed formulations
were then drawn back into the male syringe, the two syringes
decoupled, and the contents of the syringes injected without a
needle into small containers with 10 mL of water.
[0057] Each of the formulations before injection into the water was
yellow due to the color of the doxycycline, and the release of the
drug could be easily followed by observing the color of the water
receiving fluid. The solid polymer/doxycycline formulation gave a
solid intact mass immediately upon insertion into the water
receiving fluid. All of the liquid polymer/doxycycline formulations
gave liquid films upon insertion into the water receiving fluids.
Both the 60/40 liquid polymer/NMP and the 54/36/10 liquid
polymer/NMP/palmitic acid formulations gave liquid films upon the
top of the water whereas the liquid polymer/triacetin formulation
formed a liquid film at the bottom of the water container. With
time, the liquid polymer/palmitic acid formulation tended to
thicken whereas the other liquid polymer formulations remained
fluid liquids.
[0058] Surprising, after ten hours, it was apparent from the color
of the receiving fluids that the solid polymer formulation had
released more drug than the other formulations. The amount of drug
release was in the order of the solid polymer/NMP>50/50 liquid
polymer/triacetin>60/40 liquid polymer/NMP>54/36/10 liquid
polymer/NMP/palmitic acid. After 20 hours, the order of drug
release was solid polymer/NMP>50/50 liquid
polymer/triacetin>54/36/10 liquid polymer/NMP/palmitic
acid>60/40 liquid polymer/NMP. After three days, the 60/40
liquid polymer/NMP and the 54/36/10 liquid polymer/NMP/palmitic
acid still had some yellow color in the liquid implant whereas the
solid polymer/NMP implant was white. These data showed that
surprisingly the liquid polymer formulations gave less of a drug
burst and more sustained release than the solid polymer
formulation.
[0059] Although specific embodiments have been illustrated and
described herein, it will be appreciated by those of ordinary skill
in the art that any arrangement which is calculated to achieve the
same purpose may be substituted for the specific embodiments shown.
This application is intended to cover any adaptations or variations
that operate according to the principles of the invention as
described. Therefore, it is intended that this invention be limited
only by the claims and the equivalents thereof. The disclosures of
patents, references and publications cited in the application are
incorporated by reference herein.
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