U.S. patent application number 10/224444 was filed with the patent office on 2003-03-06 for gel composition and methods.
Invention is credited to Brodbeck, Kevin J., Gaynor-Duarte, Ann T., Shen, Theodore Tao-Ian.
Application Number | 20030044467 10/224444 |
Document ID | / |
Family ID | 21870398 |
Filed Date | 2003-03-06 |
United States Patent
Application |
20030044467 |
Kind Code |
A1 |
Brodbeck, Kevin J. ; et
al. |
March 6, 2003 |
Gel composition and methods
Abstract
Methods and compositions for systemically or locally
administering by implantation a beneficial agent to a subject are
described, and include, for example, compositions having burst
indices of 8 or less for systemic applications and systems
releasing 10% or less of the total dose of beneficial agent in the
first 24 hours after implantation for local applications. The
compositions include a biocompatible polymer, a biocompatible
solvent having low water miscibility that forms a viscous gel with
the polymer and limits water uptake by the implant, and a
beneficial agent.
Inventors: |
Brodbeck, Kevin J.; (Palo
Alto, CA) ; Gaynor-Duarte, Ann T.; (Oakland, CA)
; Shen, Theodore Tao-Ian; (Redwood City, CA) |
Correspondence
Address: |
ALZA CORPORATION
P O BOX 7210
INTELLECTUAL PROPERTY DEPARTMENT
MOUNTAIN VIEW
CA
940397210
|
Family ID: |
21870398 |
Appl. No.: |
10/224444 |
Filed: |
August 19, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10224444 |
Aug 19, 2002 |
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08993208 |
Dec 18, 1997 |
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6130200 |
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60033439 |
Dec 20, 1996 |
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Current U.S.
Class: |
424/486 |
Current CPC
Class: |
A61K 38/21 20130101;
A61K 47/14 20130101; A61P 41/00 20180101; A61K 38/27 20130101; A61K
9/0024 20130101; A61K 47/34 20130101; A61P 5/00 20180101; A61K
47/02 20130101; A61K 47/10 20130101; A61K 38/212 20130101; A61K
9/0019 20130101 |
Class at
Publication: |
424/486 |
International
Class: |
A61K 009/14 |
Claims
we claim:
1. A method of systemically administering a beneficial agent to a
subject which comprises implanting a system comprising a beneficial
agent dissolved or dispersed substantially throughout a viscous
gel, the system having a burst index of 8 or less.
2. The method of claim 1 wherein the viscous gel comprises a
biocompatible polymer and a solvent.
3. The method of claim 2 in which the viscous gel optionally
includes one or more of the following: an emulsifying agent, a pore
former, a solubility modulator for the beneficial agent and an
osmotic agent.
4. The method of claim 2 wherein the solvent comprises a solvent
having a miscibility in water of less than 7% by weight.
5. The method of claim 4 wherein the solvent is selected from lower
alkyl and aralkyl esters of aryl acids; aryl, aralkyl and lower
alkyl ketones; and lower alkyl esters of citric acid.
6. The method of claim 2 wherein the polymer is selected from the
group consisting of polylactides, polyglycolides,
polycaprolactones, polyanhydrides, polyamines, polyurethanes,
polyesteramides, polyorthoesters, polydioxanones, polyacetals,
polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes,
succinates, poly(malic acid), poly(amino acids),
polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose,
chitin, chitosan, and copolymers, terpolymers and mixtures
thereof.
7. The method of claim 5 wherein the polymer is a lactic acid-based
polymer and the solvent is selected from lower alkyl and aralkyl
esters of benzoic acid.
8. A method of locally administering a beneficial agent to a
subject which comprises implanting a system comprising a beneficial
agent dissolved or dispersed substantially throughout a viscous
gel, the system releasing within 24 hours after implantation not
greater than 20% by weight of the amount of beneficial agent to be
delivered over the duration of the delivery period.
9. The method of claim 8 wherein the viscous gel comprises a
biocompatible polymer and a solvent.
10. The method of claim 9 in which the viscous gel optionally
includes one or more of the following: an emulsifying agent, a pore
former, a solubility modulator for the beneficial agent, and an
osmotic agent.
11. The method of claim 10 wherein the solvent comprises a solvent
having a miscibility in water of less than 7% by weight.
12. The method of claim 11 wherein the solvent is selected from
lower alkyl and aralkyl esters of aryl acids; aryl, aralkyl and
lower alkyl ketones; and lower alkyl esters of citric acid.
13. The method of claim 9 wherein the polymer is selected from the
group consisting of polylactides, polyglycolides,
polycaprolactones, polyanhydrides, polyamines, polyurethanes,
polyesteramides, polyorthoesters, polydioxanones, polyacetals,
polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes,
succinates, poly(malic acid), poly(amino acids),
polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose,
chitin, chitosan, and copolymers, terpolymers and mixtures
thereof.
14. The method of claim 12 wherein the polymer is a lactic
acid-based polymer and the solvent is selected from lower alkyl and
aralkyl esters of benzoic acid.
15. A method of administering a beneficial agent to a subject in a
controlled manner approximating zero order release by implanting a
gel composition comprising a biocompatible polymer, a biocompatible
solvent having a solubility in water of less than 7%, and a
beneficial agent, wherein the loading of the beneficial agent in
the interior of the polymer is above that required to saturate the
beneficial agent in water.
16. A method of administering a beneficial agent to a subject which
comprises implanting a system comprising a beneficial agent
dissolved or dispersed substantially throughout a viscous gel
formed of a biocompatible polymer and a solvent having a solubility
in water of 7% or less, and a solubility modulator of the
beneficial agent, the system having a burst index of or less.
17. The method of claim 16 wherein the polymer is a lactic
acid-based polymer.
18. An implantable composition for the systemic delivery of a
beneficial agent to a subject wherein the composition comprises a
polymer; an amount of a solvent to form a viscous gel with the
polymer, and a beneficial agent dissolved or dispersed in the gel,
wherein the solvent comprises a single solvent or a mixture of
solvents with at least one solvent having a miscibility in water of
less than 7% by weight and the total amount of solvent constituting
40% or more by weight of the gel vehicle, said composition having a
burst index of 8 or less.
19. An implantable, biodegradable composition for the sustained
delivery of a beneficial agent to a subject wherein the composition
comprises a polymer; an effective plasticizing amount of a solvent
to form a viscous gel with the polymer; and a beneficial agent
dissolved or dispersed in the gel, wherein the solvent comprises a
mixture of solvents with at least one solvent in the mixture having
a miscibility in water of less than 7% by weight.
20. The composition of claim 19 wherein the miscibility in water of
the solvent mixture is 10% or less by weight.
21. An implantable, biodegradable composition for delivery of a
beneficial agent to a subject wherein the composition comprises a
polymer; an effective plasticizing amount of a solvent to form a
viscous gel with the polymer; and a beneficial agent dissolved or
dispersed in the gel, wherein the solvent comprises a single
solvent or a mixture of solvents with at least one solvent having a
miscibility in water of less than 7% by weight selected from lower
alkyl and aralkyl esters of benzoic acid.
22. An implantable gel composition for delivery of a beneficial
agent to a subject comprising: A) a biocompatible polymer; B) a
biocompatible solvent, having miscibility in water of less than 7%
by weight and capable of dissolving the polymer and forming a
viscous gel; said solvent being selected from the group comprising
compounds having the following structural formula: 4wherein R.sub.1
is lower alkyl, aryl or aralkyl and R.sub.2 is aralkyl or lower
alkyl; and R.sub.1 and R.sub.2 may be the same or different; with
the proviso that when R.sub.1 and R.sub.2 are each lower alkyl, the
number of total carbon atoms represented by R.sub.1 and R.sub.2
combined is 4 or more; C) a beneficial agent; and, optionally, one
or more of the following: D) an emulsifying agent; E) a pore
former; and F) a solubility modulator for the beneficial agent; and
G) an osmotic agent.
23. An implantable gel composition for delivery of a beneficial
agent to a subject comprising: A) a biocompatible lactic acid-based
polymer; B) a biocompatible solvent, having miscibility in water of
less than 7% by weight and capable of dissolving the polymer and
forming a viscous gel; said solvent being selected from the group
comprising compounds having the following structural formula:
5wherein R.sub.1 is lower alkyl, aryl or aralkyl and R.sub.2 is
aralkyl or lower alkyl; and R.sub.1 and R.sub.2 may be the same or
different; with the proviso that when R.sub.1 and R.sub.2 are each
lower alkyl, the number of total carbon atoms represented by
R.sub.1 and R.sub.2 combined is 4 or more; C) a beneficial agent;
and, optionally, one or more of the following: D) an emulsifying
agent; E) a pore former; F) a solubility modulator for the
beneficial agent; and G) an osmotic agent.
24. The composition of claim 23 wherein R.sub.1 is phenyl.
25. The composition of claim 24 wherein R.sub.2 is benzyl.
26. A method of preparing an injectable depot gel composition
comprising: A) mixing a biocompatible polymer and a solvent having
a miscibility in water of 7% or less selected from lower alkyl and
aralkyl esters of benzoic acid to form a viscous gel; B) dispersing
or dissolving a beneficial agent, optionally associated with a
solubility modulator, in an emulsifying agent to form a beneficial
agent containing emulsifying agent; and C) mixing the beneficial
agent containing emulsifying agent with the viscous gel, said
beneficial agent containing emulsifying agent forming a dispersed
droplet phase in the viscous gel, and optionally, D) mixing one or
more of a pore former and an osmotic agent with said viscous gel,
to provide an injectable gel composition.
27. A gel composition for systemic administration comprising: A) a
biocompatible polymer; B) a biocompatible solvent having a
miscibility in water of less than 7%; C) a beneficial agent
selected from the group consisting of cDNA, DNA, peptides, proteins
and fragments and derivatives thereof, and optionally, one or more
of the following: D) an emulsifying agent; E) a pore former; F) a
solubility modulator for the beneficial agent; and G) an osmotic
agent. wherein the composition has a burst index of less than
8.
28. A kit for administration of a beneficial agent to a subject
comprising: A) a biocompatible polymer; B) a solvent having a
miscibility in water of 7% or less by weight that is suitable for
dissolving the polymer and forming a viscous gel; C) a beneficial
agent; and optionally, one or more of the following: D) an
emulsifying agent; E) a pore former; F) a solubility modulator for
the beneficial agent, optionally associated with the beneficial
agent; and G) an osmotic agent; wherein at least the beneficial
agent, optionally associated with the solubility modulator, is
maintained separated from the solvent until the time of
administration of the beneficial agent to a subject.
29. An implantable composition for the systemic delivery of a
beneficial agent comprising a poly(lactide-co-glycolide) copolymer;
an effective plasticizing amount of a solvent to form a viscous gel
with the polymer; and a beneficial agent selected from the group
consisting of cDNA, DNA, peptides, proteins and fragments and
derivatives thereof, said composition having a burst index of equal
to or less than 8.
30. An implantable composition for the sustained delivery of a
beneficial agent comprising a poly(lactide-co-glycolide) copolymer;
an effective plasticizing amount of a solvent comprising a lower
alkyl or aralkyl ester of benzoic acid to form a viscous gel with
the polymer; and a beneficial agent.
31. The composition of claim 30 wherein the solvent has a
miscibility in water by weight of less than 7%.
32. The composition of claim 30 wherein the solvent is benzyl
benzoate.
33. The composition of claim 30 comprising a solubility modulator
of the beneficial agent.
34. The composition of claim 30 comprising a pore former.
35. The composition of claim 30 comprising an emulsifying
agent.
36. The composition of claim 30 comprising an osmotic agent.
37. The composition of claim 33 wherein the solubility modulator is
selected from salts of divalent metals.
38. The composition of claim 34 in which the pore former is water
soluble.
39. The composition of claim 34 wherein the pore former is selected
from group consisting of water soluble sugars, salts, solvents and
polymers.
40. The composition of claim 35 in which the emulsifying agent is
capable of forming a dispersed droplet phase in said viscous
gel.
41. The composition of claim 35 in which the emulsifying agent is
selected from the group consisting of alcohols, propylene glycol,
ethylene glycol, glycerol, water and solutions and mixtures
thereof.
42. The composition of claim 35 wherein the emulsifying agent is
selected from the group consisting of ethanol, isopropyl alcohol,
water, solutions thereof, and mixtures thereof.
43. The composition of claim 30 wherein the copolymer has a monomer
ratio of lactic acid to glycolic acid in the range of 100:0 to
about 15:85.
44. The composition of claim 30 wherein the copolymer has a number
average molecular weight of from 1,000 to 120,000.
45. The composition of claim 30 wherein the solvent comprises a
component solvent miscible with the solvent.
46. The composition of claim 45 wherein the component solvent is
selected from the group consisting of triacetin, diacetin,
tributyrin, triethyl citrate, tributyl citrate, acetyl triethyl
citrate, acetyl tributyl citrate, triethylglycerides, triethyl
phosphate, diethyl phthalate, diethyl tartrate, mineral oil,
polybutene, silicone fluid, glylcerin, ethylene glycol,
polyethylene glycol, octanol, ethyl lactate, propylene glycol,
propylene carbonate, ethylene carbonate, butyrolactone, ethylene
oxide, propylene oxide, N-methyl-2-pyrrolidone, 2-pyrrolidone,
glycerol formal, methyl acetate, ethyl acetate, methyl ethyl
ketone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran,
caprolactam, decylmethylsulfoxide, oleic acid, and
1-dodecylazacyclo-heptan-2-one, and mixtures thereof.
47. The composition of claim 45 wherein the component solvent is
selected from the group consisting of triacetin and
N-methyl-2-pyrrolidone, and mixtures thereof.
48. The composition of claim 45 wherein the component solvent is
triacetin.
49. The method of claim 2 wherein the beneficial agent is present
in an amount of from 1 to 50% by weight of the combined amounts of
the polymer, the solvent and the beneficial agent.
50. The method of claim 1 wherein the beneficial agent is cDNA,
DNA, a protein, a peptide, and derivatives or fragments thereof, or
a chemotherapeutic agent.
51. The method of claim 50 wherein the beneficial agent is human
growth hormone, methionine-human growth hormone, des-phenylalanine
human growth hormone, interferon alpha-2a, interferon alpha-2b, or
consensus interferon.
52. The method of claim 8 wherein the beneficial agent is cDNA,
DNA, a protein, a peptide, and derivatives or fragments thereof, or
a chemotherapeutic agent.
53. The method of claim 1 wherein the beneficial agent is released
from the system over a prolonged period.
54. The method of claim 8 wherein the beneficial agent is released
from the system over a prolonged period.
55. The method of claim 1 wherein the system is non-rigid after
implantation.
56. The method of claim 55 wherein the system maintains a glass
transition temperature below 37.degree. C. for at least 24 hours
after implantation.
57. The method of claim 9 wherein the system is non-rigid after
implantation.
58. The method of claim 57 wherein the system maintains a glass
transition temperature below 37.degree. C. for at least 24 hours
after implantation.
59. The composition of claim 18 wherein the gel remains non-rigid
after implantation.
60. The composition of claim 59 wherein the gel maintains a glass
transition temperature below 37.degree. C. for at least 24 hours
after implantation.
61. An implantable gel composition comprising a biocompatible
polymer, a biocompatible solvent forming a viscous gel with the
polymer, and a beneficial agent, the composition imbibing 40% or
less of its bulk weight in water within the first 21 days after
implantation.
62. The composition of claim 61 wherein the composition imbibes
less than 30% of its bulk weight in water within the first 14 days
after implantation.
63. The composition of claim 62 wherein the composition imbibes
less than 25% of its bulk weight in water within the first 7 days
after implantation.
Description
[0001] This application claims the priority of provisional
application Serial No. 60/033,439, filed Dec. 20, 1996, which is
incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to a gel composition that can
be implanted into a desired location and which can provide
controlled release of a beneficial agent. The present invention
also relates to methods of controlling release of a beneficial
agent from a composition.
[0004] 2. Description of the Related Art
[0005] Biodegradable polymers have been used for many years in
medical applications. Illustrative devices composed of the
biodegradable polymers include sutures, surgical clips, staples,
implants, and sustained release drug delivery systems. The majority
of these biodegradable polymers have been based upon glycolide,
lactide, caprolactone, and copolymers thereof.
[0006] The biodegradable polymers can be thermoplastic materials
which means that they can be heated and formed into various shapes
such as fibers, clips, staples, pins, films, etc. Alternatively,
they can be thermosetting materials formed by crosslinking
reactions which lead to high-molecular-weight materials that do not
melt or form flowable liquids at high temperatures.
[0007] Although thermoplastic and thermosetting biodegradable
polymers have many useful biomedical applications, there are
several important limitations to their use in the bodies of various
animals including humans, animals, birds, fish, and reptiles.
Because these polymers generally are solids, all instances
involving their use have required initially forming the polymeric
structures outside the body, followed by insertion of the solid
structure into the body. For example, sutures, clips, and staples
are all formed from thermoplastic biodegradable polymers prior to
use. When inserted into the body, they retain their original shape.
While this characteristic is essential for some uses, it is not
preferred where it is desired that the material be molded or flow
to fill voids or cavities where it may be most needed.
[0008] Drug delivery systems using thermoplastic or thermosetting
biodegradable polymers also often are or have to be formed outside
the body. In such instances, the drug is incorporated into the
polymer and the mixture is shaped into a certain form such as
cylinder, disc, or fiber for implantation. With such solid
implants, the drug delivery system has to be inserted into the body
through an incision. These incisions are sometimes larger than
desired by the medical profession and occasionally lead to a
reluctance of the patient to accept such an implant or drug
delivery system. Nonetheless, both biodegradable and
non-biodegradable implantable drug delivery systems have been
widely used successfully.
[0009] One reservoir device having a rate-controlling membrane and
zero-order release of an agent that is particularly designed for
intraoral implantation is described in U.S. Pat. No. 5,085,866. The
device is prepared from a core that is sprayed with a solution
having a polymer and a solvent that is composed of a rapidly
evaporating, low boiling point first solvent and a slowly
evaporating, high boiling point second solvent.
[0010] Other illustrative osmotic delivery systems include those
disclosed in U.S. Pat. Nos. 3,797,492, 3,987,790, 4,008,719,
4,865,845, 5,057,318, 5,059,423, 5,112,614, 5,137,727, 5,151,093,
5,234,692, 5,234,693, 5,279,608, and 5,336,057. Pulsatile delivery
devices are also known which deliver a beneficial agent in a
pulsatile manner as disclosed in U.S. Pat. Nos. 5,209,746,
5,308,348, and 5,456,679.
[0011] One way to avoid the incision needed to implant drug
delivery systems is to inject them as small particles,
microspheres, or microcapsules. For example, U.S. Pat. No.
5,019,400 describes the preparation of controlled release
microspheres via a very low temperature casting process. These
materials may or may not contain a drug which can be released into
the body. Although these materials can be injected into the body
with a syringe, they do not always satisfy the demand for a
biodegradable implant. Because they are particulate in nature, they
do not form a continuous film or solid implant with the structural
integrity needed for certain prostheses. When inserted into certain
body cavities such as a mouth, a periodontal pocket, the eye, or
the vagina where there is considerable fluid flow, these small
particles, microspheres, or microcapsules are poorly retained
because of their small size and discontinuous nature. Further, the
particles tend to aggregate and thus their behavior is hard to
predict. In addition, microspheres or microcapsules prepared from
these polymers and containing drugs for release into the body are
sometimes difficult to produce on a large scale, and their storage
and injection characteristics present problems. Furthermore, one
other major limitation of the microcapsule or small-particle system
is their lack of reversibility without extensive surgical
intervention. That is, if there are complications after they have
been injected, it is considerably more difficult to remove them
from the body than with solid implants. A still further limitation
on microparticles or microcapsulation is the difficulty in
encapsulating protein and DNA-based drugs without degradation
caused by denaturing solvents and temperature extremes used during
processing.
[0012] The art has developed various drug delivery systems in
response to the aforementioned challenges. For instance, U.S. Pat.
No. 4,938,763 and its divisional U.S. Pat. No. 5,278,201 relate to
a biodegradable polymer for use in providing syringeable, in-situ
forming, solid biodegradable implants for animals. In one
embodiment, a thermoplastic system is used wherein a non-reactive
polymer is dissolved in a water soluble biocompatible solvent to
form a liquid which is placed in the animal wherein the solvent
dissipates to produce the solid implant. Alternatively, a
thermosetting system is used wherein effective amounts of a liquid
acrylic ester-terminated, biodegradable prepolymer and a curing
agent are formed and the liquid mixture is placed within the animal
wherein the prepolymer cures to form the solid implant. It is
stated that the systems provide a syringeable, solid biodegradable
delivery system by the addition of an effective level of a
biologically active agent to the liquid before the injection into
the animal.
[0013] U.S. Pat. No. 5,599,552 describes thermoplastic and
thermoset polymer compositions that utilize solvents which are
miscible to dispersible in water, such as N-methyl-2-pyrrolidone,
resulting in polymer solutions capable of quickly absorbing water
from surrounding tissue. The polarity of the solvents is described
as being effective to provide about at least 10% solubility in
water. The polymer matrix systems are described as forming a porous
core surrounded by a porous skin.
[0014] U.S. Pat. No. 5,242,910 describes a sustained release
composition containing drugs for treating periodontal disease. The
composition comprises copolymers of lactide and glycolide,
triacetin (as a solvent/plasticizer) and an agent providing relief
of oral cavity diseases. The composition can take the form of a gel
and can be inserted into a periodontal cavity via a syringe using
either a needle or a catheter. As additional optional components,
the composition can contain surfactants, flavoring agents,
viscosity controlling agents, complexing agents, antioxidants,
other polymers, gums, waxes/oils, and coloring agents. One
illustrative viscosity controlling agent set forth in one of the
examples is polyethylene glycol 400.
[0015] U.S. Pat. No. 5,620,700 describes a polymer-drug matrix,
optionally including plasticizers in an amount up to about 30 wt %,
for local application of drug in the peridontal cavity. Among the
plasticizers listed are, inter alia, triethyl citrate, acetyl
triethyl citrate, tributyl citrate, acetyl tributyl citrate,
diethyl phthalate, diethyl tartrate, ethyl lactate, triacetin and
diacetin. The polymer matrix is non-flowable prior to
administration and is heated to become flowable so that it may be
dispensed into the peridontal cavity where it solidifies. While the
patent discusses possible systemic applications by delivery via the
ocular sacs of the eye or intravaginal delivery, it does not
address the issue of burst of drug or methods of controlling
burst.
[0016] U.S. Pat. No. 3,923,939 describes a method of reducing
initial burst of an active agent from a delivery device by
removing, prior to implantation, active agent from the exterior
surface of the delivery device and through a layer of at least 5%
of the overall body thickness extending from the exterior surface
of the device.
[0017] U.S. Pat. No. 5,556,905 describes degradable thermoplastic
compositions which are modified by plasticizers consisting of
various partial esters of citric acid.
[0018] Prior art polymer compositions for injectable implants have
used solvent/plasticizers that are very or relatively soluble in
aqueous body fluids to promote rapid solidification of the polymer
at the implant site and promote diffusion of drug from the implant.
However, it has now been observed that a serious problem associated
with prior art polymeric implants utilizing water soluble polymer
solvents is the rapid migration of water into the polymer
composition when the implant is placed in the body and exposed to
aqueous body fluids. That characteristic often results in
uncontrolled release of beneficial agent that is manifested by an
initial, rapid release of beneficial agent from the polymer
composition, corresponding to a "burst" of beneficial agent being
released from the implant. The burst often results in a substantial
portion of the beneficial agent, if not all, being released in a
very short time, e.g., hours or 1-2 days. Such an effect can be
unacceptable, particularly in those circumstances where sustained
delivery is desired, i.e., delivery of beneficial agent over a
period of a week or a month or more, or where there is a narrow
therapeutic window and release of excess beneficial agent can
result in adverse consequences to the subject being treated, or
where it is necessary to mimic the naturally-occurring daily
profile of beneficial agents, such as hormones and the like, in the
body of the subject being treated.
[0019] In an attempt to control burst and modulate and stabilize
the delivery of the beneficial agent the prior art has coated
particles of beneficial agent to retard release into an aqueous
environment and extend release of the beneficial agent over time.
Alternatively, various stabilizing or release modulating agents,
such as metal salts as described in U.S. Pat. Nos. 5,656,297;
5,654,010; 4,985,404 and 4,853,218 have been used. Notwithstanding
some success, those methods have not been entirely satisfactory for
the large number of beneficial agents that would be effectively
delivered by implants, since in many instances the modulation and
stabilization effect is the result of the formation of a complex of
the metal ion with the beneficial agent. When such complexes do not
form, the stabilization/modulation effect may not be adequate to
prevent undesirable "burst" of the beneficial agent upon its
introduction into the implant site.
[0020] Additionally, with conventional low viscosity, solvent-based
depot compositions comprised of a polymer dissolved in a solvent,
another problem which often exists is that the composition
solidifies slowly after injection as solvent diffuses from the
depot and water migrates into the depot. Since these compositions
are relatively non-viscous in order to be injected, a large
percentage of drug may be rapidly released as the system forms by
diffusion of the solvent, particularly when the beneficial agent is
soluble in the solvent and the solvent rapidly disperses into body
fluids. Rapid solvent release contributes to the "burst" effect
along with depot hardening due to water uptake. In this respect, it
is typical for conventional solvent-based compositions to have a
drug burst wherein 30-75% of the drug contained in the composition
is released within one day of the initial injection.
[0021] The rapid water uptake into the polymer implant and solvent
dispersion into body fluids exhibited by prior art devices often
results in implants having pore structures that are non-homogeneous
in size and shape. Typically, the surface pores take on a
finger-like pore structure extending for as much as 1/3 of a
millimeter or more from the implant surface into the implant, and
such finger-like pores are open at the surface of the implant to
the environment of use. The internal pores tend to be smaller and
less accessible to the fluids present in the environment of use.
Accordingly, when such devices are implanted, the finger-like pores
allow very rapid uptake of aqueous body fluids into the interior of
the implant with consequent immediate and rapid dissolution of
significant quantities of beneficial agent and unimpeded diffusion
of beneficial agent into the environment of use, producing the
burst effect discussed above.
[0022] Furthermore, rapid water uptake can result in premature
polymer precipitation such that a hardened implant or one with a
hardened skin is produced. The inner pores and much of the interior
of the polymer containing beneficial agent are shut off from
contact with the body fluids and a significant reduction in the
release of beneficial agent can result over a not insignificant
period of time ("lag time"). That lag time is undesirable from the
standpoint of presenting a controlled, sustained release of
beneficial agent to the subject being treated. What one observes,
then, is a burst of beneficial agent being released in a short time
period immediately after implantation, a lag time in which no or
very little beneficial agent is being released, and subsequently
continued delivery of beneficial agent (assuming beneficial agent
remains after the burst) until the supply of beneficial agent is
exhausted.
SUMMARY OF THE INVENTION
[0023] The present invention provides a method and an implantable
system for systemic and local delivery of a beneficial agent to a
subject. The method and system provide controlled release of
beneficial agent to the subject being treated and limit the initial
burst of beneficial agent from the implant system. Additionally,
the invention provides a method of preparing implant systems having
restricted initial burst of beneficial agent.
[0024] In one aspect, the invention comprises a method of
administering, locally or systemically, a beneficial agent to a
subject which comprises implanting a system comprising a beneficial
agent dispersed or dissolved substantially throughout a viscous
gel, the system releasing 20% or less by weight of the beneficial
agent present in the viscous gel within the first 24 hours after
implantation in the subject. Preferably, 10% or less by weight of
the beneficial agent will be released within the first 24 hours
after implantation.
[0025] In another aspect, the invention comprises a method of
systemically administering a beneficial agent to a subject which
comprises implanting a system comprising a beneficial agent
dispersed or dissolved substantially throughout a viscous gel, the
system having a burst index of 8 or less.
[0026] In still another aspect, the invention comprises a method of
systemically administering a beneficial agent to a subject in a
controlled manner approximating zero order release by implanting a
gel composition comprising a biocompatible polymer, a biocompatible
solvent having a solubility in water of less than 7% and forming a
viscous gel with the polymer, and a beneficial agent, wherein the
loading of the beneficial agent in the interior of the polymer gel
is above that required to saturate the beneficial agent in
water.
[0027] In still another aspect, the invention comprises an
implantable, biodegradable composition for the systemic delivery of
a beneficial agent to a subject wherein the composition comprises a
polymer; an amount of a solvent to form a viscous gel with the
polymer, and a beneficial agent dissolved or dispersed in the gel,
wherein the solvent comprises a single solvent or a mixture of
solvents with at least one solvent having a miscibility in water of
less than 7% by weight and the amount of solvent constituting 40%
or more by weight of the gel vehicle.
[0028] In a further aspect, the present invention comprises an
implantable, biodegradable composition for the sustained delivery
of a beneficial agent to a subject wherein the composition
comprises a polymer; an effective plasticizing amount of a solvent
to form a viscous gel with the polymer; and a beneficial agent
dissolved or dispersed in the gel, wherein the solvent comprises a
mixture of solvents with at least one solvent in the mixture having
a miscibility in water of less than 7% by weight. Preferably, the
miscibility in water of the solvent mixture is 20% or less by
weight, and more preferably 10% or less by weight.
[0029] In yet another aspect, the invention comprises an
implantable, biodegradable composition for delivery of a beneficial
agent to a subject wherein the composition comprises a polymer; an
effective plasticizing amount of a solvent to form a viscous gel
with the polymer; and a beneficial agent dissolved or dispersed in
the gel, wherein the solvent comprises a single solvent or a
mixture of solvents with at least one solvent having a miscibility
in water of less than 7% by weight selected from lower alkyl and
aralkyl esters of benzoic acid.
[0030] In another aspect the present invention provides an
implantable gel composition for systemic delivery of a beneficial
agent to a subject comprising:
[0031] A) a biocompatible polymer;
[0032] B) a biocompatible solvent, having miscibility in water of
less than 7% by weight and capable of dissolving the polymer and
forming a viscous gel, said solvent being selected from the group
comprising compounds having the following structural formula: 1
[0033] wherein R.sub.1 is lower alkyl, aryl or aralkyl and R.sub.2
is aralkyl or lower alkyl; and R.sub.1 and R.sub.2 may be the same
or different; with the proviso that when R.sub.1 and R.sub.2 are
each lower alkyl, the number of total carbon atoms represented by
R.sub.1 and R.sub.2 combined is 4 or more;
[0034] C) a beneficial agent; and, optionally, one or more of the
following:
[0035] D) an emulsifying agent;
[0036] E) a pore former;
[0037] F) a solubility modulator of the beneficial agent; and
[0038] G) an osmotic agent.
[0039] In another aspect the present invention provides an
implantable gel composition comprising:
[0040] A) a biocompatible polymer;
[0041] B) a biocompatible solvent having miscibility in water of
less than 7% by weight and capable of dissolving the polymer and
forming a viscous gel, said solvent being selected from the group
comprising compounds having the following structural formula: 2
[0042] wherein R.sub.1 and R.sub.2 are as defined above.
[0043] In a further aspect, the present invention provides a method
of restricting uptake of water by a gel composition which comprises
forming the gel composition from a polymer and a solvent that forms
a viscous gel with the polymer, the solvent having a miscibility in
water of less than 7% by weight. Preferably, the solvent will have
a miscibility in water of 6% or less by weight, and more preferably
5% or less by weight.
[0044] In another aspect, the present invention provides a method
of preparing an injectable gel composition comprising:
[0045] A) mixing a biocompatible polymer and a solvent having a
miscibility in water of 7% or less selected from lower alkyl and
aralkyl esters of benzoic acid to form a viscous gel;
[0046] B) dispersing or dissolving a beneficial agent, optionally
associated with a solubility modulator of the beneficial agent, in
an emulsifying agent to form a beneficial agent containing
emulsifying agent; and
[0047] C) mixing the beneficial agent containing emulsifying agent
with the viscous gel, said beneficial agent containing emulsifying
agent forming a dispersed droplet phase in the viscous gel, and
optionally,
[0048] D) mixing one or more of a pore former and an osmotic agent
with said viscous gel.
[0049] In another aspect, the present invention provides a method
of preparing an implantable gel composition comprising:
[0050] A) mixing a biocompatible polymer and a solvent having a
miscibility in water of 7% or less selected from lower alkyl and
aralkyl esters of benzoic acid to form a viscous gel;
[0051] B) dispersing or dissolving a beneficial agent, optionally
associated with a solubility modulator of the beneficial agent, in
the viscous gel; and;
[0052] C) optionally mixing one or more of the following: an
emulsifying agent, a pore former, a solubility modulator of the
beneficial agent and an osmotic agent, with the beneficial agent
containing gel.
[0053] In yet another aspect, the invention provides a gel
composition comprising:
[0054] A) a biocompatible polymer;
[0055] B) a biocompatible solvent having a miscibility in water of
less than 7% by weight;
[0056] C) a beneficial agent selected from the group consisting of
cDNA, DNA, peptides, proteins and fragments and derivatives
thereof, and optionally, one or more of the following:
[0057] D) an emulsifying agent;
[0058] E) a pore former;
[0059] F) a solubility modulator of the beneficial agent; and
[0060] G) an osmotic agent;
[0061] wherein the composition has a burst index of less than
8.
[0062] In still another aspect, the invention comprises a kit for
administration of a beneficial agent to a subject comprising:
[0063] A) a biocompatible polymer;
[0064] B) a solvent having a miscibility in water of 7% or less by
weight that is suitable for dissolving the polymer and forming a
viscous gel;
[0065] C) a beneficial agent; and optionally, one or more of the
following:
[0066] D) an emulsifying agent;
[0067] E) a pore former;
[0068] F) a solubility modulator of the beneficial agent,
optionally associated with the beneficial agent; and
[0069] G) an osmotic agent;
[0070] wherein at least the beneficial agent, optionally associated
with the solubility modulator, is maintained separated from the
solvent until the time of administration of the beneficial agent to
a subject.
[0071] In still another aspect, the invention comprises an
implantable composition for the systemic delivery of a beneficial
agent comprising a poly(lactide-co-glycolide) copolymer; an
effective plasticizing amount of a solvent to form a viscous gel
with the polymer; and a beneficial agent selected from the group
consisting of cDNA, DNA, peptides, proteins and fragments and
derivatives thereof, said composition having a burst index of 8 or
less.
[0072] In another aspect, the invention comprises an implantable
composition for the sustained delivery of a beneficial agent
comprising a poly(lactide-co-glycolide) copolymer; an effective
plasticizing amount of a solvent selected from lower alkyl and
aralkyl esters of benzoic acid to form a viscous gel with the
polymer; and a beneficial agent.
[0073] In a further aspect, the invention comprises an implantable
composition comprising a viscous gel and a beneficial agent
dispersed or dissolved therein, wherein the viscous gel maintains a
glass transition temperature of less than 37.degree. C. for at
least the first 24 hours after implantation.
[0074] In yet another aspect, the invention comprises a method of
administering a beneficial agent to a subject which comprises
implanting a system comprising a beneficial agent dissolved or
dispersed substantially throughout a viscous gel formed of a
biocompatible polymer and a solvent having a solubility in water of
7% or less, and a solubility modulator of the beneficial agent, the
system having a burst index of 8 or less.
[0075] In a further aspect, the invention comprises an implantable
system comprising a beneficial agent dissolved or dispersed
substantially throughout a viscous gel formed of a biocompatible
polymer and a solvent having a solubility in water of 7% or less,
and a solubility modulator of the beneficial agent, the system
having a burst index of 8 or less.
BRIEF DESCRIPTION OF THE DRAWINGS
[0076] The foregoing and other objects, features and advantages of
the present invention will be more readily understood upon reading
the following detailed description in conjunction with the drawings
in which:
[0077] FIG. 1 is a graph illustrating the dispense force required
to dispense emulsified and non-emulsified viscous gel compositions
through a 20 gauge needle in psig at 2 cc/min;
[0078] FIG. 2 is a graph illustrating the in vitro release profiles
of lysozyme from three different compositions in days;
[0079] FIG. 3 is a graph illustrating the viscosity profiles of
emulsions at different shear rates of water alone and of an aqueous
mixture of ethanol, and of the viscous gel without emulsifying
agent;
[0080] FIGS. 4A and 4B are graphs illustrating the degree of water
uptake for various polymer-solvent mixtures, some of which form a
part of this invention, and demonstrating that as the miscibility
of the solvent in water decreases, the amount of water taken up
into the implant decreases; and
[0081] FIGS. 5A and 5B are graphs of in vivo release rate profiles
of non-stabilized and zinc-stabilized human growth hormone from
gels formed from PLGA and the solvents triacetin and benzyl
benzoate, respectively.
DETAILED DESCRIPTION OF THE INVENTION
[0082] The present invention is directed to a method of
systemically or locally administering a beneficial agent to a
subject by implanting in the subject an implantable system, formed
as a viscous gel from a biocompatible polymer and a biocompatible
solvent, and a beneficial agent is substantially dissolved or
dispersed throughout the gel. By appropriate choice of solvent,
water migration from the aqueous environment surrounding the
implant system is restricted, and beneficial agent is released to
the subject over a prolonged period of time, thus providing for
delivery of the beneficial agent with a controlled burst of
beneficial agent and sustained release thereafter.
[0083] It has been discovered that when a solvent having a
solubility in water of less than 7% by weight in water is present
in the system, suitable burst control and sustained delivery of
beneficial agent is achieved, whether or not a solubility modulator
of the beneficial agent is present in the system. Typically, the
implant systems useful in this invention will release, in the first
24 hours after implantation, 20% or less of the total amount of
beneficial agent to be delivered to the subject from the implant
system, preferably 15% or less and more preferably 10% or less. The
viscous gel formed preferably is bioerodible so that the implant
system does not have to be surgically removed after beneficial
agent is depleted from the implant.
[0084] Water uptake and burst may be controlled by using
polymer-solvent compositions wherein the solvent is substantially
immiscible in water, i.e., less than 7% by weight soluble in water,
so as to control the rate of water migration into the polymer
implant and ultimately control the burst of beneficial agent and
the sustained delivery of beneficial agent. Generally, the
compositions of the invention will be gel-like and will form with a
substantially homogeneous pore structure throughout the implant
upon implantation and during drug delivery, even as it hardens.
Furthermore, while the polymer gel implant will slowly harden when
subjected to an aqueous environment, the hardened implant may
maintain a rubbery (non-rigid) composition with the glass
transition temperature being below 37.degree. C.
[0085] Since the compositions often will be highly viscous prior to
implantation, when the composition is intended for implantation by
injection, the viscosity optionally may be modified by emulsifiers
to obtain a gel composition having a viscosity low enough to permit
passage of the gel composition through a needle. Also, pore formers
and solubility modulators of the beneficial agent may be added to
the implant systems to provide desired release profiles from the
implant systems, along with typical pharmaceutical excipients and
other additives that do not change the beneficial aspects of the
present invention. The addition of a solubility modulator to the
implant system may enable the use of a solvent having a solubility
of 7% or greater in the implant system with minimal burst and
sustained delivery under particular circumstances. However, it is
presently preferred that the implant system utilize at least one
solvent having a solubility in water of less than 7% by weight,
whether the solvent is present alone or as part of a solvent
mixture. It has also been discovered that when mixtures of solvents
which include a solvent having 7% or less by weight solubility in
water and one or more miscible solvents, optionally having greater
solubility, are used, implant systems exhibiting limited water
uptake and minimal burst and sustained delivery characteristics are
obtained.
[0086] Definitions
[0087] The term "beneficial agent" means an agent that effects a
desired beneficial, often pharmacological, effect upon
administration to a human or an animal, whether alone or in
combination with other pharmaceutical excipients or inert
ingredients.
[0088] The term "AUC" means the area under the curve obtained from
an in vivo assay in a subject by plotting blood plasma
concentration of the beneficial agent in the subject against time,
as measured from the time of implantation of the composition, to a
time "t" after implantation. The time t will correspond to the
delivery period of beneficial agent to a subject.
[0089] The term "burst index" means, with respect to a particular
composition intended for systemic delivery of a beneficial agent,
the quotient formed by dividing (i) the AUC calculated for the
first twenty-four hours after implantation of the composition into
a subject divided by the number 24, by (ii) the AUC calculated for
the time period of delivery of beneficial agent, divided by the
number of hours in the total duration of the delivery period.
[0090] The phrase "dissolved or dispersed" is intended to encompass
all means of establishing a presence of beneficial agent in the gel
composition and includes dissolution, dispersion, suspension and
the like.
[0091] The term "systemic" means, with respect to delivery or
administration of a beneficial agent to a subject, that beneficial
agent is detectable at a biologically-significant level in the
blood plasma of the subject.
[0092] The term "local" means, with respect to delivery or
administration of a beneficial agent to a subject, that beneficial
agent is delivered to a localized site in the subject but is not
detectable at a biologically-significant level in the blood plasma
of the subject.
[0093] The term "gel vehicle" means the composition formed by
mixture of the polymer and solvent in the absence of the beneficial
agent.
[0094] The term "prolonged period" means a period of time over
which release of a beneficial agent from the implant of the
invention occurs, which will generally be about one week or longer,
and preferably about 30 days or longer.
[0095] The term "initial burst" means, with respect to a particular
composition of this invention, the quotient obtained by dividing
(i) the amount by weight of beneficial agent released from the
composition in a predetermined initial period of time after
implantation, by (ii) the total amount of beneficial agent that is
to be delivered from an implanted composition. It is understood
that the initial burst may vary depending on the shape and surface
area of the implant. Accordingly, the percentages and burst indices
associated with initial burst described herein are intended to
apply to compositions tested in a form resulting from dispensing of
the composition from a standard syringe.
[0096] The term "solubility modulator" means, with respect to the
beneficial agent, an agent that will alter the solubility of the
beneficial agent, with reference to polymer solvent or water, from
the solubility of beneficial agent in the absence of the modulator.
The modulator may enhance or retard the solubility of the
beneficial agent in the solvent or water. However, in the case of
beneficial agents that are highly water soluble, the solubility
modulator will generally be an agent that will retard the
solubility of the beneficial agent in water. The effects of
solubility modulators of the beneficial agent may result from
intereactions of the solubility modulator with the solvent, or with
the beneficial agent itself, such as by the formation of complexes,
or with both. For the purposes hereof, when the solubility
modulator is "associated" with the beneficial agent, all such
interactions or formations as may occur are intended. Solubility
modulators may be mixed with the beneficial agent prior to its
combination with the viscous gel or may be added to the viscous gel
prior to the addition of the beneficial agent, as appropriate.
[0097] The term "subject" means, with respect to the administration
of a composition of the invention, an animal or a human being.
[0098] Since all solvents, at least on a molecular level, will be
soluble in water (i.e., miscible with water) to some very limited
extent, the term "immiscible" as used herein means that 7% or less
by weight of the solvent is soluble in or miscible with water. For
the purposes of this disclosure, solubility values of solvent in
water are considered to be determined at 20.degree. C. Since it is
generally recognized that solubility values as reported may not
always be conducted at the same conditions, solubility limits
recited herein as percent by weight miscible or soluble with water
as part of a range or upper limit may not be absolute. For example,
if the upper limit on solvent solubility in water is recited herein
as "7% by weight", and no further limitations on the solvent are
provided, the solvent "triacetin", which has a reported solubility
in water of 7.17 grams in 100 ml of water, is considered to be
included within the limit of 7%. A solubility limit in water of
less than 7% by weight as used herein does not include the solvent
triacetin or solvents having solubilities in water equal to or
greater than triacetin.
[0099] The polymer, solvent and other agents of the invention must
be biocompatible; that is they must not cause irritation or
necrosis in the environment of use. The environment of use is a
fluid environment and may comprise a subcutaneous or intramuscular
portion or body cavity of a human or animal.
[0100] Polymers that may be useful in the invention may be
biodegradable and may include, but are not limited to polylactides,
polyglycolides, polycaprolactones, polyanhydrides, polyamines,
polyurethanes, polyesteramides, polyorthoesters, polydioxanones,
polyacetals, polyketals, polycarbonates, polyorthocarbonates,
polyphosphazenes, succinates, poly(malic acid), poly(amino acids),
polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose,
chitin, chitosan, and copolymers, terpolymers and mixtures
thereof.
[0101] Presently preferred polymers are polylactides, that is, a
lactic acid-based polymer that can be based solely on lactic acid
or can be a copolymer based on lactic acid and glycolic acid which
may include small amounts of other comonomers that do not
substantially affect the advantageous results which can be achieved
in accordance with the present invention. As used herein, the term
"lactic acid" includes the isomers L-lactic acid, D-lactic acid,
DL-lactic acid and lactide while the term "glycolic acid" includes
glycolide. Most preferred are poly(lactide-co-glycolide)copolymers,
commonly referred to as PLGA. The polymer may have a monomer ratio
of lactic acid/glycolic acid of from about 100:0 to about 15:85,
preferably from about 60:40 to about 75:25 and an especially useful
copolymer has a monomer ratio of lactic acid/glycolic acid of about
50:50.
[0102] The lactic acid-based polymer has a number average molecular
weight of from about 1,000 to about 120,000, preferably from about
5,000 to about 30,000 as determined by gas phase chromatography. As
indicated in aforementioned U.S. Pat. No. 5,242,910, the polymer
can be prepared in accordance with the teachings of U.S. Pat. No.
4,443,340. Alternatively, the lactic acid-based polymer can be
prepared directly from lactic acid or a mixture of lactic acid and
glycolic acid (with or without a further comonomer) in accordance
with the techniques set forth in U.S. Pat. No. 5,310,865. The
contents of all of these patents are incorporated by reference.
Suitable lactic acid-based polymers are available commercially. For
instance, 50:50 lactic acid:glycolic acid copolymers having
molecular weights of 5,000, 10,000, 30,000 and 100,000, preferably
about 8,000 to 13,000, and most preferably about 10,000, and a wide
variety of end groups to alter susceptibility to hydrolysis and
subsequent breakdown of the polymer chain are available from
Boehringer Ingelheim (Petersburg, Va.).
[0103] The biocompatible polymer is present in the gel composition
in an amount ranging from about 5 to about 80% by weight,
preferably from about to about 70% by weight and often 40 to 60% by
weight of the viscous gel, the viscous gel comprising the combined
amounts of the biocompatible polymer and the solvent. The solvent
will be added to polymer in amounts described below, to provide
implantable or injectable viscous gels.
[0104] The solvent must be biocompatible, should form a viscous gel
with the polymer, and restrict water uptake into the implant. The
solvent may be a single solvent or a mixture of solvents exhibiting
the foregoing properties. The term "solvent", unless specifically
indicated otherwise, means a single solvent or a mixture of
solvents. Suitable solvents will substantially restrict the uptake
of water by the implant and may be characterized as immiscible in
water, i.e., having a solubility in water of less than 7% by
weight. Preferably, the solvents are five weight percent or less
soluble in water; more preferably three weight percent or less
soluble in water; and even more preferably one weight percent or
less soluble in water. Most preferably the solubility of the
solvent in water is equal to or less than 0.5 weight percent.
[0105] Water miscibility may be determined experimentally as
follows: Water (1-5 g) is placed in a tared clear container at a
controlled temperature, about 20.degree. C., and weighed, and a
candidate solvent is added dropwise. The solution is swirled to
observe phase separation. When the saturation point appears to be
reached, as determined by observation of phase separation, the
solution is allowed to stand overnight and is re-checked the
following day. If the solution is still saturated, as determined by
observation of phase separation, then the percent (w/w) of solvent
added is determined. Otherwise more solvent is added and the
process repeated. Solubility or miscibility is determined by
dividing the total weight of solvent added by the final weight of
the solvent/water mixture. When solvent mixtures are used, for
example 20% triacetin and 80% benzyl benzoate, they are pre-mixed
prior to adding to the water.
[0106] Solvents useful in this invention are generally less than 7%
water soluble by weight as described above. Solvents having the
above solubility parameter may be selected from the lower alkyl and
aralkyl esters of aryl acids such as benzoic acid, the phthalic
acids, salicylic acid, lower alkyl esters of citric acid, such as
triethyl citrate and tributyl citrate and the like, and aryl,
aralkyl and lower alkyl ketones. Among preferred solvents are those
having solubilities within the foregoing range selected from (i)
compounds having the following structural formulas: 3
[0107] in which R.sub.1 is aryl or aralkyl, R.sub.2 is lower alkyl
or aralkyl, and R.sub.1 and R.sub.2 are optionally the same or
different, with the proviso that when each of R.sub.1 and R.sub.2
are lower alkyl, the total carbon atoms in R.sub.1 and R.sub.2
combined are 4 or more, and (ii) lower alkyl and aralkyl esters of
phthalic acid, isophthalic acid and terephtalic acid and (iii)
lower alkyl and aralkyl esters of citric acid. For the purposes
hereof, lower alkyl means straight or branched chain hydrocarbons
having 1-6 carbon atoms, optionally substituted with
non-interfering substituents; aralkyl means (lower alkyl)phenyl,
e.g., benzyl, phenethyl, 1-phenylpropyl, 2-phenylpropyl, and the
like wherein the alkyl moiety contains from 1-6 carbon atoms; and
aryl means phenyl, optionally substituted by non-interfering
substituents. Many of the solvents useful in the invention are
available commercially (Aldrich Chemicals, Sigma Chemicals) or may
be prepared by conventional esterification of the respective
arylalkanoic acids using acid halides, and optionally
esterification catalysts, such as described in U.S. Pat. No.
5,556,905, which is incorporated herein by reference, and in the
case of ketones, oxidation of their respective secondary alcohol
precursors.
[0108] Art recognized benzoic acid derivatives from which solvents
having the requisite solubility may be selected include:
1,4-cyclohexane dimethanol dibenzoate, diethylene glycol
dibenzoate, dipropylene glycol dibenzoate, polypropylene glycol
dibenzoate, propylene glycol dibenzoate, diethylene glycol benzoate
and dipropylene glycol benzoate blend, polyethylene glycol (200)
dibenzoate, iso decyl benzoate, neopentyl glycol dibenzoate,
glyceryl tribenzoate, pentaerylthritol tetrabenzoate, cumylphenyl
benzoate, trimethyl pentanediol dibenzoate.
[0109] Art recognized phthalic acid derivatives from which solvents
having the requisite solubility may be selected include: Alkyl
benzyl phthalate, bis-cumyl-phenyl isophthalate, dibutoxyethyl
phthalate, dimethyl phthalate, dimethyl phthalate, diethyl
phthalate, dibutyl phthalate, diisobutyl phthalate, butyl octyl
phthalate, diisoheptyl phthalate, butyl octyl phthalate, diisonoyl
phthalate, nonyl undecyl phthalate, dioctyl phthalate, di-iso octyl
phthalate, dicapryl phthalate, mixed alcohol phthalate,
di-(2-ethylhexyl) phthalate, linear heptyl, nonyl, phthalate,
linear heptyl, nonyl, undecyl phthalate, linear nonyl phthalate,
linear nonyl undecyl phthalate, linear dinoyl, didecyl phthalate
(diisodecyl phthalate), diundecyl phthalate, ditridecyl phthalate,
undecyldodecyl phthalate, decyltridecyl phthalate, blend (50/50) of
dioctyl and didecyl phthalates, butyl benzyl phthalate, and
dicyclohexyl phthalate.
[0110] Preferred solvents include the lower alkyl and aralkyl
esters of the aryl acids described above. Representative acids are
benzoic acid and the phthalic acids, such as phthalic acid,
isophthalic acid, and terephathalic acid. Most preferred solvents
are derivatives of benzoic acid and include, but are not limited
to, methyl benzoate, ethyl benzoate, n-propyl benzoate, isopropyl
benzoate, butyl benzoate, isobutyl benzoate, sec-butyl benzoate,
tert-butyl benzoate, isoamyl benzoate and benzyl benzoate, with
benzyl benzoate being most especially preferred. Preferred solvent
mixtures are those in which benzyl benzoate is the primary solvent,
and mixtures formed of benzyl benzoate and either triacetin,
tributyl citrate, triethyl citrate or N-methyl-2-pyrrolidone.
Preferred mixtures are those in which benzyl benzoate is present by
weight in an amount of 50% or more, more preferably 60% or more and
most preferably 80% or more of the total amount of solvent present.
Especially preferred mixtures are those of 80/20 mixtures by weight
of benzyl benzoate/triacetin and benzyl
benzoate/N-methyl-2-pyrrolidone.
[0111] It has been surprisingly found that the solvents described
above having a miscibility in water of less than 7% by weight may
be mixed with one or more additional miscible solvents ("component
solvents"). Component solvents compatible and miscible with the
primary solvent may have a higher miscibility with water and the
resulting mixtures may still exhibit significant restriction of
water uptake into the implant. Such mixtures will be referred to as
"component solvent mixtures." Useful component solvent mixtures may
exhibit solubilities in water greater than the primary solvents
themselves, typically between 0.1 weight percent and up to and
including 50 weight percent, preferably up to and including 30
weight percent, and most preferably up to an including 10 weight
percent, without detrimentally affecting the restriction of water
uptake exhibited by the implants of the invention. Especially
preferred are component solvent mixtures having a solubility in
water of about 0.1% to about 7% by weight.
[0112] Component solvents useful in component solvent mixtures are
those solvents that are miscible with the primary solvent or
solvent mixture, and include, but are not limited, to triacetin,
diacetin, tributyrin, triethyl citrate, tributyl citrate, acetyl
triethyl citrate, acetyl tributyl citrate, triethylglycerides,
triethyl phosphate, diethyl phthalate, diethyl tartrate, mineral
oil, polybutene, silicone fluid, glylcerin, ethylene glycol,
polyethylene glycol, octanol, ethyl lactate, propylene glycol,
propylene carbonate, ethylene carbonate, butyrolactone, ethylene
oxide, propylene oxide, N-methyl-2-pyrrolidone, 2-pyrrolidone,
glycerol formal, methyl acetate, ethyl acetate, methyl ethyl
ketone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran,
caprolactam, decylmethylsulfoxide, oleic acid, and
1-dodecylazacyclo-heptan-2-one, and mixtures thereof.
[0113] In an especially preferred embodiment, the primary solvent
is selected from lower alkyl and aralkyl esters of benzoic acid and
the polymer is a lactic-acid based polymer, most preferably PLGA,
having a number average molecular weight of between about 8,000 to
about 13,000, preferably about 10,000. Presently, the most
preferred solvents are benzyl benzoate and the lower alkyl esters
of benzoic acid. The benzoic acid esters may be used alone or in a
mixture with other miscible solvents, e.g., triacetin, as described
herein. Implants are prepared as viscous gels in which the
beneficial agent is dissolved or dispersed substantially
throughout, and such compositions are useful both for systemic and
local administration of beneficial agent, whether or not initial
burst is an important consideration. Additionally, use of esters of
benzoic acid provides increased control of water migration
resulting in increased stability of beneficial agent. The low water
uptake, i.e., limited water migration into the gel composition
after implantation, permits the practitioner of the invention to
limit beneficial agent transfer by diffusion and enhance control of
the delivery profile of the beneficial agent by controlling the
bioerosion characteristics of the polymer. The preferred
compositions allow beneficial agent to be loaded into the interior
of the polymer at levels that are above that required to saturate
the beneficial agent in water, thereby facilitating zero order
release of beneficial agent. Additionally, the preferred
compositions may provide viscous gels that have a glass transition
temperature that is less than 37.degree. C., such that the gel
remains non-rigid for a period of time after implantation of 24
hours or more.
[0114] The solvent or solvent mixture is capable of dissolving the
polymer to form a viscous gel that can maintain particles of the
beneficial agent dissolved or dispersed and isolated from the
environment of use prior to release. The compositions of the
present invention provide implants having a low burst index. Water
uptake is controlled by the use of a solvent or component solvent
mixture that solublizes or plasticizes the polymer but
substantially restricts uptake of water into implant.
[0115] The importance of restriction of water uptake can be
appreciated by reference to FIGS. 4A-4B illustrating bulk water
uptake for various compositions as a function of time and Table 1
illustrating representative formulations for which burst indices
have been determined.
[0116] Water uptake was determined for various polymer vehicles,
i.e., 50% polymer-50% solvent compositions, in the absence of
beneficial agent. As shown in FIG. 4A, water uptake by a gel
vehicle formed with the more water miscible solvent
N-methyl-2-pyrrolidone (NMP) is higher than that for any other
solvent-polymer combination, by about a factor of four or more.
Water uptake for the combination of 80% benzyl benzoate and 20% NMP
by weight in the solvent portion of the vehicle is less than a
third that of NMP alone. Implants with benzyl benzoate take up the
least water, whether compared to the other solvents alone or as
mixtures with benzyl benzoate. Additionally, it can be seen that
the 80/20 mixture of benzyl benzoate and triacetin takes up less
than 10% water on a weight basis, and exhibits less water uptake
than triacetin alone. FIG. 4B provides a comparison of various
solvents alone and demonstrates again the advantages of the benzoic
acid esters, particularly that of benzyl benzoate. A relative
comparison of the water uptake for the various solvents and the
burst indices reproduced in the foregoing Table 1 show a
correlation between low water uptake values and low burst indices.
Gel compositions of this invention may take up 25% or less of their
bulk weight in water within the first 7 days, 30% in the first 14
days and 40% in the first 21 days, as tested in the water migration
assay described herein.
1TABLE 1 Water Depot Zinc acetate Aninal Burst Solvent Miscibility
Gel.sup.1 Polymer.sup.2 (mM) Process.sup.3 No. Index Benzyl insol.
in water D PLGA-502 0 L 7 4.2 Benzoate (Merck) 8 2.4 K PLGA-502 0
SD 21 3.6 22 2.4 E PLGA-502 7.5 L 9 4.5 10 2.3 L PLGA-502 7.5 SD 23
2.6 24 2.1 F PLGA-502 15 L 11 1.5 12 2.0 F PLGA-502 15 L 25 2.2 26
0.64 Triacetin 7% sol. in water A PLGA-502 0 L 1 8.5 (Merck) 2 13 I
PLGA-502 0 SD 17 12 18 10 B PLGA-502 7.5 L 3 4.1 4 2.1 J PLGA-502
7.5 SD 19 6.3 20 3.5 C PLGA-502 15 L 5 4.8 6 3.5 NMP misc. with
water G PLGA-502 0 L 13 13 (Merck) 14 14 H PLGA-502 15 L 15 6.1 16
5.5 .sup.1All depot gels contained 10% hGH .sup.2For all depot
gels, hGH was loaded into (50/50) solvent/polymer vehicles .sup.3L
= Lyophilized; SD = Spray-dried
[0117] In addition to the control of water uptake and associated
initial burst by choice of solvent, agents that modulate the water
solubility of the beneficial agent can also be utilized in
conjunction with the preferred solvents to control burst of
beneficial agent from the implant. Burst indices and percent of
beneficial agent released in the first twenty-four hours after
implantation may be reduced by one-third to two-thirds or more by
the use of solubility modulators associated with the beneficial
agent. Such modulators are typically coatings, substances that form
complexes or otherwise associate with or stabilize the beneficial
agent such as metallic ions, other stabilizing agents, waxes,
lipids, oils, non-polar emulsions, and the like. Use of such
solubility modulators may permit the use of more highly water
soluble solvents or mixtures and achieve burst indices of 8 or less
for systemic applications, or with respect to local applications,
release of beneficial agent in the first 24 hours after
implantation of not greater than 20% of the beneficial agent
administered. Preferably that release will be not greater than 15%
and more preferably not greater than 10%.
[0118] Limited water uptake by the compositions of this invention
can often provide the opportunity to prepare compositions without
solubility modulators when in other compositions such modulators
would be necessary. For example with reference to Table 1, suitable
burst indices are obtained for a composition of PLGA, benzyl
benzoate and human growth hormone without the presence of Zn ion.
Similar results may be obtained with other beneficial agents, such
as the interferons, including interferon alpha-2a, interferon
alpha-2b and consensus interferon.
[0119] In instances where the choice of solvent and polymer result
in compositions severely restricting water uptake by themselves, it
may be desirable to add osmotic agents or other agents and
hydroattractants that facilitate water uptake to desired levels.
Such agents may be, for example, sugars and the like, and are well
known in the art.
[0120] Limited water uptake by the solvent-polymer compositions of
the present invention results in the implant compositions being
formed without the finger-like pores in the surface of implants
formed using prior art processes. Typically, a composition of the
present invention takes the form of a substantially, homogeneous,
sponge-like gel, with the pores in the interior of the implant
being much the same as the pores on the surface of the implant.
Compositions of the present invention retain their gel-like
consistency over a longer period than do prior art devices and
permit beneficial agent to be delivered over a prolonged period.
This is possible since the implants of the present invention
generally have a glass transition temperature, T.sub.g, of less
than body temperature of the subject, e.g. 37.degree. C. for
humans. Because of the immiscibility of the solvents that are
useful in this invention with water, water uptake by the implant is
restricted and the pores that do form tend to resemble a closed
cell structure without significant numbers of larger pores or pores
extending from the surface into the interior of the implant being
open at the surface of the implant. Furthermore, the surface pores
offer only a limited opportunity for water from body fluids to
enter the implant immediately after implantation, thus controlling
the burst effect. Since the compositions often will be highly
viscous prior to implantation, when the composition is intended for
implantation by injection, the viscosity optionally may be modified
by the use of viscosity-reducing, miscible solvents or the use of
emulsifiers, or by heating to obtain a gel composition having a
viscosity or shear resistance low enough to permit passage of the
gel composition through a needle.
[0121] The limit on the amount of beneficial agent released in the
first 24 hours that is either desired or required will depend on
circumstances such as the overall duration of the delivery period,
the therapeutic window for the beneficial agent, potential adverse
consequences due to overdosing, cost of beneficial agent, and the
type of effect desired, e.g., systemic or local. Preferably, 20% or
less of the beneficial agent will be released in the first 24 hours
after implantation, where the percentage is based on the total
amount of beneficial agent to be delivered over the duration of the
delivery period. Typically, higher percentages of release in the
first 24 hours can be tolerated if the duration of the delivery
period is relatively short, e.g., less than 7-14 days, or if the
beneficial agent has a wide therapeutic window with little
likelihood of side effects, or if the beneficial agent acts
locally.
[0122] Depending on the particular solvent or solvent mixture
selected, the polymer and beneficial agent, and optionally
solubility modulators of the beneficial agent, the compositions of
the present invention intended for systemic delivery may provide a
gel composition having a burst index of 8 or less, preferably 6 or
less, more preferably 4 or less and most preferably 2 or less.
Compositions of PLGA with solvents having a miscibility in water of
less than 7% by weight, optionally combined with the other
solvents, providing implants intended for systemic delivery of
beneficial agent having a burst index of 10 or less, preferably 7
or less, more preferably 5 or less and most preferably 3 or less,
are particularly advantageous. The use of solvent mixtures as
discussed herein can be particularly advantageous as a means of
providing sufficient plasticizing of the polymer to obtain viscous
gel formation and at the same time meet the desired burst indices
and percentage release objectives of the compositions of the
invention.
[0123] Compositions intended for local delivery of beneficial agent
are formed in the same manner as those intended for systemic use.
However, because local delivery of beneficial agent to a subject
will not result in detectable plasma levels of beneficial agent,
such systems have to be characterized by a percentage of beneficial
agent released in a predetermined initial period, rather than a
burst index as defined herein. Most typically, that period will be
the first 24 hours after implantation and the percentage will be
equal to the amount by weight of the beneficial agent released in
the period (e.g. 24 hours) divided by the amount by weight of the
beneficial agent intended to be delivered in the duration of the
delivery period; multiplied by the number 100. Compositions of the
present invention will have initial bursts of 20% or less,
preferably 15% or less, most preferably 10% or less, for most
applications. Especially preferred are implant systems having
initial bursts of 5% or less.
[0124] In many instances, it may be desirable to reduce the initial
burst of beneficial agent during local administration to prevent
adverse effects. For example, implants of the invention containing
chemotherapeutic agents are suitable for direct injection into
tumors. However, many chemotherapeutic agents may exhibit toxic
side effects when administered systemically. Consequently, local
administration into the tumor may be the treatment method of
choice. It is necessary, however, to avoid administration of a
large burst of the chemotherapeutic agent if it is possible that
such agent would enter the vascular or lymphatic systems where it
may exhibit side affects. Accordingly, in such instances the
implantable systems of the present invention having limited burst
as described herein are advantageous.
[0125] The solvent or solvent mixture is typically present in an
amount of from about 95 to about 20% by weight and is preferably
present in an amount of from about 70 to about 30% by weight and
often 60-40% by weight of the viscous gel, i.e., the combined
amounts of the polymer and the solvent. The viscous gel formed by
mixing the polymer and the solvent typically exhibits a viscosity
of from about 1,000 to about 200,000 poise, preferably from about
5,000 to about 50,000 poise measured at a 1.0 sec.sup.-1 shear rate
and 25.degree. C. using a Haake Rheometer at about 1-2 days after
mixing is completed. Mixing the polymer with the solvent can be
achieved with conventional low shear equipment such as a Ross
double planetary mixer for from about 10 minutes to about 1 hour,
although shorter and longer periods may be chosen by one skilled in
the art depending on the particular physical characteristics of the
composition being prepared. Since it is often desirable to
administer the implant as an injectable composition, a
countervailing consideration when forming implants that are viscous
gels is that the polymer/solvent/beneficial agent composition have
sufficiently low viscosity in order to permit it to be forced
through a small diameter, e.g., 18-20 gauge needle. If necessary,
adjustment of viscosity of the gel for injection can be
accomplished with emulsifying agents as described herein. Yet, such
compositions should have adequate dimensional stability so as to
remain localized and be able to be removed if necessary. The
particular gel or gel-like compositions of the present invention
satisfy such requirements.
[0126] If the polymer composition is to be administered as an
injectable gel, the level of polymer dissolution will need to be
balanced with the resulting gel viscosity, to permit a reasonable
force to dispense the viscous gel from a needle, and the potential
burst effect. Highly viscous gels enable the beneficial agent to be
delivered without exhibiting a significant burst effect, but may
make it difficult to dispense the gel through a needle. In those
instances, an emulsifying agent may optionally be added to the
composition. Also, since the viscosity may generally be lowered as
the temperature of the composition increases, it may be
advantageous in certain applications to reduce the viscosity of the
gel by heating to provide a more readily injectable
composition.
[0127] For instance, as shown in FIG. 1, a gel prepared from 40% by
weight of a 50:50 lactic acid:glycolic polymer and 60% by weight of
triacetin required about 40 psig to dispense the gel through a
standard 20 gauge needle at 2 cc/min while a gel prepared from the
same amount of polymer with 60% by weight of N-methyl-2-pyrrolidone
required only about 8 psig. FIG. 1 further shows that when the
emulsifying agent (in this case 33% by weight of a 10% ethanol
solution) is added to the viscous gel according to the invention,
the dispense force needed is only about 2 psig. The shear thinning
characteristics of the depot gel compositions of the present
invention allow them to be readily injected into an animal
including humans using standard gauge needles without requiring
undue dispensing pressure.
[0128] When the emulsifying agent is mixed with the viscous gel
formed from the polymer and the solvent using conventional static
or mechanical mixing devices, such as an orifice mixer, the
emulsifying agent forms a separate phase composed of dispersed
droplets of microscopic size that typically have an average
diameter of less than about 100 microns. The continuous phase is
formed of the polymer and the solvent. The particles of the
beneficial agent may be dissolved or dispersed in either the
continuous phase or the droplet phase. In the resulting thixotropic
composition, the droplets of emulsifying agent elongate in the
direction of shear and substantially decrease the viscosity of the
viscous gel formed from the polymer and the solvent. For instance,
with a viscous gel having a viscosity of from about 5,000 to about
50,000 poise measured at 1.0 sec.sup.-1 at 25.degree. C., one can
obtain a reduction in viscosity to less than 100 poise when
emulsified with a 10% ethanol/water solution at 25.degree. C. as
determined by Haake Rheometer.
[0129] When used, the emulsifying agent typically is present in an
amount ranging from about 5 to about 80%, preferably from about 20
to about 60% and often 30 to 50% by weight based on the amount of
the injectable depot gel composition, that is the combined amounts
of polymer, solvent, emulsifying agent and beneficial agent.
Emulsifying agents include, for example, solvents that are not
fully miscible with the polymer solvent or solvent mixture.
Illustrative emulsifying agents are water, alcohols, polyols,
esters, carboxylic acids, ketones, aldehydes and mixtures thereof.
Preferred emulsifying agents are alcohols, propylene glycol,
ethylene glycol, glycerol, water, and solutions and mixtures
thereof. Especially preferred are water, ethanol, and isopropyl
alcohol and solutions and mixtures thereof. The type of emulsifying
agent affects the size of the dispersed droplets. For instance,
ethanol will provide droplets that have average diameters that can
be on the order of ten times larger than the droplets obtained with
an isotonic saline solution containing 0.9% by weight of sodium
chloride at 21.degree. C.
[0130] FIG. 3 shows the viscosities at different shear rates using
water alone and an aqueous mixture containing 10% by volume of
ethanol at a weight ratio of 2:1 (gel:emulsifying agent) using a
viscous gel formed from 50% by weight of a 50:50 lactic
acid:glycolic acid copolymer and 50% by weight of triacetin
compared to the viscosities of the viscous gel without emulsifying
agent.
[0131] It is to be understood that the emulsifying agent does not
constitute a mere diluent that reduces viscosity by simply
decreasing the concentration of the components of the composition.
The use of conventional diluents can reduce viscosity, but can also
cause the burst effect mentioned previously when the diluted
composition is injected. In contrast, the injectable depot
composition of the present invention can be formulated to avoid the
burst effect by selecting the solvent and emulsifying agent so that
once injected into place, the emulsifying agent has little impact
on the release properties of the original system.
[0132] Since the implant systems of the present invention
preferably are formed as viscous gels, the means of administration
of the implants is not limited to injection, although that mode of
delivery may often be preferred. Where the implant will be
administered as a leave-behind product, it may be formed to fit
into a body cavity existing after completion of surgery or it may
be applied as a flowable gel by brushing or palleting the gel onto
residual tissue or bone. Such applications may permit loading of
beneficial agent in the gel above concentrations typically present
with injectable compositions.
[0133] The beneficial agent can be any physiologically or
pharmacologically active substance or substances optionally in
combination with pharmaceutically acceptable carriers and
additional ingredients such as antioxidants, stabilizing agents,
permeation enhancers, etc. that do not substantially adversely
affect the advantageous results that can be attained by the present
invention. The beneficial agent may be any of the agents which are
known to be delivered to the body of a human or an animal and that
are preferentially soluble in water rather than in the
polymer-dissolving solvent. These agents include drug agents,
medicaments, vitamins, nutrients, or the like. Included among the
types of agents which meet this description are lower molecular
weight compounds, proteins, peptides, genetic material, nutrients,
vitamins, food supplements, sex sterilants, fertility inhibitors
and fertility promoters.
[0134] Drug agents which may be delivered by the present invention
include drugs which act on the peripheral nerves, adrenergic
receptors, cholinergic receptors, the skeletal muscles, the
cardiovascular system, smooth muscles, the blood circulatory
system, synoptic sites, neuroeffector junctional sites, endocrine
and hormone systems, the immunological system, the reproductive
system, the skeletal system, autacoid systems, the alimentary and
excretory systems, the histamine system and the central nervous
system. Suitable agents may be selected from, for example,
proteins, enzymes, hormones, polynucleotides, nucleoproteins,
polysaccharides, glycoproteins, lipoproteins, polypeptides,
steroids, analgesics, local anesthetics, antibiotic agents,
anti-inflammatory corticosteroids, ocular drugs and synthetic
analogs of these species.
[0135] Examples of drugs which may be delivered by the composition
of the present invention include, but are not limited to
prochlorperzine edisylate, ferrous sulfate, aminocaproic acid,
mecamylamine hydrochloride, procainamide hydrochloride, amphetamine
sulfate, methamphetamine hydrochloride, benzamphetamine
hydrochloride, isoproterenol sulfate, phenmetrazine hydrochloride,
bethanechol chloride, methacholine chloride, pilocarpine
hydrochloride, atropine sulfate, scopolamine bromide, isopropamide
iodide, tridihexethyl chloride, phenformin hydrochloride,
methylphenidate hydrochloride, theophylline cholinate, cephalexin
hydrochloride, diphenidol, meclizine hydrochloride,
prochlorperazine maleate, phenoxybenzamine, thiethylperzine
maleate, anisindone, diphenadione erythrityl tetranitrate, digoxin,
isoflurophate, acetazolamide, methazolamide, bendroflumethiazide,
chloropromaide, tolazamide, chlormadinone acetate, phenaglycodol,
allopurinol, aluminum aspirin, methotrexate, acetyl sulfisoxazole,
erythromycin, hydrocortisone, hydrocorticosterone acetate,
cortisone acetate, dexamethasone and its derivatives such as
betamethasone, triamcinolone, methyltestosterone, 17-S-estradiol,
ethinyl estradiol, ethinyl estradiol 3-methyl ether, prednisolone,
17.alpha.-hydroxyprogesterone acetate, 19-nor-progesterone,
norgestrel, norethindrone, norethisterone, norethiederone,
progesterone, norgesterone, norethynodrel, aspirin, indomethacin,
naproxen, fenoprofen, sulindac, indoprofen, nitroglycerin,
isosorbide dinitrate, propranolol, timolol, atenolol, alprenolol,
cimetidine, clonidine, imipramine, levodopa, chlorpromazine,
methyldopa, dihydroxyphenylalanine, theophylline, calcium
gluconate, ketoprofen, ibuprofen, cephalexin, erythromycin,
haloperidol, zomepirac, ferrous lactate, vincamine, diazepam,
phenoxybenzamine, diltiazem, milrinone, mandol, quanbenz,
hydrochlorothiazide, ranitidine, flurbiprofen, fenufen, fluprofen,
tolmetin, alclofenac, mefenamic, flufenamic, difuinal, nimodipine,
nitrendipine, nisoldipine, nicardipine, felodipine, lidoflazine,
tiapamil, gallopamil, amlodipine, mioflazine, lisinolpril,
enalapril, enalaprilat, captopril, ramipril, famotidine,
nizatidine, sucralfate, etintidine, tetratolol, minoxidil,
chlordiazepoxide, diazepam, amitriptyline, and imipramine. Further
examples are proteins and peptides which include, but are not
limited to, bone morphogenic proteins, insulin, colchicine,
glucagon, thyroid stimulating hormone, parathyroid and pituitary
hormones, calcitonin, renin, prolactin, corticotrophin, thyrotropic
hormone, follicle stimulating hormone, chorionic gonadotropin,
gonadotropin releasing hormone, bovine somatotropin, porcine
somatotropin, oxytocin, vasopressin, GRF, somatostatin, lypressin,
pancreozymin, luteinizing hormone, LHRH, LHRH agonists and
antagonists, leuprolide, interferons such as interferon alpha-2a,
interferon alpha-2b, and consensus interferon, interleukins, growth
hormones such as human growth hormone and its derivatives such as
methione-human growth hormone and des-phenylalanine human growth
hormone, bovine growth hormone and porcine growth hormone,
fertility inhibitors such as the prostaglandins, fertility
promoters, growth factors such as insulin-like growth factor,
coagulation factors, human pancreas hormone releasing factor,
analogs and derivatives of these compounds, and pharmaceutically
acceptable salts of these compounds, or their analogs or
derivatives.
[0136] The present invention also finds application with
chemotherapeutic agents for the local application of such agents to
avoid or minimize systemic side effects. Gels of the present
invention containing chemotherapeutic agents may be injected
directly into the tumor tissue for sustained delivery of the
chemotherapeutic agent over time. In some cases, particularly after
resection of the tumor, the gel may be implanted directly into the
resulting cavity or may be applied to the remaining tissue as a
coating. In cases in which the gel is implanted after surgery, it
is possible to utilize gels having higher viscosities since they do
not have to pass through a small diameter needle. Representative
chemotherapeutic agents that may be delivered in accordance with
the practice of the present invention include, for example,
carboplatin, cisplatin, paclitaxel, BCNU, vincristine,
camptothecin, etopside, cytokines, ribozymes, interferons,
oligonucleotides and oligonucleotide sequences that inhibit
translation or transcription of tumor genes, functional derivatives
of the foregoing, and generally known chemotherapeutic agents such
as those described in U.S. Pat. No. 5,651,986. The present
application has particular utility in the sustained delivery of
water soluble chemotherapeutic agents, such as for example
cisplatin and carboplatin and the water soluble derivatives of
paclitaxel. Those characteristics of the invention that minimize
the burst effect are particularly advantageous in the
administration of water soluble beneficial agents of all kinds, but
particularly those compounds that are clinically useful and
effective but may have adverse side effects.
[0137] To the extent not mentioned above, the beneficial agents
described in aforementioned U.S. Pat. No. 5,242,910 can also be
used. One particular advantage of the present invention is that
materials, such as proteins, as exemplified by the enzyme lysozyme,
and cDNA, and DNA incorporated into vectors both viral and
nonviral, which are difficult to microencapsulate or process into
microspheres can be incorporated into the compositions of the
present invention without the level of degradation caused by
exposure to high temperatures and denaturing solvents often present
in other processing techniques.
[0138] The beneficial agent is preferably incorporated into the
viscous gel formed from the polymer and the solvent in the form of
particles typically having an average particle size of from about
0.1 to about 100 microns, preferably from about 1 to about 25
microns and often from 2 to 10 microns. For instance, particles
having an average particle size of about 5 microns have been
produced by spray drying or freeze drying an aqueous mixture
containing 50% sucrose and 50% chicken lysozyme (on a dry weight
basis) and mixtures of 10-20% hGH and 15-30 mM zinc acetate. Such
particles have been used in certain of the examples illustrated in
the figures. Conventional lyophilization processes can also be
utilized to form particles of beneficial agents of varying sizes
using appropriate freezing and drying cycles.
[0139] To form a suspension or dispersion of particles of the
beneficial agent in the viscous gel formed from the polymer and the
solvent, any conventional low shear device can be used such as a
Ross double planetary mixer at ambient conditions. In this manner,
efficient distribution of the beneficial agent can be achieved
substantially without degrading the beneficial agent.
[0140] The beneficial agent is typically dissolved or dispersed in
the composition in an amount of from about 1 to about 50% by
weight, preferably in an amount of from about 5 to about 30% and
often 10 to 20% by weight of the combined amounts of the polymer,
solvent and beneficial agent. Depending on the amount of beneficial
agent present in the composition, one can obtain different release
profiles and burst indices. More specifically, for a given polymer
and solvent, by adjusting the amounts of these components and the
amount of the beneficial agent, one can obtain a release profile
that depends more on the degradation of the polymer than the
diffusion of the beneficial agent from the composition or vice
versa. In this respect, at lower beneficial agent loading rates,
one generally obtains a release profile reflecting degradation of
the polymer wherein the release rate increases with time. At higher
loading rates, one generally obtains a release profile caused by
diffusion of the beneficial agent wherein the release rate
decreases with time. At intermediate loading rates, one obtains
combined release profiles so that if desired, a substantially
constant release rate can be attained. In order to minimize burst,
loading of beneficial agent on the order of 30% or less by weight
of the overall gel composition, i.e., polymer, solvent and
beneficial agent, is preferred, and loading of 20% or less is more
preferred.
[0141] Release rates and loading of beneficial agent will be
adjusted to provide for therapeutically-effective delivery of the
beneficial agent over the intended sustained delivery period.
Preferably, the beneficial agent will be present in the polymer gel
at concentrations that are above the saturation concentration of
beneficial agent in water to provide a drug reservoir from which
the beneficial agent is dispensed. While the release rate of
beneficial agent depends on the particular circumstances, such as
the beneficial agent to be administered, release rates on the order
of from about 0.1 to about 100 micrograms/day, preferably from
about 1 to about 10 micrograms per day, for periods of from about 7
to about 90 days can be obtained. Greater amounts may be delivered
if delivery is to occur over shorter periods. Generally, higher
release rate is possible if a greater burst can be tolerated. In
instances where the gel composition is surgically implanted, or
used as a "leave behind" depot when surgery to treat the disease
state or another condition is concurrently conducted, it is
possible to provide higher doses that would normally be
administered if the implant was injected. Further, the dose of
beneficial agent may be controlled by adjusting the volume of the
gel implanted or the injectable gel injected. As can be seen from
FIG. 2 with respect to lysozyme, with more highly viscous systems,
one can avoid a burst effect and deliver on the order of 1% by
weight of the beneficial agent in the composition during the first
day.
[0142] FIGS. 5A and 5B illustrate representative release profiles
of human growth hormone ("hGH") obtained in rats from preferred
compositions of this invention. The benefits of benzyl benzoate are
apparent in that comparison. The hGH-benzyl benzoate implant shows
a lower burst and a nearly zero order sustained release of hGH over
the release period for both the case wherein the hGH is not
stabilized (FIG. 5A) and the case in which hGH is stabilized with
zinc ions (FIG. 5B).
[0143] Other components may be present in the gel composition, to
the extent they are desired or provide useful properties to the
composition, such as polyethylene glycol, hydroscopic agents,
stabilizing agents, pore forming agents, and others. When the
composition includes a peptide or a protein that is soluble in or
unstable in an aqueous environment, it may be highly desirable to
include a solubility modulator, that may, for example, be a
stabilizing agent, in the composition. Various modulating agents
are described in U.S. Pat. Nos. 5,654,010 and 5,656,297 which are
incorporated herein by reference. In the case of hGH, for example,
it is preferable to include an amount of a salt of a divalent
metal, preferably zinc. Examples of such modulators and stabilizing
agents, which may form complexes with the beneficial agent or
associate to provide the stabilizing or modulated release effect,
include metal cations, preferably divalent, present in the
composition as magnesium carbonate, zinc carbonate, calcium
carbonate, magnesium acetate, magnesium sulfate, zinc acetate, zinc
sulfate, zinc chloride, magnesium chloride, magnesium oxide,
magnesium hydroxide, other antacids, and the like. The amounts of
such agents used will depend on the nature of the complex formed,
if any, or the nature of the association between the beneficial
agent and the agent. Molar ratios of solubility modulator or
stabilizing agent to beneficial agent of about 100:1 to 1:1,
preferably 10:1 to 1:1, typically can be utilized.
[0144] Pore forming agents include, biocompatible materials that
when contacted with body fluids dissolve, disperse or degrade to
create pores or channels in the polymer matrix. Typically, organic
and non-organic materials that are water soluble such as sugars
(e.g., sucrose, dextrose), water soluble salts (e.g., sodium
chloride, sodium phosphate, potassium chloride, and sodium
carbonate), water soluble solvents such as N-methyl-2-pyrrolidone
and polyethylene glycol and water soluble polymers (e.g.,
carboxmethylcellulose, hydroxypropylcellulose, and the like) can
conveniently be used as pore formers. Such materials may be present
in amounts varying from about 0.1% to about 100% of the weight of
the polymer, but will typically be less than 50% and more typically
less than 10-20% of the weight of polymer.
[0145] Compositions of this invention without beneficial agent are
useful for wound healing, bone repair and other structural support
purposes.
[0146] To further understand the various aspects of the present
invention, the results set forth in the previously described
Figures were obtained in accordance with the following
examples.
EXAMPLE 1
[0147] Lysozyme particles were made by spray drying 50% sucrose and
50% chicken lysozyme (on a dry weight basis).
[0148] A viscous gel material was prepared by heating 60% by weight
of triacetin with 40% by weight of a 50:50 lactic acid:glycolic
acid copolymer to 37.degree. C. overnight. The viscous gel was
allowed to cool to room temperature. The lysozyme particles were
added to the viscous gel in a ratio of 20:80 lysozyme particles:gel
(by weight). The combination was mixed for 5 minutes. Immediately
prior to use, a 10% ethanol, 90% isotonic saline solution was added
as the emulsifying agent. The emulsifying agent comprised 1/3 of
the total injectable depot gel composition. The prepared
compositions were suitable for injection.
[0149] FIG. 2 shows the in vitro release rates obtained from the
compositions described with regard to FIG. 1. The gel prepared from
40% by weight of a 50:50 lactic acid:glycolic polymer and 60% by
weight triacetin is thick and thus difficult to inject but shows
little burst (less than 2% of the beneficial agent is delivered in
the first eight days). The gel prepared from 40% by weight of a
50:50 lactic acid:glycolic polymer and 60% by weight
n-methyl-2-pyrrolidone is thin and injectable but shows a large
burst (greater than 70% of the beneficial agent is delivered in the
first eight days). The gel prepared from 27% by weight of a 50:50
lactic acid:glycolic polymer, 40% by weight triacetin and 33% by
weight of a 10% ethanol, 90% isotonic saline solution is thin and
injectable and shows little burst (less than 10% of the beneficial
agent is delivered in the first eight days). In each case, lysozyme
is the beneficial agent and comprises 20% by weight of the combined
beneficial agent, polymer and solvent formulation.
EXAMPLE 2
hGH Particle Preparation
[0150] Human growth hormone (hGH) particles (optionally containing
zinc acetate) were prepared as follows:
[0151] hGH solution (5 mg/ml) solution in water (BresaGen
Corporation, Adelaide, Australia) was concentrated to 10 mg/mL
using a Concentration/Dialysis Selector diafiltering apparatus. The
diafiltered hGH solution was then washed with 5 times volume of
tris or phosphate buffer solution (pH 7.6). Particles of hGH were
then formed by spray drying or lyophilization using conventional
techniques. Phosphate buffer solutions (5 or 50 mM) containing hGH
(5 mg/mL) and various levels of zinc acetate (0 to 30 mM) were
spray-dried using a Yamato Mini Spraydryer set at the following
parameters:
2 Spray Dryer Parameter Setting Atomizing Air 2 psi Inlet
Temperature 120.degree. C. Aspirator Dial 7.5 Solution Pump 2-4
Main Air Valve 40-45 psi
[0152] hGH particles having a size range between 2-100 microns were
obtained. Lyophilized particles were prepared from tris buffer
solutions (5 or 50 mM: pH 7.6) containing hGH (5 mg/mL) and various
levels of zinc acetate (0 to 30 mM) using a Durastop .mu.P
Lyophilizer in accordance with the following freezing and drying
cycles:
3 Freezing Cycle Ramp down at 2.5 C./min to -30 C. and hold for 30
minutes Ramp down at 2.5 C./min from -30 C. to -50 C. and hold for
60 minutes Drying Cycle Ramp up at 0.5 C./min to 10 C. and hold for
960 min Ramp up at 0.5 C./min to 20 C. and hold for 480 min Ramp up
at 0.5 C./min to 25 C. and hold for 300 min Ramp up at 0.5 C./min
to 30 C. and hold for 300 min Ramp down at 0.5 C./min to 5 C. and
hold for 5000 min
[0153] hGH particles having a size range between 2-100 microns were
obtained.
[0154] hGH Zinc Complexed Solution Preparation
[0155] Zinc acetate solutions were prepared with tris buffer and
phosphate buffer. Desired molar volumes of trizma hydrochloride and
trizma base were prepared separately (5 or 50 mM). The pH of trizma
base solution was measured, and the corresponding trizma
hydrochloride solution was added to adjust the pH of the trizma
base solution, resulting with a final pH of 7.6. The desired molar
volume of zinc acetate was added to the buffer solution. Desired
molar volumes of sodium phosphate monobasic and sodium phosphate
diabasic were prepared separately (5 or 50 mM). Sodium azide (0.2%
w/w) was added to each phosphate solution. The pH of the dibasic
solution was measured, and the corresponding monobasic solution was
added to adjust the pH of the dibasic solution, resulting with a
final pH of 7.6. The desired molar volume of zinc acetate was added
to the buffer solution. Tris or phosphate buffer containing zinc
acetate was added to the diafiltered hGH solution to achieve ihe
final desired zinc acetate molar volume (between 5 and 30 mM). The
final hGH concentration was 5 mg/mL.
[0156] Gel Vehicle Preparation
[0157] A glass vessel was tared on a Mettler PJ3000 top loader
balance. Poly (D,L-lactide-co-glycolide) 50:50 RESOMER.RTM. RG502
(PLGA-502) was weighed into the glass vessel. The glass vessel
containing PLGA-502 was tared and the corresponding solvent was
added. Amounts expressed as percentages for various polymer/solvent
combinations are set forth in Table 2 below. The polymer/solvent
mixture was manually stirred with a stainless steel square-tip
spatula, resulting in a sticky amber paste-like substance
containing white polymer particles. The vessel containing the
polymer/solvent mixture was sealed and placed in a temperature
controlled incubator equilibrated to 39.degree. C. The
polymer/solvent mixture was removed from the incubator when it
appeared to be a clear amber homogeneous gel. Incubation time
intervals ranged from 1 to 4 days, depending on solvent and polymer
type and solvent and polymer ratios. Additional depot gel vehicles
are prepared with the following polymers: Poly
(D,L-lactide-co-glycolide) 50:50 RESOMER.RTM. L104, PLGA-L104, code
no. 33007, Poly (D,L-lactide-co-glycolide) 50:50 RESOMER.RTM.
RG206, PLGA-206, code no. 8815, Poly (D,L-lactide-co-glycoli- de)
50:50 RESOMER.RTM. RG502, PLGA-502, code 0000366, Poly
(D,L-lactide-co-glycolide) 50:50 RESOMER.RTM. RG502H, PLGA-502H,
code no. 260187, Poly (D,L-lactide-co-glycolide) 50:50 RESOMER.RTM.
RG503, PLGA-503, code no. 0080765, Poly (D,L-lactide-co-glycolide)
50:50 RESOMER.RTM. RG506, PLGA-506, code no. 95051, Poly
(D,L-lactide-co-glycolide) 50:50 RESOMER.RTM. RG755, PLGA-755, code
no. 95037, (Boehringer Ingelheim Chemicals, Inc., Petersburg, Va.),
and the following solvents or mixtures: glyceryl triacetate
(Eastman Chemical Co., Kingsport, Tenn.), benzyl benzoate ("BB"),
ethyl benzoate ("EB"), methyl benzoate ("MB"), triacetin ("TA"),
and triethyl citrate ("TC") (Aldrich Chemical Co., St Louis, Mo.).
When solvent combinations were used, for example 20% triacetin and
80% benzyl benzoate, the solvent mixture was directly added to the
pre-weighed dry polymer. Typical polymer molecular weights were in
the range of 14,400-39,700 (M.sub.w) [6,400-12,200 (M.sub.n)].
Representative gel vehicles are described in Table 2 below.
4TABLE 2 Gel Vehicles Amount Amount Gel Solvent/Polymer Solvent
Polymer Solvent Polymer Weight Ratio 50/50 BB PLGA-502 5 g 5 g 10 g
1.0 50/50 TA/BB Mixture PLGA-502 5 g 5 g 10 g 1.0 60/40 TA/BB
Mixture PLGA-502 6 g 4 g 10 g 1.5 70/30 TA/BB Mixture PLGA-502 7 g
3 g 10 g 2.3 80/20 TA/BB Mixture PLGA-502 8 g 2 g 10 g 4.0 50/50 EB
PLGA-502 5 g 5 g 10 g 1.0 50/50 TA/EB Mixture PLGA-502 5 g 5 g 10 g
1.0 50/50 BB PLGA-502 25 g 25 g 50 g 1.0 55/45 BB PLGA-502 27.5 g
22.5 g 50 g 1.2 50/50 BB PLGA-502 50 g 50 g 100 g 1.0 50/50 TA/BB
Mixture PLGA-502 50 g 50 g 100 g 1.0 50/50 BB PLGA-502H 5 g 5 g 10
g 1.0 50/50 BB PLGA-503 50 g 50 g 100 g 1.0
[0158] Drug Loading
[0159] Spray-dried or lyophilized hGH particles (10-20% w/w), with
and without zinc acetate, prepared as above were added to a
specified clear amber depot gel vehicle and blended manually until
the dry powder was wetted completely. Then, the milky light yellow
particle/gel mixture was thoroughly blended by conventional mixing
using a Caframo mechanical stirrer with an attached square-tip
metal spatula. Resulting formulations are illustrated in Tables 3
and 4 below. "L" identifies lyophilized hGH particles and "SD"
identifies spray dried hGH particles. Final homogenous gel
formulations were transferred to 3, 10 or 30 cc disposable syringes
for storage or dispensing.
5TABLE 3 In Vivo hGH Polymer Solvent Drug Particle Trizma
Formulation Level PLGA Level Type Level Process Zinc Level (mM)
Buffer (mM) A 45% 502 45% TA 10% L 0 50 B 45% 502 45% TA 10% L 7.5
50 C 45% 502 45% TA 10% L 15 50 D 45% 502 45% BB 10% L 0 50 E 45%
502 45% BB 10% L 7.5 50 F 45% 502 45% BB 10% L 15 50 G 45% 502 45%
NMP 10% L 0 50 H 45% 502 45% NMP 10% L 15 50 I 45% 502 45% TA 10%
SD 0 50 J 45% 502 45% TA 10% SD 7.5 50 K 45% 502 45% BB 10% SD 0 50
L 45% 502 45% BB 10% SD 7.5 50
[0160]
6TABLE 4 In Vivo hGH (zinc level in all cases was 15 mM) Polymer
Solvent Drug Particle Trizma Formulation Level PLGA Level Type
Level Process Buffer (mM) F 45% 502 45% BB 10% L 50 N 45% 502 45%
80% BB/20% TA 10% L 5 P 45% 502H 45% TA 10% L 5 Q 45% 502H 45% BB
10% L 5 R 45% 502 45% EB 10% L 5 S 45% 502 45% TC 10% L 5 T 40% 502
40% BB 20% L 5 W 45% 502-2 45% 88 10% L 5 X 45% 502 45% TA 10% L
5
EXAMPLE 3
Lysozyme In Vitro Studies
[0161] Lysozyme from chicken egg white (Sigma Chemical Co., St
Louis, Mo.) in vitro release studies were used to test different
vehicle formulations with the highly water soluble solvent NMP and
the less soluble solvents triacetin and benzyl benzoate useful in
the present invention. A depot gel formulation was dispensed from a
3 cc disposable syringe and weighed onto a Delrin.TM. cup platform
or a 250 .mu. mesh 1 square inch polypropylene screen. Then, the
cup or screen containing a depot gel formulation was immersed into
a plastic vial containing 10 mL of receptor buffer. A snap-on lid
was placed onto the plastic vial to prevent evaporation. The vial
containing the depot gel formulation was immersed into a Haake
shaking water bath equilibrated to 37.degree. C. At each time
point, forceps were used to transfer Delrin.TM. cup platforms or
polypropylene screen platforms containing depot gel formulations to
new plastic vials containing 10 mL of receptor buffer. Disposable
transfer pipettes were used to transfer receptor samples to HPLC
vials. The receptor buffer was phosphate buffered saline, PBS,
adjusted to pH 7 containing sodium azide (0.2%). Receptor buffers
contained tween-80 (0.1%) for most cases. Collection intervals were
typically 2, 4, 8 hours, 1, 2, 3, 4, 7, 10 days, and 2, 3, 4, 5, 6,
7, 8 weeks. All receptor samples were analyzed for lysozyme
concentration using a gradient elution Reverse-Phase High
Performance Liquid Chromatography (RP-HPLC) assay with a
refrigerated autosampler (4.degree. C.). Results indicated that the
compositions of the present invention using benzyl benzoate and
benzyl benzoate solvent mixtures exhibited substantially less burst
of lysozyme than that exhibited by the gel compositions formed with
NMP.
EXAMPLE 4
In Vitro Water Content Studies
[0162] The same procedure was used as described in Example 3 for in
vitro drug release using the Delrin.TM. cup platform, except the
entire cup platform containing the depot gel vehicle was removed,
blotted dry, and placed in a dry plastic vial at specified time
intervals. The receptor solution was sterile water and replaced at
each time interval for the remaining samples. Initial and final
depot gel vehicle weights were recorded to observe weight change.
Water content was obtained from depot gel vehicles using a Karl
Fischer Apparatus, Mitsubishi Moisture Meter CA-06 equipped with
Vaporizer VA-06.
[0163] Results are illustrated in FIGS. 4A-4B for selected gels.
Those results demonstrate that gel compositions of this invention
take up substantially less water than gel compositions formed with
NMP alone.
EXAMPLE 5
hGH In Vivo Studies
[0164] In vivo studies in rats were performed following an open
protocol to determine serum levels of hGH upon systemic
administration of hGH via the implant systems of this invention.
Depot gel hGH formulations, spray-dried (SD) or lyophilized (L),
were loaded into customized 0.5 cc disposable syringes. Disposable
16 gauge needles were attached to the syringes and were heated to
37.degree. C. using a circulator bath. Depot gel hGH formulations
were injected into rats and blood was drawn at specified time
intervals. All serum samples were stored at 4.degree. C. prior to
analysis. Samples were analyzed for intact hGH content using a
radio immuno assay (RIA). Representative results for triacetin and
benzyl benzoate are illustrated in FIGS. 5A and 5B, and demonstrate
the superior control of burst by the compositions of the present
invention.
EXAMPLE 6
[0165] Implant systems of this invention are prepared in accordance
with Example 2 with equivalent quantities of interferon alpha-2a
and -2b, consensus interferon, methionine human growth hormone,
des-phenylalanine human growth hormone, carboplatin and
insulin-like growth factor. The amount of the viscous gel
containing drug administered to rats in accordance with Example 5
is adjusted to take into account the relative biological activity
of the separate agents. The implant systems are implanted in rats
to provide systemic levels of active agent.
EXAMPLE 7
[0166] Implant systems containing carboplatin are prepared
according to Example 6 and injected directly into solid tumors of
tumor bearing rats. The implant systems are suitable for local
delivery of carboplatin to tumors.
EXAMPLE 8
[0167] 100 Mg implantable depots containing 0.5, 1.5 and 3 mg of
interferon alpha-2b, stabilized with 0.5, 1 and 2 mg of sucrose,
respectively, and the remainder being 50 mg benzyl benzoate and
45-49 mg of PLGA 502 as applicable (number average molecular weight
of about 10,000) are prepared in accordance with Example 2 (without
the addition of zinc). The implants exhibit limited burst and are
suitable for implantation. The implant systems are implanted in
rats to provide systemic levels of interferon alpha-2b.
[0168] In accordance with various aspects of the present invention,
one or more significant advantages can be obtained. More
specifically, implantable or injectable viscous gels containing
beneficial agent for systemic and local administration are obtained
that exhibit low or minimal burst effect when implanted.
Furthermore, using simple processing steps, one can obtain a gel
composition that can be surgically implanted in an animal or
injected into place in an animal without surgery using a low
dispensing force through standard needles. Once in place, the
composition will substantially avoid a burst effect and provide the
desired beneficial agent release profile. Furthermore, once the
beneficial agent has been fully administered, there is no need to
remove the composition since it is fully biodegradable. As a still
further advantage, the present invention avoids the use of
microparticle or microencapsulation techniques which can degrade
certain beneficial agents, like peptide and nucleic acid-based
drugs and which microparticles and microcapsules may be difficult
to remove from the environment of use. Since the viscous gel is
formed without the need for water, temperature extremes, or other
solvents, suspended particles of beneficial agent remain dry and in
their original configuration, which contributes to the stability of
thereof. Further, since a mass is formed, the injectable depot gel
composition may be retrieved from the environment of use if
desired.
[0169] The above-described exemplary embodiments are intended to be
illustrative in all respects, rather than restrictive, of the
present invention. Thus the present invention is capable of many
variations in detailed implementation that can be derived from the
description contained herein by a person skilled in the art. All
such variations and modifications are considered to be within the
scope and spirit of the present invention as defined by the
following claims.
* * * * *