U.S. patent application number 09/947421 was filed with the patent office on 2002-03-21 for injectable depot gel composition and method of preparing the composition.
Invention is credited to Brodbeck, Kevin J., Shen, Theodore T..
Application Number | 20020034532 09/947421 |
Document ID | / |
Family ID | 21870398 |
Filed Date | 2002-03-21 |
United States Patent
Application |
20020034532 |
Kind Code |
A1 |
Brodbeck, Kevin J. ; et
al. |
March 21, 2002 |
Injectable depot gel composition and method of preparing the
composition
Abstract
An injectable depot gel composition containing a polymer, a
solvent that can dissolve the polymer and thereby form a viscous
gel, a beneficial agent; and an emulsifying agent in the form of a
dispersed droplet phase in the viscous gel. The injectable depot
gel composition can be prepared by mixing the polymer and the
solvent so that the solvent dissolves the polymer and forms a
viscous gel. The beneficial agent is dissolved or dispersed in the
viscous gel and the emulsifying agent is mixed with the beneficial
agent containing viscous gel. The emulsifying agent forms a
dispersed droplet phase in the viscous gel to provide the
injectable depot gel composition. The injectable depot gel
composition can deliver a beneficial agent to a human or animal
with a desired release profile.
Inventors: |
Brodbeck, Kevin J.; (Palo
Alto, CA) ; Shen, Theodore T.; (Redwood City,
CA) |
Correspondence
Address: |
ALZA CORPORATION
P O BOX 7210
INTELLECTUAL PROPERTY DEPARTMENT
MOUNTAIN VIEW
CA
940397210
|
Family ID: |
21870398 |
Appl. No.: |
09/947421 |
Filed: |
November 25, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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09947421 |
Nov 25, 2001 |
|
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|
08993031 |
Dec 18, 1997 |
|
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60033439 |
Dec 20, 1996 |
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Current U.S.
Class: |
424/422 ;
424/486 |
Current CPC
Class: |
A61K 47/02 20130101;
A61K 38/212 20130101; A61K 38/27 20130101; A61K 47/34 20130101;
A61K 9/0024 20130101; A61K 9/0019 20130101; A61P 5/00 20180101;
A61K 47/14 20130101; A61K 38/21 20130101; A61K 47/10 20130101; A61P
41/00 20180101 |
Class at
Publication: |
424/422 ;
424/486 |
International
Class: |
A61K 009/14 |
Claims
We claim:
1. An injectable depot gel composition comprising: A) a
biocompatible polymer; B) a solvent that dissolves the
biocompatible polymer and forms a viscous gel; C) a beneficial
agent; and D) an emulsifying agent in the form of a dispersed
droplet phase in the viscous gel.
2. The injectable gel depot composition of claim 1 wherein the
biocompatible 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.
3. The injectable depot gel composition of claim 1 wherein the
biocompatible polymer is a lactic acid-based polymer.
4. The injectable depot gel composition of claim 3 wherein the
lactic acid-based polymer has a monomer ratio of lactic acid to
glycolic acid in the range of 100:0 to about 15:85.
5. The injectable depot gel composition of claim 3 wherein the
lactic acid-based polymer has a number average molecular weight of
from 1,000 to 120,000.
6. The injectable depot gel composition of claim 1 wherein the
solvent that can dissolve the biocompatible polymer to form a
viscous gel is selected from the group consisting of triacetin,
n-methyl-2-pyrrolidone, 2-pyrrolidone, glycerol formal, methyl
acetate, benzyl benzoate, ethyl acetate, methyl ethyl ketone,
dimethylformamide, dimethyl sulfoxide, tetrahydrofuran,
caprolactam, decylmethylsulfoxide, oleic acid, and
1-dodecylazacyclo-heptan-2-one and mixtures thereof.
7. The injectable depot gel composition of claim 1 wherein the
solvent is selected from the group consisting of triacetin and
n-methyl-2-pyrrolidone, and mixtures thereof.
8. The injectable depot gel composition of claim 1 wherein the
solvent is triacetin.
9. The injectable depot gel composition of claim 1 wherein the
polymer is present in an amount of from 5 to 80% by weight of the
combined amounts of the polymer and the solvent.
10. The injectable depot gel composition of claim 1 wherein the
solvent is present in an amount of from 95 to 20% by weight of the
combined amounts of the polymer and the solvent.
11. The injectable depot gel composition of claim 1 wherein the
viscous gel formed by the polymer and the solvent has a viscosity
of from 1,000 to 200,000 poise.
12. The injectable depot gel composition of claim 1 wherein the
beneficial agent is a drug.
13. The injectable depot gel composition of claim 1 wherein the
beneficial agent is a peptide.
14. The injectable depot gel composition of claim 1 wherein the
beneficial agent is a protein.
15. The injectable depot gel composition of claim 1 wherein the
beneficial agent is growth hormone.
16. The injectable depot gel composition of claim 1 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.
17. The injectable depot gel composition of claim 1 wherein the
beneficial agent is in the form of particles dispersed or dissolved
in the viscous gel.
18. The injectable depot gel composition of claim 17 wherein the
beneficial agent is in the form of particles having an average
particle size of from 0.1 to 100 microns.
19. The injectable depot gel composition of claim 1 wherein the
emulsifying agent is selected from the group consisting of water,
alcohols, polyols, esters, carboxylic acids, ketones, aldehydes and
mixtures thereof.
20. The injectable depot gel composition of claim 1 wherein the
emulsifying agent is selected from the group consisting of
alcohols, propylene glycol, ethylene glycol, glycerol, water and
solutions and mixtures thereof.
21. The injectable depot gel composition of claim 1 wherein the
emulsifying agent is selected from the group consisting of ethanol,
isopropyl alcohol, water, solutions thereof, and mixtures
thereof.
22. The injectable depot gel composition of claim 1 wherein the
emulsifying agent is water.
23. The injectable depot gel composition of claim 1 wherein the
emulsifying agent is present in an amount of from 5 to 80% by
weight of the injectable depot gel composition.
24. A method of preparing an injectable depot gel composition
comprising: A) mixing a biocompatible polymer and a solvent whereby
the solvent dissolves the polymer and forms a viscous gel; B)
dispersing or dissolving a beneficial agent in the viscous gel to
form a beneficial agent containing viscous gel; and C) mixing an
emulsifying agent with the beneficial agent containing viscous gel,
said emulsifying agent forming a dispersed droplet phase in the
beneficial agent containing viscous gel to provide the injectable
depot gel composition.
25. A method of preparing an injectable depot gel composition
comprising: A) mixing a biocompatible polymer and a solvent whereby
the solvent dissolves the polymer to form a viscous gel; B)
dispersing or dissolving a beneficial agent 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 to provide the
injectable depot composition.
26. An injectable depot gel composition comprising: A) a
biocompatible polymer; B) a solvent that dissolves the polymer and
forms a viscous gel; and C) an emulsifying agent in the form of a
dispersed droplet phase in the viscous gel.
Description
[0001] This application claims the priority of provisional
application Ser. No. 60/033,439, filed Dec. 20, 1996 and is a
continuation of utility patent application Ser. No. 08/993,031,
filed on Dec. 18, 1997.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to a depot gel composition
that can be injected into a desired location and which can provide
sustained release of a beneficial agent. The present invention also
relates to a method of preparing the 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 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 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 a drawback
where it is desired that the material flow to fill voids or
cavities where it may be most needed.
[0008] Drug delivery systems using thermoplastic or thermosetting
biodegradable polymers also 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 a 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 patients 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 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 solvents and temperature extremes.
[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 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. 5,242,910 describes a sustained release
composition 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.
[0014] With solvent-based depot compositions comprised of a polymer
dissolved in a solvent, one problem which exists is that the
composition solidifies slowly after injection as solvent diffuses
from the depot. Since these compositions need to be non-viscous in
order to be injected, a large percentage of drug is released as the
system forms by diffusion of the solvent. This effect is referred
to as a "burst" effect. In this respect, it is typical for
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.
SUMMARY OF THE INVENTION
[0015] The present invention is a significant advance in the art
and in one aspect provides an injectable depot gel composition
comprising:
[0016] A) a biocompatible polymer;
[0017] B) a solvent that dissolves the polymer and forms a viscous
gel;
[0018] C) a beneficial agent; and
[0019] D) an emulsifying agent in the form of a dispersed droplet
phase in the viscous gel.
[0020] In a further aspect, the present invention provides a method
of preparing an injectable depot gel composition comprising:
[0021] A) mixing a biocompatible polymer and a solvent whereby the
solvent dissolves the polymer and forms a viscous gel;
[0022] B) dispersing or dissolving a beneficial agent in the
viscous gel to form a beneficial agent containing gel; and
[0023] C) mixing an emulsifying agent with the beneficial agent
containing gel, said emulsifying agent forming a dispersed droplet
phase in the beneficial agent containing gel so as to provide the
injectable depot gel composition.
[0024] In another aspect, the present invention provides a method
of preparing an injectable depot gel composition comprising:
[0025] A) mixing a biocompatible polymer and a solvent whereby the
solvent dissolves the polymer and forms a viscous gel;
[0026] B) dispersing or dissolving a beneficial agent in an
emulsifying agent to form a beneficial agent containing emulsifying
agent; and
[0027] 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 to
provide the injectable depot gel composition.
[0028] In yet another aspect, the invention provides an injectable
depot gel composition comprising:
[0029] A) a biocompatible polymer;
[0030] B) a solvent that dissolves the polymer and forms a viscous
gel; and
[0031] C) an emulsifying agent in the form of a dispersed droplet
phase in the viscous gel.
BRIEF DESCRIPTION OF THE DRAWINGS
[0032] 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:
[0033] FIG. 1 is a graph illustrating the dispense force required
to dispense the emulsified and non-emulsified viscous gel
compositions through a 20 gauge needle in psig at 2 cc/min;
[0034] FIG. 2 is a graph illustrating the release profiles of
lysozyme from three different compositions in days; and
[0035] FIG. 3 is a graph illustrating the viscosity profiles at
different shear rates of water alone and of an aqueous mixture of
ethanol, and of the viscous gel without emulsifying agent.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0036] As explained above, one aspect of the present invention
relates to an injectable depot gel composition comprising:
[0037] A) a biocompatible polymer;
[0038] B) a solvent that dissolves the biocompatible polymer and
forms a viscous gel;
[0039] C) a beneficial agent; and
[0040] D) an emulsifying agent in the form of a dispersed droplet
phase in the viscous gel.
[0041] The polymer, solvent and emulsifying 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.
[0042] 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.
[0043] The polymer may be a polylactide, 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. 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.
[0044] The lactic acid-based polymer has a number average molecular
weight of from about 1,000 to about 120,000, preferably from about
10,000 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 10,000, 30,000 and 100,000 are available from
Boehringer Ingelheim (Petersburg, Va.).
[0045] The biocompatible polymer is present in the composition in
an amount ranging from about 5 to about 80% by weight, preferably
from about 20 to about 50% by weight and often 35 to 45% by weight
of the viscous gel, the viscous gel comprising the combined amounts
of the biocompatible polymer and the solvent. Once in place in the
environment of use, the solvent will diffuse slowly away from the
depot and the polymer will slowly degrade by hydrolysis.
[0046] The solvent must be biocompatible and is selected so as to
dissolve 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. Illustrative
solvents which can be used in the present invention include but are
not limited to triacetin, n-methyl-2-pyrrolidone, 2-pyrrolidone,
glycerol formal, methyl acetate, benzyl benzoate, ethyl acetate,
methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide,
tetrahydrofuran, caprolactam, decylmethylsulfoxide, oleic acid, and
1-dodecylazacyclo-heptan-2-one and mixtures thereof. The preferred
solvents are triacetin and nmethyl-2-pyrrolidone. Triacetin
provides a high level of polymer dissolution which leads to greater
gel viscosities, with attendant higher force needed to dispense the
viscous gel when compared with other solvents. These
characteristics enable the beneficial agent to be maintained
without exhibiting a burst effect, but make it difficult to
dispense the gel through a needle. 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 be readily
injected into an animal including humans using standard gauge
needles without requiring undue dispensing pressure.
[0047] The solvent 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 80 to about 50% by weight and often 65 to 55% by weight
of the viscous gel, that is 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 to about 50,000 poise
measured at a 1.0 sec.sup.-1 shear rate and 25.degree. C. using a
Haake Viscometer 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 1 to about 2 hours.
[0048] 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 nutrients,
vitamins, food supplements, sex sterilants, fertility inhibitors
and fertility promoters.
[0049] 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.
[0050] 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.varies.-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,
methyidopa, 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, interleukins, growth hormones
such as human growth hormone, bovine growth hormone and porcine
growth hormone, fertility inhibitors such as the prostaglandins,
fertility promoters, growth factors, coagultion factors, human
pancreas hormone releasing factor, analogs and derivatives of these
compounds, and pharmaceutically acceptable salts of these
compounds, or their analogs or derivatives.
[0051] To the extent not mentioned in the previous paragraph, 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 microcapsulate or
process into microspheres can be incorporated into the compositions
of the present invention without the level of degradation
experienced with other techniques.
[0052] 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 spray freezing an aqueous mixture
containing 50% sucrose and 50% chicken lysozyme (on a dry weight
basis). Such particles have been used in certain of the examples
illustrated in the figures.
[0053] To form a suspension 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.
[0054] 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 25% 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. 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. While the particular release rate depends on the
particular circumstances, such as the beneficial agent to be
administered, release rates on the order of from about 1 to about
10 micrograms/day for periods of from about 7 to about 90 days can
be obtained. Further, the dose of beneficial agent may be adjusted
by adjusting the amount of injectable depot gel injected. As will
be apparent from the following results, one can avoid a burst
effect and administer on the order of 1% by weight of the
beneficial agent in the composition during the first day.
[0055] FIG. 2 shows the 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.
[0056] The emulsifying agent constitutes an important aspect of the
present invention. 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.
[0057] The emulsifying agent 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. 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.
[0058] While normally no other components are present in the
composition, to the extent that conventional optional ingredients
are desired, such as polyethylene glycol, hydroscopic agents,
stabilizing agents and others, they are used in an amount that does
not substantially affect the advantageous results which can be
attained in accordance with the present invention.
[0059] To illustrate various aspects of the invention further, 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.
[0060] It is to be understood that the emulsifying agent of the
present invention 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 emulsifying
agent so that once injected into place, the emulsifying agent has
little impact on the release properties of the original system.
[0061] Further compositions without beneficial agent may be useful
for wound healing, bone repair and other structural support
purposes.
[0062] 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 example.
EXAMPLE
[0063] Lysozyme particles were made by spray drying 50% sucrose and
50% chicken lysozyme (on a dry weight basis).
[0064] 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 while mixing continued. 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. 0.5 grams of this injectable depot composition was
then injected into a rat.
[0065] In accordance with various aspects of the present invention,
one or more significant advantages can be obtained. More
specifically, using simple processing steps, one can obtain a depot
gel composition that can be injected into place in an animal
without surgery using a low dispensing force through standard
needles. Once in place, the composition will quickly return to its
original viscosity and may exhibit rapid hardening so as to
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
microcapsulation techniques which can degrade certain beneficial
agents, like peptide and nucleic acid-based drugs and which
microparticles and microcapsules maybe 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.
[0066] 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.
* * * * *