U.S. patent application number 10/753724 was filed with the patent office on 2004-07-29 for liquid polymeric compositions for controlled release of bioactive substances.
Invention is credited to Chern, Rey T., Zingerman, Joel R..
Application Number | 20040146557 10/753724 |
Document ID | / |
Family ID | 27733049 |
Filed Date | 2004-07-29 |
United States Patent
Application |
20040146557 |
Kind Code |
A1 |
Chern, Rey T. ; et
al. |
July 29, 2004 |
Liquid polymeric compositions for controlled release of bioactive
substances
Abstract
Controlled release of hydrophobic bioactive substances in vivo
over an extended time period and without "bursts" of drug release
is achieved using a liquid polymeric composition including a
polymer such as poly(lactide-co-glycolide) copolymer in a mixture
of hydrophilic and lipophilic solvents.
Inventors: |
Chern, Rey T.; (Harteyville,
PA) ; Zingerman, Joel R.; (Doylestown, PA) |
Correspondence
Address: |
MERCK AND CO INC
P O BOX 2000
RAHWAY
NJ
070650907
|
Family ID: |
27733049 |
Appl. No.: |
10/753724 |
Filed: |
January 8, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10753724 |
Jan 8, 2004 |
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09271098 |
Mar 18, 1999 |
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6733767 |
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60079574 |
Mar 19, 1998 |
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Current U.S.
Class: |
424/468 ;
424/486 |
Current CPC
Class: |
A61K 9/0024 20130101;
A61K 47/14 20130101; A61K 47/34 20130101 |
Class at
Publication: |
424/468 ;
424/486 |
International
Class: |
A61K 009/22; A61K
009/14 |
Claims
What is claimed is:
1. A liquid polymeric composition for controlled release of
hydrophobic bioactive substances comprising: (a) 1 to 30% of a
hydrophobic bioactive substance; (b) 1 to 20% of a
poly(lactide-co-glycolide) copolymer; wherein the weight ratio of
the poly(lactide-co-glycolide) copolymer to the hydrophobic
bioactive substance is 1:1 or less; and (c) a mixture of
hydrophilic and lipophilic solvents wherein the volume ratio of the
hydrophilic and lipophilic solvents is from about 80:20 to about
5:95.
2. A composition of claim 1 wherein said bioactive substance is
present in about 1 to 10%.
3. A composition of claim 1 wherein said poly(lactide-co-glycolide)
copolymer is present in about 1 to 10%.
4. A composition of claim 1 wherein the ratio of said hydrophilic
and lipophilic solvents is from about 65:35 to about 35:65.
5. A composition of claim 1 which comprises: (a) 1 to 10% of a
hydrophobic bioactive substance; (b) 1 to 10% of a
poly(lactide-co-glycolide) copolymer, wherein the weight ratio of
the poly(lactide-co-glycolide) copolymer to the hydrophobic
bioactive substance is 1:1 or less; (c) a mixture of hydrophilic
and lipophilic solvents wherein the volume ratio of the hydrophilic
and lipophilic solvents is from about 65:35 to about 35:65.
6. A composition of claim 1 which comprises: (a) 5 to 10% of a
hydrophobic bioactive substance; (b) 5 to 10% of a
poly(lactide-co-glycolide) copolymer, wherein the weight ratio of
the poly(lactide-co-glycolide) copolymer to the hydrophobic
bioactive substance is 1:1 or less; (c) a mixture of hydrophilic
and lipophilic solvents wherein the volume ratio of the hydrophilic
and lipophilic solvents is from about 65:35 to about 35:65.
7. A composition of claim 1 wherein said bioactive substance is
selected from fipronil, the avermectins, ivermectins, eprinomectin,
milbemycins, nodulisporic acid and derivatives thereof, estradiol
benzoate, trenbolone acetate, progesterone, and norethisterone.
8. A composition of claim 1 wherein the ratio of lactide:glycolide
of the poly(lactide-co-glycolide) copolymer is from about 95:5 to
about 50:50.
9. A composition of claim 1 wherein the ratio of lactide:glycolide
of the poly(lactide-co-glycolide) copolymer is from about 75:25 to
about 65:35.
10. A composition of claim 1 wherein said hydrophilic solvent is
selected from glycerol formal, glycofural, N-methyl pyrrolidone,
2-pyrrolidone, isopropylidene glycerol, di(propylene glycol) methyl
ether, and mixtures thereof.
11. A composition of claim 1 which comprises: (a) 5 to 10% of a
hydrophobic bioactive substance; (b) 5 to 10% of a
poly(lactide-co-glycolide) copolymer, wherein the ratio of
lactide:glycolide of the poly(lactide-co-glycolide) copolymer is
from about 75:25 to about 65:35, and the weight ratio of the
poly(lactide-co-glycolide) copolymer to the hydrophobic bioactive
substance is 1:1 or less; (c) a mixture of glycerol formal and
triacetin wherein the volume ratio of glycerol formal and triacetin
is from about 65:35 to about 35:65.
12. A method for the controlled release of a hydrophobic bioactive
substance in an animal, including human, which comprises injecting
said animal with a liquid polymeric composition of claim 1.
13. A liquid polymeric composition comprising: (1) about 1-30% of
at least one bioactive substance; (2) about 1-20% of at least one
biologically acceptable polymer, wherein the weight ratio of the
polymer to the bioactive substance is 1:1 or less; and (3) at least
one lipophilic solvent or a mixture of at least one hydrophilic
solvent and at least one lipophilic solvent, wherein the volume
ratio of the hydrophilic and lipophilic solvents is from about
about 80:20 to about 0:100, and/or wherein the lipophilic solvent
is present in an amount of at least about 16.5% by weight.
14. A method for the controlled release of a hydrophobic bioactive
substance in an animal, including human, which comprises injecting
said animal with a liquid polymeric composition of claim 13.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims priority from and incorporates by
reference Chern and Zingerman, U.S. provisional application Serial
No. 60/079,574 filed, 19 Mar. 1998.
FIELD OF THE INVENTION
[0002] The present invention relates to liquid polymeric
compositions; for instance, such compositions for controlled
release of at least one bioactive substance, e.g., at least one
hydrophobic bioactive substance, such as a liquid polymeric
composition which can form a film encapsulated liquid, e.g., in
situ and/or which can achieve a long-term sustained release in a
patient or host (e.g., animal or human) such as plasma profiles
showing high efficacy (greater than about 70%, such as at least
about 80%, preferably at least about 90%, e.g., about 100% efficacy
for greater than about 12 months and/or plasma levels sustained for
at least about 50 or about 60 days or at least about two months or
at least about eight weeks, e.g., at least about 90 days or about
three months or about 12 weeks or at least about 120 days or about
four months or about 16 weeks, or at least about 150 days or about
five months or about 20 weeks, or even longer, e.g., up to about a
year or more; for instance, from 1 to 12 months.
[0003] The present invention further relates to a liquid polymeric
composition comprising: (1) about 1-30% w/v bioactive substance
(e.g., hydrophobic bioactive substance); (2) about 1-20% w/v of a
biologically acceptable "polymer" (including "copolymer", a polymer
polymerized by at least two comonomers) (e.g.,
poly(lactide-co-glycolide) copolymer), for instance, wherein the
weight ratio of the polymer to the bioactive substance can be 1:1
or less, e.g., 0.3:1 to 1:1; and (3) at least one lipophilic
solvent or a mixture of hydrophilic and lipophilic solvents herein
the volume ratio of the hydrophilic and lipophilic solvents is from
about about 80:20 to about 0:100, for instance about 80:20 to about
10:90 or 5:95, hydrophilic and lipophilic solvents, e.g., about
65:35 to about 35:65, and/or wherein the the water immiscible or
lipophilic solvent is present in an amount of at least about 16.5%
by weight (e.g., including about 16.465% by weight), such as at
least about 16.5% to about 45% by weight, for instance at least
about 16.5% to about 30% by weight (e.g., at least about 29% by
weight) or at least greater than 40% by weight (for instance and at
least about 42-45% by weight); e.g., such compositions wherein
there is less than 10% of the polymer and 1 to 10% of the bioactive
active substance or about less than 7% (e.g., 6.7%) or 5% or less
polymer, with the bioactive substance content at less than or equal
to about 10% or 5%.
[0004] The present invention yet further relates to a liquid
polymeric composition consisting essentially of the foregoing,
wherein the liquid polymeric composition is capable of forming a
film encapsulated liquid, e.g., in situ, and/or having long-term
sustained release, wherein the term "consisting essentially of" is
used in the sense attributed to it in patent documents, and the
term is exclusionary as to ingredients which may impede the
capability of the composition to so form a film encapsulated
liquid.
[0005] The present invention still further relates to methods for
making and using such compositions. For example, a method of making
such compositions comprising admixing the aforementioned
ingredients; for instance, preferably dissolving both the polymer
and the bioactive substance (as opposed to suspending,
encapsulating, or having present as a solid, the bioactive
substance, which, while not necessarily excluded by the invention,
may be less preferable to dissolving). Or, a method for using such
compositions comprising administering to a patient or host (animal,
e.g., mammal such as domesticated animal, for instance companion
animal or feedstock animal, or human) an inventive composition.
[0006] These and other areas to which the invention relates will be
apparent from the following text. Various documents are cited in
the following text, without any admission that any of these
documents are prior art as to the invention. All documents cited in
this text, as well as all documents referenced in documents cited
in this text, are hereby incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0007] Biodegradable polymers have been used in parenteral
controlled release formulations of bioactive compounds. In one
approach the polymer is fabricated into microspheres that may be
injected via syringe, and the bioative compound is entrapped within
the microspheres. This approach has not proved to be practical in
part due to the difficulty in the manufacturing procedure for
producing sterile and reproducible products, and the high cost of
manufacturing. In another approach the biodegradable polymer and
the bioactive material are dissolved in a biocompatible
water-miscible solvent to provide a liquid composition. When the
liquid composition is injected into the body, the solvent
dissipates into the surrounding aqueous environment, and the
polymer forms a solid depot from which the bioactive material is
released.
[0008] European Patent Application 0537559 concerns polymeric
compositions having a thermoplastic polymer, rate modifying agent,
water soluble bioactive material and water-miscible organic
solvent. Upon exposure to an aqueous environment (e.g. body fluids)
the liquid composition is capable of forming a biodegradable
microporous, solid polymer matrix for controlled release of water
soluble or dispersible bioactive materials over about four weeks.
The thermoplastic polymer may be, among many listed, polylactide,
polyglycolide, polycaprolactone or copolymers thereof, and is used
in high concentration (45 to 50%). The rate modifying agent may be,
among many others listed, glycerol triacetate (triacetin); however,
only ethyl heptanoate is exemplified; and the amount of the rate
modifying agent is no more than 15%.
[0009] Indeed, with respect to the patent literature, reference is
made to:
U.S. Patent No. Inventor
[0010] U.S. Pat. No. 4,150,108 Graham
[0011] U.S. Pat. No. 4,329,332 Couvreur et al.
[0012] U.S. Pat. No. 4,331,652 Ludwig et al.
[0013] U.S. Pat. No. 4,333,919 Kleber et al.
[0014] U.S. Pat. No. 4,389,330 Tice et al.
[0015] U.S. Pat. No. 4,489,055 Couvreur et al.
[0016] U.S. Pat. No. 4,526,938 Churchill et al.
[0017] U.S. Pat. No. 4,530,840 Tice et al.
[0018] U.S. Pat. No. 4,542,025 Tice et al.
[0019] U.S. Pat. No. 4,563,489 Urist
[0020] U.S. Pat. No. 4,675,189 Kent et al.
[0021] U.S. Pat. No. 4,677,191 Tanaka et al.
[0022] U.S. Pat. No. 4,683,288 Tanaka et al.
[0023] U.S. Pat. No. 4,758,435 Schaaf
[0024] U.S. Pat. No. 4,857,335 Bohm
[0025] U.S. Pat. No. 4,931,287 Bae et al.
[0026] U.S. Pat. No. 5,178,872 Ohtsubo et al.
[0027] U.S. Pat. No. 5,252,701 Jarrett et al.
[0028] U.S. Pat. No. 5,275,820 Chang
[0029] U.S. Pat. No. 5,478,564 Wantier et al.
[0030] U.S. Pat. No. 5,540,912 Roorda et al.
[0031] U.S. Pat. No. 5,447,725 Damani et al.
[0032] U.S. Pat. No. 5,599,852 Scopelianos et al.
[0033] U.S. Pat. No. 5,607,686 Totakura et al.
[0034] U.S. Pat. No. 5,609,886 Wantier et al.
[0035] U.S. Pat. No. 5,631,015 Bezwada et al.
[0036] U.S. Pat. No. 5,654,010 Herbert et al.
[0037] U.S. Pat. No. 5,700,485 Johnson et al.
[0038] U.S. Pat. No. 5,702,717 Berde et al.
[0039] U.S. Pat. No. 5,711,968 Tracy et al.
[0040] U.S. Pat. No. 5,733,566 Lewis
[0041] U.S. Pat. No. 4,938,763 Dunn et al.
[0042] U.S. Pat. No. 5,077,049 Dunn et al.
[0043] U.S. Pat. No. 5,278,201 Dunn et al.
[0044] U.S. Pat. No. 5,278,202 Dunn et al.
[0045] U.S. Pat. No. 5,288,496 Lewis
[0046] U.S. Pat. No. 5,324,519 Dunn et al.
[0047] U.S. Pat. No. 5,324,520 Dunn et al.
[0048] U.S. Pat. No. 5,340,849 Dunn et al.
[0049] U.S. Pat. No. 5,368,859 Dunn et al.
[0050] U.S. Pat. No. 5,401,507 Lewis
[0051] U.S. Pat. No. 5,419,910 Lewis
[0052] U.S. Pat. No. 5,427,796 Lewis
[0053] U.S. Pat. No. 5,487,897 Polson et al.
[0054] U.S. Pat. No. 5,599,552 Dunn et al.
[0055] U.S. Pat. No. 5,632,727 Tipton et al.
[0056] U.S. Pat. No. 5,643,595 Lewis
[0057] U.S. Pat. No. 5,660,849 Polson et al.
[0058] U.S. Pat. No. 5,686,092 Lewis et al.
[0059] U.S. Pat. No. 5,702,716 Dunn et al.
[0060] U.S. Pat. No. 5,707,647 Dunn et al.
[0061] U.S. Pat. No. 5,717,030 Dunn et al.
[0062] U.S. Pat. No. 5,725,491 Tipton et al.
[0063] U.S. Pat. No. 5,733,950 Dunn et al.
[0064] U.S. Pat. No. 5,736,152 Dunn et al.
[0065] U.S. Pat. No. 5,744,153 Yewey et al.
[0066] U.S. Pat. No. 5,759,563 Yewey et al.
[0067] U.S. Pat. No. 5,780,044 Yewey et al.
[0068] These documents tend to provide compositions that form a
solid, gel or coagulated mass; for instance, a significant amount
of polymer is contemplated in these documents, akin to European
Patent Application 0537559.
[0069] Mention is also made of: Shah et al (J. Controlled Release,
1993, 27:139-147), as relating to formulations for sustained
release of bioactive compounds containing various concentrations of
poly(lactic-co-glycolic) acid copolymer (PLGA) dissolved in
vehicles such as triacetin; Lambert and Peck (J. Controlled
Release, 1995, 33:189-195), as a study of the release of protein
from a 20% PLGA solution in N-methylpyrrolidone exposed to aqueous
fluid; and Shivley et al (J. Controlled Release, 1995, 33:237-243),
as a study of the solubility parameter of
poly(lactide-co-glycolide) copolymer in a variety of solvents, and
the in vivo release of naltrexone from two injectable implants (5%
naltrexone in either 57% PLGA and 38% N-methylpyrrolidone or 35%
PLGA and 60% N-methylpyrrolidone).
[0070] There is nonetheless a need for long term sustained-release
compositions, as well as polymeric compositions which can form film
coated or encapsulated liquids.
OBJECTS AND SUMMARY OF THE INVENTION
[0071] In contrast to previous compositions, it has surprisingly
been found that a polymeric composition containing a substantially
greater amount of water immiscible or lipophilic solvent and
substantially less polymer than contemplated by the literature
results in a formulation which tends to stay as a film-coated
(encapsulated) liquid rather than form a solid, gel or coagulated
mass (including "pore-containing" solids, gels or masses as in the
literature). It does not appear that the use or amount of the
lipophilic solvent and the low amount of polymer used in the liquid
polymeric formulations of the invention is contemplated by the
prior art.
[0072] Accordingly, an object of the invention can be any or all
of: to provide a liquid polymeric composition including a bioactive
substance, for instance, such a composition that has long-term
sustained release and/or forms a film-coated or encapsulated
liquid, as well as to provide methods for making and/or using such
a composition.
[0073] The present invention provides liquid polymeric
compositions; for instance, such compositions for controlled
release of at least one bioactive substance, e.g., at least one
hydrophobic bioactive substance, such as a liquid polymeric
composition which can form a film encapsulated liquid, e.g., in
situ and/or which can achieve a long-term sustained release in a
patient or host (e.g., animal or human) such as plasma profiles
showing high efficacy (greater than about 70%, such as at least
about 80%, preferably at least about 90%, e.g., about 100% efficacy
for greater than about 12 months and/or plasma levels sustained for
at least about 50 or about 60 days or at least about two months or
at least about eight weeks, e.g., at least about 90 days or about
three months or about 12 weeks or at least about 120 days or about
four months or about 16 weeks, or at least about 150 days or about
five months or about 20 weeks, or even longer, e.g., up to about a
year or more; or from 1 to 12 months or longer.
[0074] The present invention further provides a liquid polymeric
composition comprising: (1) 1-30% w/v of at least one bioactive
substance (e.g., hydrophobic bioactive substance); (2) 1-20% w/v of
at least one biologically acceptable "polymer" (including
"copolymer", a polymer polymerized by at least two comonomers)
(e.g., poly(lactide-co-glycolide) copolymer), for instance, wherein
the weight ratio of the polymer to the bioactive substance can be
1:1 or less, e.g., 0.5:1 to 1:1; and (3) a mixture of at least one
hydrophilic solvent and at least one lipophilic solvent, e.g., at
least one biologically or physiologically or medically or
veterinarily acceptable hydrophilic solvent and at least one
biologically or physiologically or medically or veterinarily
acceptable lipophilic solvent wherein the volume ratio of the
hydrophilic and lipophilic (or hydrophobic) solvents is from about
about 80:20 to about 0:100, for instance about 80:20 to about 10:90
or 5:95, hydrophilic and lipophilic solvents, e.g., about 65:35 to
about 35:65, and/or wherein the the water immiscible or lipophilic
solvent is present in an amount of at least about 16.5% by weight
(e.g., including 16.465% by weight), such as at least about 16.5%
to about 45% by weight, for instance at least about 16.5% to about
30% by weight (e.g., at least about 29% by weight), or at least
about 20% or about 25% by weight to about 30%, 35%, 40% or 45% by
weight, or at least greater than 40% by weight (for instance and at
least about 42-45% by weight); e.g., such compositions wherein
there is less than 10% of the polymer and 1 to 10% of the bioactive
active substance or about less than 7% (e.g., 6.7%) or 5% or less
polymer, with the bioactive substance content at less than or equal
to about 10% or 5%.
[0075] The present invention yet further provides a liquid
polymeric composition consisting essentially of the foregoing,
wherein the liquid polymeric composition is capable of forming a
film encapsulated liquid, e.g., in situ, and/or having long-term
sustained release, wherein the term "consisting essentially of" is
used in the sense attributed to it in patent documents, and the
term is exclusionary as to ingredients which may impede the
capability of the composition to so form a film encapsulated
liquid. Thus, for instance, an agent which would tend to cause the
composition, e.g., in situ, to have one or more contrary
properties, e.g., an agent which would tend to cause the
composition to solidify, such as a curing agent, or to form pores,
may not be desired in certain embodiments.
[0076] The present invention still further provides methods for
making and using such compositions. For example, a method of making
such compositions comprising admixing the aforementioned
ingredients; for instance, preferably dissolving both the polymer
and the bioactive substance (as opposed to suspending,
encapsulating, or having present as a solid, the bioactive
substance, which, while not necessarily excluded by the invention,
may be less preferable to dissolving). Or, a method for using such
compositions comprising administering to a patient or host (animal,
e.g., mammal such as domesticated animal, for instance companion
animal or feedstock animal, or human) an inventive composition.
[0077] The invention additionally provides methods consisting
essentially of at least one step for making or using such
compositions; wherein the liquid polymeric composition is capable
of forming a film encapsulated liquid, e.g., in situ, and/or having
long-term sustained release, wherein the term "consisting
essentially of" is used in the sense attributed to it in patent
documents, and the term is exclusionary as to ingredients which may
impede the capability of the composition to so form a film
encapsulated liquid. Thus, for instance, a step which would tend to
cause the composition, e.g., in situ, to have one or more contrary
properties, e.g., adding an agent which would tend to cause the
composition to solidify, such as a curing agent, or to form pores,
may not be desired in certain embodiments.
[0078] The bioactive substance may be any biologically agent which
is capable of providing a biological, physiological or therapeutic
effect in an animal or human. The biologically active agent may be
any one or more of known biologically active agents recognized in
any document cited herein or otherwise recognized in the art. The
agent may also stimulate or inhibit a desired biological or
physiological activity within the animal or human, including
without limitation, stimulate an immunogenic or immunological
response.
[0079] Accordingly, the invention provides an in situ formed film
coated or encapsulated liquid implant capable of functioning as a
delivery system of drugs, medicaments, and other
biologically-active agents to tissues adjacent to or distant from
the implant site. The biologically-active agent is preferably
incorporated into the film coated or encapsulated liquid, and
subsequently released into surrounding tissue fluids and to the
pertinent body tissue or organ. The composition may be administered
to the implant site by any suitable method for applying a liquid,
as for example, by means of a syringe, needle, cannula, catheter,
pressure applicator, and the like.
[0080] Exemplary biologically active agents or bioactive substances
include, without limitation, fipronil, avermectin, ivermectin,
eprinomectin, milbemycin, phenylpyrazole, nodulisporic acid,
estradiol benzoate, tremblone acetate, noresthisterone,
progesterone an antibiotic such as a macrolide or azalide
antibiotic, or a non-steroidal anti-inflamatory drugs (NSAID), or
combinations thereof.
[0081] Thus, an object of the invention can be to provide delivery
of at least one active ingredient, regardless of whether the
ingredient is water insoluble or immiscible; but, the invention is
especially applicable to hydrophobic biologically active
substances.
[0082] The biologically acceptable polymer can be any biologically
acceptable polymer, such as a biologically acceptable polymer
recognized in documents cited herein. For instance, the
biologically acceptable polymer can have one or more or all of the
following characteristics: be bioerodible by cellular action,
biodegradable by action of non-living body fluid components, soften
when exposed to heat but return to the original state when cooled
and are capable of substantially dissolving or dispersing in a
water-miscible carrier or solvent to form a solution or dispersion.
Upon contact with an aqueous fluid and the polymer are capable of
assisting in the formation of the film coated or encapsulated
liquid. The kinds of polymers suitable for the present composition
generally include any having the foregoing characteristics.
Examples are polylactides, polyglycolides, polycaprolactones,
polyanhydrides, polyamides, polyurethanes, polyesteramides,
polyorthoesters, polydioxanones, polyacetals, polyketals,
polycarbonates, polyorthocarbonates, polyphosphazenes,
polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates,
polyalkylene succinates, poly(malicacid), poly(amino acids),
poly(methyl vinyl ether), poly(maleic anhydride), chitin, chitosan,
and copolymers, terpolymers, or combinations or mixtures therein.
Polylactides, polycaprolactones, polyglycolides and copolymers
thereof are preferred polymers, with poly(lactide-co-glycolide)
copolymer ("PLGA") highly preferred. The constitution of PLGA can
be akin to its use in the Examples below or in documents cited
herein.
[0083] The solvents can be any biologically or physiologically or
medically or veterinarily hydrophobic and water miscible solvents
such as those recognized in documents cited herein.
[0084] The hydrophilic solvent may be chosen from propylene glycol,
PEG, polyglycols such as polyethylene glycol 200, polyethylene
glycol 300 and polyethylene glycol 400, di(ethylene glycol)ethyl
ether (Transcutol), isopropylidene glycerol(Solketal), dimethyl
isosorbide (Arlasolve DMI), propylene carbonate, glycerol,
glycofural, pyrrolidones such as N-methyl pyrrolidone and
2-pyrrolidone, isopropylidene glycerol, di(propyleneglycol) methyl
ether, and mixtures thereof. Other solvents may also be useful as
the hydrophilic solvent. For instance, the hydrophilic solvent can
be a C.sub.2 to C.sub.6 alkanol (e.g., ethanol, propanol, butanol),
acetone, alkyl esters such as methyl acetate, ethyl acetate, ethyl
lactate, alkyl ketones such as methyl ethyl ketone, dialkylamides
such as dimethylformamide, dimethyl sulfoxide, dimethyl sulfone,
tetrahydrofuran, cyclic alkyl amides such as caprolactam,
decylmethylsulfoxide, oleic acid, propylene carbonate, aromatic
amides such as N,N-diethyl-m-toluamide, and
1-dodecylazacycloheptan-2-one. The hydrophilic solvent can be a
mixture of solvents.
[0085] The lipophilic or non-water-miscible or hydrophobic solvent
may be chosen from triethyl citrate, Miglyol 812, Miglyol 840,
Crodamol GTCC, triacetin or benzyl benzoate; and additional
lipophilic solvents may be used, e.g., hydrophobic rate modifying
agents or plasticizers such as fatty acids, triglycerides,
triesters of glycerol, oils such as castor oil, soybean oil or
other vegetable oils or derivatives thereof such as epoxidized or
hydrogenated vegetable oils such as epoxidized soybean oil or
hydrogenated castor oil, sterols, higher alkanols (e.g., C6 or
higher), glycerin and the like. The lipophilic solvent can be a
mixture of solvents.
[0086] Other solvents can include: glycol ethers such as propylene
glycol monomethyl ether, dipropylene glycol monomethyl ether and
diethylene glycol ethyl ether, di(ethylene glycol)ethyl ether
acetate, di(propylene glycol)methyl ether (Dowanol DPM),
di(propylene glycol)methyl ether acetate, glycerol formal,
glycofurol, isopropyl myristate, N,N,-dimethyl acetamide, PEG 300,
propylene glycol, and polar, aprotic solvents such as DMSO.
[0087] In certain embodiments there can be less than 10% of the
polymer and 1 to 10% of the active compound; for instance, the
proportion of the PLGA polymer and the active compound is less than
or equal to 1:1. (See, e.g., the Example, wherein for instance 0.25
75/25 PLGA was dissolved in glycerol formal to provide a 2.5 ml
solution; in a separate flask 75/25 PLGA was dissolved in triacetin
to provide a 2.5 ml solution; the two solutions were mixed and
added to a flask containing 0.50 g active ingredient which was
dissolved into the mixed PLGA solutions; the amount of triacetin
present in the formulation to be about 42% by weight; other
formulations contain as little as 6.7% and 5% PLGA content with the
drug content at 10% or 5%.)
[0088] When implanted, i.e., upon injection, the inventive liquid
formulation forms what appears to be, from gross examination of the
host or patient into which the formulation is implanted, "a
semi-solid depot with a skin made of polymer." The depot, though,
without necessarily wishing to be bound by any one particular
theory, is not necessarily solid or semi-solid (as that term may be
usually understood); but rather, is a film coated or encapsulated
liquid (the polymer assisting in the skin formation). Over time,
depot loses its vehicle(s) (solvent(s) and degradation of the
polymer occurs.
[0089] While there is diffusion through the film (typically whitish
in color in preferred embodiments), it is believed that there are
no pores in the depot; and it likely that the liquid polymeric
formulation does not form in situ, a solid, or a coagulated mass or
a gelatinous mass. These beliefs are based on the fact that the
amount of polymer in the inventive formulation is substantially
less than that used in the prior art; the amount of water
immiscible or lipophilic solvent present in inventive formulations
is substantially greater than any "rate modifying agent" or similar
solvent used in the prior art (allowing the core of the depot to
remains liquid); and, as the active ingredient diffuses through the
film (a very, very thin film, usually whitish in preferred
embodiments), the polymer biodegrades. The inventive formulation,
is well-suited for delivering lipophilic (hydrophoblic) active
ingredients.
[0090] These and other embodiments are disclosed or are obvious
from and encompassed by, the following Detailed Description.
BRIEF DESCRIPTION OF FIGURES
[0091] The following Detailed Description, given by way of example,
but not intended to limit the invention to specific embodiments
described, may be understood in conjunction with the accompanying
Figures, incorporated herein by reference, in which:
[0092] FIG. 1 depicts plasma levels of
6-amino-3-cyano-1-(2,6-dichloro-4-s-
ulfurpentafluorophenyl)-4-(trifluoromethylthio)pyrazole in dogs
treated with the formulation of Example 1;
[0093] FIG. 2 depicts plasma levels of ivermectin in cattles
treated with three of the ivermection formulations of Example 2;
and,
[0094] FIG. 3 depicts plasma levels of eprinomectin in swine
treated with eprinomectin formulations of Example 3.
DETAILED DESCRIPTION
[0095] The present invention provides liquid polymeric compositions
for delivering bioactive substance(s).
[0096] The present invention provides liquid polymeric
compositions; for instance, such compositions for controlled
release of at least one bioactive substance, e.g., at least one
hydrophobic bioactive substance, such as a liquid polymeric
composition which can form a film encapsulated liquid, e.g., in
situ and/or which can achieve a long-term sustained release in a
patient or host (e.g., animal or human) such as plasma profiles
showing high efficacy (greater than about 70%, such as at least
about 80%, preferably at least about 90%, e.g., about 100% efficacy
for greater than about 12 months and/or plasma levels sustained for
at least about 50 or about 60 days or at least about two months or
at least about eight weeks, e.g., at least about 90 days or about
three months or about 12 weeks or at least about 120 days or about
four months or about 16 weeks, or at least about 150 days or about
five months or about 20 weeks, or even longer, e.g., up to about a
year or more; or from 1 to 12 months or longer.
[0097] The present invention further provides a liquid polymeric
composition comprising: (1) about 1-30% w/v of at least one
bioactive substance (e.g., hydrophobic bioactive substance); (2)
about 1-20% w/v of at least one biologically acceptable "polymer"
(including "copolymer", a polymer polymerized by at least two
comonomers) (e.g., poly(lactide-co-glycolide) copolymer), for
instance, wherein the weight ratio of the polymer to the bioactive
substance can be 1:1 or less, e.g., 0.5:1 to 1:1; and (3) at least
one lipophilic solvent or a mixture of at least one hydrophilic
solvent and at least one lipophilic solvent, e.g., at least one
biologically or physiologically or medically or veterinarily
acceptable hydrophilic solvent and at least one biologically or
physiologically or medically or veterinarily acceptable lipophilic
solvent wherein the volume ratio of the hydrophilic and lipophilic
(or hydrophobic) solvents is from about about 80:20 to about 0:100,
for instance about 80:20 to about 10:90 or about 80:20 to about
5:95, hydrophilic and lipophilic solvents, e.g., about 65:35 to
about 35:65, and/or wherein the the water immiscible or lipophilic
solvent is present in an amount of at least about 16.5% by weight
(e.g., including 16.465% by weight), such as at least about 16.5%
to about 45% by weight, for instance at least about 16.5% to about
30% by weight (e.g., at least about 29% by weight), or at least
about 20% or about 25% by weight to about 30%, 35%, 40% or 45% by
weight, or at least greater than 40% by weight (for instance and at
least about 42-45% by weight); e.g., such compositions wherein
there is less than 10% of the polymer and 1 to 10% of the bioactive
active substance or about less than 7% (e.g., 6.7%) or 5% or less
polymer, with the bioactive substance content at less than or equal
to about 10% or 5%.
[0098] The present invention yet further provides a liquid
polymeric composition consisting essentially of the foregoing,
wherein the liquid polymeric composition is capable of forming a
film encapsulated liquid, e.g., in situ, and/or having long-term
sustained release, wherein the term "consisting essentially of" is
used in the sense attributed to it in patent documents, and the
term is exclusionary as to ingredients which may impede the
capability of the composition to so form a film encapsulated
liquid. Thus, for instance, an agent which would tend to cause the
composition, e.g., in situ, to have one or more contrary
properties, e.g., an agent which would tend to cause the
composition to solidify, such as a curing agent, or to form pores,
may not be desired in certain embodiments.
[0099] The present invention still further provides methods for
making and using such compositions, as herein discussed.
[0100] The polymers and the solvents employed in the invention can
be as herein discussed.
[0101] The bioactive substance(s) can be any any biologically agent
which is capable of providing a biological, physiological or
therapeutic effect in an animal or human. The biologically active
agent may be any one or more of known biologically active agents
recognized in any document cited herein or otherwise recognized in
the art. The agent may also stimulate or inhibit a desired
biological or physiological activity within the animal or human,
including without limitation, stimulate an immunogenic or
immunological response.
[0102] The in situ formed implants may also provide a delivery
system for biologically-active agents to adjacent or distant body
tissues and organs. Biologically-active agents which may be used
alone or in combination in the present compositions and implants
include medicaments, drugs, or any suitable biologically-,
physiologically- or pharmacologically-active substance which is
capable of providing local or systemic biological or physiological
activity in an animal, including a human, and which is capable of
being released from the depot into an adjacent or surrounding
aqueous fluid.
[0103] The biologically-active agent may be miscible in the polymer
and/or solvent to provide a homogenous mixture with the polymer, or
insoluble in the polymer and/or solvent to form a suspension or
dispersion with the polymer. It is highly preferred that the
biologically-active agent be combined with the remaining components
of the inventive composition almost immediately prior to
administration of the composition to the implant site. It is also
preferred that the bioactive agent not be water-miscible, e.g., at
best only slightly soluble in water or or having low solubility in
water or being able to dissolve into the lipophilic (hydrophobic)
solvent. It is further preferred that the bioactive agent will not
contain functional groups which will interfere the polymer. These
conditions are readily determined by those of skill in the art
simply by comparing the structure of the bioactive agent and the
reacting moieties of the polymer.
[0104] The composition and in situ formed implant contain the
biologically-active agent in an amount effective to provide a
desired biological, physiological, pharmacological and/or
therapeutic effect, optionally according to a desired release
profile, and/or time duration of release. It is further preferred
that the biologically-active agent is included in the polymer
composition in an amount effective to provide an acceptable
solution or dispersion viscosity.
[0105] Suitable biologically-active agents include substances
useful in preventing infection at the implant site, as for example,
antiviral, antibacterial, antiparasitic, antifungal substances and
combinations thereof. The agent may further be a substance capable
of acting as a stimulant, sedative, hypnotic, analgesic,
anticonvulsant, and the like. The delivery system can contain a
large number of biologically-active agents either singly or in
combination. Examples of these biologically-active agents include,
but are not limited to: Anti-inflammatory agents such as
hydrocortisone, prednisone, fludrotisone, triamcinolone,
dexamethasone, betamethasone and the like. Anti-bacterial agents
such as penicillins, cephalosporins, vancomycin, bacitracin,
polymycins, tetracyclines, chloramphenicol, erythromycin,
streptomycin, and the like. Antiparasitic agents such as
quinacrine, chloroquine, quinine, and the like. Antifungal agents
such as nystatin, gentamicin, miconazole, tolnaftate, undecyclic
acid and its salts, and the like. Antiviral agents such as
vidarabine, acyclovir, ribarivin, amantadine hydrochloride,
iododeoxyuridine, dideoxyuridine, interferons and the like.
Antineoplastic agents such as methotrexate, 5-fluorouracil,
bleomycin, tumor necrosis factor, tumor specific antibodies
conjugated to toxins, and the like. Analgesic agents such as
salicylic acid, salicylate esters and salts, acetaminophen,
ibuprofen, morphine, phenylbutazone, indomethacin, sulindac,
tolmetin, zomepirac, and the like. Local anaesthetics such as
cocaine, benzocaine, novocaine, lidocaine, and the like. Vaccines,
or antigens, epitopes, immunogens of human or animal pathogens,
such as hepatitis, influenza, measles, mumps, rubella, hemophilus,
diphtheria, tetanus, rabies, polio, as well as veterinary vaccines
and the like. Central nervous system agents such as tranquilizers,
sedatives, anti-depressants, hypnotics, B-adrenergic blocking
agents, dopamine, and the like. Growth factors such as colony
stimulating factor, epidermal growth factor, erythropoietin,
fibroblast growth factor, neural growth factor, human growth
hormone, platelet derived growth factor, insulin-like growth
factor, and the like. Hormones such as progesterone, estrogen,
testosterone, follicle stimulating hormone, chorionic
gonadotrophin, insulin, endorphins, somatotropins and the like.
Antihistamines such as diphenhydramine, chlorpheneramine,
chlorcyclizine, promethazine, cimetidine, terfenadine, and the
like. Cardiovascular agents such as verapamil hydrochloride,
digitalis, streptokinase, nitroglycerine paparefine, disopyramide
phosphate, isosorbide dinitrate, and the like. Anti-ulcer agents
such as cimetidine hydrochloride, sopropamide iodide, propantheline
bromide, and the like. Bronchodilators such as metaproternal
sulfate, aminophylline, albuterol, and the like. Vasodilators such
as theophylline, niacin, nicotinate esters, amylnitrate, minoxidil,
diazoxide, nifedipine, and the like.
[0106] The bioactive agents which are used in the inventive
formulations can be well known to the practitioner to which this
invention pertains. Classes of bioactive agents contemplated by the
inventive formulations include insecticides, acaricides,
parasiticides, growth enhancers, and oil-soluble, nonsteroidal
anti-inflammatory drugs (NSAIDs). Specific classes of compounds
which fall within these classes include, for example, avermectins,
milbemycins, nodulisporic acid and its derivatives, estrogens,
progestins, androgens, substituted pyridylmethyl derivatives,
phenylpyrazoles, and COX-2 inhibitors.
[0107] The avermectin and milbemycin series of compounds are potent
anthelmintic and antiparasitic agents against a wide range of
internal and external parasites. The compounds which belong to this
series are either natural products or are semi-synthetic
derivatives thereof. The structure of these two series of compounds
are closely related and they both share a complex 16-membered
macrocyclic lactone ring; however, the milbemycin do not contain
the aglycone substitutent in the 13-position of the lactone ring.
The natural product avermectins are disclosed in U.S. Pat. No.
4,310,519 to Albers-Schonberg, et al., and the 22, 23-dihydro
avermectin compounds are disclosed in Chabala, et al., U.S. Pat.
No. 4,199,569. For a general discussion of avermectins, which
include a discussion of their uses in humans and animals, see
"Ivermectin and Abamectin," W. C. Campbell, ed., Springer-Verlag,
New York (1989). Furthermore, bioactive agents such as avermectins
or ivermectin can be used in combination with other bioactive
agents; and, with respect to avermectins, ivermectin, and bioactive
agent combinations, reference is made to Kitano, U.S. Pat. No.
4,468,390, Beuvry et al., U.S. Pat. No. 5,824,653, von Bittera et
al., U.S. Pat. No. 4,283,400, European Patent Application 0 007 812
A1, published June 2, 1980, U.K. Patent Specification 1 390 336,
published Apr. 9, 1975, European Patent Application 0 002 916 A2,
Ancare New Zealand Patent No. 237 086, Bayer New Zealand Patent
176193, published Nov. 19, 1975, inter alia.
[0108] Naturally occurring milbemycins are described in Aoki et
al., U.S. Pat. No. 3,950,360 as well as in the various references
cited in "The Merck Index" 12.sup.th ed., S. Budavari, Ed., Merck
& Co., Inc. Whitehouse Station, New Jersey (1996).
Semisynthetic derivatives of these classes of compounds are well
known in the art and are described, for example, in U.S. Pat. No.
5,077,308, U.S. Pat. No. 4,859,657, U.S. Pat. No. 4,963,582, U.S.
Pat. No. 4,855,317, U.S. Pat. No. 4,871,719, U.S. Pat. No.
4,874,749, U.S. Pat. No. 4,427,663, U.S. Patent-4,310,519, U.S.
Pat. No. 4,199,569, U.S. Pat. No. 5,055,596, U.S. Pat. No.
4,973,711, U.S. Pat. No. 4,978,677, and U.S. Pat. No.
4,920,148.
[0109] Nodulisporic acid and its derivatives are a class of
acaricidal, antiparasitic, insecticidal and anthelminitic agents
known to a practitioner of the art. These compounds are used to
treat or prevent infections in humans and animals. These compounds
are described, for example, in U.S. Pat. No. 5,399,582 and WO
96/29073. Additionally, the compounds can be administered in
combination with other insecticides, parasiticides, and acaricides.
Such combinations include anthelminitic agents, such as those
discussed above which include ivermectin, avermectin, and
emamectin, as well as other agents such as thiabendazole, febantel
or morantel; phenylpyrazoles such as fipronil; and insect growth
regulators such as lufenuron. Such combinations are also
contemplated in the present invention.
[0110] Generally, all classes of such insecticides may be used in
this invention. One example of this class include substituted
pyridylmethyl derivatives such as imidacloprid. Agents of this
class are described, for example, in U.S. Pat. No. 4,742,060 or in
EP 892,060.
[0111] Pyrazoles such as phenylpyrazoles and N-arylpyrazoles are
another class of insecticides which possess excellent insecticidal
activity against all insect pests including blood-sucking pests
such as ticks, fleas etc., which are parasites on animals. This
class of agents kills insects by acting on the gamma-butyric acid
receptor of invertebrates. Such agents are described, for example,
in U.S. Pat. No. 5,567,429, U.S. Pat. No. 5,122,530, EP 295,117,
and EP 846686 A1 (or Banks GB 9625045, filed Nov. 30, 1996 also
believed to be equivalent to U.S. Ser. No. 309,229, filed Nov. 17,
1997). It would be well within the skill level of the practitioner
to decide which individual compounds can be used in the inventive
formulations.
[0112] Insect growth regulators are another class of insecticides
or acaricides, which are also provided for in the inventive
formulations. Compounds belonging to this group are well known to
the practitioner and represent a wide range of different chemical
classes. These compounds all act by interfering with the
development or growth of the insect pests. Insect growth regulators
are described, for example, in U.S. Pat. No. 3,748,356; U.S. Pat.
No. 3,818,047; U.S. Pat. No. 4,225,598; U.S. Pat. No. 4,798,837;
and U.S. Pat. No. 4,751,225, as well as in EP 179,022 or U.K.
2,140,010. Again, it would be well within the skill level of the
practitioner to decide which individual compounds can be used in
the inventive formulation.
[0113] Estrogens, progestins, and androgens refers to classes of
chemical compounds which are also well known to a practitioner in
this art. In fact, estrogens and progestins are among the most
widely prescribed drugs and are used, for example, alone or in
combination for contraception or hormone replacement therapy in
post menopausal women. Estrogens and progestins occur naturally or
are prepared synthetically. This class of compounds also includes
estrogens or progesterone receptor antagonists. Antiestrogens, such
as tamoxifen and clomiphene, are used to treat breast cancer and
infertility. Antiprogestives are used as contraceptives and
anticancer drugs, as well as to induce labor or terminate a
pregnancy.
[0114] The androgens and antiandrogens structurally related to the
estrogens and progestins as they are also biosynthesized from
cholesterol. These compounds are based on testosterone. Androgens
are used for hypogonadism and promote muscle development
Antiandrogens are used, for example, in the management of
hyperplasia and carcinoma of the prostate, acne, and male pattern
baldness as well as in the inhibition of the sex drive in men who
are sex offenders. Estrogen, progestins, and androgens are
described, for example, in "Goodman & Gilman's The
Pharmacological Basis of Therapeutics," 9.sup.th ed., J. G. Handman
and L. Elimbird, eds., Ch. 57 to 60, pp. 1411-1485, McGraw Hill,
New York (1996) or in "Principles of Medicinal Chemistry," 2.sup.nd
ed., W. O. Foye, ed., Ch. 21, pp. 495-559, Lea & Febiger,
Philadelphia (1981).
[0115] Estrogens, progestins and androgens are also used in animal
husbandry as growth promoters for food animals. It is known in the
art that compounds of these classes act as growth-promoting
steroids in animals such as cattle, sheep, pigs, fowl, rabbits,
etc. Delivery systems to promote the growth of animals are
described, for example, in U.S. Pat. No. 5,401,507, U.S. Pat. No.
5,288,469, U.S. Pat. No. 4,758,435, U.S. Pat. No. 4,686,092, U.S.
Pat. No. 5,072,716 and U.S. Pat. No. 5,419,910.
[0116] NSAIDs are well known in the art. The classes of compounds
which belong to this group include salicylic acid derivatives,
para-aminophenol derivatives, indole and indene acetic acids,
heteroaryl acetic acids, arylpropionic acids, anthranilic acids
(fenamates), enolic acids, and alkanones. NSAIDs exert their
activity by interfering with prostaglandin biosynthesis by
irreversibly or reversibly inhibiting cycloxygenase. Also included
are COX-2 inhibitors which act by inhibiting the COX-2 receptor.
Compounds of this group possess analgesic, antipyretic and
nonsteroidal anti-inflammatory properties. Compounds belonging to
these classes are described, for example, in Chapter 27 of Goodman
and Gilman on pages 617 to 658 or in Ch. 22 of Foye on pages 561 to
590 as well as in U.S. Pat. No. 3,896,145; U.S. Pat. No. 3,337,570;
U.S. Pat. No. 3,904,682; U.S. Pat. No. 4,009,197; U.S. Pat. No.
4,223,299; and U.S. Pat. No. 2,562,830, as well as the specific
agents listed in The Merck Index.
[0117] Macrolides are a class of antibiotics which contain a
many-membered lactone ring to which are attached one or more deoxy
sugars. Macrolides are generally bacteriostatic, but have been
shown to be acteriocidal in high concentration against very
susceptible organisms. Macrolides are most effective against
gram-position cocci and bacilli, although they do possess some
activity against some gram-negative organism. Macrolides exert
their bacteriostatic activity by inhibiting bacterial protein
synthesis by binding reversibly to the 50 S ribosomal subunit.
("Goodman & Gillman's the Pharmacological Basis of
Therapeutics," 9th ed., J. G. Hadman & L. E. Limbird, eds., ch.
47, pp. 1135-1140, McGraw-Hill, New York (1996)).
[0118] The macrolides as a class are colorless and usually
crystalline. The compounds are generally stable in near neutral
solution, but they only have limited stability in acid or base
solutions. The reason for this is because the glycosidic bonds
hydrolyze in acid and the lactone ring saponifies in base
("Principles of Medicinal Chemistry," 2nd ed., W. F. Foye, ed., ch.
31, pp. 782-785, Lea & Febiger, Philadelphia (1981)). Hence,
there is a need for pharmaceutical or veterinary compositions for
parenteral, e.g., intravenous, intramuscular, subcutaneous,
administration of macrolide antibiotics.
[0119] The bioactive agent in the present invention can be a
macrolide, as macrolides are soluble in many organic solvents but
are only slightly water soluble. Solutions of macrolides in organic
solvent systems are used in human and veterinary practice for
administration by the intramuscular and subcutaneous routes.
[0120] Macrolides as a class include the erythromycin and its
derivatives as well as other derivatives such as the azalides.
Erythromycin (MW 733.94 daltons) is the common name for a macrolide
antibiotic produced by the growth of a strain of Streptomyces
erythreous. It is a mixture of three erythromycins, A, B and C
consisting largely of erythromycin A. Its chemical name is
(3R*,4S*5S*,6R*,7R*,9R*,11R*,12R*,13S*,14R*)-4-[(2,6-did-
eoxy-3-C-methyl-3-O-methyl-.alpha.-L-ribo-hexopyranosyl)-oxy]-14-ethyl-7,1-
2,13-trihydroxy-3,5,7,9,11,13-hexamethyl-6[[3,4,6-trideoxy-3-(dimethylamin-
o)-.beta.-D-xylo-exapyranosyl]oxy]oxacyclotetradecane-2,10-dione,
(C.sub.37H.sub.67NO.sub.13).
[0121] Erythromycin has a broad and essentially bacteriostatic
action against many Gram-positive and some Gram-negative bacteria
as well as other organisms including mycoplasmas, spirochetes,
chlamydiae and rickettsiae. In humans, it finds usefulness in the
treatment of a wide variety of infections. It finds wide
application in veterinary practice in the treatment of infectious
diseases such as pneumonias, mastitis, metritis, rhinitis, and
bronchitis in cattle, swine and sheep.
[0122] Other derivatives of erythromycins include carbomycin,
clarithromycin, josamycin, leucomycins, midecamycins, mikamycin,
miokamycin, oleandomycin, pristinamycin, rokitamycin, rosaramicin,
roxithromycin, spiramycin, tylosin, troleandomycin, and
virginiamycin. As with the erythromycins, many of these derivatives
exist as component mixtures. For example, carbomycin is a mixture
of carbomycin A and carbomycin B. Leucomycin exists as a mixture of
components A.sub.1, A.sub.2, A.sub.3, A.sub.9, B.sub.1-B.sub.4, U
and V in various proportions. Component A.sub.3 is also known as
josamycin and leucomycin V is also known as miokomycin. The major
components of the midecamycins is midecamycin A and the minor
components are midecamycins A.sub.2, A.sub.3 and A.sub.4. Likewise,
mikamycin is a mixture of several components, mikamycin A and B.
Mikamycin A is also known as virginiamycin M.sub.1. Pristinamycin
is composed of pristinamycins I.sub.A, I.sub.B, and I.sub.C, which
are identical to virginiamycins B.sub.2, B.sub.13 and B.sub.2
respectively, and pristinamycin II.sub.A and II.sub.B, which are
identical to virginiamycin M.sub.1 and 26,27-dihydrovirginiamycin
M.sub.1. Spiramycin consists of three components, spiromycin I, II,
and III. Virginiamycin is composed of virginiamycin S.sub.1 and
virginiamycin M.sub.1. All these components may be used in this
invention. Sources of these macrolides are well known to the
practitioner and are described in the literature in references such
as "The Merck Index," 12th ed., S. Budarari, ed., Merck & Co.,
Inc., Whitehouse Station, N.J. (1996).
[0123] The azalides are semisynthetic macrolide antibiotics related
to erythromycin A and exhibit similar solubility characteristics.
The structure of azithromycin is known. Useful azalide compounds
are disclosed in EP 508699, herein incorporated by reference. The
corresponding basic and acid addition salts and ester derivatives
of the acrolides compounds are also contemplated for use in this
invention. These salts are formed from the corresponding organic or
inorganic acids or bases. These derivatives include the customary
hydrochloride and phosphate salts as well as the acetate,
propionate and butyrate esters. These derivatives may have
different names. For example, the phosphate salt of oleandomycin is
matromycin and the triacetyl derivative is troleandomycin.
Rokitamycin is leucomycin V 4-B-butanoate, 3B-propionate.
[0124] Other antibiotics may also be used as a bioactive agent in
the practice of this invention.
[0125] The bioactive agent can be, for example a peptide or
protein. The biologically-active agent may also be a substance, or
metabolic precursor thereof, which is capable of promoting growth
and survival of cells and tissues, or augmenting the activity of
functioning cells, as for example, blood cells, neurons, muscle,
bone marrow, bone cells and tissues, and the like. For example, the
biologically-active agent may be a nerve growth promoting
substance, as for example, a ganglioside, phosphatidylserine, a
nerve growth factor, brain-derived neurotrophic factor, a
fibroblast growth factor, and the like. To promote tissue growth,
the biologically-active agent may be either a hard or soft tissue
promoting substance or combinations thereof. Suitable tissue growth
promoting agents include, for example, fibronectin (FN),
endothelial cell growth factor (ECGF), cementum attachment extracts
(CAE), human growth hormone (HGH), a Periodontal ligament cell
growth factor, fibroblast growth factor (FGF), animal growth
hormones, platelet derived growth factor (PDGF), epidermal growth
factor (EGF), protein growth factor interleukin-1 (IL-1),
transforming growth factor (TGF.beta.-2), insulin-like growth
factor II (ILGF-II), human alpha thrombin (HAT), osteoinductive
factor (OIF), bone morphogenetic protein (BMP) or protein derived
therefrom, demineralized bone matrix, and releasing factors
thereof. Further, the agent may be a bone growth promoting
substance such as hydroxyapatite, tricalcium phosphate, a di- or
polyphosphonic acid, an anti-estrogen, a sodium fluoride
preparation, a substance having a phosphate to calcium ratio
similar to natural bone, and the like. A bone growth promoting
substance may be in the form, as for example, of bone chips, bone
crystals or mineral fractions of bone and/or teeth, a synthetic
hydroxyapatite, or other suitable form. The agent may further be
capable of treating metabolic bone disorders such as abnormal
calcium and phosphate metabolism by, for example, inhibiting bone
resorption, promoting bone mineralization, or inhibiting
calcification. See, for example, U.S. Pat. No. 4,939,131 to
Benedict et al., U.S. Pat. No. 4,942,157 to Gall et al., U.S. Pat.
No. 4,894,373 to Young, U.S. Pat. No. 4,904,478 to Walsdorf et al.,
and U.S. Pat. No. 4,911,931 to Baylink, U.S. Pat. No. 4,916,241 to
Hayward et al., U.S. Pat. No. 4,921,697 to Peterlik et al., U.S.
Pat. No. 4,902,296 to Bolander et al., U.S. Pat. No. 4,294,753 to
Urist, U.S. Pat. No. 4,455,256 to Urist, U.S. Pat. No. 4,526,909 to
Urist, U.S. Pat. No. 4,563,489 to Urist, U.S. Pat. No. 4,596,574 to
Urist, U.S. Pat. No. 4,619,989 to Urist, U.S. Pat. No. 4,761,471 to
Urist, U.S. Pat. No. 4,789,732 to Urist, U.S. Pat. No. 4,795,804 to
Urist, and U.S. Pat. No. 4,857,456 to Urist, the disclosures of
which are incorporated by reference herein.
[0126] Further still, the biologically active agent or bioactive
agent can be an antineoplastic, antitumor or anticancer agent.
[0127] The biologically-active agent may be included in the
compositions in the form of, for example, an uncharged molecule, a
molecular complex, a salt, an ether, an ester, an amide, or other
form to provide the effective biological or physiological
activity.
[0128] With respect to biologically active agents useful in the
practice of this invention, reference is also made to the U.S. and
PCT applications of Williams and Chern, "Long Acting Injectable
Formulations Containing Hydrogenated Castor Oil," filed Sep. 14,
1998, U.S. Ser. No. 09/15277 and PCT application Number
US98/190.and claiming priority from U.S. application Serial No.
60/067,374, incorporated herein by reference.
[0129] From the foregoing, the bioactive agent can be varied. The
mount suitable for use in a formulation according to the invention
can be determined by the skilled artisan without any undue
experimentation from the knowledge in the art, and this disclosure,
taking into consideration factors typically considered by those
skilled in the medical, veterinary or pharmaceutical arts, such as
the species involved, the age, weight, general health, and sex of
the host or patient or animal or human, and the condition being
treated and the LD.sub.50 and other characteristics of the
bioactive substance(s).
[0130] Thus, administration of the composition of the invention
ultimately will be accomplished according to the wisdom and
protocol of the patient's or host's or animal's or human's
attending health care professional such as a physician or
veterinarian, or if appropriate, a dentist. Choice of the
particular composition will depend upon the malcondition or
condition to be treated, which choice will be made by the attending
health care professional. Application by syringe, or other means
for applying a liquid to or into a tissue may be employed. The
amounts and concentrations of composition administered to the
patient, host, animal or human will generally be sufficient to
accomplish the task intended. For administration of bioactive
agent, the amounts and release rates will follow recommendations of
the manufacturer of the bioactive agent. Generally, the
concentration of bioactive agent in the liquid polymer formulation
can be from 0.01 mg per g of mixture to 400 mg per g of
mixture.
[0131] In certain embodiments, the present invention provides a
liquid polymeric composition for controlled release of hydrophobic
bioactive substances comprising:
[0132] (a) 1 to 30% w/v of a hydrophobic bioactive substance;
[0133] (b) 1 to 20% w/v of a poly(lactide-co-glycolide)
copolymer;
[0134] (c) a mixture of hydrophilic and lipophilic solvents wherein
the volume ratio of the hydrophilic and lipophilic solvents is from
about 80:20 to about 5:95.
[0135] In a certain preferred embodiment, the bioactive substance,
e.g., at least one hydrophobic bioactive substance, is present in a
concentration of 1 to 10% w/v; more preferably 5 to 10% w/v.
[0136] In another preferred embodiment, polymer, e.g., the
poly(lactide-co-glycolide) copolymer, is present in a concentration
of 1 to 10% w/v; more preferably 1 to 5% w/v.
[0137] In another preferred embodiment, the weight ratio of the
polymer, e.g., poly(lactide-co-glycolide) copolymer, to the
bioactive substance, e.g., at least one hydrophobic bioactive
substance, is 1:1 or less; more preferably 0.5:1 to 1:1.
[0138] In yet another preferred embodiment, the volume ratio of the
hydrophilic and lipophilic solvents is from about 65:35 to about
35:65.
[0139] In another aspect of the present invention there is provided
a liquid polymeric composition for controlled release of
hydrophobic bioactive substances comprising:
[0140] (a) a hydrophobic bioactive substance;
[0141] (b) a poly(lactide-co-glycolide);
[0142] (c) a mixture of glycerol formal and triacetin.
[0143] In another aspect of the present invention there is provided
a method for controlled release of at least one bioactive
substance, e.g., at least one hydrophobic bioactive substance,
which comprises injecting an animal with a liquid polymeric
composition described herein.
[0144] In addition to the foregoing, as used herein the following
terms are as defined below, unless otherwise specified:
[0145] "Polymer" includes "copolymers"; a "copolymer" is a polymer
from the polymerization of at least two monomers; and thus, a
"copolymer" can include a "terpolymer" or a polymer from two, three
or more monomers.
[0146] "Hydrophobic bioactive substance" means compounds useful in
human or animal health having a water solubility of <2%,
preferably <1%, at room temperature. Examples of hydrophobic
bioactive substances suitable for the present invention include,
but are not limited to, avermectins (e.g. ivermectin, eprinomectin,
etc), milbemycins, phenylpyrazoles, nodulisporic acid and
derivatives such as those disclosed in U.S. Pat. No. 5,399,582 and
WO96/29073, estradiol benzoate, trenbolone acetate, progesterone,
norethisterone, non-water-soluble NSAIDs, etc.
[0147] "Poly(lactide-co-glycolide)" means a copolymer of lactic and
glycolic acids having a lactide:glycolide ratio of from 95:05 to
50:50, preferably 75:25 to 65:35. The lactic acid can be d- or l-
or dl-. The copolymer may be a single copolymer of a mixture of
copolymers within the above-defined parameters.
[0148] "Hydrophilic solvent" means water miscible solvents,
preferably those when mixed with water in a ratio from 1:9 to 9:1
form a single-phase solution. Examples of hydrophilic solvents
suitable for the present invention include, but not limited to
glycerol formal, glycofural, N-methyl pyrrolidone, 2-pyrrolidone,
isopropylidene glycerol, di(propylene glycol) methyl ether, and
mixtures thereof.
[0149] "Lipophilic solvent" means water immiscible solvents,
preferably with a solubility in water of less than 10% at room
temperature. Examples of lipophilic solvents suitable for the
present invention include, but not limited to triacetin, benzyl
benzoate, and mixtures thereof.
[0150] The liquid composition of the present invention is capable
of providing prolonged drug release once it is injected, without
the bursting drug release typical of existing liquid injectable
formulations. Without being bound by theory, it is hypothesized
that upon injection the liquid formulation of the present invention
initially forms a depot with a skin made of the polymer surrounding
a liquid core (which may appear "semi-solid"), while some of the
hydrophilic solvent diffuses away from the depot carrying the
dissolved bioactive compound with it. The initial drug release from
the depot is mostly by permeation through the skin. The
permeability of the skin and the rate of initial drug delivery are
controlled by the proportions of the hydrophilic and lipophilic
solvents in the liquid vehicle, at given polymer and drug
concentrations. Over time, the depot loses its liquid vehicles and
degradation of the polymer gradually becomes a significant
drug-release mechanism. Proper adjustment of the liquid formulation
composition thus allows overlap of the permeation-controlled and
erosion-controlled drug delivery and results in a flattened and
extended drug-release profile over a long period of time. And thus,
the depot biodegrades, without wishing to necessarily be bound by
any one particular theory, without necessarily forming a solid or
other physical form associated with prior art compositions.
[0151] The presence of the lipophilic solvent in the liquid
composition of the present invention reduces the initial delivery
of bioactive compound, thus eliminating the bursting drug release
typical of existing liquid injectable formulations where a large
portion of hydrophilic vehicle is used. The presence of the
hydrophilic solvent facilitates the formation of the polymer skin
while preventing precipitation of the bioactive compound, thus
allowing a much higher level of drug delivery than possible when
only lipophilic vehicles are used. In the present invention, the
prefered hydrophilic:lipophilic solvent ratio is between 80:20 to
20:80, most preferably between 65:35 to 35:65.
[0152] Other factors that may influence the performance of the
present liquid formulation include: (1) the polymer, e.g., PLGA
polymer concentration, (2) the relative proportion of the bioactive
compound and the polymer, (3) the comonomer, e.g.,
lactide:glycolide raito in the polymer, and (4) the molecular
weight of the polymer. Factors (3) and (4) were well known in the
art (see documents cited herein). This invention, however, differs
considerably from the existing art, especially in aspects (1) and
(2).
[0153] The liquid formulation of the present invention contains no
more than 20% polymer, e.g., PLGA polymer, preferably less than 10%
of the polymer, in order to maintain a relatively constant drug
delivery rate at the same time ensuring a reasonably long drug
delivery duration (greater than 3 months). The concentration of
polymer, e.g., PLGA in the present formulation is therefore in
sharp contrast to the known formulations where substantially larger
proportion of polymer such as PLGA polymer is prescribed. The
concentration of the bioactive substance in the liquid formulation
may be from 1% to 30%. Preferably, the proportion of polymer, e.g.,
PLGA polymer relative to the bioactive compound is less than or
equal to 1:1; a ratio that is also substantially below those
commonly prescribed. Within the range described herein, higher
polymer concentrations reduce the drug delivery rate, and
increasing the polymer:bioactive compound ratio also reduces the
delivery rate.
[0154] The liquid composition may be prepared by dissolving all the
solid ingredients in the vehicle under normal manufacturing
conditions used for sterile injectable products. The present
composition may contain additional inert substances commonly used
in parenteral formulations including, but not limited to,
antimicrobial agents, antioxidants, and the like.
[0155] The instant liquid compositions are administered to a
warm-blooded animal such as human, cattle, sheep, pigs, dogs,
horses, cats, and the like (e.g., mammals such as humans and
companion and feedstock animals) by intramuscular or subcutaneous
injection. The formulations will generally be prepared to contain
from 1 to 30%, preferably from 1 to 10% of the bioactive compound.
For instance, at a preferred dose volume of about 1 ml to treat a
cattle of 50 kg body weight the formulation contains from 50 to 100
mg of avermectin compound per ml of solution or about 5 to 10% w/v.
However, depending upon the activity of the compound and the animal
being treated, concentrations as low as 1% of bioactive compound
are usable.
[0156] The following examples are provided to illustrate the
invention and are not to be construed as limiting the invention in
any manner.
EXAMPLE 1
[0157] Preparation of Long-Acting Injectable Formulation Containing
6-amino-3-cyano-1-(2,6-dichloro-4-sulfurpentafluorophenyl)-4-(trifluorome-
thylthio) pyrazole
[0158] Poly(DL-lactide/glycolide) 75/25 (PLGA, 0.25 g) was
dissolved in sufficient glycerol formal to provide a 2.5 ml
solution. In a separate flask poly(DL-lactide/glycolide) 75/25
(0.25 g) was dissolved in sufficient triacetin to provide a 2.5 ml
solution. The two PLGA solutions were mixed well and added to a
flask containing the active ingredient (0.50 g). The contents of
the flask were mixed until the active ingredient dissolved, and the
resulting solution was sterile filtered into a vial and sealed.
EXAMPLE 2
[0159] Preparation of Long-Acting Injectable Formulation Containing
Ivermectin
[0160] The general procedure of Example 1 was followed to provide
the following ivermectin formulations:
1 PLGA Solvent drug content content ratio polymer No. % w/v % w/v
TA/GF* type 1 10 10 20/80 7525 2 10 10 35/65 7525 3 10 6.7 50/50
7525 4 10 5 50/50 7525 5 10 5 50/50 5050 *TA = triacetin; GF =
glycerol formal
[0161] For comparison purposes, i.e. to illustrate just how much
more solvent is used in the present invention in comparison to
prior art compositions: In preparation 1 of this example, the
triacetin, the lipophilic solvent, is present at about 16.45% by
weight. In preparation 2 of this example, the triacetin, the
lipophilic solvent is present at about 29% by weight. In
preparation 3 of this example, the triacetin, the lipophilic
solvent is present at about 42% by weight. In preparation 4 of this
example, the triacetin, the lipophilic solvent, is present at about
43% by weight.
EXAMPLE 3
[0162] Preparation of Long-Acting Injectable Formulation Containing
Eprinomectin
[0163] The general procedure of Example 1 was followed to provide
the following eprinomectin formulations:
2 PLGA Solvent drug content content ratio polymer No. % w/v % w/v
TA/GF type 1 10 10 50/50 7525 2 5 5 50/50 6535
[0164] For comparison purposes, i.e., to illustrate just how much
more solvent is used in the present invention in comparison to
prior art compositions: In preparation 2 of this example, the
triacetin, the lipophilic solvent, is present at about 45% weight
percent. And, it is noted that the lipophilic solvent, in
preparations according to this invention can be 100% of the volume
of solvents present, as discussed in the foregoing general
description.
EXAMPLE 4
[0165] Activity of Long-Acting Injectable Formulation Containing
6-amino-3-cyano-1-(2,6-dichloro-4-sulfurpentafluorophenyl)-4-(trifluorome-
thylthio) Pyrazole Against Fleas in Dogs
[0166] Three beagle dogs were treated with the formulation of
Example 1 at a single subcutaneous dose of 10 mg/kg. Dogs were
fasted for at least 6 hours before and 6 hours after the treatment.
On day 1 (day 0=day of drug administration) the animals were
infested with approximately 100 fleas. Animals were combed and
fleas counted and removed approximately 48 hours after infestation.
Animals were infested on days 12 and 26, and combed and fleas
counted and removed approximately 48 hours after infestation.
Infestation/counting were repeated approximately monthly.
[0167] Blood samples were collected from animals on Day 0 at 1, 2,
3 and 6 hours after treatment, on Day 1 at 24 hours after
treatment, and if emesis was observed. Blood samples were also
collected when flea counts were determined. Animals were observed
hourly for 6 hours post treatment for emesis. Close to 100%
efficacy has been demonstrated for >12 months without any
occurrence of emesis in the treated animals. The plasma level
profiles for the individual dogs are shown as FIG. 1.
EXAMPLE 5
[0168] Plasma Level Profiles of Long-Acting Ivermectin Formulations
in Cattle
[0169] Plasma levels of ivermectin were determined in healthy
cattles treated with ivermectin formulations 1, 2 and 3 of Example
2. Each formulation was given to a group of five cattles (generally
weighing 125 to 250 kg) as a single subcutaneous injection dosed at
1 mg/kg. Ten ml haparinized blood samples were collected from each
treated animal on Days 1-7 (daily), 10, 14, and weekly thereafter
for 15 weeks. The plasma level profiles (average of the five
animals in each group) are shown in FIG. 2.
EXAMPLE 6
[0170] Plasma Level Profiles of Long-Acting Eprinomectin
Formulation in Swine
[0171] Plasma levels of eprinomectin were determined in swine
treated with eprinomectin formulation 2 of Example 3. Three swine
(inoculated with 2,000 infective ova of Trichuris suis on day -50,
and orally with 15,000 infective larvae of Oesophagostomum sp. on
day 0) were injected subcutaneously with formulation 2 of Example 3
at a dose of 1.5 mg/kg. Ten ml blood samples were collected from
each animal on days 3, 7 and weekly thereafter. The plasma level
profile is shown in FIG. 3 (with alternate formulation of drug/PLGA
in 100 glycerol formal).
[0172] Having thus described in detail preferred embodiments of the
present invention, it is to be understood that the invention
defined by the appended claims is not to be limited to particular
details set forth in the above description as many apparent
variations thereof are possible without departing from the spirit
or scope of the present invention.
* * * * *