U.S. patent application number 11/888621 was filed with the patent office on 2008-06-26 for high viscosity liquid controlled delivery system and medical or surgical device.
This patent application is currently assigned to Durect Corporation. Invention is credited to John W. Gibson, John C. Middleton, Stacey S. Miller, Arthur J. Tipton.
Application Number | 20080152708 11/888621 |
Document ID | / |
Family ID | 32505948 |
Filed Date | 2008-06-26 |
United States Patent
Application |
20080152708 |
Kind Code |
A1 |
Gibson; John W. ; et
al. |
June 26, 2008 |
High viscosity liquid controlled delivery system and medical or
surgical device
Abstract
The present invention relates to novel nonpolymeric compounds
and compositions that form liquid, high viscosity materials
suitable for the delivery of biologically active substances in a
controlled fashion, and for use as medical or surgical devices. The
materials can optionally be diluted with a solvent to form a
material of lower viscosity, rendering the material easy to
administer. This solvent may be water insoluble or water soluble,
where the water soluble solvent rapidly diffuses or migrates away
from the material in vivo, leaving a higher viscosity liquid
material.
Inventors: |
Gibson; John W.;
(Springville, AL) ; Miller; Stacey S.;
(Birmingham, AL) ; Middleton; John C.;
(Birmingham, AL) ; Tipton; Arthur J.; (Birmingham,
AL) |
Correspondence
Address: |
Thomas P. McCracken;Durect Corporation
2 Results Way
Cupertino
CA
95014
US
|
Assignee: |
Durect Corporation
|
Family ID: |
32505948 |
Appl. No.: |
11/888621 |
Filed: |
July 31, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10316441 |
Dec 10, 2002 |
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11888621 |
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Current U.S.
Class: |
424/456 ; 424/45;
424/49; 424/490; 514/56; 514/784; 514/785 |
Current CPC
Class: |
A61L 2300/402 20130101;
A61L 24/0015 20130101; A61K 9/0019 20130101; A61K 47/34 20130101;
A61K 9/0024 20130101; A61K 47/14 20130101; A61K 9/4858 20130101;
A61Q 5/006 20130101; A61L 2300/43 20130101; A61K 9/7015 20130101;
A61L 31/16 20130101; A61L 24/0026 20130101; A61K 9/0073 20130101;
A61L 27/54 20130101; A61L 26/0066 20130101; A61K 9/1647 20130101;
A61K 47/26 20130101; A61K 47/10 20130101; A61L 15/44 20130101; A61L
2300/252 20130101; A61K 8/60 20130101; A61K 9/0014 20130101; A61L
2300/602 20130101; A61L 15/20 20130101 |
Class at
Publication: |
424/456 ;
514/784; 514/785; 424/45; 424/49; 514/56; 424/490 |
International
Class: |
A61K 9/52 20060101
A61K009/52; A61K 47/12 20060101 A61K047/12; A61K 47/14 20060101
A61K047/14; A61K 9/12 20060101 A61K009/12; A61K 8/30 20060101
A61K008/30; A61K 31/727 20060101 A61K031/727; A61K 9/14 20060101
A61K009/14 |
Claims
1-45. (canceled)
46. A composition for the controlled release delivery of a
substance, said composition comprising: sucrose acetate isobutyrate
(SAIB); a solvent in which the SAIB is soluble; and a substance to
be delivered.
47. The composition of claim 46, wherein the solvent is selected
from the group consisting of ethanol, dimethylsulfoxide, ethyl
lactate, ethyl acetate, benzyl alcohol, triacetin,
N-methylpyrrolidone, propylene carbonate or glycofurol.
48. The composition of claim 46, wherein the substance to be
delivered is a biologically active substance.
49. The composition of claim 48, wherein the biologically active
substance is a drug, peptide, protein, carbohydrate, nucleoprotein,
mucoprotein, lipoprotein, synthetic polypeptide or protein, or a
small molecule linked to a protein, glycoprotein, steroid, nucleic
acid or a fragment thereof, nucleotide, nucleoside,
oligonucleotide, gene, lipid, hormone or vitamin.
50. The composition of claim 49, wherein the drug is an
immunosuppressant, antioxidant, anesthetic, chemotherapeutic agent,
steroid, hormone, antibiotic, antiviral, antifungal,
antiproliferative, antihistamine, anticoagulant, antiphotoaging
agent, melanotropic peptide, nonsteroidal or steroidal
anti-inflammatory compound, antipsychotic or a radiation
absorber.
51. The composition of claim 46, wherein said composition is
suitable for administration by injection.
52. The composition of claim 46, wherein said composition is
suitable for forming a medical or surgical implant.
Description
[0001] This application claims benefit of the filing date of U.S.
Ser. No. 09/699,002, filed Oct. 26, 2000, which is a divisional of
U.S. Ser. No. 09/385,107, filed Aug. 27, 1999, now U.S. Pat. No.
6,413,536, which claims benefit of the filing date of U.S. Ser. No.
08/944,022, filed Sep. 15, 1997, now U.S. Pat. No. 5,968,542, which
is a continuation-in-part of U.S. Ser. No. 478,450, filed Jun. 7,
1995, now abandoned, and which is a continuation-in-part of U.S.
Ser. No. 08/474,337, filed Jun. 7, 1995, now U.S. Pat. No.
5,747,058, the entire contents of each of which are hereby
incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to novel nonpolymeric
compounds and compositions that form liquid, high viscosity
materials suitable for the delivery of biologically active
substances in a controlled fashion, and for use as medical or
surgical devices. The materials can optionally be diluted with a
solvent to form a material of lower viscosity, rendering the
material easy to administer. This solvent may be water insoluble or
water soluble, where the water soluble solvent rapidly diffuses or
migrates away from the material in vivo, leaving a higher viscosity
liquid material.
[0004] 2. Description of Related Art
[0005] There has been extensive research in the area of
biodegradable controlled release systems for bioactive compounds.
Biodegradable matrices for drug delivery are useful because they
obviate the need to remove the drug-depleted device.
[0006] The most common matrix materials for drug delivery are
polymers. The field of biodegradable polymers has developed rapidly
since the synthesis and biodegradability of polylactic acid was
reported by Kulkarni et al., in 1966 ("Polylactic acid for surgical
implants," Arch. Surg., 93:839). Examples of other polymers which
have been reported as useful as a matrix material for delivery
devices include polyanhydrides, polyesters such as polyglycolides
and polylactide-co-glycolides, polyamino acids such as polylysine,
polymers and copolymers of polyethylene oxide, acrylic terminated
polyethylene oxide, polyamides, polyurethanes, polyorthoesters,
polyacrylbnitriles, and polyphosphazenes. See, for example, U.S.
Pat. Nos. 4,891,225 and 4,906,474 to Langer (polyanhydrides),
4,767,628 to Hutchinson (polylactide, polylactide-co-glycolide
acid), 4,530,840 to Tice, et al. (polylactide, polyglycolide, and
copolymers), and 5,234,520 (Dunn et al., biodegradable polymers for
controlled delivery in treating periodontal disease).
[0007] Degradable materials of biological origin are well known
including, for example, crosslinked gelatin. Hyaluronic acid has
been crosslinked and used as a degradable swelling polymer for
biomedical applications (U.S. Pat. No. 4,957,744 to Della Valle et
al.; (1991) "Surface modification of polymeric biomaterials for
reduced thrombogenicity," Polym. Mater. Sci. Eng., 62:
731-735]).
[0008] Biodegradable hydrogels have also been developed for use in
controlled drug delivery as carriers of biologically active
materials such as hormones, enzymes, antibiotics, antineoplastic
agents, and cell suspensions. Temporary preservation of functional
properties of a carried species, as well as the controlled release
of the species into local tissues or systemic circulation, have
been achieved. See for example, U.S. Pat. No. 5,149,543 to Cohen.
Proper choice of hydrogel macromers can produce membranes with a
range of permeability, pore sizes and degradation rates suitable
for a variety of applications in surgery, medical diagnosis and
treatment.
[0009] Many dispersion systems are currently in use as, or being
explored for use as, carriers of substances, particularly
biologically active compounds. Dispersion systems used for
pharmaceutical and cosmetic formulations can be categorized as
either suspensions or emulsions. Suspensions are defined as solid
particles ranging in size from a few nanometers up to hundreds of
microns, dispersed in a liquid medium using suspending agents.
Solid particles include microspheres, microcapsules, and
nanospheres. Emulsions are defined as dispersions of one liquid in
another, stabilized by an interfacial film of emulsifiers such as
surfactants and lipids. Emulsion formulations include water in oil
and oil in water emulsions, multiple emulsions, micro emulsions,
microdroplets, and liposomes. Microdroplets are unilamellar
phospholipid vesicles that consist of a spherical lipid layer with
an oil phase inside, as defined in U.S. Pat. Nos. 4,622,219 and
4,725,442 issued to Haynes. Liposomes are phospholipid vesicles
prepared by mixing water-insoluble polar lipids with an aqueous
solution. The unfavorable entropy caused by mixing the insoluble
lipid in the water produces a highly ordered assembly of concentric
closed membranes of phospholipid with entrapped aqueous
solution.
[0010] U.S. Pat. No. 4,938,763 to Dunn, et al., discloses a method
for forming an implant in situ by dissolving a non-reactive, water
insoluble thermoplastic polymer in a biocompatible, water soluble
solvent to form a liquid, placing the liquid within the body, and
allowing the solvent to dissipate to produce a solid implant. The
polymer solution can be placed in the body via syringe. The implant
can assume the shape of its surrounding cavity. In an alternative
embodiment, the implant is formed from reactive, liquid oligomeric
polymers which contain no solvent and which cure in place to form
solids, usually with the addition of a curing catalyst.
[0011] While a number of materials have been evaluated for use in
the controlled delivery of substances, there remains a need to
provide more simple systems with low toxicity for the controlled
delivery of substances. The delivery systems described above, for
example, require the preparation of polymers and loaded polymeric
matrices, or hydrogels, or other complex or fragile compositions.
In particular, there is a need to provide a liquid-based delivery
system that is easily formulated with a substance to be delivered
and easily administered.
[0012] Therefore, it is an object of the invention to provide a
simple system for the delivery of substances.
[0013] It is another object of the invention to provide a
liquid-based delivery system that is easily formulated with a
substance to be delivered and easily administered.
[0014] It is another object of the present invention to provide a
method for the controlled delivery of substances in a simple
liquid-based system.
SUMMARY OF THE INVENTION
[0015] The invention relates to compounds, and to compositions
containing them, as well as to methods of using these compounds and
compositions as delivery vehicles, for example as controlled
delivery vehicles, for substances, such as bioactive substances.
The invention also relates to these compounds, compositions, and
methods of using them as medical or surgical devices, such as
medical or surgical implants, films, or graft compositions. The
compositions are generally in liquid form, and contain at least one
non-water soluble, high viscosity, liquid carrier material.
[0016] In one aspect, the invention relates to a liquid composition
for the delivery of biologically active substances having (a) a
non-polymeric, non-water soluble high viscosity liquid carrier
material having a viscosity of at least 5,000 cP at 37.degree. C.
that does not crystallize neat under ambient or physiological
conditions, and is present in an amount from about 99.5 percent to
about 1 percent by weight, more particularly from about 95 percent
to about 10 percent by weight, relative to the total weight of the
composition; and (b) a biologically active substance.
[0017] In another aspect, the invention relates to a liquid
composition for the delivery of biologically active substances
having (a) a non-polymeric, non-water soluble high viscosity liquid
carrier material having a viscosity of at least 5,000 cP at
37.degree. C. that does not crystallize neat under ambient or
physiological conditions; (b) a biologically active substance; and
(c) a solvent in which the non-polymeric non-water soluble liquid
carrier material is soluble.
[0018] In another aspect, the invention relates to a liquid
composition for the delivery of biologically active substances
having (a) a non-polymeric, non-water soluble high viscosity liquid
carrier material having a viscosity of at least 5,000 cP at
37.degree. C. that does not crystallize neat under ambient or
physiological conditions; (b) a biologically active substance; and
(c) an additive.
[0019] In another aspect, the invention relates to a liquid
composition for the delivery of biologically active substances
having (a) a non-polymeric, non-water soluble high viscosity liquid
carrier material having a viscosity of at least 5,000 cP at
37.degree. C. that does not crystallize neat under ambient or
physiological conditions; (b) a biologically active substance; and
(c) a solvent in which the non-polymeric non-water soluble liquid
carrier is soluble, and (d) an additive.
[0020] In another aspect, the invention relates to a liquid
composition for the delivery of biologically active substances and
suitable for topical, systemic, parenteral, rectal, vaginal, nasal,
pericardial, or oral administration, or a combination thereof,
having (a) a non-polymeric, non-water soluble high viscosity liquid
carrier material having a viscosity of at least 5,000 cP at
37.degree. C. that does not crystallize neat under ambient or
physiological conditions; and (b) a biologically active
substance.
[0021] In another aspect, the invention relates to a liquid
composition for the delivery of biologically active substances
having (a) a non-polymeric, non-water soluble high viscosity liquid
carrier material having a viscosity of at least 5,000 cP at
37.degree. C. that does not crystallize neat under ambient or
physiological conditions; (b) a biologically active substance; and
(c) a lower viscosity liquid carrier material.
[0022] In another aspect, the invention relates to a liquid
composition for the delivery of biologically active substances
having (a) a non-polymeric, non-water soluble high viscosity liquid
carrier material having a viscosity of at least 5,000 cP at
37.degree. C. that does not crystallize neat under ambient or
physiological conditions; and (b) a biologically active substance
useful for agricultural, human therapy, veterinary, or pesticidal
purposes, or a combination thereof.
[0023] The carrier material may comprise a nonpolymeric ester or
mixed ester of one or more carboxylic acids. In particular, the
carrier material can have a viscosity of at least 5,000 cP at
37.degree. C. In addition, the carrier material may possess the
property that it does not crystallize neat under ambient or
physiological conditions.
[0024] The compositions can be dissolved in a physiologically
acceptable solvent to lower their viscosity, rendering them easier
to administer. After administration of compositions containing
water-soluble solvents, however, the solvent diffuses or otherwise
dissipates away from the material, which thus increases
significantly in viscosity, and thereby forms a controlled release
matrix for a bioactive substance, or a medical or surgical implant,
film, or graft. Non-water soluble solvents may also be used, but
will diffuse away from the nonpolymeric ester or mixed ester much
more slowly.
[0025] Dissolution in solvent is particularly useful with
nonpolymeric esters or mixed esters having very high viscosities,
e.g., on the order of 100,000 cP at 37.degree. C. Some nonpolymeric
esters or mixed esters suitable for use in the invention, while
having viscosities above 5,000 cP at 37.degree. C., are not as
viscous, and may be administered neat, i.e., without the addition
of a solvent.
[0026] In another aspect, the invention relates to a method of
administering a biologically active substance to a plant or an
animal (including humans) by administering to the plant or animal a
composition containing a non-water soluble, high viscosity, liquid
carrier material comprising a nonpolymeric ester or mixed ester of
one or more carboxylic acids, having a viscosity of at least 5,000
cP at 37.degree. C., that does not crystallize neat under ambient
or physiological conditions and a biologically active substance.
The particular method of administration may vary, and may include
topical, oral (e.g., as a solution, emulsion, or in a gelatin
capsule), nasal, pulmonary, rectal, vaginal, or injectable routes
for animals, and topical or injectable routes for plants.
[0027] In another aspect, the invention relates to a medical or
surgical implant, film, or graft composition containing a non-water
soluble, high viscosity, liquid carrier material comprising a
nonpolymeric ester or mixed ester of one or more carboxylic acids,
having a viscosity of at least 5,000 cP at 37.degree. C., that does
not crystallize neat under ambient or physiological conditions.
[0028] In yet another aspect, the invention relates to a method for
the in vivo formation of an implant, film, or graft in a patient in
need thereof, including:
[0029] (1) contacting with the tissue of the patient a mixture
containing: [0030] (a) a non-water soluble, high viscosity, liquid
carrier material comprising a nonpolymeric ester or mixed ester of
one or more carboxylic acids, having a viscosity of at least 5,000
cP at 37.degree. C., that does not crystallize neat under ambient
or physiological conditions; and [0031] (b) a solvent in which the
non-polymeric, non-water soluble liquid carrier material is
soluble; wherein the mixture has a viscosity of less than the
viscosity of the high viscosity liquid carrier material; and
[0032] (2) allowing the solvent to dissipate or diffuse into the
tissue of the patient, thereby forming an implant, film, or graft
of the non-polymeric, non-water soluble, high viscosity liquid
carrier material. In an even more particular aspect of the
invention, the mixture has a viscosity of less than approximately
6,000 cP, more particularly less than approximately 4,000 cP, even
more particularly, less than approximately 1,000 cP, at 37.degree.
C.
[0033] In yet another aspect, the invention relates to novel
compounds having a structure selected from the group consisting
of:
##STR00001##
wherein R.sup.1, R.sup.2, and R.sup.3 are independently selected
from the group consisting of hydrogen, alkanoyl having 2 to 6
carbons, hydroxy-substituted alkanoyl having 2 to 6 carbons, and
acyloxy-substituted alkanoyl having 2 to 6 carbons, wherein n is
between 1 and 20, and wherein at least one of R.sup.1, R.sup.2, and
R.sup.3 is other than hydrogen;
R.sup.1--O--(CH.sub.2).sub.n--O--R.sup.2 III
wherein n is an integer between 4 and 8, and R.sup.1 and R.sup.2
are independently selected from the group consisting of hydrogen,
alkanoyl having 2 to 6 carbons, hydroxy-substituted alkanoyl having
2 to 6 carbons, and acyloxy-substituted alkanoyl having 2 to 6
carbons, and wherein at least one of R.sup.1 and R.sup.2 is other
than hydrogen;
##STR00002##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are
independently selected from the group consisting of hydrogen,
alkanoyl having 2 to 6 carbons, hydroxy-substituted alkanoyl having
2 to 6 carbons, and acyloxy-substituted alkanoyl having 2 to 6
carbons, and wherein at least one of R.sup.1, R.sup.2, R.sup.3,
R.sup.4, and R.sup.5 is other than hydrogen;
##STR00003##
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, and R.sup.6
are independently selected from the group consisting of hydrogen,
alkanoyl having 2 to 6 carbons, hydroxy-substituted alkanoyl having
2 to 6 carbons, and acyloxy-substituted alkanoyl having 2 to 6
carbons, and wherein at least one of R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, and R.sup.6 is other than hydrogen;
##STR00004##
wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently
selected from the group consisting of hydrogen, alkanoyl having 2
to 6 carbons, hydroxy-substituted alkanoyl having 2 to 6 carbons,
and acyloxy-substituted alkanoyl having 2 to 6 carbons, and wherein
at least one of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 is other
than hydrogen.
[0034] In a more particular aspect, the novel compound has the
structure:
##STR00005##
wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently
selected from the group consisting of hydrogen, alkanoyl having 2
to 6 carbons, hydroxy-substituted alkanoyl having 2 to 6 carbons,
and acyloxy-substituted alkanoyl having 2 to 6 carbons, and wherein
at least one of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 is other
than hydrogen.
[0035] The liquid compositions of the invention can be used in any
of the utilities or applications disclosed for HVLCM or LVLCM in
U.S. Pat. Nos. 5,968,542 and 5,747,058, the entire contents of each
of which are hereby incorporated by reference.
BRIEF DESCRIPTION OF DRAWINGS
[0036] The invention can be better understood by reference to the
following illustrative drawings, which are intended to illustrate
and not to limit the scope thereof.
[0037] FIG. 1 is a graph showing the cumulative release profiles
for bupivacaine from decaglycerol tetraoleate and from a
1,6-hexanediol lactate .epsilon.-hydroxycaproic acid according to
the invention.
[0038] FIG. 2 is a graph showing the cumulative release profile for
estradiol from a glycerol lactate glycolate according to the
invention.
[0039] FIG. 3 is a graph showing the cumulative release profile for
progesterone from a 1,6-hexanediol lactate glycolate according to
the invention.
[0040] FIG. 4 is a graph showing the cumulative release profile for
lysozyme from hexaglycerol dioleate and a glycerol lactate
glycolate according to the invention.
[0041] FIG. 5 is a graph showing the cumulative release of cromolyn
sodium from poly(carpolactone) particles suspended in an
SAIB/benzyl benzoate formulation according to the invention.
[0042] FIG. 6 is a graph showing the cumulative release of cromolyn
sodium from a formulation of SAIB/benzyl benzoate containing
polymer additive according to the invention.
DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS
Non-Water-Soluble, High Viscosity, Liquid Carrier Material
[0043] The high viscosity liquid carrier material should be
selected that is non-polymeric, non-water soluble, and has a
viscosity of at least 5,000 cP, (and optionally at least 10,000,
15,000; 20,000; 25,000 or even 50,000 cP) at 37.degree. C. that
does not crystallize neat under ambient or physiological
conditions. The term "non-water soluble" refers to a material that
is soluble in water to a degree of less than one percent by weight
under ambient conditions. The term "non-polymeric" refers to esters
or mixed esters having essentially no repeating units in the acid
moiety of the ester, as well as esters or mixed esters having acid
moieties wherein functional units in the acid moiety are repeated a
small number of times (i.e., oligomers). Generally, materials
having more than five identical and adjacent repeating units or
mers in the acid moiety of the ester are excluded by the term
"nonpolymeric" as used herein, but materials containing dimers,
trimers, tetramers, or pentamers are included within the scope of
this term. When the ester is formed from hydroxy-containing
carboxylic acid moieties that can further esterify, such as lactic
acid or glycolic acid, the number of repeat units is calculated
based upon the number of lactide or glycolide moieties, rather than
upon the number of lactic acid or glycolic acid moieties, where a
lactide repeat unit contains two lactic acid moieties esterified by
their respective hydroxy and carboxy moieties, and where a
glycolide repeat unit contains two glycolic acid moieties
esterified by their respective hydroxy and carboxy moieties. Esters
having 1 to about 20 etherified polyols in the alcohol moiety
thereof, or 1 to about 10 glycerol moieties in the alcohol moiety
thereof, are considered nonpolymeric as that term is used
herein.
[0044] In a particular embodiment, the high viscosity liquid
carrier material (HVLCM) decreases in viscosity, in some cases
significantly, when mixed with a solvent to form a low viscosity
liquid carrier material (LVLCM) that can be administered as a
medical or surgical implant, graft, or film, or mixed with a
biologically active substance for controlled delivery, or a
combination thereof. The LVLCM/biologically active substance
composition is typically easier to place in the body than a
HVLCM/biologically active substance composition, because it flows
more easily into and out of syringes or other implantation means.
It also can easily be formulated as an emulsion. The LVLCM can have
any desired viscosity, but its viscosity is generally lower than
the corresponding HVLCM. As an example, viscosity ranges for the
LVLCM of less than approximately 6,000 cP, more particularly, less
than approximately 4,000 cP, even more particularly, less than
approximately 1,000 cP, and yet even more particularly less than
200 cP, are typically useful for in vivo applications.
[0045] The particular HVLCM used in the invention can be one or
more of a variety of materials. Suitable materials include
nonpolymeric esters or mixed esters of one or more carboxylic
acids. In a particular embodiment, the ester is formed from
carboxylic acids that are esterified with a polyol having from
about 2 to about 20 hydroxy moieties, and which may include 1 to
about 20 etherified polyols. Particularly suitable carboxylic acids
for forming the acid moiety of the ester of the HVLCM include
carboxylic acids having one or more hydroxy groups, e.g., those
obtained by ring opening alcoholysis of lactones, or cyclic
carbonates or by the alcoholysis of carboxylic acid anhydrides.
Amino acids are also suitable for forming esters with the polyol.
In a particular embodiment, the ester or mixed ester contains an
alcohol moiety having one or more terminal hydroxy moieties that
have been esterified with one or more carboxylic acids obtained by
alcoholysis of a carboxylic acid anhydride, such as a cyclic
anhydride.
[0046] Nonlimiting examples of suitable carboxylic acids that can
be esterified to form the HVLCM of the invention include glycolic
acid, lactic acid, .epsilon.-hydroxycaproic acid, serine, and any
corresponding lactones or lactams, trimethylene carbonate, and
dioxanone. The hydroxy-containing acids may themselves be further
esterified through the reaction of their hydroxy moieties with
additional carboxylic acid, which may be the same as or different
from other carboxylic acid moieties in the material. Suitable
lactones include, but are not limited to, glycolide, lactide,
.epsilon.-caprolactone, butyrolactone, and valerolactone. Suitable
carbonates include but are not limited to trimethylene carbonate
and propylene carbonate.
[0047] The alcohol moiety of the ester or mixed ester may be
derived from a polyhydroxy alcohol having from about 2 to about 20
hydroxy groups, and as indicated above, may be formed by
etherifying 1 to 20 polyol molecules. Suitable alcohol moieties
include those derived by removing one or more hydrogen atoms from:
monofunctional C.sub.1-C.sub.20 alcohols, difunctional
C.sub.1-C.sub.20 alcohols, trifunctional alcohols,
hydroxy-containing carboxylic acids, hydroxy-containing amino
acids, phosphate-containing alcohols, tetrafunctional alcohols,
sugar alcohols, monosaccharides, and disaccharides, sugar acids,
and polyether polyols. More specifically, the alcohol moieties may
include one or more of: dodecanol, hexanediol, more particularly,
1,6-hexanediol, glycerol, glycolic acid, lactic acid,
hydroxybutyric acid, hydroxyvaleric acid, hydroxycaproic acid,
serine, ATP, pentaerythritol, mannitol, sorbitol, glucose,
fructose, sucrose, glucuronic acid, polyglycerol ethers containing
from 1 to about 10 glycerol units, polyethylene glycols containing
1 to about 20 ethylene glycol units.
[0048] In particular embodiments of the invention, at least one of
the carboxylic acid moieties of the esters or mixed esters of the
invention comprise at least one oxy moiety In an even more
particular embodiment, each of the carboxylic acid moieties
comprise at least one oxy moiety.
[0049] In another particular embodiment, at least one of the
carboxylic acid moieties of the esters or mixed esters of the
invention contains 2 to 4 carbon atoms. In an even more particular
embodiment, each of the carboxylic acid moieties of the esters or
mixed esters of the invention contain 2 to 4 carbon atoms.
[0050] In another more particular embodiment of the invention, at
least one of the carboxylic acid moieties of the ester or mixed
ester of the invention has 2 to 4 carbon atoms and contains at
least one oxy moiety. In another more particular embodiment of the
invention, each of the carboxylic acid moieties of the ester or
mixed ester of the invention has 2 to 4 carbon atoms and contains
at least one oxy moiety.
[0051] In a particular embodiment, the HVLCM may be sucrose acetate
isobutyrate (SAIB) or some other ester of a sugar alcohol moiety
with one or more alkanoic acid moieties.
[0052] In a particular embodiment, the invention includes
compounds, compositions, and methods of use as described above,
wherein the HVLCM has a structure selected from the group
consisting of:
##STR00006##
[0053] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, and R.sup.8 are independently selected from the
group consisting of hydrogen, alkanoyl, hydroxy-substituted
alkanoyl, and acyloxy-substituted alkanoyl;
[0054] wherein at least three of R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are other than
hydrogen; and
[0055] wherein when R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, and R.sup.8 are selected from the group
consisting of acetyl and isobutyryl, at least three of R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8
are acetyl;
##STR00007##
[0056] wherein R.sup.1, R.sup.2, and R.sup.3 are independently
selected from the group consisting of hydrogen, alkanoyl,
hydroxy-substituted alkanoyl, and acyloxy-substituted alkanoyl and
wherein n is between 1 and 20;
R.sup.1O--(CH.sub.2).sub.n--O--R.sup.2 III
wherein n is an integer between 4 and 8, and R.sup.1 and R.sup.2
are independently selected from the group consisting of hydrogen,
alkanoyl, hydroxy-substituted alkanoyl, and acyloxy-substituted
alkanoyl;
##STR00008##
wherein in formulae IV and V, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
and R.sup.5 are independently selected from the group consisting of
hydrogen, alkanoyl, hydroxy-substituted alkanoyl, and
acyloxy-substituted alkanoyl;
##STR00009##
wherein in formulae VI and VII, R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, and R.sup.6 are independently selected from the group
consisting of hydrogen, alkanoyl, hydroxy-substituted alkanoyl, and
acyloxy-substituted alkanoyl;
##STR00010##
wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are independently
selected from the group consisting of hydrogen, alkanoyl,
hydroxy-substituted alkanoyl, and acyloxy-substituted alkanoyl.
[0057] In each of formulae I through VIII, one or more of the
alkanoyl, hydroxy-substituted alkanoyl, and acyloxy-substituted
alkanoyl groups may comprise alkanoyl moieties having 2 to 6 carbon
atoms, including the carbonyl carbon. Moreover, in another more
particular embodiment of the invention, each of formulae I through
VIII comprise at least one hydroxy-substituted or
acyloxy-substituted alkanoyl moiety. In an even more particular
embodiment, at least one of these hydroxy-substituted or
acyloxy-substituted alkanoyl moieties comprise alkanoyl moieties
having 2 to 6 carbon atoms, including the carbonyl carbon.
[0058] The acyl groups forming the acyloxy substituents of the
invention may be any moiety derived from a carboxylic acid in
accordance with the commonly accepted definition of the term
"acyl." More particularly, the acyl groups of the compositions of
the invention may be of the form R.sup.9CO--, where R.sup.9 is
optionally oxy-substituted alkyl of 2-6 carbon atoms. This
oxy-substitution may take the form of hydroxy substitution, or
substitution with additional acyl moieties. For example R.sup.9 may
be an oligomer of oxy-substituted carboxylic acids, linked by ester
bonding between the hydroxy of one acid and the carboxy of another
acid. In a more particular example, R.sup.9 may comprise 1 to 5
lactide or glycolide units, where a lactide unit contains two
lactic acid moieties esterified together and a glycolide unit
contains two glycolic acid moieties esterified together.
Alternatively, R.sup.9 may contain mixed lactide and glycolide
units, or may contain mixed lactic acid and glycolic acid, without
the presence of lactide or glycolide units.
[0059] Particular HVLCM materials include components according to
formulae II or III, wherein R.sup.1, R.sup.2, and R.sup.3 are
independently lactoyl, polylactoyl, .epsilon.-caproyl,
hydroxyacetyl, or polyhydroxyacetyl, in particular, polylactoyl and
.epsilon.-caproyl, or polylactoyl and polyhydroxyacetyl.
[0060] The use of relatively small chain (2 to 6 carbon atoms),
oxy-substituted carboxylic acid moieties in the ester or mixed
ester of the invention is advantageous. When these acid moieties
are present in the form of oligomeric esters (i.e., a subsequent
acid moiety joined to the previous acid moiety through
esterification of the subsequent carboxy with the previous oxy),
hydrolysis of the material is considerably easier than for
oligomers made with more than 6 carbon atoms because the material
is more hydrophilic. In general, for drug delivery it is desired
that the HVLCM be water insoluble, but it may be somewhat
hydrophilic. In general, HVLCMs synthesized with more hydrophilic
units (as determined by a higher O:C ratio) will be expected to
absorb water more rapidly and degrade more quickly. For example, a
HVLCM made by covalently linking 4 moles of glycolide to one mole
of glycerol will be expected to absorb water more rapidly and
degrade more quickly than a HVLCM made by covalently linking 2
moles of glycolide and 2 moles of lactide to one mole of glycerol.
Similar increases can be expected for more flexible molecules and
for more branched, spherical molecules based on free volume
arguments. Use of flexible and branched molecules may also have the
benefit of lowering the viscosity of the LVLCM. Using carboxylic
acids and/or polyols of different chain length and using carboxylic
acids having oxy-substitution allows a precise control of the
degree of hydrophilicity and of the solubility of the resulting
ester. These materials are sufficiently resistant to dissolution in
vivo that they are able to provide a controlled release of
bioactive substances into the body accompanied or followed by oxy
bonds hydrolyzing in vivo.
[0061] In an even more particular embodiment, the invention
excludes the acetate and isobutyrate ester of sucrose having a
ratio of acetate to isobutyrate acid moieties of 2:6. However,
sucrose acetate isobutyrate ester having a ratio of acetate to
isobutyrate moieties of 2:6 is included within the scope of the
invention for use in aerosol formulations, as well as for the
delivery of lysozyme, paclitaxel, 5-fluorouracil, and
antiretroviral drugs like AZT and ddC, as described and exemplified
below. This material can be made according to the procedures
described in U.S. Pat. No. 2,931,802.
[0062] In general, the HVLCM esters of the invention can be made by
reacting one or more alcohols, in particular one or more polyols,
which will form the alcohol moiety of the resulting esters with one
or more carboxylic acids, lactones, lactams, carbonates, or
anhydrides of the carboxylic acids which will form the acid
moieties of the resulting esters. The esterification reaction can
be conducted simply by heating, although in some instances addition
of a strong acid or strong base esterification catalyst may be
used. Alternatively, an esterification catalyst such as stannous
2-ethylhexanoate can be used. The heated reaction mixture, with or
without catalyst, is heated with stirring, then dried, e.g., under
vacuum, to remove any unreacted starting materials, to produce a
liquid product. Sucrose acetate isobutyrates can be made by
following the procedures described in U.S. Pat. No. 2,931,802.
[0063] In this regard, the polyol can be viewed as an
oligomerization initiator, in the sense that it provides a
substrate for esterification of carboxylic acids, in particular, of
oligomers of lactide, glycolide, or other esterified
hydroxy-substituted carboxylic acids.
Solvents
[0064] As described above, in one embodiment of the invention, the
HVLCM can be mixed with a viscosity lowering solvent to form a
lower viscosity liquid carrier material (LVLCM), which can then be
mixed with the biologically active substance to be delivered, prior
to administration. These solvents can be water soluble, non-water
soluble, or water miscible, and can include, acetone, benzyl
alcohol, benzyl benzoate, N-(betahydroxyethyl) lactamidebutylene
glycol, caprolactam, caprolactone, corn oil, decylmethylsulfoxide,
dimethyl ether, dimethyl sulfoxide, 1-dodecylazacycloheptan-2-one,
ethanol, ethyl acetate, ethyl lactate, ethyl oleate, glycerol,
glycofurol (tetraglycol), isopropyl myristate, methyl acetate,
methyl ethyl ketone, N-methyl-2-pyrrolidone, MIGLYOLs.RTM. (esters
of caprylic and/or capric acids with glycerol or alkylene glycols,
e.g., MIGLYOL.RTM. 810 or 812 (caprylic/capric triglycerides),
MIGLYOL.RTM. 818 (caprylic/capric/linoleic triglyceride),
MIGLYOL.RTM. 829 (caprylic/capric/succinic triglyceride),
MIGLYOL.RTM. 840 (propylene glycol dicaprylate/caprate)), oleic
acid, peanut oil, polyethylene glycol, propylene carbonate,
2-pyrrolidone, sesame oil, SOLKETAL
([.+-.]-2,2-dimethyl-1,3-dioxolane-4-methanol), tetrahydrofuran,
TRANSCUTOL.RTM. (diethylene glycol monoethyl ether, carbitol),
triacetin, triethyl citrate, diphenyl phthalate, and combinations
thereof. Additionally, if the composition is to be applied as an
aerosol, e.g. for topical application, the solvent may be or may
include one or more propellants, such as CFC propellants like
trichlorofluoromethane and dichlorofluoromethane, non-CFC
propellants like tetrafluoroethane (R-134a),
1,1,1,2,3,3,3-heptafluoropropane (R-227), dimethyl ether, propane,
and butane.
[0065] Particularly suitable solvents and/or propellants include
benzyl benzoate, benzyl alcohol, triacetin, triethyl citrate,
dimethyl sulfoxide, ethanol, ethyl lactate, glycerol, glycofurol
(tetraglycol), N-methyl-2-pyrrolidone, MIGLYOL.RTM. 810,
polyethylene glycol, propylene carbonate, 2-pyrrolidone, and
tetrafluoroethane.
[0066] Other possible solvents include perfluorodecalin,
perfluorotributylamine, methoxyflurane, glycerolformal,
tetrahydrofurfuryl alcohol, diglyme, and dimethyl isosorbide.
[0067] When the composition is used as a LVLCM in conjunction with
administration of a biologically active substance, it should
contain a solvent that the HVLCM is soluble in. In certain
instances, the substance to be delivered is also soluble in the
solvent. The solvent should be non-toxic and otherwise
biocompatible. Solvents that are toxic should not be used for
pharmaceutical or agricultural purposes. The solvents used to
inject the composition into animals should not cause significant
tissue irritation or necrosis at the site of implantation, unless
irritation or necrosis is the desired effect.
[0068] In one embodiment, the solvent should be at least water
soluble, so that it will diffuse quickly into bodily fluids or
other aqueous environment, causing the composition to coagulate or
solidify. In another embodiment, the solvent is not completely
miscible with water or bodily fluids so that diffusion of the
solvent from the composition, and the corresponding increase in
viscosity of the composition, are slowed. Suitable solvents that
have this property, at least to some extent, include benzyl
benzoate, MIGLYOL.RTM. 810, benzyl alcohol, and triethylcitrate.
Benzyl alcohol can be particularly suitable, as it also provides an
anesthetizing effect, which can relieve discomfort resulting from
injection.
[0069] When esters of 1,6-hexanediol or glycerol are used as the
HVLCM, some possible solvents are ethanol, N-methylpyrrolidone,
propylene carbonate, and PEG 400.
[0070] The solvent is typically added to the compositions in an
amount in the range from about 0.5 percent to about 99.7 percent,
more particularly from about 1 percent to about 95 percent by
weight, more particularly from about 5 to about 90 wt %, relative
to the total weight of the composition. Even more particularly, the
solvent is present in the composition in an amount in the range
from about 10 percent to about 55 percent by weight. Other
particular ranges include from about 10 percent to 50 percent by
weight, and from about 10 to about 30 percent by weight.
[0071] A further embodiment involves the use of solvents that are
not solvents for the HVLCM such that when combined with the HVLCM
singularly or in combination with a solvent for the HVLCM, the
resulting composition forms an emulsion. Such emulsions may contain
the HVLCM in the dispersed phase such as in the case of
SAIB/MIGLYOL.RTM. mixtures that are emulsified in water or
glycerol, or they may contain the HVLCM as a component of the
continuous phase such as in the case of an aqueous solution that is
emulsified in the HVLCM or a solution of the HVLCM in a water
immiscible solvent.
Substance to be Delivered
[0072] When the HVLCM or LVLCM is to be used as a vehicle for
delivery or controlled release of a substance to an animal or
plant, this substance may be any substance that exhibits a desired
property. In a particular embodiment, the substance is a
biologically active substance.
[0073] The term "biologically active substance" as used herein
refers to an inorganic or organic molecule including a drug,
peptide, protein, carbohydrate (including monosaccharides,
oligosaccharides, and polysaccharides), nucleoprotein, mucoprotein,
lipoprotein, synthetic polypeptide or protein, or a small molecule
linked to a protein, glycoprotein, steroid, nucleic acid (any form
of DNA, including cDNA, or RNA, or a fragment thereof), nucleotide,
nucleoside, oligonucleotides (including antisense
oligonucleotides), gene, lipid, hormone, vitamin, including vitamin
C and vitamin E, or combination thereof, that causes a biological
effect when administered in vivo to an animal, including but not
limited to birds and mammals, including humans.
[0074] Suitable proteins include, but are not limited to, human
growth hormone, fibroblast growth factor (FGF), erythropoietin
(EPO), platelet derived growth factor (PDGF), granulocyte colony
stimulating factor (g-CSF), bovine somatotropin (BST), tumor
necrosis factor (TNF), transforming growth factor-beta (TGF-Beta),
interleukins, insulin, and interferons, such as .alpha.-interferon,
.beta.-interferon, and the like.
[0075] The term drug, as used herein, refers to any substance used
internally or externally as a medicine for the treatment, cure, or
prevention of a disease or disorder, and includes but is not
limited to immunosuppressants, antioxidants, anesthetics,
analgesics, chemotherapeutic agents, steroids (including
retinoids), hormones, antibiotics, antivirals, antifungals,
antiproliferatives, antihistamines, anticoagulants, antiphotoaging
agents, melanotropic peptides, nonsteroidal and steroidal
anti-inflammatory compounds, antipsychotics, and radiation
absorbers, including UV-absorbers.
[0076] The term biologically active substance also includes agents
such as insecticides, pesticides, fungicides, rodenticides, and
plant nutrients and growth promoters.
[0077] In one embodiment, the composition functions as a vaccine
and the substance to be delivered is an antigen. The antigen can be
derived from a cell, bacteria, or virus particle, or portion
thereof. As defined herein, antigen may be a protein, peptide,
polysaccharide, glycoprotein, glycolipid, nucleic acid, or
combination thereof, which elicits an immunogenic response in an
animal, for example, a mammal, bird, or fish. As defined herein,
the immunogenic response can be humoral or cell-mediated. In the
event the material to which the immunogenic response is to be
directed is poorly antigenic, it may be conjugated to a carrier
such as albumin or to a hapten, using standard covalent binding
techniques, for example, with one of the several commercially
available reagent kits.
[0078] Examples of preferred antigens include viral proteins such
as influenza proteins, human immunodeficiency virus (HIV) proteins,
and hepatitis A, B, or C proteins, and bacterial proteins,
lipopolysaccharides such as gram negative bacterial cell walls and
Neisseria gonorrhea proteins, and parvovirus. The composition of
the invention can also be used to elicit both mucosal and systemic
immune responses by administration of the HVLCM of the invention,
optionally with a solvent to decrease its viscosity as described
above, in combination with an immunogenic material, in a vaccine
that is administered to a mucosal surface, e.g., intranasally,
intravaginally, or intrarectally. The immunogenic material may be
any immunogenic agent whose delivery to mucosal tissue is desired.
In an even more particular aspect of this embodiment, the HVLCM or
LVLCM is selected from formulae II through VIII above. Vaccines of
this type can be prepared and administered by delivering an
immunogenic material to the mucosal tissues, particularly to the
mucosally associated lymphoid tissues of animals, particularly
mammals. Administering immunogenic materials, in particular,
immunogenic material combined with a carrier containing the
non-polymeric, non-water-soluble, high viscosity liquid and a
solvent therefore to the folliculi lymphatic aggregati which are
found in the mucosal tissues can be an effective delivery
technique. The solvent rapidly dissipates, resulting in a highly
viscous liquid formulation that holds the immunogenic material over
the muscosal tissue and allows the immunogenic material to
stimulate a mucosal immune response and/or a systemic immune
response. Administration of the formulation may include
aerosolizing the formulation or a water emulsion thereof and
administering this formulation intranasally, intravaginally (e.g.,
as a douching liquid, vaginal suppository, or bougie), or
intrarectally (e.g., as an enema, suppository or bougie). In
particular embodiments, the solvent can be, or the formulation can
include, a penetration enhancer that facilitates the absorption of
the immunogenic material into the lymphatic tissue. The
non-polymeric, non-water-soluble, high viscosity liquid material
provides controlled release of the immunogenic material from a
viscous liquid film that forms over the lymphoid tissue.
[0079] The immunogenic material may be any immunogenic agent whose
delivery to mucosal tissue, and in particular to mucosally
associated lymphoid tissue (MALT), is desired. Even more
particularly, the mucosal tissue may be nasally associated lymphoid
tissue, Waldeyer's ring, or analogous tissue in non-human species.
Examples of suitable immunogenic materials include, but are not
limited to, antigens to vaccinate against viral, bacterial,
protozoan, fungal diseases such as respiratory syncytial,
parainfluenza viruses, Hemophilus influenza, Bordetella pertussis,
Neisseria gonorrhoeae, Streptococcus pneumoniae, and Plasmodium
falciparum or other diseases caused by pathogenic micro-organisms,
antigens to vaccinate against diseases caused by macro-organisms
such as helminthic pathogens, antigens to vaccinate against
allergens.
[0080] In another embodiment, the composition functions as a
controlled release composition for reproductive therapy, in humans
or animals. For example, the HVLCM or LVLCM may be combined with
gonadotropin releasing hormone or its analogs or agonists. In a
particular aspect of this embodiment, the HVLCM or LVLCM is not
SAIB having an acetate to butyrate ratio of 2:6. In an even more
particular aspect of this embodiment, the HVLCM or LVLCM is
selected from formulae II through VIII above. These compositions
can be prepared and administered by following the procedures
described for SAIB in U.S. Pat. No. 6,051,558, the entire contents
of which are hereby incorporated by reference.
[0081] Non-limiting examples of pharmacological materials include
anti-infectives such as nitrofurazone, sodium propionate,
antibiotics, including penicillin, tetracycline, oxytetracycline,
chlorotetracycline, bacitracin, nystatin, streptomycin, neomycin,
polymyxin, gramicidin, chloramphenicol, erythromycin, and
azithromycin; sulfonamides, including sulfacetamide,
sulfamethizole, sulfamethazine, sulfadiazine, sulfamerazine, and
sulfisoxazole, and anti-virals including idoxuridine;
antiallergenics such as antazoline, methapyritene,
chlorpheniramine, pyrilamine prophenpyridamine, hydrocortisone,
cortisone, hydrocortisone acetate, dexamethasone, dexamethasone
21-phosphate, fluocinolone, triamcinolone, medrysone, prednisolone,
prednisolone 21-sodium succinate, and prednisolone acetate;
desensitizing agents such as ragweed pollen antigens, hay fever
pollen antigens, dust antigen and milk antigen; vaccines such as
smallpox, yellow fever, distemper, hog cholera, chicken pox,
antivenom, scarlet fever, diphtheria toxoid, tetanus toxoid, pigeon
pox, whooping cough, influenzae rabies, mumps, measles,
poliomyelitic, and Newcastle disease; decongestants such as
phenylephrine, naphazoline, and tetrahydrazoline; miotics and
anticholinesterases such as pilocarpine, esperine salicylate,
carbachol, diisopropyl fluorophosphate, phospholine iodide, and
demecarium bromide; parasympatholytics such as atropine sulfate,
cyclopentolate, homatropine, scopolamine, tropicamide, eucatropine,
and hydroxyamphetamine; sympathomimetics such as epinephrine;
antipsychotics, such as olanzapine, risperidone; narcotic
antagonists, such as naltrexone, naloxone, nalnothene; sedatives
and hypnotics such as pentobarbital sodium, phenobarbital,
secobarbital sodium, codeine, (a-bromoisovaleryl) urea, carbromal;
psychic energizers such as 3-(2-aminopropyl) indole acetate and
3-(2-aminobutyl) indole acetate; tranquilizers such as reserpine,
chlorpromayline, and thiopropazate; anesthetics, such as
benzocaine, bupivacaine, etidocaine, lidocaine, mepivacaine,
pramoxine, prilocalne, procaine, proparacaine, ropivacaine,
tetracaine, levobupivacaine, chloroprocaine, butacaine,
propoxycaine, phenacaine, hexylcaine, isobucaine, cyclomethycaine,
benoxinate, diperodon, dibucaine, meprylcaine, dimethisoquin,
pramoxine, butamben, dyclonine (with and without augmenting agents
such as dexamethasone or epinephrine); tricyclic antidepressants
such as amitriptyline or nortryptyline; androgenic steroids such as
methyl-testosterone and fluorymesterone; estrogens such as estrone,
17-fl-estradiol, ethinyl estradiol, and diethyl stilbestrol;
progestational agents such as progesterone, megestrol,
melengestrol, chlormadinone, ethisterone, norethynodrel,
19-norprogesterone, norethindrone, medroxyprogesterone and
17-0-hydroxy-progesterone; humoral agents such as the
Prostaglandins, for example PGEI, PGE2 and PGF2; antipyretics such
as aspirin, sodium salicylate, and salicylamide; antispasmodics
such as atropine, methantheline, papaverine, and methscopolamine
bromide; antimalarials such as the 4-aminoquinolines,
8-aminoquinolines, chloroquine, and pyrimethamine, antihistamines
such as diphenhydramine, dimenhydrinate, tripelennamine,
perphenazine, and chlorphenazine; cardioactive agents such as
dibenzhydroflume thiazide, flumethiazide, chlorothiazide, and
aminotrate; statins, such as atorvastatin, cerivastatin,
fluvastatin, lovastatin, pravastatin, simvastatin, and related
compounds; antiasthmatics, such as cromolyn; bone resorption
prevention agents, such as bisphosphonates, including as
nonlimiting examples alendronate, risendronate, zolendronate,
pamidronate, and ibandronate; calcium regulating hormones, such as
calcitonin; nutritional agents such as vitamins, natural and
synthetic bioactive peptides and proteins, including growth
factors, cell adhesion factors, cytokines, and biological response
modifiers.
[0082] The active compound is included in the composition in an
amount sufficient to deliver to the host animal or plant an
effective amount to achieve a desired effect. The amount of drug or
biologically active agent incorporated into the composition depends
upon the desired release profile, the concentration of drug
required for a biological effect, and the desired period of release
of the drug.
[0083] The concentration of active compound in the composition will
also depend on absorption, inactivation, and excretion rates of the
drug as well as other factors known to those of skill in the art.
It is to be noted that dosage values will also vary with the
severity of the condition to be alleviated. It is to be further
understood that for any particular subject, specific dosage
regimens should be adjusted over time according to the individual
need and the professional judgment of the person administering or
supervising the administration of the compositions, and that the
concentration ranges set forth herein are exemplary only and are
not intended to limit the scope or practice of the claimed
composition. The composition may be administered in one dosage, or
may be divided into a number of smaller doses to be administered at
varying intervals of time.
[0084] The biologically active substance is typically present in
the composition in the range from about 0.1 percent to about 90
percent by weight, more particularly from about 0.5 percent to
about 70 percent by weight relative to the total weight of the
composition, and more typically, between approximately 1 percent to
about 50 percent by weight. However, ranges having upper endpoints
as low as about 40%, 30%, 20%, or 10% can be used, as can ranges
having lower limits as high as about 5%, 3%, or 2%. For very active
agents, such as growth factors, preferred ranges are less than 1%
by weight, and possibly less than 0.0001%.
[0085] Both soluble and insoluble substances can be distributed in
the HVLCM or LVLCM for controlled delivery. Moreover, the
formulations containing biologically active substances and an HVLCM
or LVLCM may be further formulated with polymeric excipients to
provide a drug delivery matrix with modified properties, for
example a faster or slower degradation rate. The resulting
composition may be formed into microspheres, or into a macroscopic
implant, or other geometries and sizes according to techniques
known in the art. Alternatively, a pre-formed microsphere, implant,
or polymer/drug particle with a biologically active substance or
substances incorporated therein can be combined with the HVLCM or
LVLCM.
[0086] Microspheres may be prepared by a number of methods known in
the art, as well as methods described in U.S. Pat. Nos. 6,291,013
and 6,440,493. The polymer/drug particle may be created by melt
extrusion, granulation, solvent mixing, or absorption, or the drug
may be adsorbed onto a polymer matrix, such as an ion exchange
resin. The resulting material, when combined with a biologically
active agent and LVLCM, may be administered orally or parenterally.
In other embodiments, the drug may be combined with a non-polymeric
material, such as calcium phosphate or sucrose, to provide
layering/barrier properties that lengthen degradation. The HVLCM or
LVLCM will form an secondary barrier to provide enhanced drug
delivery. The HVLCM or LVLCM phase may or may not contain other
biologically active substances, according to the specific
biological requirement. These other biologically active substances
may be any of those described above, provided that the biologically
active substance must be suitable for incorporation into
microspheres or implants according to techniques known in the
art.
Additives
[0087] A variety of additives can optionally be added to the HVLCM
or LVLCM to modify the properties of the material as desired, and
in particular to modify the release properties of the composition
with respect to biologically active substances contained therein.
The additives can be present in any amount which is sufficient to
impart the desired properties to the composition.
[0088] The amount of additive used will in general be a function of
the nature of the additive and the effect to be achieved, and can
be easily determined by the routineer. Suitable additives are
described in U.S. Pat. No. 5,747,058, the entire contents of which
are hereby incorporated by reference. More particularly, suitable
additives include water, biodegradable polymers, non-biodegradable
polymers, natural oils, synthetic oils, carbohydrates or
carbohydrate derivatives, inorganic salts, BSA (bovine serum
albumin), surfactants, organic compounds, such as sugars, and
organic salts, such as sodium citrate. Some of these classes of
additives are described in more detail below. In general, the less
water soluble, i.e., the more lipophilic, the additive, the more it
will decrease the rate of release of the substrate, compared to the
same composition without the additive. In addition, it may be
desirable to include additives that increase properties such as the
strength or the porosity of the composition.
[0089] The addition of additives can also be used to lengthen the
delivery time for the active ingredient, making the composition
suitable for treatment of disorders or conditions responsive to
longer term administration. Suitable additives in this regard
include those disclosed in U.S. Pat. No. 5,747,058. In particular,
suitable additives for this purpose include polymeric additives,
such as cellulosic polymers and biodegradable polymers. Suitable
cellulosic polymers include cellulose acetates, cellulose ethers,
and cellulose acetate butyrates. Suitable biodegradable polymers
include polylactones, polyanhydrides, and polyorthoesters, in
particular, polylactic acid, polyglycolic acid, polycaprolactone,
and copolymers thereof.
[0090] When present, the additive is typically present in the
compositions in an amount in the range from about 0.01 percent to
about 20 percent by weight, more particularly from about 0.1
percent to about 20 percent by weight, relative to the total weight
of the composition, and more typically, is present in the
composition in an amount in the range from about 1, 2, or 5 percent
to about 10 percent by weight. Certain additives, such as buffers,
are only present in small amounts in the composition.
[0091] The following categories are nonlimiting examples of classes
of additives that can be employed in the composition.
[0092] Given the disclosure herein and the objects to be achieved,
one of skill in the art will easily know how to select other
additives to achieve a desired purpose. All of these embodiments
are considered to fall within the disclosed invention.
[0093] A. Biodegradable Polymers
[0094] One category of additives are biodegradable polymers and
oligomers. The polymers can be used to alter the release profile of
the substance to be delivered, to add integrity to the composition,
or to otherwise modify the properties of the composition.
Non-limiting examples of suitable biodegradable polymers and
oligomers include: poly(lactide), poly(lactide-co-glycolide),
poly(glycolide), poly(caprolactone), polyamides, polyanhydrides,
polyamino acids, polyorthoesters, polycyanoacrylates,
poly(phosphazines), poly(phosphoesters), polyesteramides,
polydioxanones, polyacetals, polyketals, polycarbonates,
polyorthocarbonates, degradable polyurethanes,
polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates,
polyalkylene succinates, poly(malic acid), chitin, chitosan, and
copolymers, terpolymers, oxidized cellulose, or combinations or
mixtures of the above materials.
[0095] Examples of poly(.alpha.-hydroxy acid)s include
poly(glycolic acid), poly(DL-lactic acid) and poly(L-lactic acid),
and their copolymers. Examples of polylactones include
poly(s-caprolactone), poly(.delta.-valerolactone) and
poly(.gamma.-butyrolactone).
[0096] While not wishing to be bound by any theory, it is believed
that when the composition contains a biodegradeable polymer, a
portion of the polymer may precipitate or coagulate at the surface
of the composition as the solvent diffuses away from the material
after administration to the patient. The polymer may have been
added as a release modifying agent to affect the release of a
biologically active compound, or may have been added as part of a
composition containing preformed microspheres, implants, or ground
polymer particles. The precipitation or coagulation of the polymer
forms a skin at least partially surrounding the liquid core of the
composition. This skin is porous, and allows the solvent to
continue to diffuse through it into surrounding tissue. The rate of
solvent release and the extent of formation of the skin, as well as
its porosity, can be controlled by the amount and type of solvent
and polymer used in the composition.
[0097] B. Non-biodegradable Polymers
[0098] Another additive for use with the present compositions are
non-biodegradable polymers. Non-limiting examples of nonerodible
polymers which can be used as additives include: polyacrylates,
ethylene-vinyl acetate polymers, cellulose and cellulose
derivatives, acyl substituted cellulose acetates and derivatives
thereof, non-erodible polyurethanes, polystyrenes, polyvinyl
chloride, polyvinyl fluoride, polyvinyl (imidazole),
chlorosulphonated polyolefins, polyethylene oxide, and
polyethylene.
[0099] Preferred non-biodegradable polymers include polyvinyl
pyrrolidone, ethylene vinylacetate, polyethylene glycol, cellulose
acetate butyrate ("CAB") and cellulose acetate propionate
("CAP").
[0100] C. Oils and Fats
[0101] A further class of additives which can be used in the
present compositions are natural and synthetic oils and fats. Oils
derived from animals or from plant seeds of nuts typically include
glycerides of the fatty acids, chiefly oleic, palmitic, stearic,
and linoleic. As a rule the more hydrogen the molecule contains the
thicker the oil becomes.
[0102] Non-limiting examples of suitable natural and synthetic oils
include vegetable oil, peanut oil, medium chain triglycerides,
soybean oil, almond oil, olive oil, sesame oil, fennel oil,
camellia oil, corn oil, castor oil, cotton seed oil, and soybean
oil, either crude or refined, and medium chain fatty acid
triglycerides.
[0103] Fats are typically glyceryl esters of higher fatty acids
such as stearic and palmitic. Such esters and their mixtures are
solids at room temperatures and exhibit crystalline structure. Lard
and tallow are examples. In general oils and fats increase the
hydrophobicity of the HVLCM, slowing degradation and water
uptake.
[0104] D. Carbohydrates and Carbohydrate Derivatives Another class
of additives which can be used in the present compositions are
carbohydrates and carbohydrate derivatives. Non-limiting examples
of these compounds include monosaccarides (simple sugars such as
fructose and its isomer glucose (dextrose); disaccharides such as
sucrose, maltose, cellobiose, and lactose; and polysaccharides.
[0105] E. Multivalent Metals
[0106] Another class of additives includes multivalent metals, such
as zinc, useful in ionic form as protein stabilizers. The zinc may
be present in the formulation as zinc carbonate, zinc acetate, zinc
sulfate, zinc chloride, or other zinc salts as appropriate. Other
non-limiting examples of compounds to provide metal cations in the
formulation include magnesium carbonate, calcium carbonate,
magnesium acetate, magnesium sulfate, magnesium chloride, magnesium
oxide, magnesium hydroxide, and the like. The amount of such agents
used in the formulation will depend upon the amount of protein in
the formulation and the nature of the interaction between the
protein and the stabilizer.
Uses of the LVLCM and HVLCM Compositions
[0107] The composition described herein can be administered to the
host through a variety of methods which can vary depending on the
result to be achieved. When the host is an animal, such as a human,
the composition can be administered, for example, topically,
systematically (for example, mucosally (orally, rectally,
vaginally, or nasally), parenterally (intravenously,
subcutaneously, intramuscularly, or intraperitoneally), or through
the pulmonary system, in an appropriate carrier, if desired. When
the composition is used for administration to humans or animals, or
used for agricultural purposes, it can be applied via injection,
pouring, spray dip, aerosol, or coating applicator. Aerosols or
mists of the composition can be administered using an aerosol
propellant, e.g., for topical administration, or using a suitable
nebulizer, e.g., for pulmonary, nasal, or oral mucosal
administration. In addition, pericardial administration may be used
when the composition is used to deliver compounds such as growth
factors (e.g., transforming growth factors (TGF's), fibroblast
growth factors (FGF's), vascular endothelial growth factor (VEGF)),
antiarrhythmics (e.g., sotalol, propanolol), antianginals, and
antihypertensives.
[0108] Preferably, for pharmaceutical or veterinary purposes, the
present compositions are administered as liquids via injection, or
in an aerosol, paste or emulsion. When administered via injection
as a LVLCM, if a water-soluble solvent has been used in the
composition, the solvent leaches into the aqueous fluid of the
host, forming a highly viscous depot for the controlled delivery of
substances or a coating for tissue that can prevent or minimize
adhesions. As explained above, the use of a water soluble solvent
in making the LVLCM significantly decreases the leaching time. When
used in an aerosol, the small amount of solvent in the solution
evaporates upon application allowing the LVLCM to set-up as an
HVLCM. Alternatively, the aerosol or emulsion may be prepared
without a solvent. In this situation, the aerosol propellant can
also function as a solvent. Formation of aerosols and emulsions can
be accomplished using techniques known to those skilled in the art.
See, for example, Ansel, H. C. et al., Pharmaceutical Dosage Forms
and Drug Delivery Systems, sixth ed., 1995.
[0109] In addition to the uses described above, the HVLCM and LVLCM
materials can be administered through osmotic pumps. In one
embodiment, the device is designed to be implanted in the tissue of
the patient, and designed to effect sustained release over time. In
a different embodiment, the device is orally administrable, such as
an OROS-type osmotic pump. An example of an implantable osmotic
pump suitable for use with the compositions of the invention is the
DUROS pump, described in U.S. Pat. Nos. 5,985,305 and 5,728,396,
and in WO 97/27840, the entire contents of each of which are
incorporated herein by reference.
[0110] It is also possible to administer the compositions of the
invention using a porous or nonporous tube, desirably made of
extruded biodegradeable polymer. The tube may be prepared with
varying degrees of porosity depending on the characteristics of the
composition and the release characteristics desired. The
composition of the invention is inserted into the tube, and the
ends of the tube may be left open, allowing biologically active
compound to diffuse out of the ends of the tube, or may be closed
off with additional porous or nonporous polymer. Porous endcaps and
porous tubes allow active compound to diffuse through the pores
over time. Nonporous endcaps, as well as nonporous tubes, allow
biologically active compounds that are soluble in the polymer to
diffuse through it and into surrounding tissues. Nonporous
materials that are not solvents for the biologically active
compound, but that are biodegradable, will release the active
compounds when they degrade sufficiently. The compositions of the
invention may be prepared and stored as multi-component systems
until ready for administration. The number of different components
will depend, in part, on the characteristics of the composition.
For example, one component may contain the HVLCM or LVLCM, while
other components contain the active compound or compounds to be
administered. Prior to administration, the components are combined
and mixed, e.g., to achieve a homogeneous composition, which can
then be administered to the patient. Solvents or additives may be
added to one or all of the components, or may form a separate
component, which is also mixed with the others prior to
administration. Separation of the composition into a multicomponent
mixture allows the storage conditions for each component to be
optimized, and minimizes any detrimental interactions between
components over time. The result is increased storage
stability.
[0111] The compositions can be used to form protective tissue
coatings, and in particular, can be used to prevent the formation
of surgical adhesions. The HVLCM can adhere to the surrounding
tissue or bone, and can thus be injected subdermally like collagen
to build up tissue or to fill in defects. It can also be injected
into wounds including burn wounds to prevent the formation of deep
scars. The degradation time of the HVLCM can be modulated, for
example, by using a polymer as an additive to the HVLCM. Then the
implant formed by the HVLCM will slowly biodegrade within the body
and allow natural tissue to grow and replace the implant as it
disappears. These compositions may optionally contain biologically
active substances including but not limited to, anesthetics,
analgesics, antibiotics, and antinflammatories.
[0112] As indicated above, the HVLCM and LVLCM materials of the
invention can be used not only for the controlled release and
delivery of substances, such as bioactive substances, to plants or
animals, but also as medical or surgical devices, as described in
U.S. Pat. No. 5,968,542, the entire contents of which are
incorporated by reference.
[0113] Device utilities for the compositions of the invention
include, but are not limited to blocking surgical adhesions, void
filling, guided tissue regeneration, inducing hemostasis, tissue
adhesive, scaffolding, and wound dressing. Each of these
applications can optionally include release of a biologically
active substance, or drug delivery. For example, the nonpolymeric
ester or mixed ester composition as a wound dressing readily
accommodates various growth factors to accelerate healing of the
wound. In general, for these utilities a composition can be used
having the non-polymeric non-water-soluble liquid carrier material
present in an amount from about 99.5 percent to about 25 percent by
weight, relative to the total weight of the composition. These
compositions can be diluted with a solvent, including but not
limited to one or more of ethanol, dimethylsulfoxide, ethyl
lactate, ethyl acetate, benzyl alcohol, triacetin, 2-pyrrolidone,
N-methylpyrrolidone, propylene carbonate, glycofurol,
capric/caprylic triglycerides, benzyl benzoate, ethyl oleate,
isopropyl myristate, triethyl citrate, and any aerosol propellant,
to a concentration of the non-polymeric non-water-soluble liquid
carrier material of about 10 to about 90% by weight, calculated
based on the total weight of the composition, to obtain an
implantable or sprayable composition.
[0114] For blocking surgical adhesions, a sprayed-on or painted-on
film to block adhesion of similar or dissimilar organs is suitable.
The nonpolymeric ester or mixed ester composition is formulated in
any of a variety of solvents, including ethanol, ethyl lactate,
N-methyl-2-pyrrolidone, or any common aerosol propellant, dimethyl
ether, or any propellant, with or without an additive, and can be
applied as an aerosol spray. The resulting film may effect
adhesion, cohesion, degradation or porosity, or a combination
thereto.
[0115] For void filling, the nonpolymeric ester or mixed ester
composition is typically suitable like collagen for cosmetic
repair. In related applications, the nonpolymeric ester or mixed
ester composition is useful for holding bone chips together in a
fracture, and may optionally include an anesthetic, antibiotic, or
growth factor for local delivery.
[0116] Guided tissue regeneration is another application, such as
periodontal repair to block epithelial migration. Advantageously,
the compositions of the present invention are applied from
solution. Typical drugs incorporated into these compositions for
guided tissue regeneration include but are not limited to a variety
of growth factors and cell reattachment factors.
[0117] Hemostasis or stopping blood flow is another utility,
typically in a surgical setting. The compositions of the present
invention are biodegradable. Suitable additives include, but are
not limited to polyvinyl alcohol, polyethylene glycol or
carboxymethyl cellulose. Suitable solvents include ethyl lactate
and propylene carbonate.
[0118] A spray-on or paint-on formulation of the nonpolymeric ester
or mixed ester composition is suitable as a tissue adhesive for
wound closure, either as a primary sealant or in conjunction with
sutures or staples. Suitable additives include but are not limited
to carboxymethylcellulose or polyvinylpyrrolidone. Suitable
solvents include but are not limited to propylene carbonate, ethyl
lactate, glycofural, dimethylsulfoxide, 2-pyrrolidone,
N-methyl-2-pyrrolidone, and ethanol. Biologically active substances
incorporated into these compositions for tissue adhesion include
but are not limited to antibiotics, anti-inflammatory compounds,
analgesics, anesthetics and growth factors.
[0119] Scaffolding is another device utility for the compositions
of the present invention, and is particularly adaptive to hew
tissue growth. A typical formulation includes polyvinylpyrrolidone
and tricalcium phosphate. The scaffolding provides a matrix
suitable for the attachment and growth of bone or nerve cells.
Biologically active substances incorporated into these compositions
for scaffolding include but are not limited to growth factors.
[0120] Another application of the compositions of the present
invention is a wound dressing, with or without appropriate drugs
incorporated therein. The wound dressing functions to protect the
wound and accelerate the healing process. In one typical
application, the nonpolymeric ester or mixed ester composition is
applied as an aerosol spray. Biologically active substances
incorporated into these compositions in wound dressing include but
are not limited to antibiotics, such as amikacin, anti-inflammatory
compounds, analgesics, anesthetics, or growth factors such as
fibroblast growth factors. Alternatively, the nonpolymeric ester or
mixed ester composition with the biologically active substance is
applied to a gauze or other matrix material which is then applied
to the wound.
[0121] Whether the compositions of the invention are used as for
controlled release delivery of biologically active substances, or
as devices or implants, the compositions can have very high
viscosities. As described above, the HVLCM materials have a
viscosity at 37.degree. C. of at least 5,000 cP. In a more
particular embodiment, the HVLCM materials have viscosities above
10,000 cP, more particularly above 15,000 cP, even more
particularly above 20,000, 25,000, or 50,000 cP at 37.degree.
C.
[0122] As apparent from the discussion above, the amount of HVLCM
present in the composition may vary considerably, depending upon
such factors as the number and amount of other components included
in the composition, the use to which the composition will be put,
and the method of administration of the composition. In general the
HVLCM can be present in amounts as high as 99.5 wt % to much lower
amounts, provided that the HVLCM continues to perform its function
as a carrier material. Lower limits of 45 wt %, 25 wt %, 10 wt %,
or even 1 wt % or lessare contemplated, depending upon the factors
mentioned above. For example, an emulsion may use 0.03 wt %.
Examples of applications where lower concentrations of HVLCM may be
useful include: oil in water emulsion, where the active compound is
dissolved or suspended in the HVLCM, which is then suspended in a
continuous phase (e.g., an aqueous phase) as an emulsion;
formulations where the HVLCM functions to enhance the solubility of
the active compound in the formulations; and formulations where
only a slight increase in delayed release is desired.
Example 1
High Viscosity Liquids of DL-Lactide/.epsilon.-Caprolactone 75/25
Initial Mole Concentration, Reacted with 1,6-Hexanediol
[0123] A clean, one liter glass reaction flask was fitted with a
stainless steel mechanical stirrer rinsed with acetone, and dried
for 3 hours under 0.5 mm Hg vacuum, while immersed in a 150.degree.
C. oil bath. The reaction vessel was removed from the bath, allowed
to cool, then charged with 197.5 grams (1.37 mol) of DL-Lactide,
52.5 grams (0.46 mol) of .epsilon.-Caprolactone, and 40 grams (0.34
mol) of 1,6-Hexanediol. Following addition, the reaction flask was
purged 5 times with nitrogen, and immersed in the oil bath at
150.degree. C. The mixture was stirred slowly after a majority
appeared to have been melted to facilitate phase change. After all
contents had melted, 1.28 mL (210 .mu.mol) of a 0.164M stannous
2-ethylhexanoate solution in toluene was added. Stirring continued
to disperse the catalyst for a period of approximately 1 hour. The
solution was maintained, without stirring, for 18 hrs. at
150.degree. C. The resulting compound was then dried under vacuum
(<0.5 mm Hg) at 150.degree. C. for a period of 4-5 hours to
remove any unreacted starting materials, with slow stir speed
applied. The resulting product had an inherent viscosity of 0.049
dL/g in CHCl.sub.3 at 30.degree. C.
Example 2
High Viscosity Liquid of DL-Lactide/Glycolide at 75/25 Initial Mole
Concentration, Reacted with 1,6-Hexanediol
[0124] The procedure detailed in Example 1 was used to prepare a
material using 247.13 g (1.71 mol) DL-Lactide, 62.87 g (0.54 mol)
Glycolide, and 49.6 g (0.42 mol) 1,6-Hexanediol. Following initial
melting, 1.84 mL (260 .mu.mol) of a 0.141M stannous
2-ethylhexanoate solution in toluene was added. The resulting
product had an inherent viscosity of 0.058 dL/g in CHCl.sub.3 at
30.degree. C. The material was a liquid at room temperature.
Example 3
High Viscosity Liquid of DL-Lactide/.epsilon.-Caprolactone at 75/25
Initial Mole Concentration, Reacted with Glycerol
[0125] The procedure described in Example 1 was used to prepare a
material using 198.14 g (1.37 mol) DL-Lactide, 54.8 g (0.47 mol)
.epsilon.-caprolactone, and 40 g (0.43 mol) Glycerol. Following
initial melting, 1.36 mL (210 .mu.mol) of a 0.154M stannous
2-ethylhexanoate solution in toluene was added. The resulting
product had an inherent viscosity of 0.038 dL/g in CHCl.sub.3 at
30.degree. C. The product was a liquid at room temperature.
Example 4
High Viscosity Liquid of DL-Lactide/Glycolide at 75/25 Initial Mole
Concentration, reacted with Glycerol
[0126] The procedure described in Example 1 was used to prepare a
compound using 247.33 g (1.72 mol) DL-Lactide, 62.87 g (0.54 mol)
Glycolide, and 50.0 g (0.54 mol) Glycerol. Following initial
melting, 1.46 mL (260 .mu.mol) of a 0.179M stannous
2-ethylhexanoate solution in toluene was added. The resulting
product had an inherent viscosity of 0.028 dL/g in CHCl.sub.3 at
30.degree. C. The material was a liquid at room temperature.
Example 5
High Viscosity Liquid of Glycolide Reacted with Glycerol
[0127] A clean, one liter glass reaction flask was fitted with a
stainless steel mechanical stirrer rinsed with acetone, and dried
for 3 hours under 0.5 mm Hg vacuum, while immersed in a 150.degree.
C. oil bath. The reaction vessel was removed from the bath, allowed
to cool, then charged with 174 grams (1.5 mol) of glycolide and 92
grams (1.0 mol) of glycerol. Following addition, the reaction flask
was purged 5 times with nitrogen, and immersed in the oil bath at
150.degree. C. The mixture was stirred slowly to facilitate phase
change after a majority of the mixture appeared to have been
melted. After all contents had melted, 1.28 mL (210 .mu.mol) of a
0.164M stannous 2-ethylhexanoate solution in toluene was added.
Stirring was continued to disperse the catalyst for a period of
approximately 1 hour. The solution was maintained, without
stirring, for 18 hrs. at 150.degree. C. The resulting compound was
then dried under vacuum (<0.5 mm Hg) at 150.degree. C. for a
period of 4-5 hours with slow stir speed applied to remove any
unreacted starting materials.
Example 6
[0128] High Viscosity Liquid of .epsilon.-Caprolactone Reacted with
1-Dodecanol.
[0129] The procedure described in Example 5 was used to prepare a
material using 513 gms (4.5 mol) .epsilon.-caprolactone and 93 g
(0.5 mol) 1-dodecanol. Following addition of reagents, 1.36 mL (210
.mu.mol) of a 0.154M stannous 2-ethylhexanoate solution in toluene
was added. The reaction proceeded as described in Example 5 and was
purified as described therein.
[0130] Methods of using the compositions of the invention are
exemplified below.
Example A
[0131] CAPROL 10G4O (decaglycerol tetraoleate) was dissolved in
benzyl benzoate at a weight ratio of 50:50. Bupivacaine was
dissolved in this mixture at a concentration of 8.75 wt %. Drops
weighing approximately 100 mg were precipitated into a test tube
containing 40 mL of buffer. Samples of the buffer were removed at
specified time points and replaced with fresh buffer. The samples
were analyzed by UV-vis spectrophotometry at 265 nm to determine
the concentration of bupivacaine in each buffer sample. At 4 hours,
less than 7.5 wt % of the bupivacaine in the drop had been released
to the buffer. At 48 hours, around 24.0 wt % of the bupivacaine had
been released. The cumulative release profile is shown in FIG.
1.
Example B
[0132] The 1,6-hexanediol lactate .epsilon.-hydroxycaproic acid
produced in Example 1 was dissolved in N-methylpyrrolidone at a
weight ratio of 70:30. 10 wt % bupivacaine base was then added to
this mixture and dissolved. Drops weighing approximately 100 mg
were precipitated into 40 mL buffer. Samples of buffer were removed
at specified times and replaced with fresh buffer. Buffer samples
were analyzed by UV-vis spectrophotometry at 265 nm to determine
the concentration of bupivacaine in each buffer sample. At 4 hours,
around 4.1 wt % of the bupivacaine contained in the precipitated
drop had been released. At 24 hours, around 8.6 wt % of the
bupivacaine had been released. The cumulative release profile is
shown in FIG. 1.
Example C
[0133] The glycerol lactate glycolate prepared according to Example
4 was dissolved in ethanol at a weight ratio of 70:30. 10 wt %
estradiol was then added to this mixture as a suspension. The
formulation was homogenized prior to testing to ensure adequate
mixing. Drops of this formulation were injected into a test tube
containing buffer. The glycerol lactate glycolate precipitated,
forming a depot from which the estradiol was slowly released.
Samples of the buffer were removed at specified times and replaced
with fresh buffer. The buffer samples removed from each test tube
were analyzed by UV-vis spectrophotometry at 280 nm to determine
the estradiol concentration in each sample. The assayed
concentration was used to calculate the percent of estradiol
released from the drop. FIG. 2 shows a cumulative release profile
for estradiol.
Example D
[0134] The 1,6-hexanediol lactate glycolate prepared according to
Example 2 was dissolved in propylene carbonate at a weight ratio of
80:20. 10 wt % of progesterone was incorporated as a suspension
into this mixture. The formulation was homogenized prior to testing
to ensure adequate mixing. The resulting formulation was analyzed
to determine its in vitro dissolution profile. Drops of the
formulation were injected into a test tube containing buffer. The
1,6-hexanediol lactate glycolate precipitated, forming a depot from
which the progesterone was slowly released. Samples of the buffer
were removed at specified times and replaced with fresh buffer. The
buffer samples were analyzed by UV-vis spectrophotometry at 244 nm
to determine drug concentration in each sample. The assayed
concentration was used to calculate the percentage of progesterone
that had been released from the drop. The cumulative release
profile is shown in FIG. 3.
Example E
[0135] The glycerol lactate E.epsilon.-hydroxycaproic acid prepared
according to Example 3 was dissolved in polyethylene glycol (PEG)
400 at a weight ratio of 36:64. Lysozyme was ground with a mortar
and pestle and the resulting powder was incorporated into the
mixture as a suspension at a concentration of 10 wt %. The
formulation was mixed thoroughly with a spatula. Samples of the
formulation, approximately 500 .mu.L in volume, were injected into
three test tubes each containing 10 mL of buffer. Aliquots of
buffer (8 mL) were removed at specified times and replaced with
fresh buffer. Each sample of buffer containing lysozyme was
analyzed with a micro BCA protein assay reagent kit to determine
protein content in the dissolution sample. The assayed lysozyme
concentration was used to calculate the percent of lysozyme that
had been released from the drop. The cumulative release profile is
shown in FIG. 4.
Example F
[0136] CAPROL 6G2O (hexaglycerol dioleate) was dissolved in benzyl
benzoate at a weight ratio of 25:75. Lysozyme was ground with a
mortar and pestle and the resulting powder was incorporated into
the mixture as a suspension at a concentration of 10 wt %. The
formulation was mixed thoroughly with a spatula. Samples of the
formulation, approximately 500 .mu.L in volume, were injected into
three test tubes each containing 10 mL of buffer. Aliquots of
buffer (8 mL) were removed at specified times and replaced with
fresh buffer. Each sample of buffer containing lysozyme was
analyzed with a micro BCA protein assay reagent kit to determine
protein content in the dissolution sample. The assayed lysozyme
concentration was used to calculate the percent of lysozyme that
had been released from the drop. The cumulative release profile is
shown in FIG. 4.
Example G
[0137] Two solutions were prepared in which 1,6-hexanediol lactate
.epsilon.-hydroxycaproic acid (prepared according to Example 1) and
1,6-hexanediol lactate glycolate (prepared according to Example 2)
were dissolved in polyethylene glycol (PEG) 400 at weight ratios of
34:66 and 33:67, respectively. A drop of each formulation was
injected into a test tube containing deionized water, and the
1,6-hexanediol lactate .epsilon.-hydroxycaproic acid and
1,6-hexanediol lactate glycolate were precipitated at the bottom of
the test tubes. The drops retained their shapes for longer than one
week.
Example H
[0138] The formulations listed in the Table below were prepared
using the esters prepared in Examples 1 through 4. In each case,
the mixture resulted in a homogeneous solution.
TABLE-US-00001 Ester:Solvent Ester Solvent Wt Ratio 1,6-hexanediol
lactate Ethanol 80:20 glycolate 1,6-hexanediol lactate Ethanol
80:20 .epsilon.-hydroxycaproic acid glycerol lactate .epsilon.-
Ethanol 80:20 hydroxycaproic acid glycerol lactate glycolate
Ethanol 80:20 1,6-hexanediol lactate Propylene carbonate 80:20
glycolate 1,6-hexanediol lactate Propylene carbonate 80:20
.epsilon.-hydroxycaproic acid glycerol lactate .epsilon.- Propylene
carbonate 80:20 hydroxycaproic acid glycerol lactate glycolate
Propylene carbonate 80:20 1,6-hexanediol lactate Polyethylene
glycol 36:64 glycolate (PEG) 400 1,6-hexanediol lactate
Polyethylene glycol 34:66 .epsilon.-hydroxycaproic acid (PEG) 400
glycerol lactate .epsilon.- Polyethylene glycol 33:67
hydroxycaproic acid (PEG) 400 glycerol lactate glycolate
Polyethylene glycol 37:63 (PEG) 400 1,6-hexanediol lactate
N-methyl-2- 80:20 glycolate pyrrolidone 1,6-hexanediol lactate
N-methyl-2- 80:20 .epsilon.-hydroxycaproic acid pyrrolidone
glycerol lactate .epsilon.- N-methyl-2- 80:20 hydroxycaproic acid
pyrrolidone glycerol lactate glycolate N-methyl-2- 80:20
pyrrolidone 1,6-hexanediol lactate Benzyl benzoate 70:30 glycolate
1,6-hexanediol lactate Glycofurol 70:30 glycolate 1,6-hexanediol
lactate Dimethyl sulfoxide 70:30 glycolate 1,6-hexanediol lactate
Propylene glycol 50:50 .epsilon.-hydroxycaproic acid 1,6-hexanediol
lactate Benzyl benzoate 70:30 .epsilon.-hydroxycaproic acid
1,6-hexanediol lactate Glycofurol 70:30 .epsilon.-hydroxycaproic
acid 1,6-hexanediol lactate Dimethyl sulfoxide 70:30
.epsilon.-hydroxycaproic acid glycerol lactate .epsilon.- Propylene
glycol 50:50 hydroxycaproic acid glycerol lactate .epsilon.- Benzyl
benzoate 70:30 hydroxycaproic acid glycerol lactate .epsilon.-
Glycofurol 70:30 hydroxycaproic acid glycerol lactate .epsilon.-
Dimethyl sulfoxide 70:30 hydroxycaproic acid glycerol lactate
glycolate Propylene glycol 50:50 glycerol lactate glycolate
Glycofurol 70:30 glycerol lactate glycolate Dimethyl sulfoxide
70:30 glycerol lactate glycolate, Ethanol 70:30 acid end glycerol
lactate glycolate, Propylene carbonate 70:30 acid end glycerol
lactate glycolate, N-methyl-2- 70:30 acid end pyrrolidone glycerol
lactate glycolate, Propylene glycol 50:50 acid end glycerol lactate
glycolate, Glycofurol 70:30 acid end glycerol lactate glycolate,
Dimethyl sulfoxide 70:30 acid end
Example I
[0139] 5.33 g of a 10 wt % solution of bupivacaine in a composition
containing 70:30 SAIB/NMP, prepared as described in U.S. Pat. No.
5,747,058, was added to an aerosol container. 14.32 g of propellant
R-134a (1,1,1,2-tetrafluoroethane) was added. The mixture formed a
solution that was easily sprayed with no bubbling or foaming.
Example J
[0140] 5.44 g of a 10 wt % solution of bupivacaine in a composition
containing 70:30 SAIB/NMP, prepared as described in U.S. Pat. No.
5,747,058, was added to an aerosol container. 16.55 g. of
propellant R-134a (1,1,1,2-tetrafluoroethane) was added. The
mixture formed a solution that was easily sprayed with no bubbling
or foaming.
Example K
[0141] 0.87 g of bupivacaine base was added to an aerosol
container. 8.47 g of an SAIB/propylene carbonate solution (70:30)
containing 2.5 wt % of a biodegradable polymer (65:35 DLPLG) was
added to the container. 0.98 g of ethanol was added to help the
drug dissolve. Once dissolved, approximately 16 g of propellant
R-134a (1,1,1,2-tetrafluoroethane) was added. The mixture formed a
solution that was easily sprayed with no bubbling or foaming.
Example L
[0142] SAIB was dissolved in propellants 134a
(1,1,1,2-tetrafluoroethane) and 227
(1,1,1,2,3,3,3-heptafluoropropane) at levels of 5 and 10 wt %.
Clear solutions were formed.
Example M
[0143] An additional example was conducted to evaluate a novel
controlled-release system, which uses a high-viscosity compound,
sucrose acetate isobutyrate (SAIB), for use in providing sustained
release of lysozyme. A small amount of solvent converts SAIB to an
easily injectable liquid. Once injected, the solvent dissipates
forming a high viscosity, biodegradable implant. Release profiles
can be altered with different solvents and additives.
[0144] Ground lysozyme (10 wt %) was suspended in SAIB/solvent
mixtures including the solvents ethyl lactate,
N-methyl-2-pyrrolidone (NMP), MIGLYOL 810, and benzyl benzoate.
Three poly (DL-lactide-co-glycolide) polymers with either acid,
ester, or PEG end groups were evaluated as additives. To determine
release rates, drops of formulation were injected into test tubes
with pH 6.24 buffer and then incubated in a shaker at 37.degree. C.
At certain times, aliquots of buffer were removed and replaced with
fresh buffer. Lysozyme concentration in buffer was determined by
the BCA protein assay. Protein activity was determined with an
enzymatic assay measuring cell lysis of a suspension of Micrococcus
lysodeikticus spectrophotometrically. Decrease in absorbance at 450
nm was recorded as a function of time, which is directly related to
active lysozyme concentration.
[0145] At 6 hours, release ranged from 1.3 wt % for the 70:30
SAIB/NMP formulation (110.3 .+-.5.0% activity) to 4.5 wt % for the
40:60 SAIB/ethyl lactate formulation (107.6.+-.6.1% activity). The
percent released at 7 days ranged from 46.7% for 40:60 SAIB/ethyl
lactate (88.9.+-.6.8% activity) to 96.4% for 70:30 SAIB/MIGLYOL
(107.6.+-.7.0% activity). Addition of 0.5 wt % of each of the three
polymers to an SAIB/NMP formulation did not significantly affect
the release profile.
[0146] These results demonstrate that the SAIB/solvent delivery
system described above is capable of providing sustained release of
proteins in an active state, and that the rate of release can be
modulated to provide a range of release profiles.
Example N
[0147] An additional example was conducted to evaluate the effects
of formulation variables on release of chemotherapeutic
agents--paclitaxel and 5-flubrouracil (5-FU)--from formulations
based on an SAIB delivery system. It will be understood from the
description above that the SAIB delivery system uses sucrose
acetate isobutyrate (SAIB), a fully-esterified, water-insoluble
sucrose derivative, as an excipient. It can be formulated as a low-
to medium-viscosity liquid by the addition of small amounts of
solvents such as ethanol, MIGLYOL, ethyl lactate, propylene
carbonate, or DMSO, resulting in an easily injectable
formulation.
[0148] Solutions of SAIB in the appropriate solvent were prepared
with and without the incorporation of an additive. The active was
weighed into a test tube and the SAIB/mixture was added and mixed
thoroughly to yield a solution or suspension at the desired drug
loading. Single drops of the mixture were precipitated into buffer
by injection with standard syringes and needles. Samples were
maintained at 37.degree. C. in a shaker, sampled periodically, and
analyzed by UV-vis spectrophotometry for active release. Paclitaxel
and 5-FU samples were analyzed at 232 nm and 266 nm,
respectively.
[0149] The effect of drug loading was evaluated for paclitaxel.
Drug loadings of 5, 25, and 50 mg/mL were compared. After 7 days,
the cumulative release for these three drug loading were 106.4%,
85.9%, and 33.8%, respectively. The effect of surfactant additives
was also evaluated. A 25 mg/mL paclitaxel formulation and a 10
mg/mL 5-FU formulation, both in 85:15 SAIB/EtOH, were made and 5 wt
% Cremophore.RTM. EL was added. The addition of this surfactant
increased the rate of release for both formulations. The percent
released from the paclitaxel formulation increased from 56.0% to
77.0% after two days in vitro. Likewise, the percent released from
the 5-FU formulation increased from 80.6% to 106.0% after two days.
A second surfactant, Pluronic.RTM.L-101, was added to a 10 mg/mL
5-FU in 85:15 SAIB/EtOH formulation. This surfactant also increased
the amount released from 80.6% to 102.0% after two days.
[0150] The rate of release of drugs such as paclitaxel and
5-fluorouracil from the SAIB delivery system can be modulated by
formulation variables including drug loading and surfactant type.
Also, the duration of release of these drugs from this system can
be varied from a few hours to several days with the shorter
duration seen at the lower drug loading and with the addition of a
surfactant.
Example O
[0151] Another example was conducted to evaluate the potential of
the SAIB delivery system to provide extended release following oral
administration of antiretroviral drugs used for treating HIV
infections. As indicated above, the SAIB delivery system uses
sucrose acetate isobutyrate (SAIB), a fully-esterified,
water-insoluble sucrose derivative, as an excipient.
[0152] Zidovudine (AZT) and dideoxycytodine (ddC) suspensions were
prepared by mixing drug with SAIB/solvent solutions with and
without a cellulosic coexcipient. Approximately 1 g of each
formulation was filled into soft gelatin capsules, which were heat
sealed. Dissolution profiles were determined using Apparatus 2,
Method B (USP XXII) at a paddle speed of 50 rpm. Individual gelcaps
were placed in separate dissolution vessels, and samples of the
buffer in each vessel were obtained at 0.25, 0.5, 1, 2, 3, 6, and
24 hours. The samples were analyzed at 266 and 272 nm on a Perkin
Elmer Lambda 20 UV-vis spectrophotometer for AZT and ddC drug
content, respectively.
[0153] Release of AZT and ddC can be modulated simply by the use of
different solvents in the SAIB delivery system. By using a 70:30
SAIB/Migylol.RTM. 810 combination, the cumulative percent released
at 2 hours for an 11.1 wt % AZT formulation was 104.1% and 74.2%
for a 0.225 wt % ddC formulation. Comparatively, when an 85:15
SAIB/EtOH combination was used, 71.2% of the drug in the AZT
formulation had been released and 59.5% of the drug in the ddC
formulation. Release can also be modified by altering drug loading.
When the active loading of an 85:15 SAIB/EtOH formulation was
doubled from 11.1 to 22.2 wt %, the cumulative percent released was
increased from 71.2% to 93.8%. The use of a polymeric additive,
cellulose acetate butyrate (CAB), to modulate release was also
evaluated. For an 11.1 wt % AZT in 85:15 SAIB/EtOH formulation,
addition of 0.02 and 0.2 wt % CAB decreased the amount released at
2 hours from 71.2% to 25.6% and 7.6%, respectively. For a 0.225 wt
% ddC in 85:15 SAIB/EtOH formulation, addition of 0.5 and 1.0 wt %
CAB decreased the amount released at 2 hours from 59.5% to 39.4%
and 13.5%, respectively.
[0154] These data show that formulations of the SAIB delivery
system can be modified to provide a range of dissolution profiles
for AZT and ddC. By providing controlled release of these actives,
this system can reduce the number of pills needed per day, reduce
cost of manufacture, and improve patient compliance.
Example P
[0155] A depot formulation was prepared by suspending 0.83 g of a
3:2 (w/w) solid mixture of cromolyn sodium (disodium cromoglycate)
and polycaprolactone (PCL, Birmingham Polymers, Inc.) in 9.17 g of
a 70:30 (w/w) mixture of SAIB and benzyl benzoate. The solid
cromolyn sodium/PCL mixture was prepared by dissolving 12 g PCL in
100 mL of methylene chloride and mixing 18 g cromolyn sodium into
this solution. The solution was poured onto TEFLON film, and the
methylene chloride evaporated to a solid film, which was then
ground into particles, which were then added to the SAIB/benzyl
benzoate mixture.
[0156] The resulting depot suspension was incubated and assayed to
determine the rate of cromolyn release. The formulation was found
to release a cumulative total of about 9 mg or 10% of available
cromolyn over a 35-day period as shown in FIG. 5.
Example Q
[0157] Cromolyn sodium (1.5 g) was added to a solution of
SAIB:benzyl benzoate (74:26 w/w) containing 5 wt % DL-polylactide
(DL-PL). The final cromolyn concentration was 10 wt %. After mixing
thoroughly, 500 mg of the resulting suspension was added to a
dissolution buffer (PBS, pH of 7.4 with sodium azide). Samples were
removed at selected time points and analyzed to determine the
amount of cromolyn sodium released. This formulation released
cromolyn for approximately ten days, as shown in FIG. 6
Example R
[0158] A hollow tube of 65:35 poly(dl-lactide-co-glycolide)
containing 5 wt % PEG-1000 as a porosigen is extruded on a
Randcastle extruder using a standard tubing dye. The resulting
hollow rods, having a diameter of 2.0 mm are cut to the desired
length of 20 mm and filled with a mixture of SAIB and fibroblast
growth factor (FGF). The rod ends are closed by heat sealing. The
rods are assayed for release of FGF by placing them in 40 mL of
HEPES dissolution buffer at 37.degree. C. without agitation. After
approximately 1 hour incubation, 5 mL of buffer solution is removed
for analysis and replaced with fresh buffer. Daily sampling is
conducted, and the samples analyzed for FGF content by ELISA. The
formulation shows a release lag of 2 days, followed by release of
about 3 wt % of the original FGF loading per day for 30 days.
[0159] The present invention having been thus described, variations
and modifications thereof as would be apparent to those of skill in
the art will be understood to be within the scope of the appended
claims.
* * * * *