Note: Descriptions are shown in the official language in which they were submitted.
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BACKGROUND OF THE INVENTION
Field of the Invention
This invention relates to novel polymer-drug compounds
and their use in providing sustained release drug delivery to
human and other warm-blooded animals. The polymer-drug compounds
provide a mechanism whereby the rate of release and availability
s of the drug may be regulated so that the quantity of a drug which
is released at a particular time or at a particular site is rela-
tively constant and uniform over extended periods of time.
Description of Prior Art
Drugs are conve~tionally administered orally or via in-
jection, often at a site remote from the target. Over a rela-
tively short period of time, the drug diffuses into the cir-
culation system of the patient and is distributed to the various
organs, at least one of which is the intended target for the
drug. The action of the drug on organs other than the target
may result in undesirable side effects. Finally, the drug is
metabolized or otherwise irreversi~ly removed from the organism
by excretion or chemical deactivation.
When drugs are delivered orally or by injection, the
level and duration of availability of the drug cannot be con-
trolled independently; only the size and frequency of the dose
can be manipulated. Typically, there is an initially high con-
centration of available drug at the site of injection or in the
circulatory system which then decreases gradually as the drug is
distributed and consumed within the body of the patient.
~' `
ETH-430
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_
In controlled sustained delivery, a formulation of
the drug and a carrier is administered to the patient by injec-
tion or implantation. The caxrier forms a drug reservoir that
protects the stored drug from extraneous removal mechanisms and
releases the drug to the biological reservoir at a predetermined
rate. Controlled sustained delivery of a drug prevents un-
desirable peaking of blood levels and makes the drug available
at an optimum and uniform concentration over an extended period
of time. Only the released drug is subject to removal via meta-
bolism and excretion.
U.S. Patents Nos. 3,773,919, 3,755,558, and 3,997,512describe formulations of various polylactides, polyglycolides
and copolymers of glycolide and lactide with some well-known
drugs in order to achieve slow release of the drugs when ~m-
planted or applied topically to humans. These compositions aredesigned to release the drug over an extended period of time as
the polymer of the mixture is slowly absorbed in the s~stem.
The polymer itself is nonreactive to body tissue and degrades
into harmless products which are metabolized or excreted by the
host body.
We have discovered that polymers of ~-dioxanone are also
absorbed slowly in animal tissue without significant adverse
tissue reaction. Such polymers and their method of preparation
are known in the art. U.S. Patents Nos. 3,063,967 and~3,063,968,
for example, describe the polymerization of p-dioxanone and the
preparation of films and fibers therefrom. There was, however,
no appreciation in the prior art of the absorbability of
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p-dioxanone polymers, and fibers of such polymers were reported
to be resistent to the effects of saline and distilled water.
Other references dealing with the polymerization of
p-dioxanone include, but are not limited to U.S. Patents Nos.
3,190,858, 3,391,126 and 3,645,941 which disclose various cata-
lysts for the polymerization of }actones such as ~-dioxanone,and
U.S. Patent No. 3,020,289 which describes the polymerization of
p-dioxanone in the presence of sulfuric acid. None of these
references 3uggest that polymers of ~-dioxanone are useful in the
preparation of absorbable polymer-drug compositions in accordance
_ with the present invention.
SU~RY
Pharmaceutical depot compositions for parenteral ad-
ministration of effective amounts of drugs over an extended
period of time comprise mixtures and combinations of one or more
drugs with absorbable polymers of ~-dioxanone, or methyl or ethyl
substituted ~-dioxanone. The polymers are conveniently prepared
by known polymerization techniques. Polymers and drugs are com-
bined as physical mixtures ox, in some instances, as chemical
combination6. ~he polymer-drug composition may be administered
to the patient by implantation as a solid pellet, by injection as
a suspension in a biologically acceptable fluid, or by other con-
venient means.
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DESCRIPTION OF THE INVENTION
The formulations of this invention are absorbable, non-
irritating pharmaceutical compositions consisting of one or more
drugs intimateIy mixed with or coated by an absorbable polymer
designed to release effective amounts of a drug over a predeter-
mined period of time. The invention is of particular value fordrugs that require prolonged administration or slow sustained
release, for example, certain fertility-control drugs or hormones
used for hormone-replacement therapy. The absorbable polymer
may be considered as a carrier or matrix for the drug.
The novel formulations permit prolonged release of drugs
for a controlled period of time from the sites of parenteral
administration and minimize the frequency and thus the discomfort
and inconvenience associated with conventional injection formu-
lations. Unlike conventional depot injections, the formulations
of this invention undergo biodegradation in the body into prod-
ucts which are nonreactive toward body tissue, and can be de-
signed, by ~ontrolling molecular weight and composition, to
undergo hydrolysis and to release drug from the depot at a de-
sired rate.
The_Dru~
The term "drug" is intended in its broadest sense as
defined in the Yederal Food, ~rug and Cosmetic Act, Section
201(2)g:
j
: - c
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,.
1) Articles recognized in the official United States
Pharmacopoeia, official Homeopathic Pharmacop~eia
of the United States, or official National Formulary,
.
or any supplement of any of them; and
2) articles intended for use in the diagnosis, cure,
mitigation, treatment, or prevention of disease in
man or other animals, and
3) articles (other than food) intended to affect the
structure or any ~unction of the body of man or
other animals; and
4) articles intended for use as a component of any-
article specified in clauses 1, 2 or 3; but does not
include devices or their components, parts, or ac-
cessories.
Classes of drug which may be specifically mentioned in-
. clude agents affecting the central nervous system, e.g., narcot-
ics, such as, for example, morphine; narcotic antagonists, such
as naloxone; antipsychotic agents, such as chlorpromazine and
molindone; antianxiety agents, such as sodium ~entobarbital,
chlorproma2ine, and molindone; antidepressives, such as
- imipramine hydrochloride; stimulants, such as methyl phenadate
and nikethamide; hallucinogens; analgesics, such as numorphan,
meperidine, and morphine; and anorexigenic agents.
Other classes are pharmacodynamic agents, e.g., anti-
hypertensive agents as reserpine, and chlorisondamine chloride,
and antianginal agents, such as papaverine, and drugs for therapy
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of pulmonars~ disorders, such as theophylline ethylenediamine
salt and epinephrine. Additional classes are chemotherapeutic
agents, e.g., antiviral; antiparasitic, such as emetine hydro-
chloride and stibophen; antifungal agents, such as cycloheximide;
and antineoplastic agents, such as triethylene thiophosphoramide;
agents affecting metabolic diseases and endocrine functions, e.g.,
prostaglandins; athersclerosins, such as heparin; steroids and
biologically related compounds; polypeptides, such as bacitracin,
polymixin B sulfate, and sodium colistimethate; natural and
synthetic hormones, such as estradiol dipropionate, progesterone,
and hydroxy progesterone caproate; steroid and nonsteriodal anti-
inflammatory agents, such as gold sodium thiomalate and hydro-
cortisone sodium succinate; and agents affecting throm~osis,
such as crystalline trypsin; vitamins, such as vitamin B12; anti-
epilepsy agents, such as phenobarbital; and the like. It shouldbe understood that the specific drugs mentioned by name a~e ~
illustrative and not limitative.
Endrocrine agents comprise a particularly useful class
of compounds in this invention and can be defined either as
natural hormones or as synthetic drugs that to some extent act
like, or antagonize, natural hormones. Endocrine agents include,
but are not limited to, both steroids and nonsteroids that func- -~
tion as fertility-control agents; progestogens, estrogens, andro-
gens, antiandrogens, corticoids, anabolic agents, and anti-
inflammatory agents.
Examples of specific endocrine agents that can be usedin the formulations of the invention are set forth in U.S. Patent
No. 3,773,gl9, particularly Columns 3 to 7.
",.:,.
.,,
107~ ~ ~ 3
The Absorbable Polvmer
.
Polymers useful in the preparation of polymer-drug
compounds of the present invention are those having the formula
0 R R R
11 l
_ -C - CH - 0 - C - CH - ~ _
R _ x
wherein each R is individually hydrogen, methyl or ethyl and x
is the degree of polymerization resulting in a polymer having 7~n
inherent viscosity of at least about 0.20 measured at 25C in a
0.1% solution in tetrachloroethane, and having a crystallinity
of at least about 20% as determined by X-ray diffraction. Par-
ticularly preferred polymers are those derived from ~-dioxanone,
methyl-p-dioxanone and dimethyl-~-dioxanone.
A particulaxly preferred polymer-is poiy(~-dioxanone~,
and the following description and examples presented by way of
illustration are directed primarily to the preparation of that
polymer, it being understood that certain variations may apply
to the preparation of other polymers encompassed by the above
formula as will be readily apparent to those skilled in the art.
In these examples, all parts and percentages are ~y weight unless
otherwise noted.
Thus, in accordance with the present teachings, an
improvement is provided in a pharmaceutical depot composition
for parenteral administration of effective amounts of a drug
released slowly over an extended period of time which comprises
a combination of
a) from 1% to 99% by weight of composition of a drug
in an effective depot amount greater than the single dose amount,
and
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b) a solid, abso ~0a~8 polymer which is nonreactlve
towards body tissue and which undergoes biodegradation in the
presence of body fluids into products wnich are metabolized or
excreted by the body without adverse body reaction. The improve-
ment which is provided comprises employing as the absorbable
polymer a polymer of p-dioxanone having the formula
~ I 1 7 R R
t C - CH - O - C - CH - O ~
R x
wherein each R individually is hydrogen, methyl or ethyl and x
is the degree of polymerization resulting in a polymer having an
inherent viscosity of at least about 0.20 measured at 25C in a
0.1~ solution in tetrachloroethane and has a crystallinity of
at least about 20~ as determined by X-ray diffraction.
~XAMPLE I
Highly purified ~-dioxanone monomer is polymerized in
the presence of an organometallic catalyst such as diethyl zinc
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~)98~3
or zirconium acetyl acetonate to obtain high molecular weight
polymers according to the following typical procedure:
0.1 M (10.2g) of dry, 99+% pure _~dioxanone monomer
is weighed into a dry flask under an iner~ atmosphere of dry
nitrogen and 0.36 ml of n .138 M diethyl zinc in heptane are
added. The monomer to catalyst ratio is calculated as 2000:1.
After completely mixing the catalyst and monomer, the flask is
swirled at intervals ovar a period of about one hour or less at
room temperature until initiation and polymerization is evident
by the occurrence of gelation. The flask is then connected to
a vacuum of about 14 inches of Hg. The sealed flask is main-
tained at 80C in a constant temperature bath for about 72 hours
to complete the polymerization. The resulting polymer is
characterized by an inherent viscosity (I.V.) of 0.70 measured on
a 0.1% solution of polymer in tetrachloroethane at 25C, a glass
transition temperature Tg of -16C, a melting temperature Tm of
110C, and a crystallinity of 37 percent.
In the polymerization procedure, the initial one hour
hold time ~or polymerization initiation is required only when
using volatile catalysts which would be lost if the polymeriza-
tion mixture was immediately placed under vacuum. When non-
volatile catalysts such as zirconium acetyl acetonate are used,
this hold time may be omitted and the polymerization reaction
mixture placed undex vacuum immediately following addition and
mixing of catalyst. As a further alternative, the entire poly-
merization reaction may be conducted under an inert atmosphere
at atmospheric pressure.
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EXAMPLE II
The method of Example I was repeated using 0.13 ml of
zirconium acetyl acetonate catalyst (7500:1 monomer to catalyst
ratio) in the polymerization reaction. Proper~ies of polymer
were as follows:
I.V. - 0.71
Tg - -16C
Tm - 111C
Crystallinity - 49%
EXAMPLE III
The method of Example I was repeated at a monomer to
catalyst ratio of 4000:1 and with a polymerization reaction of
three days at 80C. The resulting polymer had an inherent vis-
cosity of 0.86 and crystallinity of 30 percent.
EXAMPLE IV
The method of Example I was repeated using tetra-
octylene glycol titanate as the polymerization catalyst. The
monomer to catalyst ratio was 12,300:1 based on titanium cont~nt,
and the polymerization reaction was maintained at 80C for six
days. The resulting polymer had an inherent viscosity of 0.86
and a crystallinity of 33 percent.
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EXAMPLE V
In Vivo Absorption
The absorbability of poly(~-dioxanone) in animal tissue
at a desirable rate and without adverse tissue reaction was
demonstrated by melt ex~xuding the polymer into filaments and
implanting the filaments in t~st animals as follows:
Two 2 cm segments of monofilament extruded from the poly-
mer of Example I and having a diamet~r of approximately 0.30 mm
were implanted aseptically into the left gluteal muscles of
24 ~emale Long-Evans rats. The implant sites were recovered
ater periods of 60, 90, lZ0 and 180 days and examined micro-
scopically to determine the extent of absorption.
After 60 days the filament cross sections were still
transparent and intact. The tissue reactions were slight and
most filaments were encapsulated with fibrous tissue. The fila-
ments at this period remained birefringent under polarized light.
At 90 days the filaments were becoming translucent and
had lost some of their birefringent properties. A few of the
filament cross sections stained pink teosinophilic) around the
periphery and the edges were indistinct, indicating the onset of
absorptionO The tissue reactions generally consisted of a
fibrous capsule and a layer of macrophages interposed between it
and the filament surface.
At 120 days the filaments were translucent, most cross
sections had taken on an eosinophilic stain, and the material
appeared to be in the process of active absorption. The tissue
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reactions consisted of an outer layer of fibroblasts with an
interface of macrophages several cell layers thick. Absorption
at 120 days was estimated to be approximately 70 percent com-
plete.
At 180 days, absorption of the material was substantial-
ly complete. The incision healed with minimal adverse tissue
reaction.
While the preceding examples have been direc~ed to the
preparation of homopolymers of ~-dioxanone, these examples are
for purposes of illustration only and are not limiting of the
inventlon. Polymers of methyl-~-dioxanone, dimethyl-p-dioxanone,
copolymers of two or more of these monomers, copolymers of these
monomers with up to about 50% by weight of other copolymerizable
monomers which produce nontoxic and absorbable polymers, and mix-
tures of these polymers with other absorbable polymers are like-
wise included within the present invention. For example, mix.
tures of ~-dioxanone with lactide and/or glycolide are useful
in the preparation of absorbable copolymers, and the physical
and chemical properties of such polymers including the rate of
absorption can be controlled by varying the relative proportions
of the monomer constituents. In addition, such copolymers may be
prepared by random, block or graft polymerization techniques in
order to obtain particular combinations of compositions and
physical and chemical properties. In cextain applications where
the rate of absorption of poly(p-dioxanone) is less than desired,
copolymers of p-dioxanone with from about 5 to 25 percent or
more glycolide which have a faster ratP of absorption may be pre-
ferred.
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~9t~4~3
Polymers of the present invention are adversely affected
by moisture and are accordingly preferably prepared and stored
in a substantially moisture free environment and in hermetically
sealed packages. Polymers which have been dried under vacuum at
elevated temperatures and subsequently stored under vacuum or in
a dry nitrogen environment are found to be quite storage stable.
Preparation and Administration of
Polymer-Drug Compositions
The drug and the polymer can be mixed, and the intimacy
of mixing, particle size, and particle shape of the formulation
can be varied, by any of a number of known methods. Intimacy of
mixing, particle size, and particle shape of the formulations of
the invention will depend to some extent on the intended use.
High homogeneity can be obtained by mixing the components in the
molten state, cooling, and grinding the result~ng solid. A
formulation so obtained is suitable for injection as 0.1 ~ to
1000 p particles suspended in saline solution or a pharmaceuti-
cally acceptable oil. In some cases particles with cores of pure
drug coated with various thicknesses of polymer can be preferred
for delayed and/or sustained release. Relatively large pellets
(1-10 mm) may be preferred for re~ersible implantation in animals
by surgery or by injection a projectiles. For this use adequate
homogeneity can usually be realized by grinding or milling the
drug and the polymer together before forming pellets under pres-
sure. Known techniques of encapsulation,including microencapsu-
lation, can be used to mix the polymer and the drug. The
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8443
formulations of this invention provide a slow,steady release of
drug ;in contradistinction to conventional preparations which
generi~lly produce a rapid surge followed by a fairly quick
decli1le in drug effect.
Polymer-drug mixtures of the invention may contain
pharmaceutically acceptable inert additives such as plasticizers.
Typical plasticizers are Carbowax polyethylene glycols, glycer-
ides and ethylcellulose.
The relative proportions of the drug and ~-dioxanone poly-
mer can be varied over a wide range depending on the desired
effect. The druy can be present in an amount which will be re-
leased over controlled periods of time. This necessarily implies
a quantity of drug greater than the conventional single do~e and
requires that the polymer must not break down or become absorbed
by the body so rapidly as to release undue quantities o~ drug.
Proportions may range from 1 percent of drug and 99 percent of
the polymer to 99 percent of drug and 1 percent of the polymer.
Preferred ratios include 1 part of drug to from 4 to 20 parts of
polymer.
These formulations can be injected as fluid suspensions
by syringe into subcutaneous cellular tissue or muscular tissue,
or Lmplanted in pellet form subcutaneously or intramuscularly.
Liquid vehicles useful for suspensions of the drug-polymer formu-
lation include water or aqueous solutions such as normal sodium
chloride solution or sodium carboxymethyl cellulose in water.
Oils such as sesame oil or peanut oil containing, if desired,dis-
solved adjuvants such as benzyl alcohol, may also be used to pre-
pare suspensions of the polymer-drug formulation.
B
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Dr~g compounds of the classes mentioned earlier may be
coated, embedded, or intimately mixed in or with a matrix of one
or a combination of different chain-length biodegradable poly-
mers to give a drug-polymer mixture which will provide a control-
led sustained release of the drug compound over a period of
8 hours to 2 months or longer when administered parenterally.
Coating, embedding or intimately mixing the drug com-
pound with the polymer can be accomplished in the followlng ways:
(A) Coating the discrete drug particles or drug-particle
aggregates, agglomerates or flocs bY:
(1) Spray drying: Finely divided drug particles are
suspended in a solvent system in which the drug is not
soluble containing the dissolved polymer and other agents,
e.g., extenders, plasticizers, dyes, etc., in the drug/
po~ymer ratio from 1/99 to 99/1, followed by spray dry-
ing. For example: ~rug particle~ 0.2 to 10 microns in
size and equal to the weight of polymer used are sus-
pended in a solvent solution of polymer in such a con-
centration so as to give a liquid viscosity suitable for
atomizing. The drug-polymer mixture is spray-dried using
conventional methods of atomizing, e.g., centrifugal
wheel, pressure, and two-fluid nozzle using appropriate
drying conditions and temperatures that do not exceed the
softening point of the polymer and do not exceed the
melting point or decomposition point of the drug. Sol-
vents useful in preparing solutions of the polymers of
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ETH-430
iO98443
the present invention include, but are not limited to,
hexafluoroisopropyl alcohol, hexafluoroacetone, trichloro-
ethane, tetrachloroethane and trifluoroacetone.
(2) Pan coating or fluid-bed coating: Place granules
or pellets, 5 microns to 20 mm, preferably between 0.25
and 10 mm diameter, in a rotating coating pan or fluid-
bed drier, and apply polymer (dissolved in a carrier to
a suitable viscosity for spraying) by spraying until a
suitable coating quantity has been deposited to give the
required xelease-rate characteristics. For example:
Granules of drug are prepared by extrusion of a wet
granulation or other suitable methods known to the art,
and dried. 16-to-40-Mesh granules are placed in a
rotating coating pan and a solution o polymer, dis-
solved in a suitable nonaqueous volatile solvent, is
sprayed onto the moving granules with a continuous fine
spray under conditions known to the art, until a coat-
ing giving the desired release rate has been applied.
The granules are then dried.
(3) Microencapsulat1on: Suspend drug particles,
~ granules or pellets (.1 to 2000 microns diameter) in a
solvent system in which the drug is not soluble, and
which contains the polymer in solution. Add an agen~
incompatible with the polymer-solvent system, such as
an incompatible polymer, a nonsolvent for the polymer,
or a salt, or vary ~onditions such as temperature and
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ETH-430
10Cal!349~3
pressure. One or a combination of the above will pre-
cipitate the polymer, coating the drug particles,
granules or pellets. For example- 0.5 to 25 micron
drug particles are suspended in a low viscosity solution
of the polymer-in a suitable solvent in which the drug
is not soluble. A miscible solvent in which the polymer
is not soluble, such as hexane, is then added slowly to
precipitate the poly~er. The coated particles are fil-
tered and washed with hexane and allowed to dry. The
powder is stored for use in the suitable dosage form.
(B) Embedding
The polymer or pol~mer mixture is melted and a nonheat-
labile drug is suspended and thoroughly dispersed in the
melt. The melt is congealed by spraying, or in a mass
and ground into small particles to give a polymer matrix
with the drug embedded. For example: the poly(~-
dioxanone) pol~mer is melted and 0.5-to-400-micron
(preferably 0.5 to 25 micron) drug particles are suspend-
ed and thoroughly dispersed in the molten polymer in a
concentration necessary to give the desired release rate
patterns. The polymer is solidified by cooling and
ground into small pieces 1 to 200 microns in size.
(C) Intimate mixing
The drug and polymer are dissolved in a common solvent
and the solvent is removed in some suitable way
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. .
(spray-drying, flash-evaporation, etc.). For example:
- the drug and polymer are dissolved in the solvent in a
1:1 ratio and to a concentration of 2~. The solvent is
fla h-evaporated and the resulting f~lm is scraped from
tne flask and powdered.
The above sustained-release powder, granular or pellet
forms may be included in the following type formulations:
- ~1) Suspensions: Active ingredients of low solubility
which have been embedded in or coated with the polymer
and are in a finely divided state, 200 microns diameter
or less, preferably S0 microns or less, may be sus-
pended in a suitable pharmaceutical vehicle for injec-
tion. This vehicle may also contain suspending and
thickening agents, e.gr, methyl cellulose, and preserva-
tives. These ingredients are combined to give a stable
suspension which will release the active ingredient over
the time period desired.
(2) Emulsions: Active ingredients insoluble in oil in
fine powder form, preerably 10 microns or less, are
thoroughly dispersed in a suitable oil, which is, in
turn, emulsified in an external aqueous phase (oil in
water) using suitable emulsifying agents, e.g., tri-
ethanolamine oleate, polyoxyethylene sorbitan monooleate,
acacia, gelatin, etc. The aqueous phase may also con-
tain agents such as protective colloids and preserva-
tives, formulated to give a stable emulsion which will
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:l~q~3~4-3
.
provide a controlled release of the active ingredient
over the time period desired.
- (3) ~queous suspensions: The active ingredient em-
bedded and/or coated with the polymer in a particle
size no greater than 200 microns and preferably no
greater than 50 microns is suspended in an aqueous solu-
~ion which may contain thickening agents, e.g., carboxy-
methylcellulose; preservatives, e.g., phenol; suspending
agents, e.g., polyvinylpyrrolidone; surface active
agents; buffers and dextrose or saline to adjust for
isotonicity.
(4) Nonaqueous suspensions: The active ingredient em-
bedded and/or coated with the polymer in a particle size
usually no greater than 200 microns and preferably no
greater than 50 microns is suspended in a suitable
oil, etc. The suspension may contain preservatives,
e.g., chlorbutanol or methylparaben and propylparaben
mixtures, and suspending agents such as aluminum mono-
~ stearate.
In both the aqueous and nonaqueous preparations, the
final product is sterilized by heat, radiation, ethylene oxide
or other suitable means prior to use.
The use of absorbable polymer-drug formulations in the
controlled administration of fertility control agents over
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ETH-43~
~0984~3
extended periods of time is well-known. U. S. Patent No.
3,773,919, for example, describes the combination of poly-L-
lactide polymers with endocrine agents such as 17~ -estradiol;
2~ ,17~ -diethynyl-A-nor-5 ~ -androstane-2~ ,17~ -diol; 17~ -estra-
diol; 6,6-difluoro-17~ -ethynyl-17~ -hydroxyestr-4-en-3-one;.
and 17~ -hydroxyestr-4-en-3~one adamantane-l'-methanolcarbonate.
The poly(~-dioxanone) polymers of the present invention are ef-
fectively substituted for the poly-L-lactide polymers of U.S.
Patent No. 3,773,919 to obtain an alternative polymer-drug com-
position of similar effect.
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