U.S. patent number 3,888,975 [Application Number 05/318,890] was granted by the patent office on 1975-06-10 for erodible intrauterine device.
This patent grant is currently assigned to Alza Corporation. Invention is credited to Peter W. Ramwell.
United States Patent |
3,888,975 |
Ramwell |
June 10, 1975 |
Erodible intrauterine device
Abstract
An intrauterine device for administering drug locally to the
uterus at a controlled rate for a prolonged period of time is
disclosed. The device contains a body of polymer capable of
bioeroding in the environment of the uterus over a prolonged period
of time. This body has the drug dispersed throughout so that as the
body gradually bioerodes, it slowly releases the dispersed drug. In
a preferred embodiment, the device releases a uterine
contraction-inducing prostaglandin locally to the uterus at a
controlled rate over a prolonged period of time.
Inventors: |
Ramwell; Peter W. (Palo Alto,
CA) |
Assignee: |
Alza Corporation (Palo Alto,
CA)
|
Family
ID: |
23239996 |
Appl.
No.: |
05/318,890 |
Filed: |
December 27, 1972 |
Current U.S.
Class: |
424/432; 424/433;
128/833; 424/486 |
Current CPC
Class: |
A61K
9/2063 (20130101); A61K 9/0039 (20130101); A61K
31/557 (20130101); A61F 6/144 (20130101) |
Current International
Class: |
A61K
9/00 (20060101); A61K 9/20 (20060101); A61F
6/00 (20060101); A61F 6/14 (20060101); A61K
31/557 (20060101); A61k 027/12 () |
Field of
Search: |
;424/15-22
;128/260,130 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Karim, "The Prostaglandins," (1973), Coiley-Interscience, N.Y.,
N.Y. (May 22, 1973), pages 67-72, 95-104, 123-131,
156-164..
|
Primary Examiner: Rose; Shep K.
Attorney, Agent or Firm: Sabatine; Paul L. Benz; William H.
Mandell; Edward L.
Claims
We claim:
1. An intrauterine device for the controlled local administration
of prostaglandin to the uterus comprising a hollow cervical
cylindrical body having a central passageway shaped and sized for
insertion and retention in the uterus, the body made of a release
rate controlling material consisting essentially of cross-linked
gelatin that is cross-linked with a member selected from the group
consisting of an aldehyde, ketone, carbodimide and dicarboxylic
acid at a concentration of 0.01 to 60% by weight of gelatin at a
temperature of 4.degree.C to 35.degree.C for a reaction period of
0.1 hour to 5 days, the material containing from about 250
micrograms to about 100 milligrams of a prostaglandin that induces
uterine contractions, the release rate controlling material
bioeroding at a controlled rate over a period of 3 hours to 30 days
in response to the environment of the uterus and concurrently
therewith releasing 1 microgram to 25 micrograms per hour of the
dispersed prostaglandin to the uterus to produce the desired
result.
2. The device in accordance with claim 1 wherein the prostaglandin
is selected from the group consisting of
11.alpha.,15(S)-dihydroxy-9-oxo-13-trans-prostenoic acid;
11.alpha.,15(S)-dihydroxy-9-oxo-5-cis-13trans-prostadienoic acid;
9.alpha.,11.alpha.,15(S)-trihydroxy-5-cis-13-trans-prostatrienoic
acid; and methyl
9.alpha.,11.alpha.,15(S)-trihydroxy-5-cis-13-trans-prostatrienoate.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a bioerodible intrauterine device for
delivering drugs to the uterus at a controlled, continuous rate
over a prolonged period of time. In preferred embodiments it
concerns a bioerodible intrauterine device which enables the
improved administration of pregnancy-interrupting drugs.
2. The Prior Art
Presently, a critical need exists for an acceptable means for the
direct continuous delivery of drugs directly to the uterus for
gynecological, endocrinological and reproductive physiological
purposes.
In the prior art, it is most common to administer such drugs
systemically, such as by injection, by ingestion or by intravenous
infusion. Often, with systemic administration, the amount of drugs
needed to achieve the desired gynecological, endocrinological or
reproductive physiological purpose is so large that serious
undesirable side effects occur, ranging from migraine headaches,
vomiting, fatigue and nausea, to jaundice and pulmonary embolism.
It has been found in many cases that direct local application of
these agents to the uterus in smaller than systemic dosages can
bring about the desired effects with much reduced side effects. For
example, Wiqvist and Bygleman (Lancet, 1970, ii, page 716) showed
that prostaglandins, drugs useful for reproductive physiological
purposes, are 10 times more active as agents for causing uterine
contractions when administered locally to the uterus than when
administered intravenously. Side effects were reduced as well.
Miller, Calder and MacNaughton (Lancet, July 1, 1972, page 5)
showed that dosages of drugs for certain purposes can be reduced
even further by applying them locally to the uterus in a continuous
fashion. These investigators required a complicated system of
pumps, tubes and catheters to achieve a continuous flow of drugs to
the uterus, however. Thus it would not be possible for the patient
to be ambulatory. Neither would it be convenient to deliver a
continuous flow of drugs to the uterus over a prolonged period, as
is often desirable, with such an apparatus.
Vaginal suppositories are a well known drug form which has been
used to administer drugs to the uterus, since some of the vaginally
administered drug which is absorbed through the vaginal walls
passes via the circulatory system to the uterus. This method of
delivery is essentially systemic and thus has the same serious side
effects.
A device capable of locally releasing drugs to the uterus at a
controlled rate over a prolonged period of time which is small
enough to be contained within the uterus and simple enough in
operation to give reliability and avoid mechanical malfunctions
would be of great utility. Such a device would, for example, fill
the critical need which now exists for an acceptable method for
delivering progestational and estrogenic hormones directly to the
uterus, and for delivering uterine contraction-inducing agents
directly to the uterus.
OBJECTS OF THE INVENTION
Accordingly, it is an object of the present invention to provide a
device for the local delivery of drugs to the uterus.
Another object of the present invention is to provide a device
which may be contained within the uterus and/or the cervix uteri
and which is capable of delivering drugs locally to the uterus
continuously over a prolonged period of time.
Yet another object of the present invention is to provide an
intrauterine device which is of simple operation and which reliably
delivers drug over a prolonged period of time.
A further object of this invention is to provide an improved method
for delivering drugs to the uterus at a controlled, and if desired,
constant rate.
Another object of this invention is to provide a drug dispensing
uterine insert for delivering drugs to the uterus with increased
efficacy.
A still further object of this invention is to provide a
drug-releasing intrauterine device which will be of a
uterine-retentive configuration during the period of drug release
but of a configuration suitable for removal from the uterus
following drug delivery.
Yet another object of this invention is to provide a device for
locally administering a controlled amount of a uterine
contraction-inducing drug to the uterus at a controlled rate which
will remain in the uterus or cervix uteri during the term of drug
administration.
These and other objects, features and advantages of the present
invention will be readily apparent to those versed in the art from
the following description of the invention and the accompanying
claims.
STATEMENT OF THE INVENTION
In attaining the objects of this invention, a drug delivery device
is provided which, in its broadest aspects, comprises a body of a
polymer having drug dispersed therethrough, said polymer being
capable of bioeroding in the environment of the uterus over a
prolonged period of time. The device is of a shape and size adapted
for insertion and retention in the uterus and/or cervix uteri. As
the body of polymer gradually erodes it releases the dispersed drug
at a controlled rate.
In one embodiment, the device is adapted to deliver estrogenic
hormones to the uterus over periods of from a few hours to several
weeks.
In another embodiment the device incorporates a progestational
agent and gradually releases said agent over a prolonged period of
time.
In a preferred embodiment this invention involves a device of a
shape suitable for insertion and retention in the uterus or cervix
uteri of a pregant female comprising a body of polymer bioerodible
in the environment of the uterus which contains a uterine
contraction-inducing prostaglandin dispersed therethrough. The
prostaglandin is released continuously over a period of several
hours as the polymer erodes, and induces uterine contractions
during the period of release. This induction of uterine
contractions finds application in the area of childbirth and in the
area of therapeutic abortion.
BRIEF DESCRIPTION OF THE DRAWINGS
In the drawings wherein like reference numerals designate like
parts.
FIG. 1 is an elevational cross-sectional view showing an
intrauterine drug delivery device in accord with this invention in
place in a uterus.
FIGS. 2, 3 and 4 are cut-away views of a section of the device
illustrated in FIG. 1 in enlarged scale showing alternate
constructions of such a device.
FIG. 5 is an elevational view of another typical configuration for
a device in accord with the present invention.
FIG. 6 is an elevational cross-sectional view showing a device of
this invention in use in a pregnant uterus.
FIG. 7 is a partially sectioned elevational view of a device of
this invention adapted for placement in the cervix of a pregnant
female.
DETAILED DESCRIPTION OF THE INVENTION
In attaining the novel objects, features and advantages of the
invention, it has now been surprisingly found that drugs may be
most advantageously locally delivered to the uterus over a
prolonged period of time by being incorporated in a body of
material which slowly bioerodes in the environment of the uterus,
said body of material being incorporated in a device adapted for
insertion and retention in the uterus or cervix uteri throughout
the period of drug administration.
The term "bioerodible," as used in the specification and claims, is
defined as the property or characteristic of a body of material to
innocuously disintegrate or break down as a unit structure or
entity, over a prolonged period of time, in response to the
environment in the uterus by one or more physical or chemical
degradative processes, for example by enzymatic action, oxidation
or reduction, hydrolysis (proteolysis), displacement, e.g., ion
exchange, or dissolution by solubilization, emulsion or micelle
formation. The products of such bioerosion are thereafter absorbed
by the uterus and surrounding tissues, or otherwise dissipated,
such as by elimination from the uterine cavity.
As used in the instant specification and appended claims, the term
"prolonged period of time" is meant to include time intervals of
from at least 3 hours to approximately 30 days or higher and
preferably periods of from 4 hours to 48 hours. It should be noted
that this term is applied with reference to the time interval over
which the drug is released and also with reference to the time
interval over which the uterine device and its component materials
bioerode in the environment of the uterus, although each of the
aforesaid time periods may not necessarily be concurrently
coextensive in duration.
With these definitions in mind, and before examining the materials
employed in and delivered by the instant devices, let us now turn
to the drawings in more detail.
In FIG. 1 there is depicted an intrauterine drug delivery device in
accord with the present invention. This device, drug delivery
device 10, is in a shape suitably described as a T. Device 10 is
comprised of a cross bar 11 and a depending member or leg 12.
Device 10 is of a size and shape adapted to be inserted into the
uterus 14 and be retained there over the prolonged period of time
for which drug is delivered. The device suitably contacts the sides
15 of the uterus as well as the fundus uteri 16. Device 10 is
preferably designed with rounded non-traumatizing ends and a thread
13, attached to the trailing end of leg 12 for manually removing
device 10 from uterus 14.
Device 10 is formed of a bioerodible material as will be described
and contains drug dispersed therethrough. This construction is
shown in FIG. 2, an expanded and cut away view of device 10 at A.
As shown in FIG. 2 Device 10 can be a solid body 21 of erodible
material which has drug 22 dispersed throughout. As body 21
bioerodes, it releases entrapped drug 22 and delivers it locally to
the uterus in which it is positioned. Drug 22 may be in the form of
solid particles, liquid droplets, colloidal particles, or gels,
depending upon the nature of the drug. When device 10 is of the
construction shown in FIG. 2, it releases drug at a controlled rate
over a prolonged period of time. As the device erodes, its surface
area decreases. This decrease in area causes the rate of drug
release to decrease as well. One way to achieve a more constant
rate of drug release is to vary the concentration of drug within
the body of erodible material 21, increasing the concentration in
the inner areas of device 10 so as to compensate for the decrease
in area. As an aside, it will be readily appreciated that other
variations of drug concentrations throughout the body of erodible
material can bring other patterns of drug release, for example
sinusoidal, intermittant and the like.
Another way to achieve an essentially uniform rate of drug release,
that is, a release having a more nearly zero order time dependence,
involves constructing the device as illustrated in FIG. 3. In FIG.
3 erodible material 21 and drug 22 are in the form of an outer
layer surrounding an inner core 31. Core 31 is made of a
nonerodible material which does not contain drug. It functions as a
structural member. It is preferably formed of a flexible material,
very suitably a polymer, having an elastic memory. This enables
device 10 to be compressed into an easily insertable form for
insertion and then to expand in the uterus to a more retentive
form. By employing erodible material 21 and drug 22 only as an
outer layer, the variation in surface area of drug-containing
material is reduced and a more nearly constant rate of drug release
is achieved.
In FIG. 4, yet another alternative construction for device 10 is
illustrated. In FIG. 4, an inner core 41 is employed. Core 41
differs from core 31 in that it is formed of an erodible material.
This construction offers the advantages of a more constant rate of
release, as does the construction shown in FIG. 3 and, also,
eliminates the need to remove the device from the uterus at the
completion of the drug delivery.
With any of the constructions shown, it would be possible to employ
more than one drug either together or in separate layers. For
example, in the construction set forth in FIG. 4, one drug could be
present and released from material 21 while a second drug could
later be released from the erodible inner core.
The T shape of device 10 as illustrated in FIG. 1, while a form
which is excellently retained in the uterus, is merely
illustrative. FIG. 5 shows another suitable shape for an
intrauterine device in accord with the present invention. FIG. 5
illustrates device 50, which is in the shape of a double loop, that
when inserted into uterus 14 touches the walls 15 and the fundus
uteri 16.
The devices of this invention may take on a great variety of sizes
and shapes. For application and retention in the human uterus, they
generally range in size from about 2 cm to about 6 cm in length and
width. For uterine devices for other animals, larger or smaller
sizes may be used as required for comfort and uterine retention.
The device may take forms such as cylindrical, bullet, elliptical,
circular, bulbous, loop, bow, which lend themselves to intrauterine
placement or lodging in the cervix uteri. Specific suitable forms
include, without limitation, Birnberg's Bow shown in U.S. Pat. No.
3,319,625, the comet shown in U.S. Pat. No. 3,256,878, the spring
of U.S. Pat. No. 3,397,691, Lippes' Loop, the ring with tail, the
Ota ring, and the like.
When the device itself is bioerodible it is possible to employ many
configurations having excellent uterine retention characteristics
which were not of choice previously. A very retentive shape, almost
be definition, would be very difficult to remove from the uterus or
cervix uteri conventionally, without risk of harm to the delicate
tissues in these areas. When the body of the device itself, in
addition to its drug release components, is bioerodible, it can
break down from a retentive form to an easily removed or expelled
form. The entire body may be erodible or only parts, such as
joints, may be erodible. Either way, the retentive configuration
can be destroyed.
This feature is of especial advantage when delivering drugs which
cause uterine contractions, that is, oxytocic drugs. In such
applications, it is desired to have a configuration which will
remain in the uterus or cervix uteri throughout the period of drug
administration. Such a configuration must be very highly retentive
as the contracting uterus is attempting to expel its contents,
including the drug delivery device.
Devices capable of remaining in the uterus during uterine
contractions would in many cases be most difficult to remove
manually. Thus, it is very desirable to fabricate them at least in
part from an erodible material.
Drugs which induce uterine contractions are administered to bring
about childbirth or to cause therapeutic abortion. In either case
the placement of a drug delivery device in the uterus or cervix
uteri will have to take into account the presence of the embryo or
fetus in the uterus. The device must also be of a design which will
permit the contents of the uterus, save the device, to be
expelled.
FIGS. 6 and 7 are enlarged views of two typical devices suitable
for administering uterine contraction inducing drugs in use. In
FIG. 6 a device 60 in accord with the invention is shown positioned
within uterus 14 defined by fundus uteri 16 and walls 15 which
walls also define cervix uteri 61. Present in uterus 14 is embryo
62 surrounded by amnion 63 and amnionic fluid. Device 60 is in the
form of a multi cross-armed T having a center post 64 and a
plurality of cross arms 65. Device 60 is highly flexible and is
inserted into the uterus around embryo 62 in an easily insertable
collapsed form. Device 60 does not block the path from the uterus
14 through cervix 61. Firmly attached to device 60 is a sleeve 66
of bioerodible material having uterine contraction inducing drug
dispersed therethrough. In the uterus the bioerodible material
bioerodes and releases its drug causing the uterus to contract and
expel embryo 62, amnion 63 and the like. Device 60 remains in the
uterus. Cross arms 65 are bonded to center bar 64 via erodible
bridges 67. At a point in time after the drug has been released,
bridges 67 erode, causing the cross arms 65 to drop off device 60.
The resulting separate cross arms and center bar are not retained
in the uterus and are easily and harmlessly expelled.
Turning to FIG. 7, the uterus and embryo of FIG. 6 are again shown.
A device 70, in the form of a hollow cervical cylinder, is
illustrated. Device 70 is shown inserted into the cervix uteri 61.
Because of its hollow configuration, it does not block the path
through cervix. In fact, it actually serves to dilate the cervix.
Device 70, as the cut away shows, is in the form of two axially
joined coaxial rings, a top ring of bioerodible polymer 21
containing uterine contraction inducing drug 22 and a bottom ring
71 not containing drug. In use drug 22 is released causing uterus
14 to contract and expel embryo 62 through the center hole of
device 70. Bottom ring 71 may be erodible if desired. It may also
be of a material swellable in uterine fluids to enhance its
retention in the uterus.
It will be appreciated that the device of this invention may take
on many other forms, these shown being merely illustrative.
Turning now to the materials employed in these devices, bioerodible
materials suitable for fabricating the intrauterine devices are the
materials that are non-toxic and non-irritating to the endometrium
of the uterus, and which upon bioerosion produce end products that
are also nontoxic, non-irritating and safely and easily eliminated
from the body.
Exemplary bioerodible materials include both natural and synthetic
materials such as (a) structural proteins and hydrocolloids of
animal origin; (b) polysaccharides and other hydrocolloids of plant
origin; and (c) synthetic polymers. Some of these matrix materials
are suitable as in their native form but others, particularly
hydrocolloids, require insolubilization either by chemical
modification, or physical modification, such as orientation,
radiation cross-linking, etc. Exemplary of the first category are:
native and modified collagens, muscle proteins, elastin, keratin,
resilin, fibrin, etc. Exemplary of polysaccharides and plant
hydrocolloids are: algin, pectin, carrageenin, chitin, heparin,
chondroitin sulfate, Agar-agar, Guar, locust bean gum, gum arabic,
gum Karaya, tragacanth, gum Ghatti, starch, oxystarch, starch
phosphate, carboxymethyl starch, sulfaethyl starch, aminoethyl
starch, amido ethyl starch, starch esters such as starch maleate,
succinate, benzoate and acetate, and mixtures of starch and
gelatin; cellulose and its derivatives such as modified
cellulosics, such as partially hydroxyethylated cotton obtained by
the treatment of cotton with ethylene oxide or partially
carboxymethylated cotton obtained by the treatment of cotton with
caustic and choroacetic acid. Exemplary of synthetic polymers are:
poly(vinyl alcohol), poly(ethylene oxide), poly(acrylamide),
poly(vinyl pyrrolidone), poly(ethyleneimine), poly(vinyl
imidazole), poly(phosphate), synthetic polypeptides, polyvinyl
alkyl ether, polyacryl-and polymethacrylamides, and copolymers of
acrylamide and methacrylamide with up to 40% by weight of
N-methylene bisacrylamide or N,N-dimethylol urea; polyalkyl
aldehydes, water soluble hydrophilic polymers of uncross-linked
hydroxyalkyl acrylates and methacrylates, polyalkylene carbonates,
and the like. The list is illustrative. Any bioerodible material
which is compatible with the drug and non-toxic and which has the
desired erosion and release rates can be used.
Without intent to limit the scope of the present invention, the
following materials are preferred for use as erodible materials in
the intrauterine drug delivery devices:
1. Cross-Linked Gelatin
Gelatin is obtained by the selective hydrolysis of collagen by
means well known to those skilled in the art and comprises a
complex mixture of water soluble proteins of high molecular weight.
As used herein, the term cross-linked gelatin means the reaction
product of gelatin or a gelatin derivative with a cross-linking
agent reactive with either the hydroxyl, carboxyl or amino
functional groups of the gelatin molecule and substantially
unreactive with the peptide linkage of the gelatin molecule, the
product of reaction having an average molecular weight of from
2,000 to 50,000 between cross-links, although higher values can be
employed. Such a product is biodegradable in the environment of the
uterus over a prolonged period of time.
Cross-linked gelatin materials are well known to those skilled in
the art and can be prepared by reacting the cross-linking agent
with gelatin under suitable reaction conditions. The degree to
which the gelatin is cross-linked is dependent upon the processing
conditions employed to carry out the reaction and markedly affects
its characteristics with regard to the time required in order for
the material to biodegrade in the eye. The rate and, therefore, the
degree of cross-linking of the gelatin is primarily determined by:
(1) the effective concentration of reactive groups present; (2)
reaction time; (3) temperature at which the reaction is carried
out; and (4) pH of the reaction environment. The choice of the
particular conditions will of course depend on the properties
desired for the end product as hereinafter discussed.
Exemplary of suitable cross-linking agents are: aldehydes, such as
monoaldehydes, e.g., C.sub. 1 -C.sub.4 aldehydes, e.g.,
acetaldehyde, formaldehyde, acrolein, crotonaldehyde, 2-hydroxy
adipaldehyde; dialdehydes, such as glutaraldehyde, glyoxal, other
aldehydes such as starch dialdehyde, paraldehyde, furfural and
aldehyde bisulfite addition compounds such as formaldehyde
bisulfite; aldehyde sugars, e.g., glucose, lactose, maltose, and
the like; ketones such as acetone; methylolated compounds such as
dimethylol urea, trimethylol melamine; "blocked" methylolated
compounds such as tetra(methoxymethyl) urea, melamine; and other
reagents such as C.sub. 1 -C.sub.4 disubstituted carbodiimides;
epoxides such as epichlorohydrin, Eponite 100 (Shell); para-benzene
quinone; dicarboxylic acids, e.g., oxalic acid; disulfonic acids,
e.g., m-benzene disulfonic acid; ions of polyvalent metals, e.g.,
chromium, iron, aluminum, zinc, copper; amines such as
hexamethylene tetramine; and aqueous peroxydisulfate. See H. L.
Needles, J. Polymer Science, Part A-1, 5 (1) 1 (1967).
Still another suitable method for cross-linking gelatin is that
using irradiation; see for example Y. Tomoda and M. Tsuda, J. Poly.
Sci., 54, 321 (1961).
The reactive groups present in gelatin, i.e., hydroxyl, carboxyl
and amino functions are present per 100 grams of high quality
gelatin in the following approximate amounts: 100, 75 and 50 meq of
each of these groups, respectively. The number of reactive sites do
not vary appreciably from one gelatin to another, i.e., Type A or B
gelatins, unless major hydrolytic breakdown has occurred. These
quantities may serve as a general guide in determining the amount
of cross-linking agent to be used. However, any discussion of the
chemical reactions of gelatin must be made with regard to its very
heterogeneous composition. Moreover, actual degradation rates are
preferably determined experimentally as hereinafter exemplified in
the Examples for a material prepared under a given set of
conditions. For example, using formaldehyde as the cross-linking
agent, concentrations thereof from 0.01% to 50% by weight, based on
the weight of the gelatin in combination with reaction times of 0.1
hours to 5 days and at temperatures of from 4.0.degree. to
35.degree.C will yield suitable products, the exact combination of
concentration, temperature and time depending on the desired
dissolution rate. General information on cross-linked gelatin can
be found in Advances in Protein Chemistry, Vol. VI, Academic Press,
1951, "Cross Linkages in Protein Chemistry," John Bjorksten.
2. Polyesters
Polyesters of the general formula: ##SPC1##
and mixtures thereof, wherein:
W is a radical of the formula --CH.sub.2 --; or ##SPC2##
Y has a value such that the molecular weight
of the polymer is from about 4,000 to 100,000. These polymers are
polymerization condensation products of monobasic hydroxy acids of
the formula:
C.sub.n H.sub.2n (OH)COOH II
wherein n has a value of 1 or 2, especially lactic acid and
glycolic acid. Also included are copolymers derived from mixtures
of these acids. The preparation of polymers of formula I per se,
forms no part of the present invention. Several procedures are
available and reported by Filachione, et al., Industrial and
Engineering Chemistry, Vol. 36, No. 3, pp. 223-228, (March 1944;
Tsuruta, et al., Macromol. Chem., Vol. 75, pp. 211-214 (1964), and
in U.S. Pat. Nos. 2,703,316; 2,668,162; 3,297,033; and
2,676,945.
3. Cross-Linked Anionic Polyelectrolytes
Cross-linked substantially water-insoluble polymeric coordination
complexes may be used. A device of these materials can be made by
several alternative procedures. Method A comprises the sequential
steps of:
a. preparing an aqueous solution containing an initially water
soluble anionic polyelectrolyte, and adding thereto a polyvalent
metal cation capable of coreacting therewith to form a water
insoluble cross-linked precipitate;
b. adding to said mixture drug and a sufficient amount of
complexing reagent in the form of an electron donor molecule to
render the reaction product water soluble by forming a coordination
complex with the reactants;
c. fabricating the solution into the desired device shape; and
then
d. substantially removing the electron donor molecule from the
system to cross-link the polyelectrolyte and recovering the
thus-prepared solid shaped structures.
Alternatively, the complexing reagent and drug can be added to the
solution of anionic polyelectrolyte prior to the addition of the
polyvalent cation to maintain the reaction product in solution in
lieu of resolubilizing the precipitate. Method B comprises the
sequential steps of:
a. fabricating a solution of an initially water soluble plasticized
anionic polyelectrolyte containing dispersed drug into the desired
shape;
b. dipping the thus-formed shape into an aqueous solution of a
polyvalent metal cation to cross-link the anionic polyelectrolyte;
and
c. recovering the thus prepared water insoluble cross-linked
structure.
This material, and the methods for its preparation are the sole
invention of Alan S. Michaels. It is more fully described and
claimed in his copending application Ser. No. 248,168 owned by the
assignee of this invention, filed on Apr. 27, 1972, and generally
described below.
Among the anionic polyelectrolyte polymers which may be interacted
to produce the cross-linked structures which are useful in the
present invention are those which are soluble in uterine fluids and
have a sufficiently high molecular weight, typically at least
10,000, to be solid and capable of forming the required solid body.
They contain a plurality of functional groups which are reactive
with the polyvalent metal cation to form a salt therewith.
Preferably, the functional group is an alkali metal or ammonium
salt of a carboxylate, sulfate, sulfonate or phosphate. These
functional groups can be characterized as being dissociable anionic
groups which are chemically bonded to the polymeric chain.
Exemplary of these polymers are: polysaccharides, e.g.,
K-carrageenin, pectinic acid, heparin sulfate, hyaluronic acid,
heparin, natural gums such as algin, locust bean gum, agar, pectin,
gum arabic, gum tragacanth; modified natural and synthetic polymers
such as carboxymethylcellulose, carboxymethyl starch, polystyrene
sulfonic acid, polyvinyl sulfuric acid, poly(vinyl sulfonic acid),
polyvinyl methylol sulfonic acid, hydrolyzed poly(vinyl
acetate/maleic anhydride), polyvinyl ether-maelic anhydride,
poly(ethylene-maleic anhydride), poly(acrylic acid),
poly(methacrylic acid) and copolymers thereof with acrylic or
methacrylic esters, poly(vinyl acetate), poly(vinyl alcohol),
poly(vinyl chloride) poly(styrene), and other materials of the same
general type.
Preferred embodiments of these materials are the
naturally-occurring vegetable-derived water-soluble polysaccharide
polymers which are essentially devoid of animal or human toxicity,
and which decompose in the body into simple sugars.
The polyvalent metal cations which are interacted with the
initially water soluble anionic polyelectrolytes include di, tri or
tetra valent metals such as copper, mercury, chromium, nickel,
zinc, cobalt, ferric and ferrous iron, aluminum, tin, bismuth,
calcium, magnesium, and the like. It is to be understood that any
polyvalent metal can be employed which is capable of coreacting
with the polyelectrolyte to form a water-insoluble precipitate and
which is innocuous in the body. The anion associated with the metal
cation is preferably a halide, e.g., chloride, sulfate or nitrate,
although any innocuous ion can be used.
The complexing reagents employed in Method A are any of those
materials which are capable of solubilizing or maintaining the
polyelectrolyte-polyvalent cationic reaction product in solution so
as to enable fabrication of the solution into the desired shape.
Exemplary of these materials are primary, secondary and tertiary
amines such as mono, di, or trimethyl amine, mono, di or
tri-ethanolamine, morpholine, pyridine, piperidine, piperazine,
aniline, 2-methyl imidazole, ethylene diamine and higher
polyethylene polyamines, and ammonia.
The complexing reagent must be present in solution in an amount
sufficient to prevent precipitation of the reactive components.
This amount will usually be at least about 0.5% by weight of the
total solution, preferably about 5% by weight. Although amounts as
great as 50% or more by weight of the total solution may be used,
it is unnecessary and frequently undesirable to employ any more
than the minimum required to prevent precipitation of the
polyelectrolytes. In general, the concentration of the
polyelectrolyte must be at least 0.5% by weight and preferably
above 1% by weight of the mixture in order to obtain continuous
solids in the subsequent processing. Molar ratios of anionic
polyelectrolyte to polyvalent metal of from 1 to 10, and preferably
from 2 to 5, are satisfactory. The solution thus prepared is then
caused to gel by changing conditions so as to permit precipitation
to occur by breaking down the coordinate complex so as to
cross-like the polymer with metal. Gelation of the polymeric
complex solute can be effected by reducing the effective
concentration of the complexing reagent by neutralization thereof
with acid, or removal in the case of volatile reagents by
evaporation in the presence of heated moist air. The required
structure can be obtained by the usual process of casting,
extruding the mixture, or coating onto a suitable substrate and
then drying the formed object by suitable means.
The degree of cross-linking of the polymer by the metal ion can be
controlled by adjusting the ratio of metal to polymer in the
initial solution, thereby producing materials of varying
hydrophilicities. When placed in contact with a uterine fluid,
these polymeric structures biodegrade by virtue of the gradual
extraction and chelation of the polyvalent ion by endogenous
proteins, polysaccharides, and other substances present in this
fluid. By varying the degree of cross-linking, the rate of drug
release and biodegration can be varied over wide limits. If a
natural gum (i.e., algin) is used in the formulation, after
dissolution, enzymatic hydrolytic processes will cleave the
solubilized polymer into innocuous sugars which are absorbed into
the tissues surrounding the uterus.
It is often desired to incorporate plasticizers in the bioerodible
materials to improve or vary their physical properties, such as to
make them more flexible. Exemplary plasticizers suitable for
employment for the present purpose are the pharmaceutically
acceptable plasticizers conventionally used, such as acetyl
tri-n-butyl citrate, epoxidized soy bean oil, glycerol monoacetate,
polyethylene glycol, propylene glycol dilaurate, decanol,
dodecanol, 2-ethyl hexanol, 2,2-butoxyethoxyethanol and the like.
The proportion of optional plasticizer used will vary within broad
limits depending upon the characteristics of the bioerodible
material involved. In general, from about 0.01 parts to about 0.2
parts by weight of plasticizer for each part by weight of the
bioerodible material can be used.
When plasticizers are included in the bioerodible materials they
are most suitably added prior to shaping the final formed
structure, such as by dissolving or dispersing them in the solution
from which the device is formed.
Drug is released from the delivery devices of this invention by
erosion of the polymeric body through which the agent is dispersed.
As the body erodes, it releases the dispersed, entrapped drug. The
erodible polymer from which the bodies of the device of this
invention are formed are substantially imperforate and impermeable
to the passage of active agent by diffusion. Hence, the rate of
drug release is usually proportional to the rate of material
bioerosion. When the rate of bioerosion is constant the rate of
release of drug will also be constant, assuming that the dispersion
of drug through the body is uniform and that the area of the device
which is eroding remains constant.
The aforementioned bioerodible materials erode at a controlled rate
when placed in the weakly alkaline aqueous environment of the
uterus.
In the devices of this invention, non-erodible materials are often
employed as structural elements or core parts. Any polymeric
material which is compatible with the tissues and fluids of the
uterus may be used including, without limitation, polyolefins,
acrylics, non-erodible polyesters and the like. In certain
embodiments, it may be of use to employ a swellable hydrophilic
polymer in the devices to anchor the devices. Suitable hydrophilic
polymers include, for example, polyhydroxyethylmethacrylate and the
cross-linked polyacrylamides.
Devices of this invention are useful for delivering all types of
drugs to the uterus. In the specification and accompanying claims,
the term "drug" broadly includes physiologically or
pharmacologically active substances for producing effects in
mammals, including humans and primates; avians such as chickens and
turkeys; valuable domestic household, sport or farm animals such as
horses, dogs, cats, cattle, sheep and the like; or laboratory
animals such as mice, monkeys, rats, guinea pigs; and the like.
While the devices of this invention operate with special
effectiveness with drugs which have a locallized effect in or upon
the uterus, systemically active drugs which act at a point remote
from the uterus may be administered as well and are included within
the term "drugs." Thus, drugs that can be administered by the
intrauterine device of the invention include, without limitation:
drugs acting on the central nervous system such as, hypnotics and
sedatives such as pentobarbital sodium, phenobarbital,
secobarbital, thiopental, etc.; heterocyclic hypnotics such as
dioxopiperidines, and glutarimides; hypnotics and sedatives such as
amides and ureas exemplified by diethylisovaleramide and
.alpha.-bromoisovaleryl urea and the like; hypnotics and sedative
alcohols such as carbomal, naphthoxyethanol, methylparaphenol and
the like; and hypnotic and sedative urethans, disulfanes and the
like; psychic energizers such as isocarboxaxid, nialamide,
phenelzine, imipramine, tranylcypromine, pargylene isocarboxazid,
the like; tranquilizers such as chloropromazine, promazine,
fluphenazine reserpine, deserpidine, meprobamate, benzodiazepines
such as chlordiazepoxide and the like; anticonvulsants such as
primidone, diphenylhydantoin, ethotoin, pheneturide, ethosuximide
and the like; muscle relaxants and anti-parkinson agents such as
mephenesin, methocarbomal, trihexylphenidyl, biperiden, levo-dopa,
also known as L-dopa and L-.beta.-3-4-dihydroxyphenylalanine, and
the like; analgesics such as morphine, codeine, meperidine,
nalorphine and the like; anti-pyretics and anti-inflammatory agents
such as aspirin, salicylamide, sodium salicylamide and the like;
local anesthetics such as procaine, lidocaine, naepaine,
piperocaine, tetracaine, dibucaine and the like; antispasmodics and
anti-ulcer agents such as atropine, scopolamine, methscopolamine
oxyphenonium, papaverine; anti-microbials such as penicillin,
tetracycline, oxytetracycline, chlorotetracycline, chloramphenicol,
sulfonamides and the like; anti-malarials such as
4-aminoquinolines, 8-aminoquinolines and pyrimethamine; hormonal
agents such as prednisolone, cortisone, cortisol and triamcinolone;
sympathomimetic drugs such as epinephrine, amphetamine, ephedrine,
norephineprine and the like; cardiovascular drugs, for example,
procainamide, amyl nitrate, nitroglycerin, dipyridamole, sodium
nitrate, mannitol nitrate and the like; diuretics, for example,
chlorothiazide, flumethiazide and the like; antiparasitic agents
such as bephenium hydroxynaphthoate and dichlorophen, dapsone and
the like; neoplastic agents such as mechlorethamine, uracil
mustard, 5-fluorouracil, 6-thioguanine, procarbazine and the like;
hypoglycemic drugs such as insulins, protamine zinc insulin
suspension, globin zinc insulin, isophane insulin suspension, and
other art known extended insulin suspensions, sulfonylureas such as
tolbutamide, acetohexamide, tolazamide, and chloropropamide, the
biguanides and the like; nutritional agents such as vitamins,
essential amino acids, essential fats and the like; and other
physiologically or pharmacologically active agents.
The devices of this invention deliver with special efficiency
progestational substances that have anti-fertility properties and
estrogenic substances that have anti-fertility properties. These
substances can be of natural or synthetic origin. They generally
possess a cyclopentanophenanthrene nucleus. The term progestational
substance as used herein embraces "progestogen" which term is used
in the pharmaceutically acceptable steroid art to generically
describe steroids possessing progestational activity, and the
former also includes "progestins," a term widely used for synthetic
steroids that have progestational effects. The active
anti-fertility progestational agents that can be used to produce
the desired effects in mammals, including humans, and primates
include without limitations: pregn-4-ene-3,20-dione, also known as
progesterone; 19-nor-pregn-4-ene-3,20-dione;
17-hydroxy-19-nor-17.alpha.-pregn-5(10)-3n3-20-yn-3-one;
dl-11.beta.-ethyl-17-ethinyl-17-ethinyl-17-.beta.-hydroxygon-4-ene-3-one;
17.alpha.-ethinyl-17-hydroxy-5(10)-estren-3-one;
17.alpha.-ethinyl-19-norestosterone;
6-chloro-17-hydroxypregna-4,6-diene-3,20-dione;
17.beta.-hydroxy-6.alpha.-methyl-17-(1-propynyl)androst-4-ene-3-one;
9.beta.,10.alpha.-pregna-4,6-diene-3,20-dione;
17-hydroxy-17.alpha.-pregn-4-en-20-yne-3-one;
19-nor-17.alpha.-pregn-4-3n-20-yen-3.beta.,17-dial;
17-hydroxy-pregn-4-ene-3,20-dione; 17.alpha.-hydroxyprogesterone;
17-hydroxy-6.alpha.-methylpregn-4-ene-3,20-dione; mixtures thereof,
and the like.
The estrogenic anti-fertility agents useful herein also include the
compounds known as estrogens and the metabolic products thereof
that possess anti-fertility properties or that are converted to
active anti-fertility agents in the uterine environment. Exemplary
estrogenic compounds include .beta.-estradiol, .beta.-estradiol
3-benzoate, 17-.beta.-cyclopentanepropionate estradiol,
1,3,4(10)-estratriene-3,17.beta.-diol dipropionate,
estra-1,3,5(10)-triene-3,17-.beta.-diol valerate, estrone, ethinyl
estradiol, 17-ethinyl estradiol-3 methyl ether, 17-ethinyl
estradiol-3-cyclopentoether, estriol, mixtures thereof, and the
like.
Another group of drugs which may be delivered with high efficiency
by the devices of this invention include drugs for including
uterine contractions such as the oxytocic agents, for example,
oxytocin, ergot alkaloids such as ergonovine and methylergonomine,
quinine, quinidine, histamine and sparteine.
Yet another group of drugs preferred for delivery from the devices
of this invention are the prostaglandins. Prostaglandins have a
wide range of biological activities.
Prostaglandins occur as natural body humoral agents and are
produced synthetically. Such compounds contain an oxygenated
cyclopentane nucleus to which two side-chains are attached in the
vicinal positions. The hypothetical completely saturated and
unsubstituted parent compound of the prostaglandins is called
prostanoic acid and is represented by the structural formula:
##SPC3##
Nomenclature of the prostaglandins is derived from the above
formula and numbering system. Therefore, the structure of the
prostaglandin nucleus and side-chains can be described according to
the structure of prostanoic acid shown in Formula I.
It has been found that four types of prostaglandin nuclei are
present in prostaglandins, which gives rise to four series of
prostaglandins commonly designated as E, F, A, and B, which are
shown in Formulas II - IV inclusive. In structural formulae II - V,
a dotted line represents a valency bond in the
.alpha.-configuration and the solid line represents a bond in the
.beta.-configuration. ##SPC4##
Among naturally occurring prostaglandins, two side-chains have been
described. One contains a terminal carboxylic acid group and may
also contain a double bond, while the other contains a hydroxyl
functional group together with one or two double bonds. These
side-chains are present in natural prostaglandins in three
combinations designated 1, 2, and 3, depending upon the total
number of double bonds present, so that the natural prostaglandins
are designated as E.sub.1, E.sub.2, E.sub.3, F.sub.1, F.sub.2, etc.
These specific side-chains are as follows:
Prostaglandins R.sub.1 R.sub.2
__________________________________________________________________________
E.sub.1 F.sub.1 A.sub.1 B.sub.1 --(CH.sub.2).sub.6 --COOH
--CH:CHCH(OH) (CH.sub.2).sub.4 CH.sub.3 E.sub.2 F.sub.2 A.sub.2
B.sub.2 --CH.sub.2 CH:CH(CH.sub.2).sub.3 COOH --CH:CHCH(OH)
(CH.sub.2).sub.4 CH.sub.3 E.sub.3 F.sub.3 A.sub.3 B.sub.3
--CH.sub.2 CH:CH(CH.sub.2).sub.3 COOH --CH:CHCH(OH)CH.sub.2
CH:CHCH.sub.2 CH.sub.3
__________________________________________________________________________
In addition to the foregoing natural compounds, various
biologically active substituted prostaglandins and prostaglandin
analogues are known to the art. These include 19-hydroxy
prostaglandins, acyl prostaglandins, alkoxy prostaglandins, esters
or amides of the carboxyl group in R.sub.1, as well as
prostaglandins having alkyl substituents on the R.sub.1 and R.sub.2
side chains.
While any of the natural and synthetic prostaglandins may be
delivered by the present devices, those of A, E and F nuclei which
have been shown to be most useful for producing uterine
contractions comprise a preferred group for use in these devices, a
group herein defined to be the uterine-contraction inducing
prostaglandins. A more preferred group of prostaglandins comprises
those of E.sub.1, E.sub.2, F.sub.1 or F.sub.2 configurations, with
from 0 to 2 additional alkyl substituents (preferably methyl
substituents) on chains R.sub.1 and R.sub.2. A most preferred group
of prostaglandins consists of Prostaglandin E.sub.1
(11.alpha.,15(S)-dihydroxy-9-oxo-13-trans-prostenoic acid);
Prostaglandin E.sub.2
(11.alpha.,15(S)-dihydroxy-9-oxo-5-cis-13-trans-prostadienoic
acid); Prostaglandin F.sub.2.sub..alpha.
(9.alpha.,11.alpha.,15(S)-trihydroxy-5-cis-13-trans-prostatrienoic
acid) and the 15-methyl derivative of prostaglandin
F.sub.2.sub..alpha.. Mixtures of the various prostaglandins, either
alone or with added hormonal agents, oxytocin, polypeptides and the
like, may be used as well.
The pharmaceutically acceptable, non-toxic salts of the
prostaglandins can also be used including the non-toxic alkali
metal and alkaline earth metal bases such as sodium, potassium,
calcium, lithium, copper, and magnesium hydroxides and carbonates
and the ammonium salts and substituted ammonium salts, for example,
the non-toxic salts of trialkylamines such as triethylamine,
trimethylamine, trisopropylamine, procaine, dibenzylamine,
triethanolamine, N-benzyl-beta-phenylethylamine,
ethyldimethylamine, benzylamine, N-(lower) alkylpiperdine,
N-ethylpiperidine, 2-methylpiperidine and other physiologically
acceptable amines and bases.
The above-described prostaglandins are known to the prior art and
they are amply described in references such as Pharmacological
Reviews, Vol. 20, pages 1 to 48, 1968; Progress In The Chemistry of
Fats and Other Lipids, Vol. IX, pages 231 to 273, 1968; Science,
Vol. 157, pages 382 to 391; Angewandte Chemie, Vol. 4, pages 410 to
416, 1965; The Journal of Biological Chemistry, Vol. 238, pages
3555 to 3564, 1963; and other literature references.
The drug is mixed with the bioerodible material and the mixture is
fabricated by casting, and the like, into a form suitable for use
in the uterus. The erodible material containing drug may be present
as the actual intrauterine device or may as well be present as a
pendant, flag, or other suitable attachment auxillary thereto.
The amount of drug present in the device is dependent upon dosage
requirements and the length of time the device is to be in place in
the uterus and may vary from a single does of a very potent drug,
which may be as little as a few micrograms, to an amount sufficient
for several hundred or even a thousand doses of a less potent drug,
such as up to several grams (for example, 5 grams) of drug. In any
event, the amount of drug must be small enough that the erodible
material is a continuous phase and the drug is a dispersed phase
therein. In general, drug is present in an amount equal to up to
about 90% of the weight of bioerodible material. Drug loadings of
from about 0.01%, basis bioerodible material, to about 40% are
preferred.
The devices of this invention are intended to release drugs locally
to the uterus over prolonged periods of time, that is, for periods
of from about 3 hours to 30 days or longer. With the progestational
and estrogenic substances, delivery times of from about 1 day to 30
days or a year or more are preferred, with dosage rates of from
about 10 to 200 mg per day being preferred, thus making it
desirable to incorporate at least from about 10 mg to about 6 grams
of these substances in a delivery device. When prostaglandins are
administered for uterine-contraction inducing purposes, it is
preferred to administer the drug over a period of from about 4
hours to about 24 hours at a rate of about 1 microgram/minute to
about 25 micrograms/minute. Thus the loading of prostaglandins in
the present devices may suitably vary from about 250 micrograms up
to as much as about 100 milligrams, depending on the dosage rate
and period desired, preferably the loading of prostaglandin would
be between about 1 milligram and about 100 milligrams. Similar drug
loadings could be determined for the many other drugs suitably
delivered by these devices based on their dosage periods and
amounts.
The intrauterine devices gradually erode in the uterus and release
their drug. The rate of erosion will depend in part on the
recipient's temperature (generally from about 35.degree. to
43.degree.C), uterine pH (generally pH 7-8) and the amount of
uterine fluids presently available to contact the device.
The rate of erosion and drug release of materials employed in the
invention can be determined experimentally in vitro by testing them
under simulated environmental conditions. For example, the rate of
erosion of a device in uterine fluids, as would occur with an
intrauterine drug delivery device, may be measured by placing a
small weighed sample of the material in physiological saline
solution -- a solution of pH about 7.4 (simulated uterine fluid) at
body temperature (37.degree.C), agitating for a timed interval, and
periodically measuring the amount of material eroded into the
solution. To accurately predict in vivo results, it is necessary to
multiply the in vitro rates by an experimentally determined
constant which takes into account differences in stirring rate and
fluid volumes between the living body and the in vitro test
apparatus. This constant may be derived in the cast just set forth
by first placing a plurality of small weighed samples of material
in a plurality of uteri and sequentially, over a period of time,
removing and weighing the samples. The rate thus determined,
divided by the rate of erosion observed in vitro with the same
material, equals the necessary constant.
For a more complete understanding of the nature of this invention,
reference should be made to the following examples which are given
merely as further illustrations of the invention and are not to be
construed in a limiting sense.
EXAMPLE 1
A bioerodible intrauterine device containing progesterone is
prepared in the following manner:
A. Preparation of zinc alginate
1. seven grams of sodium alginate (Keltone, Kelco Co., KT-9529-21)
is dissolved in 350 ml of distilled water by means of efficient
stirring, to yield a slightly viscous solution.
2. In a separate preparation, 10 grams of zinc chloride is
dissolved in 600 ml of distilled water and the pH is adjusted to 3
by drop-wise addition of concentrated hydrochloric acid.
3. To the zinc chloride is added in small proportions the sodium
alginate solution under moderate agitation. The mixture is
vigorously stirred for 10-15 minutes, and allowed to stand
overnight.
4. The precipitate is washed continuously with distilled water to a
negative silver chloride test (or to the same conductivity reading
as distilled water). The aqueous suspension of the sodium
chloride-free zinc alginate is isolated by lyophilization and
vacuum-dried at 40.degree.C overnight.
B. Preparation of Progesterone Uterine Insert
1. The mixture containing 1.5 grams of micronized progesterone in
3.5 grams of glycerine is homogenized by means of a suitable
colloid mill or by simple grinding of the mixture with mortar and
pestle.
2. The resulting white paste is slowly poured into 100 ml of 1.2%
ammonium hydroxide solution under vigorous agitation. To this
suspension is added 5 grams of zinc alginate previously prepared,
and the vigorous agitation is continued until the complete
dissolution of the zinc alginate results; if marked thickening
occurs, more ammonia solution can be added.
3. The viscous dispersion of (5) is drawn on a glass plate with a
wet thickness of ca. 10 mils. The cast plate is placed in a
circulating stream of warm, moisturized air at 40.degree.C, and
allowed to dry thoroughly.
4. The resulting film is removed from the plate by stripping, and
is cut into desired shape and size. For example, a 3 mm .times. 10
mm device of 3 mil thickness contains about 0.45 mg of
progesterone. When inserted in a monkey's uterus, the resulting
device releases the drug over a 2-day period.
EXAMPLE 2
Cross-linked gelatin devices containing oxytocin are used for the
induction of uterine contractions and are prepared as follows:
A phosphate buffer is prepared by addition of one liter of
distilled water to 7.1 grams of disodium hydrogen phosphate and 6.9
grams of sodium dihydrogen phosphate monohydrate. The pH is
determined to be 6.8. A solution of 0.9 gm glycerin in 40 ml of the
phosphate buffer is prepared and 0.15 gm chlorobutanol is added.
Upon heating to 90.degree.C and stirring the chlorobutanol is
dissolved. Nine grams of gelatin (Atlantic Pharmagel 250 Bloom Type
A USP) is added slowly with stirring to the above prepared buffer
solution at 90.degree.C. Alternatively, to be more efficient, the
gelatin can be added to the vigorously stirred buffer solution
after it is colled to room temperature and then the mixture heated
at 90.degree.C until solution is complete.
3.1 grams of oxytocin is added to the stirred gelatine solution as
it cools to approximately 50.degree.C. The final mixture is stirred
thoroughly for 4 minutes until the temperature falls to
40.degree.C. It is then poured onto a sheet of polyvinyl chloride
which is flattened against a glass plate after moistening the back
with water. A film is cast with a doctor's blade adjusted for a wet
thickness of 5 mils. The film is allowed to dry by standing at room
temperature one day.
To cross-link the gelatin a solution of 1% formaldehyde by weight
is prepared by addition of 13.1 grams of 38% formaldehyde reagent
to 487 grams phosphate buffer (pH 6.8). This volume is sufficient
for the treatment of the amount of film prepared as described
above. The gelatin films are submerged in this buffered
formaldehyde solution for 20 minutes at room temperature, the
solution is discarded, and the films are rinsed with water quickly
and soaked in ice water for 2 hours. After removal from the ice
water and overnight standing at room temperature, the films are
prepared for cutting by dipping in water for a few minutes. Excess
water is removed and strips are cut from the flexible film and
dried at room temperature for several hours. The strips are 25
millimeters in length, 5 millimeters in width and 0.16 millimeter
thick. They weight about 20 mg and contain about 5 mg of oxytocin.
The strips are glued to the upper inner surface of plastic cervical
rings 2 cm long having outside diameters of 4 cm and inside
diameters of 3.5 cm. These rings are inserted in the cervix uteri
of first trimester pregnant women. The strips gradually erode
releasing oxytocin over a period of about 18 hours thus causing
therapeutic abortion. The rings, which additionally serve to dilate
the cervix when in place, are then removed.
EXAMPLES 3 and 4
An intrauterine device which releases a prolonged flow of
.beta.-estradiol by means of erosion of a body of polymer is
fabricated as follows:
First, a mixture of sodium alginate and .beta.-estradiol is
formed.
1. A paste containing 0.85 grams of micronized .beta.-estradiol and
5.0 grams of glycerine plasticizer is prepared by grinding the
mixture with mortar and pestle.
2. The paste is transferred into a blender containing 0.03 gram
Tween 80 (Atlas Chemical Industries), 150 ml distilled water and
7.5 grams of sodium and stirred to complete solution of the
alginate.
This liquid mixture is then applied to the bottom 3 cm of
conventional Lippes' loops fabricated of 0.2 mm diameter flexible
polyethylene rod. This application is by repeated dipping and
drying at 40.degree.C. 25 milligrams of dried sodium
alginate-plasticizer-.beta.-estradiol are deposited on each loop.
The average deposit thickness is about 0.08 mm. Some of the coated
loops are immersed in a 5.5% by weight zinc chloride solution (pH
4.5) for 5 hours and some are immersed for 5 hours in a 10% alum
(KAl(SO.sub.4).sub.2) solution (pH 3.1) to insolubilize the
alginate. The loops are then washed in a 50% glycerine bath until
there is no evidence of sodium, potassium, chloride or sulfate ions
in the wash.
When the above-coated Lippes' loops are inserted in uteri, they
releast .beta.-estradiol at a controlled and substantially constant
rate. The zinc-containing material erodes over a period of about 6
days, releasing drug at a rate of about 15 micrograms per hour. The
aluminum-containing material erodes over about 15 days, releasing
drug at a rate of about 5 micrograms per hour. At the completion of
therapy, both devices are removed.
EXAMPLES 5 and 6
The preparations of Examples 3 and 4 are repeated with two changes.
First, the amount of .beta.-estradiol in the liquid preparation is
reduced from 0.85 grams to 0.21 grams. Second, the dipping and
drying is continued until 125 milligram deposits are obtained.
These devices release drug at 1/4 the rates of their Example 3 and
4 counterparts, i.e., at 4 and 1.2 micrograms per hour
respectively, but do so for 5 times as long, i.e., 30 days and 75
days respectively.
EXAMPLES 7 - 9
Bioerodible intrauterine devices containing prostaglandins are
prepared as follows:
A solution of gelatin (Atlantic Gelatin Pharmagel, A grade) is
prepared. To three portions of this solution, each containing the
equivalent of 10 grams of dry gelatin, are added respectively: 1.0
grams of the prostaglandin commonly known as PGF.sub.2.sub..alpha.,
0.2 grams of the prostaglandin known as PGE.sub.2 and 0.4 grams of
PGE.sub.2. The drug-gelatin liquid mixtures are then cast on
cellulose triacetate surfaces and dried. The materials are then
stripped and cut into pieces. Pieces of each of the three materials
are placed in 0.05%w formaldehyde (buffered to pH 7.0) at
25.degree.C for 20 minutes to cross-link the gelatin. The
cross-linked product is removed, dried and cut into pieces weighing
about 150 milligrams. When these pieces are inserted in a uterus
(attached to an intrauterine device) they erode at a constant rate
and release respectively:
10 micrograms/minute of PGF.sub.2.sub..alpha.
2 micrograms/minute of PGE.sub.2, and
4 micrograms/minute of PGE.sub.2
all for periods of about 24 hours.
These releases of prostaglandins are sufficient to cause uterine
contractions and are suitable for effecting therapeutic abortion.
Varying the concentration of prostaglandin from about 1% to about
20% basis polymer would give delivery rates of from about 1
.mu.g/minute to about 20 .mu.g/minute.
* * * * *