U.S. patent number 3,887,699 [Application Number 05/102,431] was granted by the patent office on 1975-06-03 for biodegradable polymeric article for dispensing drugs.
Invention is credited to Seymour Yolles.
United States Patent |
3,887,699 |
Yolles |
June 3, 1975 |
Biodegradable polymeric article for dispensing drugs
Abstract
An article for dispensing drugs is disclosed which is formed
from a biodegradable polymeric material and a drug. The drug is
intimately dispersed throughout the polymer and the combination is
formed into a solid, shaped article which controllably dispenses
the drug.
Inventors: |
Yolles; Seymour (Newark,
DE) |
Family
ID: |
26799371 |
Appl.
No.: |
05/102,431 |
Filed: |
December 29, 1970 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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809946 |
Mar 24, 1969 |
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Current U.S.
Class: |
424/477; 424/426;
424/469; 424/482; 424/444; 424/473; 514/177 |
Current CPC
Class: |
A61K
9/2027 (20130101); A61K 9/1647 (20130101); A61K
9/7007 (20130101); A61K 9/0024 (20130101) |
Current International
Class: |
A61K
9/00 (20060101); A61K 9/70 (20060101); A61K
9/20 (20060101); A61K 9/16 (20060101); A61k
027/12 () |
Field of
Search: |
;128/260,335.5BO
;424/141.6,19,22,28,78,32 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Rudel et al. Fertility & Sterility 18;219-222 (1967) "Hormonal
Fertility Control : A Working Hypothesis For Population Control"
.
Kincl et al. J. Reprod. Fertil. 10:105-113 (1965) "Antifertility
Activity of Various Steroids in the Female Rat".
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Primary Examiner: Rose; Shep K.
Parent Case Text
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a continuation-in-part of Yolles, Ser. No.
809,946, filed Mar. 24, 1969 now abandoned.
Claims
What is claimed is:
1. An article for controllably dispensing drugs comprising:
a. a plurality of spheroidal shaped, homopolymers and copolymers of
lactic acid, said polymers being prepared from cyclic esters of
optically active or inactive lactic acids, or mixtures thereof,
having a sufficiently high molecular weight to retain structural
integrity of said spheroids for an effective period of time upon
implantation, with the proviso that crystalline spheroids having
relatively long duration upon implantation are formed from pure
optically active lactic acids and spheroids having rapid release
upon implantation are formed from lactic acid polymers having a
lower degree of crystallinity with
b. an effective amount of a solution of a drug said solution of
drug substantially at the center of said spheroids exuding or
migrating, upon implantation, from the interior to the surface of
the spheroid until said surface is coated with a drug and an
equilibrium is established between the surface layer and the drug
at the interior of the polymeric material such that if the surface
layer is partially or totally removed the equilibrium is destroyed
and further amounts of the drug migrate to the surface until
equilibrium is reestablished so that this cycle repeats itself
until the supply of drug is exhausted.
2. An article according to claim 1 wherein said drug comprises a
contraceptive steroid present in an effective contraceptive
amount.
3. An article according to claim 2 wherein said contraceptive
steroid comprises a progestin.
4. An article according to claim 2 wherein said contraceptive
steroid comprises a combination of a progestin and an estrogen.
5. A method for administering predetermined, effective amounts of a
drug from an implant to a mammal which comprises implanting the
article of claim 1 in a mammal whereby said predetermined effective
amount of the drug is released and administered to said mammal.
6. A method according to claim 5 wherein said drug comprises a
contraceptive steroid present in an effective contraceptive
amount.
7. A method according to claim 6 wherein said contraceptive steroid
comprises a progestin.
8. A method according to claim 6 wherein said contraceptive steroid
comprises a combination of a progestin and an estrogen.
9. A method according to claim 5 wherein said article is implanted
subcutaneously.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates broadly to the controlled release of drugs
to the bloodstream of mammals and more particularly to a shaped
article formed from a biodegradable polymer which contains a drug
so that the article is suitable for implantation in a mammal to
controllably release the drug.
2. Description of the Prior Art
Medical science has long recognized the need for methods to
controllably release therapeutic agents and other drugs to the
blood stream of patients. Recently, a great deal of research has
been initiated in attempting to find new release systems to fulfill
this need. Several such systems have been recommended.
One common method for obtaining controlled release is to envelop
the active substance with coatings which are attacked by digestive
juices in the stomach. This technique has been widely used recently
for time-release analgesics. There are some problems with this
method, however, such as: (1) it is difficult to obtain the proper
distribution of coating thicknesses to give the desired release;
and (2) the sojourn time of the coated agent in the digestive tract
is relatively short, thereby making this method unsuitable for
long-term release.
Another method of obtaining controlled release is to mix the active
substance with various binders such as fats, waxes, and natural or
synthetic polymers to slow down release. Many of the binders,
however, are unsuitable for use with many drugs. Furthermore, these
combinations of binders and drugs tend to disperse quickly after
they enter the body due to the binder's solubility in body fluids,
the washing effect of the body fluids and/or the attack of
digestive juices. After the binder has been so dispersed, all
control over the release of the drug is lost.
Other researchers have even suggested that drugs be chemically
modified to affect their release and absorption into the
bloodstream. The degree of difficulty of this method for obtaining
controlled release is clear.
More recently, the possibility of somehow incorporating drugs into
polymeric materials to control drug release has been considered.
Thus Furuse et al., U.S. Pat. No. 3,514,517, teach that
suppositories containing spermicidal agents can be formed by
blending the agents with low molecular weight polyethylene glycols;
Hill, U.S. Pat. No. 3,458,622, teaches that tablets for controlling
the release of medicinal agents for up to 8 hours can be formed
from a blend of a polymeric vinyl pyrrolidone with a carboxy vinyl
hydrophilic polymer; Weil et al., U.S. Pat. No. 3,469,005, teach
that drugs for reducing blood pressure in mammals can be
incorporated into solid vehicles such as lactose, cornstarch,
microcrystalline cellulose, talc, stearic acid, magnesium stearate,
gums, etc.; Merabi et al., U.S. Pat. No. 3,495,000, have found that
controlled release matrices can be prepared consisting of a
dialdehyde starch and ethyl cellulose, polyvinyl chloride or
polyvinylpyrrolidone, but that mixtures of the same starches with
other pharmaceutically acceptable polymers such as methylcellulose
or carboxymethylcellulose do not yield compositions suitable for
controlled release; and Herrmann, U.S. Pat. No. 2,155,658, teaches
that medical preparations for injection into the body which are
flowable above body temperature but solid at body temperature after
injection can be made from polymerized vinyl alcohols and their
water soluble derivatives and a solvent for such material.
Another technique for incorporating drugs into polymeric matrices
is described in Levesque, U.S. Pat. No. 2,987,445 and in Endicott,
U.S. Pat. No. 3,087,860. These patents teach a drug dispenser
formed from synthetic polymers containing solid particles of a
water-leachable drug. Usually the polymer matrix is shaped in the
form of a pill which is intended to be orally ingested. This drug
dispenser is limited, however, to watersoluble drugs and has
relatively short release times, i.e., typically 8-12 hours.
While the above-mentioned patents describe various mixtures of
drugs with polymers, Long et al. have taught another method for
constructing a controlled release device from polymers in U.S. Pat.
No. 3,279,996. Long et al. form a capsule or container from
polysiloxane which is intended for implantation. This device has
the advantage of making extended time-release treatment possible,
but suffers a disadvantage since the possibility exists that the
polysiloxane container will develop pinholes or a rupture resulting
in an undesired and potentially harmful large amount of drug being
released almost instantaneously.
A polymeric drug dispenser formed from crystalline polymeric
materials is disclosed in my copending application Ser. No. 102,432
filed concurrently herewith. The device described therein offers
many improvements over existing controlled release devices, but
suffers a disadvantage when subcutaneously implanted since the
polymers described therein are not biodegradable. Thus, a separate
removal step often necessitating minor surgery is required. This
invention overcomes that problem.
SUMMARY OF THE INVENTION
A drug dispersed in a biodegradable polymeric material can be
formed to a solid shape which will unexpectedly exude the drug to
the surface of the polymeric article. For purposes of this
description, the term exude is used to mean the migration from the
interior of the polymeric material to its surface until the surface
is covered with a layer of the drug and an equilibrium is
established between the surface layer and the drug at the interior
of the polymeric material. If the surface layer is partially or
totally removed, the equilibrium is destroyed and further amounts
of the drug permeate to the surface until equilibrium is
re-established. This cycle will repeat itself until the supply of
drug has been exhausted from the polymeric material. The surface
layer can be removed in many ways, including but not limited to:
rubbing it off; brushing it off; washing it off; dissolving it off;
etc.
Relying upon this discovery, a novel article for dispensing drugs
has been invented which comprises:
1. a biodegradable polymeric material formed to a solid shaped
article; and,
2. a drug substantially uniformly and intimately dispersed
throughout portions of the polymeric article.
This drug dispenser has the same advantages over prior art
dispensers as the dispenser described in my above-mentioned
copending application. For example, this drug dispenser provides an
economical and reliable method for automatically dispensing
controlled quantities of a drug over a short or an extended period
of time. Such a device can be implanted within a mammal's body so
that it will dispense the required amounts of one or more drugs
continuously over extended periods of time without the patient
having to rely on periodic injections or oral ingestion of drugs.
Once implanted, the dispenser can be forgotten and the patient can
rest assured that his body is continuously and automatically
receiving the prescribed amount of drug.
A particularly unique advantage of this device is found in the
types of therapy where it is desirable to insure that a patient
receives a certain amount of a drug, and it is desirable to place
control of administering the drug beyond the patient. This obviates
the possibility that the patient will forget to administer the
drug. It also prevents the patient from deliberately not
administering the drug on his own volition, which has heretofore
been a serious problem in many types of medical treatment. Once
implanted, the drug dispensing devices of this invention are
effectively out of the control of the patient.
A most important advantage of the polymeric drug dispenser
described herein is the degree of flexibility which can be obtained
in administration techniques. As stated above, one suitable method
for releasing the drug from this device to a mammals bloodstream is
to subcutaneously implant the device. There are many other methods,
however. For example, the device can be extruded into the shape of
thin "spaghetti" which can be injected into the bloodstream, or the
polymeric material can be formed into various sized spheroids for
ingestion or injection by a patient. Additionally, the polymeric
material can be formed into hollow tubing suitable for catheters.
In short, the dispenser of this invention can be formed into
limitless solid shapes each suitable for particular methods of
controllably releasing a drug to the patient's bloodstream.
As mentioned above, the drug dispenser described herein has the
additional advantage of a biodegradable polymeric matrix. It should
be clear that this is particularly important when the device is
subcutaneously implanted .
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graphical representation of the controlled release of
the drug cyclazocine from three devices of this invention to the
bloodstream of rats;
Figs. ii (a)-( c) are perspective views of some of the variety of
shapes of controlled-release, biodegradable drug dispensers of this
invention;
Fig. iii is a perspective view showing the subcutaneous
implantation of a controlled release film device of this invention
into the back of a rat.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The polymeric materials used to manufacture the instant device must
have high melting points so that they won't soften when exposed to
fairly high temperatures such as those encountered with human body
fluids. Preferably the material will have a melting point of
100.degree.C. or more so that the device can be sterilized at high
temperatures.
A further limitation on suitable polymeric materials is that they
be biodegradable. The term "biodegradable" is used to mean
materials which are attacked and broken down into simpler chemical
species by substances found in mammals such as enzymes.
Some naturally occurring polymers such as sugar phosphates are
known to be biodegradable.
Synthetic polymers can also be prepared which are biodegradable.
Examples include polylactides and polyglycolic acid. These are the
preferred biodegradable polymers for use in this invention because
they are broken down into innocuous products like carbon dioxide
and water and because they are commercially available.
Useful polylactides include both homopolymers and copolymers.
Usually, these polylactides are prepared from the cyclic esters of
lactic acids. Both L(+) and D(-) forms of lactic acid may be used
to prepare the polylactides as well as the optically inactive
DL-lactic acid mixture or any desired mixtures of D(-) and L(+)
lactic acids.
Lactide copolymers offer an important degree of flexibility in
choosing the life of a polymer matrix since this can be controlled
through the amount and type of comonomer used. Some illustrative
examples of suitable comonomers include: glycolide,
.beta.-propiolactone, tetramethylglycolide, .beta.-butylrolactone,
tetramethylglycolide, .beta.-butyrolactone, gamma-butyrolactone,
pivalolactone, and intermolecular cyclic esters of
.alpha.-hydroxybutyric acid, .alpha.-hydroxyisobutyric acid,
.alpha.-hydroxyvaleric acid, .alpha.-hydroxyisovaleric acid,
.alpha.-hydroxycaproic acid, .alpha.-hydroxy-.alpha.-ethylbutyric
acid, .alpha.-hydroxyisocaproic acid,
.alpha.-hydroxy-.beta.-methylvaleric acid, .alpha.-hydroxyheptanoic
acid, .alpha.-hydroxyoctanoic acid, .alpha.-hydroxydecanoic acid,
.alpha.-hydroxymyristic acid, .alpha.-hydroxystearic acid,
.alpha.-hydroxylignocenic acid, and .beta.-phenyllactic acid.
Methods of preparing polylactides are well documented in the patent
literature. The following U.S. Pat. Nos., the teachings of which
are hereby incorporated by reference, describe in detail suitable
polylactides, their properties and their preparation: Dorough,
1,995,970; Schneider, 2,703,316; Salzberg, 2,758,987; Zeile,
2,951,828; Higgins, 2,676,945; 2,683,136; Trehu, 3,531,561; British
Patent specification Nos. 755,447; 779,291; 825,335; 901,037;
932,382; 1,048,088; 1,123,445; West German Pat. Nos. 946,664;
975,191; 1,112,293; 1,152,258; 1,153,902; East German Pat. Nos.
14,548; French Pat. Nos. 1,425,333; 1,478,694; 1,512,182;
Netherlands Pat. No. 99,836; Netherlands Patent application Nos.
6,605,197; 6,605,292; Japanese Nos. 17,675 (1966); 7,796 (1967);
2,948 (1968); 15,789 (1969).
Polyglycolic acids have recently been found to possess excellent
biodegradable properties. Polyglycolic acid is the homopolymer of
glycolic acid (hydroxyacetic acid). In the conversion of glycolic
acid to polyglycolic acid, glycolic acid is initially reacted with
itself to form the cyclic ester glycolide, which in the presence of
heat and a catalyst is converted to a high molecular weight
linear-chain polymer. Polyglycolic acids and their properties are
described in more detail in the following article, the teachings of
which are hereby incorporated by reference: "Cyanamid Research
Develops World's First Synthetic Absorbable Suture"; Chemistry and
Industry, July 11, 1970, page 905.
The molecular weights of polypeptides and polyglycolic acid are
closely related to both the exudation of the drug and the
biodegradation of the matrix. It has been found that high molecular
weights, i.e., Mw=90,000 or higher result in polymer matrices which
retain their structural integrity for longer periods of time; while
lower molecular weights, i.e., Mw=30,000 or below, result in both
slower exudation and shorter matrix lives.
Crystallinity also affects the exudation and biodegradability
rates. The polymer matrices having higher degrees of crystallinity
have slower exudation rates and slower biodegradability. It is
known, of course, that crystallinity has a marked effect on
physical properties. See Flory, Paul J., Principles of Polymer
Chemistry, 5th printing, 1966 at pages 49 et seq. It has also been
reported in the literature that gaseous diffusion through polymeric
membranes is slower, in general, for those polymers having higher
degrees of crystallinity than for those with lower degrees of
crystallinity. See Michaels, A. S. and Bixler, H. J., "Flow of
Gases through Polyethylene and Rubbery Polymers," J. Poly. Sci.,
vol. 50, pages 413-439 (1961).
A good amount of control over the release of drug can be obtained
by choosing appropriate molecular weights and degrees of
crystallinity in the polymer matrix. For example, if a relatively
long release duration is desired, a high molecular weight polymer
formed from a pure optical isomer of lactic acid can be used for
the matrix; on the other hand, if a rapid release rate is desirable
over a short duration, a low molecular weight lactide copolymer
having a lower degree of crystallinity can be synthesized for use
as the polymer matrix. Those skilled in the art will know or be
able to determine by routine experimentation many suitable
combinations of molecular weights and degrees of crystallinities of
polylactides or polyglycolic acid to accomplish a desired release
rate and duration.
Surprisingly, it has also been found that the drug release rate can
be controlled at the time the polymer matrix is formed into a
shaped article. This can be seen from the data presented in Example
I. The release rate for poly(L-)lactide films is faster for films
pressed at lower temperatures than for films pressed at higher
temperatures.
Using one or more of the above parameters, polymeric matrices can
be designed which have a great variety of exudation rates and
biodegradability. Matrices can be synthesized to have lives shorter
than, equal to or longer than the period of effective drug
delivery. For the shorter matrix lives, drug delivery will be
accomplished by a combination of drug exudation and matrix
biodegradation; for the longer matrix lives, drug delivery will be
substantially dependent on only drug exudation. The degree of
flexibility thus offered in designing drug dispensing systems of
this invention is of great significance.
The biodegradable polymeric materials described above have drugs
incorporated in them to form the article of this invention. The
term drug is used in this description in its broadest sense and
covers drugs useful to any mammals including, but not limited to,
human beings, wild animals, household animals, and animals raised
for their meat or other products such as farm animals and cattle.
The term drug is further used in describing this invention to
include, but not limited to, the following classes of drugs: (1)
therapeutic drugs; (2) preventative drugs; and, (3) diagnostic
drugs. It should be understood that a variety of classes,
subclasses, and specific examples of drugs not expressly mentioned
herein are within the scope of this invention, and these other
drugs will be well known or easily ascertainable to those skilled
in the art.
Some specific examples of drugs which can be incorporated in
crystalline polymers to form a device of this invention are
described infra.
As is well known, people suffering from sugar diabetes are required
to take daily doses of diabetes control agents. Insulin or the
active ingredients in some of the commercially available control
agents such as tolbutamide ("Orinase" by Upjohn), chloropropamide
("Diabinese" by Pfizer) and tolazamide ("Tolinase" by Upjohn) could
be dispensed with an article of this invention.
Many drugs are presently being used to treat rheumatoid arthritis
and other forms of arthritis. These include, but are not limited
to, narcotic pain relievers, gold salts, corticosteroids,
adrenocorticotropic hormones, phenylbutazone and its derivatives,
antimalarials, and indole derivatives. A comprehensive listing of
specific drugs used to treat the various forms of arthritis is
given in the Aug. 12, 1968 edition of Chemical and Engineering News
at pages 54 and 55, which listing is herein incorporated by
reference. These drugs could be dispensed with the instant
article.
Antibiotics are a further group of drugs which can be dispensed.
Some examples of suitable antiobiotics include the tetracyclines,
penicillan, streptomycin, and aureomycin.
Deworming and distemper drugs such as those given to household pets
and/or cattle are another group of drugs capable of being dispensed
by the device of this invention. An example of such a drug is
phenothiazine.
Sulfur drugs such as sulfisoxazole diolamine ("Gantrisin" by Roche
Laboratory), useful in treating urinary tract infections, could
also be exuded from a crystalline polymeric article.
Another group of drugs suitable for use in the crystalline
polymeric articles are the cancer-control agents. An example would
be the drugs or combinations of drugs useful for treating leukemia
such as the nitrogen mustard p-(di-2-chlorethyl)
amino-phenylbutyric acid.
Two further groups of drugs which could be advantageously dispensed
with the hereindescribed device are alcohol-addiction control
agents and tobacco-smoking addiction control agents.
Closely related are the addictive drug antagonists. If an addictive
drug such as heroin, morphine, codeine, neopine, etc. is taken
while the blood still contains the antagonist, the addictive drug
will pass through the body and be harmless to the taker in the
sense that the taker will not experience "a high" and the drug will
not be addictive. Such antagonists have offered a very successful
method for treating drug addicts while the addicts are at clinics;
however, it has been noted that once an addict returns to his
original environment, and is out of control of the clinic, he is
likely to stop taking the antagonist and resume taking one of the
addictive drugs. For this reason, the article of this invention
offers unique advantages in treating drug addicts by this method
since such an article containing an antagonist could be implanted
within the addict's body, thereby giving him no control over the
administering of the antagonist. This will extend the addict's
period of cure beyond the time that he can actually be confined to
a clinic. Some examples of specific drug antagonists suitable for
incorporation into the polymeric dispenser include
N-allylnoroxymorphone ("Naloxone" ) and
2-cyclopropylmethyl-2'-hydroxy-5, 9-dimethyl-6,7-benzomorphone
("Cyclazocine"). Other drug control agents such as "Methadone" can
also be used.
Two further groups of closely related drugs are the thyroid gland
regulating drugs and weight-control drugs. Here again, there is a
particular advantage to the use of the polymeric dispenser since
such a device can be implanted within the body of the patient and
thereby supply the required amount of drug without the patient
having any control over this. Also, it is known that these types of
drugs are extremely dangerous when taken in large doses, and the
use of this device would help assure that an overdose did not get
into the patient's bloodstream.
Another group of drugs which could be dispensed are the analgesic
drugs. These drugs have little or no therapeutic effect, but serve
to lessen or eliminate the severe pain often encountered with many
diseases or operations. For example, in the cases of chest cancer,
morphine or codeine are often prescribed. Also, for patients
suffering from cancer of the prostate glands, progesterone is often
prescribed. One particularly advantageous use of the polymeric
dispenser would be in serious surgical operations which result in
severe pain to the patient after the operation is completed and the
patient regains consciousness. In these cases, the body is going to
be opened for the operation, and a device of this invention
containing a pain killer could be inserted into the body during the
operation to ease the pain to the patient during the recovery
period. Of course, there are many other types of analgesic drugs
and many other examples of when such drugs could be used which will
be apparent to those knowledgeable in the field of medicine.
Another group of drugs suitable for being dispensed from the
polymeric article are the hormone-regulating drugs to aid
fertilization or to act as contraceptives. One preferred embodiment
using hormone-regulating drugs is formed using the active
ingredients in oral contraceptives. The advantage is that a device
containing the active ingredients of oral contraceptives could be
designed to last over extended periods of time thereby relieving
the taker from a daily routine of orally taking the contraceptives.
Suitable examples of the active ingredients in oral contraceptives
include a progestin or a combination of a progestin and an
estrogen. For example, a homogeneous dispersion of the active
ingredient in "Norethindrone" and "Mestranol" in a ratio of 20:1 by
weight could be prepared and incorporated into the solid polymeric
material. Other examples of synthetic progesterones and estrogens
suitable for use with this invention include: Norethynodrel,
Medroxyprogesterone acetate, Dimethisterone, Ethynodiol diacetate,
and Chlormadinone acetate, Norethindrone acetate and
Ethynylestradiol.
Other drugs which can be incorporated in the systems of this
invention include: drugs for reducing blood pressure such as those
described in U.S. Pat. NO. 3,469,005; pharmaceutical compositions
for the control of appetite such as the combinations of
amphetamines and thioridazines described in U.S. Pat. No.
3,495,005; and, agents for treating psychosis in mammals such as
those described in U.S. Pat. No. 3,495,007.
The above listing of drugs is not intended to be comprehensive, but
merely representative of the wide variety of drugs which can be
used with this invention. Those skilled in the art will know or be
able to determine by routine experimentation that many other
specific drugs are also suitable.
The amount of drug dispersed in the polymeric article will depend,
of course, on many factors including the specific drug, the
function to be accomplished, the length of time it is desired to
dispense the drug, the amount of drug to be dispensed in a
specified time, the size of the device, and many other factors. In
general, amounts ranging from about 0.5 percent to about 50 percent
by weight of the polymeric material can be incorporated.
Particularly good results can be obtained with from at least about
10 percent to about 20 percent,
The amount of drug to be dispensed in a specified time, will of
course, depend on such factors as the particular application, the
particular drug, the age of the patient, etc. In general, what will
constitute an "effective amount" will be known or easily
ascertainable by those skilled in the art. Much of this type of
data is published in the literature or easily determined by routine
experimentation. Examples of the published literature on effective
amounts of progestin-type steroids, in this case for topical
application, can be found at: Shipley, "Effectiveness of Topical
Application of a Number of Progestins," Steroids 5(5): 699-717, May
1965; and Ringler, "Efficacy of Topically Applied Progestational
Agents," Steroids 7 (4): 341-349, April, 1966. In a like manner,
the following literature describes effective amounts of addictive
drug antagonists: Martin, W. R., "Opioid Antagonists,"
Pharmacological Reviews, vol. 19, no. 4, pages 463-521 (1967) and
references contained therein; Freedman, A. M., "Cyclazocine and
Methadone in Narcotic Addiction," The Journal of the American
Medical Association, October 16, 1967, vol. 202, pages 191-194.
Also, the patents mentioned above often contain data on effective
amounts for any particular application.
In addition to the control over delivery of drug which can be
obtained through proper choice and design of the polymer matrix as
discussed supra, the dosage administered by this dispenser can be
controlled by the size and shape of the article, concentration of
the drug in the polymer, surface area, pore size, matching of the
polymer and drug, nature of the surroundings, etc. This is a
particular advantage where it is desirable to deliver a metered
amount of the drug over a specified period of time.
Of course, combinations of drugs and substances in addition to
drugs can also be incorporated into the polymeric material. For
example, radioactive tracers such as carbon-14, nonradioactive
tracers such as barium sulfate, carriers which would transport the
drug through skin such as dimethylsulfoxide and dimethylsulfone,
water-soluble excipients, etc. could be incorporated with certain
drugs for particular applications. The amount of auxiliary agent
used will depend, of course, on the specific agent, drug and
polymer used to fabricate the article as well as the purpose for
incorporating the auxiliary agent.
As has been described, the polymeric article dispenses the drug it
contains by exuding it to the surface of the article. The mechanism
of how the drug enters the body from the polymer surface is not
critical and can be accomplished with a variety of techniques. For
example, the article may be placed upon a person's body in contact
with the skin so that the particular drug could be absorbed through
the person's skin into the bloodstream. An alternative technique is
to implant the device within the patient's body at a location where
the surface layer of drug will be in contact with any of the
various body fluids or tissue so that the drug could be dissolved
and/or carried away by such body fluids or rubbed off and absorbed
by the tissue. Subcutaneous implantation of a film drug dispenser
under the skin on the back of a rat is shown in FIG. III; a more
detailed description of such implantation techniques is presented
in the Example. Intramuscular implantation is also contemplated.
Still another technique would be to prepare the article for use in
the patient's mouth so that the saliva would carry the drug into
the body. In certain cases, it might be advantageous to insert the
dispenser in other body cavities such as the uterus. Other
techniques for getting the material from the surface of the article
into the body will be readily apparent to the medical
profession.
The dispensing articles described herein can be formed by
pre-mixing the polymer, drug and any auxiliary agents to be
incorporated with the drug and then following conventional
techniques to shape and set the article. For example, the polymer
and drug can be mixed together in a suitable solvent until a
homogeneous solution is formed. After driving off solvent, the
residue can be molded, extruded, etc. to the desired shape. Another
method of forming the dispenser might be to compact at elevated
pressures a dry mixture of drug and polymer. Also, monomer and drug
can be mixed with subsequent polymerization of the monomer.
Another method of forming the drug dispensers is to soak a
previously shaped piece of polymeric material in a solution of the
drug to be incorporated, and subsequently drying the surface of the
article. This technique must be distinguished, however, from simply
dipping a polymeric article in a solution to coat the surface of
the article with a substance. In the soaking technique of this
invention, the conditions, i.e., solvent, polymer, temperature,
etc., must be carefully chosen to insure that the active ingredient
penetrates deeply into the polymer matrix instead of remaining only
on the surface or penetrating a small distance below the surface as
a coating does. One way to accomplish the desired deep penetration
is to choose a solvent which causes the polymer to swell in the
solution of drug. Some solvents cause swelling at room
temperatures; others require elevated temperatures. Once the
polymer has swollen, solvent and active ingredient can penetrate
deeply into the polymer matrix. With rapid cooling, the polymer
returns its non-swollen condition trapping solvent and active
ingredient within it. If the solvent chosen is highly volatile,
while the active ingredient is not, the solvent can be driven out
of the article by continuous pumping, i.e., exposing the article to
reduced pressures. Those skilled in the art will be able to select
appropriate conditions for carrying out this technique.
Other methods for making the polymeric dispensing articles will be
apparent to those skilled in the art.
An important feature of the dispenser, which results from the way
it is prepared, is that there is a substantially intimate and
uniform dispersion of drug throughout the polymer. This is to be
contrasted with a foraminous plastic matrix containing discrete
solid particles of a drug only within the voids, such as described
in U.S. Pat. Nos. 2,987,445 and 3,087,860. In these patented
systems, drug release is predicated upon water or other liquids
leaching the drug from the voids; in the dispenser of this
invention, drug release is predicated upon exudation of the drug to
the polymer surface.
Another important feature of the dispenser, which also results from
the way it is prepared, is that the dispenser can be made to have
"structural integrity". This means that the shaped dispenser will
remain intact after prolonged exposure to body fluids. Although it
is difficult to list all of the factors which contribute to the
structural integrity, some include: substantial non-solubility and
non-swellability in water or body fluids; relatively high tensile
strengths; and good elongation at break and tensile modulus.
Additionally, the polymeric matrices of this invention do not
soften appreciably at temperatures as high as 100.degree.C. as many
of the prior art waxy binders do.
A test to establish structural integrity is as follows. The shaped
drug carrier is immersed in distilled water at 37.degree.C. for 7
days. After this period, weight loss of carrier and dimensional
changes of carrier should be less than 10 percent of their original
values. The polymeric matrices of this invention meet this
test.
The shape of the dispenser will depend on its intended use. Any
shape is within the scope of this invention. Some possible and
preferred shapes are illustrated in FIG. 11 wherein (a) illustrates
a film, (b) illustrates a piece of hollow tubing, and (c)
illustrates various sized solid spheroids which could be injected
into a patient or orally ingested by the patient. Other shapes
contemplated but not shown include solid "sphagetti-like" and
"fiber-like" configurations and a mesh configuration which would be
expected to minimize the possibility of a device subcutaneously
implanted causing blood clotting. Another embodiment comprises a
sphere formed from an outer coating of polylactide with a solution
of drug at the center.
As is evident from the forgoing discussion, the article of this
invention has many uses, all of which fall within the general
utility of dispensing drugs to mammals.
The following Example serves to further illustrate the invention.
All parts and percentages are by weight, unless otherwise
specified.
EXAMPLE I
IMPLANT PREPARED FROM A POLYLACTIDE FILM CONTAINING CYCLAZOCINE
Six grams of polylactide with a molecular weight of about 40,000
prepared from L(-) lactide according to Example I of British Patent
specification 1,040,168 is dissolved in 250 milliliters of
chloroform. Three grams of tributylcitrate and 2.25 grams of
cyclazocine are added to the hot stirred solution. This is followed
by the addition of five milliliters of a trace of radioactive
cyclazocine to monitor drug release. The solution is evaporated to
about one-half its original volume and poured onto glass plates.
The residue on the plate is air-dried for 20 minutes and oven-baked
at 100.degree.C. for 1/2 hour. Films are prepared by pressing the
dried material between sheets of aluminum foil on a Carver press at
140.degree.C., 135.degree.C., and 130.degree.C., all at 10,000
p.s.i.
Pieces of a film prepared as above were cut into two centimeter
square areas. Some pieces were weighed, combusted and radioassayed
to provide a measure of the concentration of radioactivity present
in each piece. Other pieces of the same film were implanted
subcutaneously in the backs of rats under light ether anesthesia.
The stab wounds were sutured and remained so until the end of the
experiment at which time the wounds were reopened and remaining
implants were removed for final radioassay. Little remained of
initial implant, after 62 days.
The rats were placed in Acme metabolism cages for 62 days for the
separation and collection of urine and samples. Total daily urinary
radioactivity was measured daily for the first ten days and every
four days thereafter. This was accomplished by liquid scintillation
techniques and the data was reported as "percent of dose excreted
per day" and also as "cumulative percent of dose." The final
radioassay indicated that all of the cyclazocine was released from
each device in each rat.
The results are presented in Table I.
TABLE I
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% CYCLAZOCINE RELEASED, CUMULATIVE
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Film Pressed at 140.degree.C. Day: 1 2 3 4 5 6 7 8 9 10 11 12 13 14
15 16 17 18 19 20
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Rat: A 6.9 11.9 14.9 16.1 17.0 18.0 18.7 19.4 20.0 20.7 21.0 21.3
21.6 21.9 22.2 22.5 22.8 23.1 23.4 23. B 4.4 7.7 9.2 10.5 11.6 12.3
13.5 14.3 15.4 16.7 17.3 17.9 18.5 19.1 19.3 19.5 19.7 19.9 20.1
20. C 0.8 4.1 6.1 7.5 9.3 10.5 11.3 12.3 13.3 14.1 14.6 15.1 15.6
16.1 16.6 17.1 17.6 18.1 18.3 18. Film Pressed at 135.degree.C.
Day: 1 2 3 4 5 6 7 8 9 10 Rat: D 38.0 63.6 76.9 78.4 80.8 81.5 81.8
82.2 82.4 82.5 E 17.0 32.0 39.3 45.1 50.0 53.6 56.8 60.2 63.4 65.9
F 14.0 24.3 25.3 28.2 32.1 34.6 37.7 40.1 41.5 42.5 Film Pressed at
130.degree.C. Day: 1 2 3 4 5 6 7 8 9 10 Rat: G 30.7 62.4 81.9 89.0
89.5 89.8 90.0 90.2 90.5 91.7 H 15.2 37.0 58.6 75.5 83.8 84.6 84.8
84.9 85.1 85.8 RAT AND IMPLANT DATA Initial Initial Implant Initial
Weight gm. Weight, gm. DPM Rat A 645 0.0671 1,970,000 B 520 0.0708
2,080,000 C 350 0.0732 2,150,000 D 690 0.0512 1,475,000 E 670
0.0548 1,580,000 F 530 0.0690 1,990,000 G 520 0.0791 2,070,000 H
580 0.0942 2,450,000
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