U.S. patent number 3,625,214 [Application Number 05/038,237] was granted by the patent office on 1971-12-07 for drug-delivery device.
This patent grant is currently assigned to Alza Corporation. Invention is credited to Takeru Higuchi.
United States Patent |
3,625,214 |
Higuchi |
December 7, 1971 |
DRUG-DELIVERY DEVICE
Abstract
A drug-delivery device for prolongedly delivering drugs to
patients according to any predetermined time release profile, e.g.,
increasing, decreasing, constant, pulsing, sinusoidal, and like
patterns of release, is fabricated by applying a drug coating of
varying or uniform thickness to a relatively drug-impermeable film
soluble in body fluids and thence rolling said coated film about
itself in spiral or "jellyroll" fashion. Upon administration to the
body, the outermost extremities of the film gradually erode at a
predetermined rate in body fluids thus exposing coextensive
extremities of the drug coating, also soluble in body fluids, and
drug is released to the tissues of the body. Suitable design of the
drug coating along the spiral, e.g., of varying thickness, etc.
provides for the aforesaid release patterns as the device
disintegrates.
Inventors: |
Higuchi; Takeru (Lawrence,
KS) |
Assignee: |
Alza Corporation (N/A)
|
Family
ID: |
21898792 |
Appl.
No.: |
05/038,237 |
Filed: |
May 18, 1970 |
Current U.S.
Class: |
424/424; 424/426;
424/427; 424/434; 424/436; 424/472; 424/433; 424/435; 424/443;
424/484 |
Current CPC
Class: |
A61M
31/002 (20130101); A61K 9/2086 (20130101); A61K
9/70 (20130101); A61D 7/00 (20130101); A61K
9/2072 (20130101) |
Current International
Class: |
A61D
7/00 (20060101); A61K 9/70 (20060101); A61K
9/20 (20060101); A61M 31/00 (20060101); A61m
007/00 () |
Field of
Search: |
;128/260-264
;424/14,19,21 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Mancene; Louis G.
Assistant Examiner: Weinhold; D. L.
Claims
What is claimed is:
1. A drug-delivery device for prolongedly delivering drugs
according to any predetermined time release profile comprised of a
spirally rolled substrate, said substrate being comprised of a
relatively drug impermeable, flexible film erodible in body fluids
and being coated with a drug-containing matrix composition, which
matrix itself is erodible in body fluids.
2. The drug-delivery device as defined by claim 1, wherein the
matrix composition is more rapidly erodible in body fluids than
said film.
3. The drug-delivery device as defined by claim 1, wherein the drug
is uniformly distributed throughout the matrix composition.
4. The drug-delivery device as defined by claim 3, wherein the drug
coating is of constant thickness along the spiral.
5. The drug-delivery device as defined by claim 3, wherein the drug
coating is of varying thickness.
6. The drug-delivery device as defined by claim 3, wherein the
thickness of the drug coating increases along the spiral.
7. The drug-delivery device as defined by claim 3, wherein the
thickness of the drug coating decreases along the spiral.
8. The drug-delivery device as defined by claim 3, wherein the drug
coating is of sinusoidal thickness along the spiral.
9. The drug-delivery device as defined by claim 5, wherein the film
is comprised of a polymeric material which slowly dissolves in body
fluids.
10. The drug-delivery device as defined by claim 3, wherein the
film is comprised of polymeric material which hydrolyzes in body
fluids.
11. The drug-delivery device as defined by claim 3, wherein the
membrane is comprised of polymeric material which is cleaved by
enzymes present in body fluids.
12. The drug-delivery device as defined by claim 1 bearing an
external coating of said drug-containing matrix composition.
13. A device for prolongedly delivering active ingredient to a
given fluid environment according to any predetermined time release
profile comprised of a spirally rolled substrate said substrate
being comprised of a relatively active ingredient impermeable,
flexible film erodible in a given fluid environment, said film
being coated with an active ingredient containing matrix
composition, which matrix itself is erodible in said given fluid
environment.
14. The method of prolongedly delivering drug to a patient
according to any predetermined time release profile comprising
administering to said patient the drug-delivery device as defined
by claim 1.
Description
BACKGROUND OF THE INVENTION
This invention relates to a device for delivering drugs to patients
according to a programmed schedule and, more especially, to a
device which can deliver drugs according to any desired program of
release which may be therapeutically desired.
In the pharmaceutical field, most prolonged or sustained action
medicators have had as their objective to release medication at a
constant rate. However, many programs of therapy require that the
quantity of medication administered vary with time. For example, in
antibiotic therapy, it is common to administer a large initial dose
of drug followed by smaller doses. Conversely, in desensitizing
against allergens, therapeutic regimes often call for dose of the
allergen to progressively increase over the time of treatment. More
complex regimes, in which the dose of medication varies through
periodic high and low points, are also known. In general, these
therapeutic programs are practiced by periodically administering
different amounts of medication in separate dosage forms. Such
practice requires frequent acts by the patient or trained attendant
and departures from the therapeutic program often occur. Thus, a
need exists for a drug-delivery device that can provide any desired
time profile for drug administration.
SUMMARY OF THE INVENTION
Accordingly, it is a primary object of this invention to provide a
device for delivering drugs to patients according to any
predetermined time release profile.
In attaining the objects of this invention, one feature resides in
the application of a drug coating of varying or uniform thickness
to a relatively impermeable film soluble in body fluids. To provide
the drug-delivery unit, the coated film is spirally wound or rolled
about itself in "jellyroll" fashion. When the device is physically
inserted or implanted in the body or administered via the
gastrointestinal tract, the film gradually erodes or dissolves at a
predetermined rate in body fluids thus exposing the drug coating.
By suitable design of the film and of the drug coating, which
itself dissolves in body fluids, one can obtain any desired release
pattern including increasing, decreasing, pulsing, constant,
sinusoidal, etc.
Other objects, features and advantages of this invention will
become more apparent from the following description when taken in
conjunction with the accompanying drawings, and wherein like
reference numerals are used to indicate like or equivalent
parts.
BRIEF DESCRIPTION OF THE DRAWINGS
In the drawings:
FIG. 1 is a side view of the coated substrate precursor structure
of a drug-delivery device of this invention;
FIG. 1a is a top view of a drug-delivery device of this invention,
formed from the structure of FIG. 1;
FIG. 1b is a side view of the structure of FIG. 1a;
FIG. 2 is a side view of a coated substrate precursor structure of
another drug-delivery device of this invention;
FIG. 2a is a top view of another drug-delivery device of this
invention, formed from the structure of FIG. 2;
FIG. 2b is a top view of another drug-delivery device of this
invention, also formed from the structure of FIG. 2;
FIG. 2c is a side view of the structures of both FIG. 2a and FIG.
2b;
FIG. 3 is a side view of a coated substrate precursor structure of
yet another drug-delivery device of this invention;
FIG. 3a is a top view of yet another drug-delivery device of this
invention, formed from the structure of FIG. 3;
FIG. 3b is a side view of the structure of FIG. 3a;
FIG. 4 is a side view of a coated substrate precursor structure of
still another drug-delivery device of this invention;
FIG. 4a is a top view of still another drug-delivery device of this
invention, formed from the structure of FIG. 4;
FIG. 4b is a side view of the structure of FIG. 4a;
FIG. 5 is a top view of still another drug-delivery device of this
invention;
FIG. 6 is a side view of still another drug-delivery device of this
invention;
FIG. 7 is a side view of still another coated substrate precursor
structure of another drug-delivery device of this invention;
FIG. 7a is a top view of still another drug-delivery device of this
invention, formed from the structure of FIG. 7; and
FIG. 7b is a side view of the structure of FIG. 7a.
DETAILED DESCRIPTION OF THE INVENTION
This invention has for its essence an assemblage of relatively
impermeable film separating slowly soluble, medicament-containing
matrix composition. Referring particularly to FIGS. 1 and 1a, a
relatively impermeable film 10 is shown which dissolves at a slow
predetermined rate in body fluids. The film 10 is coated with a
medicament 11 containing matrix composition 12 of constant
thickness, which matrix is soluble in body fluids (FIG. 1).
The coated film is next spirally wound or rolled about itself in
"jellyroll" fashion to provide the drug-delivery device 13 of FIGS.
1a and 1b.
To use the drug-delivery device of this invention, it is either
physically inserted or surgically implanted in the body or is
administered via the gastrointestinal tract. As the film is eroded
away by the action of either gastrointestinal tissue or other body
fluids, the drug matrix layer becomes exposed and it too erodes,
thus releasing the drug to the tissues of the body. When the matrix
layer is thin, relatively small amounts of medication are released
per amount of film eroded. Conversely, if the matrix layer is thick
the amount of medicament released will be enhanced. By adjusting
the thickness of the matrix or the concentration of drug therein,
any desired time release profile can be programmed.
By use of the drug-delivery device of FIGS. 1a and 1b which is
comprised of a drug-matrix coating of constant thickness, there is
provided a drug dosage unit which can exhibit a constant slow rate
of release of drug.
In FIG. 2 a relatively impermeable film 10 is also shown which
dissolves very slowly in body fluids. However, in this embodiment
the said film 10 is coated with a medicament 11 containing matrix
composition 12 of uniformly varying thickness, namely, the drug or
matrix layer is spread thin at a proximal end of the surface of the
film but uniformly progressively thicker across to the distal end
of the surface of the film.
It will thus be appreciated that, depending upon from which end the
assemblage is wound about itself, there can be conveniently
prepared drug-delivery devices which will provide constantly
decreasing slow rate of release of drug (FIG. 2a) or constantly
increasing slow rate of release of drug (FIG. 2b). In either event
such devices would be identical in side plan view (FIG. 2c).
As described and illustrated above, the drug-delivery device of
this invention may be comprised of a drug-matrix layer such as to
program any desired time release profile, and two other of such
forms are illustrated in FIGS. 3, 3a, 3b, 4, 4a and 4b, with the
FIGS. 3 depicting a unit which provides a pulsing release pattern
and the FIGS. 4 a unit which provides a sinusoidal release
pattern.
Moreover, even though in the figures of the drawing cylindrical
structures are shown, it is apparent that flattened (FIG. 5) or
other configurations can be easily provided. The drug-delivery
device of the invention is also advantageously capped at either end
with a material 14 slowly soluble in body fluids so as to prevent
even the slightest amount of drug from prematurely exuding out of
said ends (see FIG. 6).
In many instances, it is desirable to provide for release of the
drug immediately upon administration of the device. This can be
achieved by coating the preformed device, as illustrated in any of
FIGS. 1a, 2a, 2b, 3a, 4a and 5, with a layer of the matrix 12
containing drug 11. Alternatively, as illustrated in FIG. 7, film
10 can be coated with medicament 11 containing matrix composition
12 on both face surfaces thereof. Upon rolling this coated film
about itself, the resulting device will bear a drug-containing
coating on its exterior surface (FIG. 7a). In either event, the
resulting device initially will release drug by dissolution of the
exteriorly exposed coating of the matrix. Thereafter, the film will
dissolve, eventually releasing drug disposed within the interior of
the spirally wound device.
The film or carrier materials 10 are flexible and relatively
resistant to erosion in body fluids to provide for medicating
action over a prolonged period of time and are preferably polymeric
in nature. Exemplary materials include polymers of the following
three general classes: (1) those which slowly dissolve in body
fluids, for example, gelatin, glycerinated gelatin, formalin
treated gelatin, collagen, polyvinylalcohol, and the like; (2)
those which hydrolyze in body fluids, for example, the polymeric,
essentially linear, dibasic acid anhydrides of the formula:
##SPC1##
especially the polyanhydride polymers of sebacic and azelaic acids,
polyhydroxyacetic acid such as described in U.S. Pat. Nos.
2,668,162 and 2,676,945, and polysulfite polymers; and (3) polymers
cleaved by enzymes present in body fluids, for example, chitin,
which is enzymatically cleaved by lysozyme.
The polyanhydride polymers of the above type (2) can be
conveniently prepared by condensing the respective dibasic acids in
the presence of SOCl.sub.2, benzene and ethyl acetate.
The film or carrier material should be relatively impermeable to
passage of the drug by diffusion or leaching. Otherwise, the rate
of release of the drug will depend, at least in part, upon
diffusion through the film rather than upon erosion of the film and
matrix. Selection of appropriate membrane materials will be
dependent on the particular drug to be used, and those skilled in
the art can readily make the appropriate choices.
Matrix materials used in fabricating the drug coating of constant
or varying thickness are soluble in body fluids. The drug matrix
substance must erode faster than the film such that, when
physically inserted or implanted in the body or administered via
the gastrointestinal tract, the film first erodes or dissolves in
body fluids thus exposing the drug coating which thence itself
erodes or dissolves and hence provides a slow rate of release of
drug, albeit the erosion or dissolution is more rapid than that of
the film material. In this manner, erosion or dissolution of the
film is the rate controlling step for drug administration; for once
the film erodes at its predetermined rate, the drug is released
relatively rapidly by dissolution of the matrix. Exemplary matrix
materials include polyvinylpyrrolidone, water soluble starch, gum
acacia, gum tragacanth, or the like, or even those film materials
hereinbefore delineated, so long as the requirement is observed
that the selected drug matrix substance must erode or dissolve
faster than the selected film.
Any of the drugs used to treat the body can be incorporated in the
drug layer of the drug-delivery device of this invention. "Drug" is
used herein in its broadest sense as including any composition or
substance that will produce a pharmacologic response.
Suitable drugs for use in therapy with the device of the invention
include without limitation:
1. Protein drugs such as insulin;
2. Desensitizing agents such as ragweed pollen antigens, hay fever
pollen antigens, dust antigen and milk antigen;
3. Vaccines such as smallpox, yellow fever, distemper, hog cholera,
fowl pox, antivenom, scarlet fever, dyptheria toxoid, tetanus
toxoid, pigeon pox, whooping cough, influenzae, rabies, mumps,
measles, poliomyelitis, Newcastle disease, etc.;
4. Antiinfectives, such as antibiotics, including penicillin,
tetracycline, chlortetracycline bacitracin, nystatin, streptomycin,
neomycin, polymyxin, gramicidin, oxytetracycline, chloramphenicol,
and erythromycin; sulfonamides, including sulfacetamide,
sulfamethizole, sulfamethazine, sulfadiazine, sulfamerazine, and
sulfisoxazole; anti-virals including idoxuridine; and other
antiinfectives including nitrofurazone and sodium propionate;
5. Antiallergenics such as antazoline, methapyrilene,
chlorpheniramine, pyrilamine and prophenpyridamine;
6. Antiallergenics such as hydrocortisone, cortisone,
hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate,
fluocinolone, triamcinolone, medrysone, prednisolone, prednisolone
21-phosphate, and prednisolone acetate;
7. Decongestants such as phenylephrine, naphazoline, and
tetrahydrazoline;
8. Miotics and anticholinesterases such as pilocarpine, eserine
salicylate, carbachol, diisopropyl fluorophosphate, phospholine
iodide, and demecarium bromide;
9. mydriatics such as atropine sulfate, cyclopentolate,
homatropine, scopolamine, tropicamide, eucatropine, and
hydroxyamphetamine;
10. Sympathomimetics such as epinephrine;
11. Sedatives and Hypnotics such as pentabarbital sodium,
phenobarbital, secobarbital sodium, codeine,
(.alpha.-bromoisovaleryl) urea, carbromal;
12. Psychic Energizers such as 3-(2-aminopropyl) indole acetate and
3-(2-aminobutyl) indole acetate;
13. Tranquilizers such as reserpine, chlorpromayline, and
thiopropazate;
14. Androgenic steroids such as methyltestosterone and
fluorymesterone;
15. Estrogens such as estrone, 17 .beta.-estradiol, ethinyl
estradiol, and diethyl stilbesterol;
16. Progestational agents such as progesterone, megestrol,
melengestrol, chlormadinone, ethisterone, norethynodrel,
19-nor-progesterone, norethindrone, medroxyprogesterone and 17
.beta.-hydroxy-progesterone;
17. Humoral agents such as the prostaglandins, for example
PGE.sub.1, PGE.sub.2 and PGF.sub.2 ;
18. Antipyretics such as aspirin, sodium salicylate, and
salicylamide;
19. Antispasmodics such as atropine, methantheline, papaverine, and
methscopolamine bromide;
20. Antimalarials such as the 4-aminoquinolines, 8-aminoquinolines,
chloroquine, and pyrimethamine;
21. Antihistamines such as diphenhydramine, dimenhydrinate,
tripelennamine, perphenazine, and chlorophenazine;
22. Cardioactive agents such as dibenzhydroflumethiazide,
flumethiazide, chlorothiazide, and aminotrate;
23. Nutritional agents such as vitamins, essential amino acids and
essential fats.
Other drugs having the same or different physiological activity as
those recited above can be employed in drug-delivery devices within
the scope of the present invention.
Drugs can be in various forms, such as uncharged molecules,
components of molecular complexes, or nonirritating,
pharmacologically acceptable salts such as hydrochloride,
hydrobromide, sulfate, phosphate, nitrate, borate, acetate,
maleate, tartrate, salicylate, etc. For acidic drugs, salts of
metals, amines, or organic cations (e.g., quaternary ammonium) can
be employed. Furthermore, simple derivatives of the drugs (such as
ethers, esters, amides, etc.) which have desirable retention and
release characteristics but which are easily hydrolyzed by body pH,
enzymes, etc., can be employed.
The amount of drug incorporated in the drug-delivery device varies
widely depending on the particular drug, the desired therapeutic
effect, and the time span for which it takes the film barrier and
matrix material to erode or dissolve. Since a variety of devices in
a variety of sizes and shapes are intended to provide complete
dosage regimes for therapy for a variety of maladies, there is no
critical upper limit on the amount of drug incorporated in the
device. The lower limit too will depend on the activity of the drug
and the time span of its release from the device. Thus it is not
practical to define a range for the therapeutically effective
amount of drug to be released by the device.
To prepare the drug-delivery device of the invention, the drug is
mixed with the matrix material either at ambient or elevated
temperatures to form a settable mixture. The settable mixture,
whether a dispersion or true solution, is then simply spread on the
film substrate in constant or varying thicknesses (see the FIGS. of
the drawing) and allowed to set, for example, by drying or
hardening. The coated film is next spirally wound or rolled about
itself in "jellyroll" fashion to provide the subject device.
In applying the drug-containing matrix to the film, the drug
release profile of the device is determined. In most instances, a
matrix of uniform drug concentration is applied over one entire
surface of the film, at a constant or varying thickness. However,
the matrix can be printed onto the film in various patterns,
providing different rates of drug release. In addition, different
portions of the film can be coated with matrix portions having
different drug concentration. In each of these ways, the rate of
release of drug from the device can be controlled and a wide
variety of release patterns obtained.
The drug-delivery device can be fabricated in any convenient shape
for either physical insertion or implantation in the body or for
administration via the gastrointestinal tract. Dimensions of the
device can thus vary widely and are not of controlling importance.
The lower limit of the size of the device is governed by the amount
of the particular drug to be supplied to the body to elicit the
desired pharmacologic response, as well as by the form the dosage
unit takes, for example, implantate, suppository, peroral pellet,
oral bolus, vaginal pessory, buccal or sublingual lozenge, ocular
insert (e.g. as described in U.S. Pat. No. 3,416,530), and the
like. Likewise with respect to the upper limit on the size of the
device. One of the prime advantages of the dosage form of the
invention over the capsule types of the prior art is that any
inadvertent flaw in the protective film barrier will not suddenly
release the entire drug content. Another advantage, if used as an
implantate or the like, is the total disappearance of the film
barrier when its function has been completed. Likewise as regards
the drug matrix material.
It too will be appreciated that the principle of providing any
predetermined time release profile can be embodied in devices other
than drug-delivery devices, namely, in any device where it is
desired to provide for the prolonged release of any active
ingredient according to any desired release pattern.
While there have been shown and described and pointed out the
fundamental novel features of the invention as applied to the
preferred embodiment, those skilled in the art will appreciate that
various modifications, changes, and omissions in the drug-delivery
device illustrated and described can be made without departing from
the spirit of the invention. It is the intention, therefore, to be
limited only by the scope of the following claims.
* * * * *