U.S. patent number 3,929,132 [Application Number 05/490,934] was granted by the patent office on 1975-12-30 for osmotic dispenser.
This patent grant is currently assigned to Alza Corporation. Invention is credited to Takeru Higuchi.
United States Patent |
3,929,132 |
Higuchi |
December 30, 1975 |
Osmotic dispenser
Abstract
An osmotic dispenser is described which is capable of releasing
to its outside environment concentrations of active agent at an
osmotically controlled rate over a prolonged period of time, and
the active agent content of which dispenser is formulated in a form
other than wholly in solution, namely, the active agent is
formulated as a dispersion, suspension, emulsion, cream, gel,
paste, slurry, or the like, and most preferably all of the above
are characterized by the consistency of either the semisolid or
solid state.
Inventors: |
Higuchi; Takeru (Lawrence,
KS) |
Assignee: |
Alza Corporation (Palo Alto,
CA)
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Family
ID: |
26996342 |
Appl.
No.: |
05/490,934 |
Filed: |
July 23, 1974 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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349774 |
Apr 10, 1973 |
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Current U.S.
Class: |
604/892.1;
222/95 |
Current CPC
Class: |
A61K
9/0004 (20130101) |
Current International
Class: |
A61K
9/00 (20060101); A61M 031/00 () |
Field of
Search: |
;128/260,261,213,271,127-131,172 ;424/19-22 ;222/95,386.5 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Medbery; Aldrich F.
Attorney, Agent or Firm: Bacon & Thomas
Parent Case Text
This is a continuation of application Ser. No. 349,774, filed Apr.
10, 1973, and now abandoned.
Claims
What is claimed is:
1. An osmotic active agent dispenser comprised of a first
compartment of relatively impervious material containing an active
agent and provided with means for releasing the active agent to the
exterior of the dispenser, and a second compartment of controlled
permeability to water containing a solution of an osmotically
effective solute which exhibits an osmotic pressure gradient
against water, the said first and second compartments having a
barrier member such that the said first compartment diminishes in
volume in response to an increase in volume of the solution in the
said second compartment via absorption of water by osmosis therein
and defining a means for establishing a substantially zero order
rate of release as water flows into the dispenser in a tendency
towards osmotic equilibrium with its environment, so that the
active agent is continuously squeezed thereout at an osmotically
controlled rate over a prolonged period of time; said active agent
being formulated in a form other than wholly in liquid solution,
and characterized by a consistency at least as firm as that of the
semisolid state, whereby the uniformity of dosage of the said
active agent over the said prolonged period of time is assured.
2. The osmotic dispenser as defined in claim 1, wherein the active
agent formulation is a semisolid.
3. The osmotic dispenser as defined in claim 1, wherein the active
agent formulation is a solid.
4. The osmotic dispenser as defined by claim 1, wherein the active
agent formulation is a thickened liquid having a viscosity of at
least 1,000 centipoises at 20.degree.C.
5. The osmotic dispenser as defined in claim 1, wherein the active
agent formulation further comprises a nonionic surfactant.
6. The osmotic dispenser as defined in claim 5, wherein the
surfactant is selected from the group consisting of sorbitan
mono-stearate, sorbitan monooleate, polyoxyethylene (20) sorbitan
monooleate, and polyoxyethylene 40 stearate.
7. The osmotic dispenser as defined in claim 1, wherein the active
agent formulation further comprises an anti-oxidant.
8. The osmotic dispenser as defined in claim 7, wherein the
anti-oxidant is selected from the group consisting of
2,6-ditertiary-butyl-p-cresol, propyl gallate, tertiary
butyl-4-methoxyphenol, ethoxyquin and nordihydroguaiaretic
acid.
9. The osmotic dispenser as defined by claim 1, wherein the active
agent formulation further comprises an inert particulate solid
filler.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
Takeru Higuchi copending application, Ser. No. 106,131, now U.S.
Pat. No. 3,760,805 filed Jan. 13, 1971, assigned to the assignee of
the present invention;
Takeru Higuchi and Harold M. Leeper copending application, Ser. No.
106130, now U.S. Pat. No. 3732865, filed Jan. 13, 1971, also
assigned to the assignee of the present invention;
Harold M. Leeper copending application, Ser. No. 106132, now U.S.
Pat. No. 376806 filed Jan. 13, 1971, also assigned to the assignee
of the present invention; and
Takeru Higuchi and Harold M. Leeper copending application, Ser. No.
106161, now abandoned, filed Jan. 13, 1971, also assigned to the
assignee of the present invention.
PRIOR ART
Rose and Nelson, Austral. J. exp. Biol., 33 pp. 415 - 420 (1955);
Rose and Nelson, Austral. J. exp. Biol., 33 pp. 411 - 414
(1955).
FIELD OF THE INVENTION
This invention relates to an osmotic dispenser, and more
especially, to an osmotic dispenser, simple in construction,
capable of releasing to its outside enivronment concentrations of
active agent at an osmotically controlled rate over a prolonged
period of time.
DEFINITION OF TERMS
The expression "active agent" as used herein denotes any drug (as
defined, infra); composition in any way affecting any biological
entity; substance having a nutrient or stimulating action, or
growth inhibiting, destroying or any regulating action on plant
growth, controlled or otherwise; substance to be assimilated by any
organism, e.g., human being, animal, or lower order organism, for
its nourishment or for regulating its growth; substance exhibiting
any of the above activities to be directly applied to the habitat,
surroundings or environment of any of the above organisms; and
substance having any other effect on any other environment,
especially any aqueous environment.
Therefore, suitable active agents for use with the dispenser of
this invention include, without limitation, those which are
generally capable of:
1. Preventing, alleviating, treating or curing abnormal and
pathological conditions of the living body by such means as
destroying a parasitic organism or limiting the effect of the
disease or abnormality by chemically altering the physiology of the
host or parasite;
2. Maintaining, increasing, decreasing, limiting or destroying a
physiologic body or plant function, e.g., vitamin compositions, sex
sterilants, fertility inhibitors, fertility promoters, growth
promoters, and the like;
3. Diagnosing a physiological condition or state;
4. Controlling or protecting an environment or living body by
subtracting, disabling, inhibiting, killing, modifying, repelling
or retarding an animal or microorganism, such as food and non-food
baits, attractants and lures, biocides, pesticides, algicides,
parasiticides, rodenticides, insecticides, fungicides, and the
like;
5. Preserving, disinfecting or sterilizing; and
6. Controlling or affecting generically an environment, as by
introducing a catalyst or metering a reactant into a reacting
chemical system, or by effecting any chemical process therein, such
as a fermentation, including propagation and/or attenuation of a
microorganism.
The terms "environment," "surroundings" and "habitat" as used
hereinabove and herein denote any prospective situs for the osmotic
dispenser of this invention, or at least for the water permeable
membrane component thereof, which is comprised of or will provide
sufficient water for absorption into the device to develop the
needed osmotic pressure on which its motive force depends; and
implicit in the foregoing definition of "active agent" -- one that
will develop its action in the presence of such environment,
surroundings or habitat, or one that will develop its action in a
remote and/or another environment, which need not be aqueous.
Any of the drugs used to treat the body, both topical and systemic,
can be compartmentalized as the active agent in any of the osmotic
dispensers of this invention. "Drug" is used herein in its broadest
sense as including any composition of substance that will produce a
pharmacological or biological response.
Suitable drugs for use in therapy with the dispenser 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 small pox, yellow fever, distemper, hog
cholera, fowl pox, antivenom, scarlet fever, diphtheria toxoid,
tetanus toxoid, pigeon pox, whooping cough, influenzae, rabies,
mumps, measles, poliomyelitis, Newcastle disease, etc.;
4. Anti-infectives, such as antibiotics, including penicillin,
tetracycline, chlortetracycline, bacitracin, nystatin,
streptomycin, neomycin, polymyxin, gramicidin, oxytetracycline,
chloramphenicol, and erythromycin; sulfonamide, including
sulfacetamide, sulfamethizole, sulfamethazine, sulfadiazine,
sulfamerazine, and sulfisoxazole; anti-virals including
idoxuridine; and other anti-infectives including nitrofurazone and
sodium propionate;
5. Anti-allergenics such as antazoline, methapyrilene,
chlorpheniramine, pyrilamine and prophenpyridamine;
6. Anti-inflammatories 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
tetrahydrozoline;
8. Miotics and anticholinesterases such as pilocarpine, eserine
salicylate, carbachol, di-ispropyl 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 pentobarbital 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 reserpino, chlorpromazine, and
thiopropazate;
14. Androgenic steroids such as methyltestosterone and
fluoxymesterone;
15. Estrogens such as estrone, 17 .beta.-estradiol, ethinyl
estradiol, and diethyl stilbesterol;
16. Progestational agents such as progesterone, megestrol,
melengestrol, chlormadinone, ethisterone, norethylnodrel,
19-nor-progesterone, norethindrone, medroxyprogesterone and 17
.alpha.-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. Anti-malarials such as the 4-aminoquinolines,
8-aminoquinolines, chloroquine, and pyrimethamine;
21. Antihistamines such as diphenhydramine, dimenhydrinate;
tripelennamine, perphenazine, and carphenazine;
22. Cardioactive agents such as hydrochlorothiazide, flumethiazide,
chlorothiazide, and trolnitrate;
23. Nutritional agents such as vitamins, essential amino acids and
essential fats;
24. Anti-Parkinsonism agents such as L-dopa,
(L-3,4-dihydroxyphenylalanine);
25. Investigative antihypotensive agents such as dopamine,
4-(2-aminoethyl)pyrocatechol.
Other drugs having the same or different physiological activity as
those recited above can be employed in osmotic dispensers within
the scope of the present invention. Suitable mixtures of drugs can,
of course, be dispensed with equal facility as with single
component systems.
Drugs can be in various forms, such as uncharged molecules,
components of molecular complexes, or non-irritating
pharmacologically acceptable salts such as hydrochloride,
hydrobromide, sulphate, 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, amide, 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 osmotic dispenser varies
widely depending on the particular drug, the desired therapeutic
effect, and the time span for which it takes the drug to be
released. Since a variety of dispensers 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 dispenser. The lower limit too
will depend on the activity of the drug and the time span of its
release from the dispenser. Thus it is not practical to define a
range for the therapeutically effective amount of drug to be
released by the disperser.
BACKGROUND OF THE INVENTION
Osmotic dispensers have heretofore been proposed, each of which is
capable of dispensing concentrations of active agent at an
osmotically controlled rate over a prolonged period of time.
Typically, these osmotic dispensers are comprised of a first
compartment of relatively impervious material containing an active
agent and a second compartment or chamber of controlled
permeability to water containing a solution of an osmotically
effective solute which exhibits an osmotic pressure gradient
aganist water. Such devices are so constructed that, when placed in
or functionally exposed to* a hypotonic aqueous environment, water
is absorbed therefrom by osmosis and diffuses into the solution
contained in the second compartment. As the water flows into the
second compartment, the solution contained therein and in certain
instances the compartment itself increase in volume, thus
generating, either directly or indirectly, mechanical pressure or
force on the active agent containing first compartment. The said
first compartment is provided with any suitable dispensing head for
releasing its active agent content to the exterior of the dispenser
and individually is of a construction that its active volume is
inversely responsive to the pressure thus exerted, i.e., is of such
construction that, in use, the volume of same diminishes in a
direct proportion to and as a consequence of increase in volume in
the said second compartment. Hence, the rate and amount of release
of the active agent are directly proportional to the change in
volume in the second compartment, but inversely proportional to the
volume change in the first. That is, as the water flows into the
device, the second compartment increases in volume generating
corresponding pressure for force on the first, either directly or
indirectly, as by transmitting pressure against a separate or
common wall member thereof, which wall member is yielding to such
pressure, or by biasing a movable barrier into or against the first
compartment or a wall member defining the same. The volume of said
first compartment is thus constantly diminished and active agent is
correspondingly continuously squeezed thereout at an osmotically
controlled rate over a prolonged period of time.
In the aforementioned related applications, the disclosures of
which are hereby incorporated by reference and are relied upon,
there are described and claimed several osmotic active agent
dispensers of the immediately above type.
For example, in Higuchi copending application, Ser. No. 106131, now
U.S. Pat. No. 3760805 filed Jan. 13, 1971, osmotic dispenser is
comprised of a water permeable housing member, advantageously
rigid, confining a first flexible bag of relatively impervious
material containing the active agent, advantageously a drug,
preferably in a gel, paste or other semisolid state (albeit a
solution or a concentrated solution of active agent will sometimes
suffice), and a second bag of controlled permeability to moisture
containing a solution of an osmotically effective solute which
exhibits an osmotic pressure gradient against water. The said first
and second bags are disposed within the said water permeable
housing member or porous shell such that water permeates from the
environment through the porous shell or housing and migrates by
osmosis into the solution contained in the second bag. The solution
in the second bag increases in volume, exerting mechanical force on
the active agent containing first bag, which mechanical force in
turn ejects the active agent out of the apparatus. For purposes of
permitting the active agent to be squeezed out of the said first
flexible bag, same is provided with any suitable active agent
release means or dispensing head to the exterior of the device,
e.g., long plastic tubing extending through the porous shell, or
ductlike fine tubule connections therethrough.
Higuchi and Leeper copending application, Ser. No. 106130, now U.S.
Pat. No. 3732865, filed Jan. 13, 1971, relates to an osmotic
dispenser comprised of a first compartment of relatively impervious
material containing an active agent and a second compartment
containing a solution of an osmotically effective solute which
exhibits an osmotic pressure gradient against water. Separating the
said first from the said second compartment, and defining a wall
member common to each of said compartments, is a sliding or movable
barrier of impervious material. The enclosure, whether of integral
construction or not, defining the remainder of the second
compartment, wherein the osmotic motive force of the dispenser is
developed, is at least in part comprised of membrane which exhibits
controlled permeability to water. When placed in a hyptonic aqueous
environment, water, by osmosis, is absorbed therefrom through the
membrane and diffuses into the solution contained in the said
second compartment. As the water flows into the second compartment,
the solution contained therein increases in volume exerting
corresponding pressure behind the movable barrier divider. Such
pressure serves to drive the said barrier forward and into the
active agent compartment thus diminishing the volume of same, and
which sliding barrier in turn ejects the active agent out of the
apparatus at an osmotically controlled rate over a prolonged period
of time. For purpose of permitting the active agent to be squeezed
out of the first compartment, same also is provided with any
suitable dispensing head or active agent release means to the
exterior of the device, for example, capillary ducts therethrough.
A further feature of this invention resides in an osmotic active
agent dispenser comprised of a plurality of capsule half shells,
similar in shape to pharmaceutical hard gelatin half shells, with a
first and a second half shell being securedly affixed in capsular
configuration, and a third half shell frictionally disposed in such
capsule but free to slidably move therein. The said capsule is
thereby divided into the two compartments with the third half shell
defining the wall member common to each of same.
And Leeper copending application Ser. No. 106132, now U.S. Pat. No.
37360806, filed Jan. 13, 1971, describes an osmotic dispenser
comprised of a first helical compartment of relatively impervious
material containing an active agent and a second helical
compartment containing a solution of an osmotically effective
solute which exhibits an osmotic pressure gradient against water.
The two helical compartments are interconnected so as to define a
continuous helix. Separating the first helical compartment from the
second helical compartment, and defining a wall member common to
each of said compartments, is a sliding or movable barrier of
impervious material capable of traversing the helix, advantageously
a plastic or glass ball separator. The enclosure, whether of
integral construction or not, defining the remainder of the second
compartment wherein the osmotic motive force of the dispenser is
developed, is at least in part comprised of membrane material which
exhibits controlled permeability to water. When placed in a
hypotonic aqueous environment, water, by osmosis, is absorbed
therefrom through the membrane and diffuses into the solution
contained in the second compartment. As the water flows into the
second compartment, the solution contained therein increases in
volume exerting corresponding pressure behind the movable barrier
divider. Such pressure serves to drive the said barrier forward and
into the active agent compartment thus diminishing the volume of
the same, and which sliding or rolling barrier in turn ejects the
active agent out of the apparatus at an osmotically controlled rate
over a prolonged period of time. For the purpose of permitting the
active agent to be squeezed out of the first compartment, the same
is provided at its terminal point with any suitable dispensing head
or active agent release means to the exterior of the device, for
example, a capillary duct therethrough. A further feature of this
invention resides in an osmotic active agent dispenser comprised of
a dispenser according to the forgoing description enveloped by a
relatively rigid, highly permeable housing member. The housing
member serves both as a protective means for the dispenser and also
to restrict expansion of the dispenser due to internal pressure.
Alternatively, such expansion may be in and of itself restricted by
means of any suitable band or tie member.
The osmotic active agent dispenser described in Higuchi and Leeper
copending application, Ser. No. 106161, now abandoned, filed Jan.
13, 1971, is comprised of a chamber having controlled permeability
to water and containing a solution of an osmotically effective
solute which exhibits an osmotic pressure gradient against water,
said chamber housing a flexible bag of relatively impervious
material containing an active agent and provided with means or
dispensing head for releasing said active agent to the exterior of
the dispenser. The flexible bag is disposed within the said housing
chamber such that as water permeates from the external environment
through the permeable walls of the chamber and migrates or diffuses
by osmosis into the solution contained therein, same increases in
volume thereby generating mechanical compressing or deflating force
on the flexible bag, which force in turn ejects the active agent
out of the apparatus at an osmotically controlled rate over a
prolonged period of time.
The osmotic dispenser proposed in the Rose and Nelson article,
supra, too is capable of delivering drug solution at a relatively
constant rate. This injection consists of three components and a
clamp to hold a semi-permeable membrane. The motive force of the
injector depends on the osmotic pressure developed by a saturated
aqueous solution of Congo red against water. This solution is
contained in a partially collapsed rubber compartment and is
separated from a second water compartment by the semi-permeable
cellophane membrane. The partially collapsed bag is placed in a
glass ampoule, with the drug compartment of the device being
defined by the space between the Congo red bag and the glass
ampoule. The ampoule is also provided with drug release means and
when the drug compartment is charged with a drug solution water
will move by osmosis into the Congo red solution, thus expanding
the rubber compartment and providing the mechanical force to eject
the drug out of the apparatus.
The compartment or chamber of the aforesaid osmotic active agent
dispensers containing the solution of the osmotically effective
solute, wherein the osmotic motive force of the respective devices
is developed, is at least in part comprised of membrane which
exhibits controlled permeability to water. Such membrane can be
formed from a wide variety of materials permeable or semi-permeable
to solvent (water) but not to solute, i.e., those suitable for the
construction of an osmotic cell. Typical membranes are isotropic
membranes such as unplasticized cellulose acetate, plasticized
cellulose acetate, reinforced cellulose acetate, cellulose di- and
triacetate, ethyl cellulose; anisotropic reverse osmosis membrane
which typically are made of cellulose acetate; silicone rubbers,
polyurethanes, natural rubber, and hydrolyzed ethylene/vinyl
acetate polymers. Isotropic membranes have less water permeability
than do the anisotropic membranes. Also, with both types of
membranes, increasing the acetate content of the cellulose acetate
polymer decreases the water permeability. In devices, the surface
areas of the membranes of which are relatively limited, it will be
preferred to use semi-permeable membranes allowing relatively rapid
water transmission. Thus, in such embodiments the anisotropic
membranes are the preferred. For drug depot applications as
heretofore described, the membranes are also biologically inert,
non-irritating to body tissues and non-allergenic. So too in such
applications are the other materials from which the topic
dispensers are fabricated. For best results, the membrane should be
substantially impermeable to passage of the osmotically effective
solute so as to prevent loss thereof.
In the osmotic dispenser proposed by Rose and Nelson, supra, the
active agent is employed in the form of a solution. Consequently,
there result several disadvantages as regards the handling of such
osmotic devices, e.g., spillage and loss of active ingredient, as
well as in their storage capabilities since drug containing
solutions generally have a relatively short shelf life, and many
chemical substances on prolonged storage in a dissolved state
undergo chemical deterioration. Furthermore, the use of solutions
in osmotic devices places an absolute upper limit on the
concentration of active agent that can be administered from a given
volume of composition. This latter limitation is of great
importance when overall size limitations of such devices are
considered. Moreover, drug or other active agent solutions exhibit
the deleterious tendency to be released from an osmotic device by
simple leaching.
SUMMARY OF THE INVENTION
Accordingly, it is a primary object of this invention to provide an
osmotic dispenser, simple in construction, which exhibits all of
the practical benefits of long term continuous administration of
various active agents both to animals, humans and into other
environments.
Another object of this invention is to provide an improved osmotic
dispenser which overcomes handling and storage problems inherent in
related devices heretofore proposed.
Another object of the invention resides in the provision of an
improved osmotic dispenser which enables high concentrations of
active agent to be administered therefrom, and which high
concentrations of active agent will not exhibit the tendency to be
leached from the device, nor be decreased in potency by chemical
breakdown.
In attaining the objects of this invention, one feature resides in
an osmotic active agent dispenser, the active agent of which is
formulated in a form other than wholly in liquid solution. That is
to say, the active agent is formulated in the form of for example a
dispersion, a suspension, an emulsion, a cream, a gel, a paste, a
slurry, or any other physical or chemical form which does not
wholly involve solvation of the active agent molecules. In a
preferred embodiment, the active agent formulation is in the form
of a paste, cream, gel or other at least semisolid. Optionally,
there may be incorporated into the active agent formulation one or
more additional ingredients, such as surfactants, antioxidants,
perservatives, and/or dispersed inert particulate solid fillers or
gellants.
Other objects, features and advantages of this invention will
become more apparent from the following description.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with this invention, it has been discovered that
significant advantages are obtained by employing in the subject
osmotic dispensers an active agent formulated in a form other than
wholly in liquid solution form. Thus, the active agent formulation
may comprise an active agent dispersed, suspended, emulsified,
etc., in a carrier which is typically but not necessarily liquid at
the storage temperatures of the subject devices, advantageously
room temperature. Active agent formulations of the invention may
take on the physical characteristics of a solid, semi-solid or a
thickened liquid; however, it is preferred that the formulations
exhibit the characteristics of a semi-solid and only somewhat less
preferably those characteristics of a liquid of relatively high
viscosity, e.g., a liquid having a viscosity of at least 1,000
centipoises at 20.degree.C. Liquid active agent formulations having
lower viscosities are of course feasible but less advantageous in
certain contemplated applications of the subject devices. By
employing the topic active agent formulations, the dispensers of
the invention are characterized by improved handling convenience
because there is little or no possibility for spillage or loss of
active ingredient from the devices, thereby assuring uniformity of
dosage at all times subsequent to fabrication of the same.
Moreover, in active agent formulations wherein the active agent is
not wholly in solution, the tendency for chemical breakdown of the
active agent is markedly decreased, and also such non-solution
formulations are characterized by storage stability greatly
improved as compared with liquid solution active agent formulations
which typically have a relatively short shelf life. In another
aspect, by removing the solubility limitations inherent in active
agent formulations of the solution type, higher concentrations of
active agent can be administered from the same volume of
composition in accordance with the active agent formulations of the
present invention, and there is considerably less tendency for the
active agent formulated in solid, semi-solid or high viscosity
formulations to be leached from the topic devices. Thus, the
devices of this invention are capable of administering a wide range
of active agent dosages while at the same time conforming to
inherent overall size limitations.
Active agent formulations containing an active agent formulated
other than wholly in solution form may consist of active agent
compounds or compositions per se provided that such compounds or
compositions are capable of being forced out of the device as a
result of the osmotic pressure developed therein. More typically,
however, the active agent formulation comprises an active agent in
combination with a carrier. Any suitable carrier for the active
agent may in general be employed in the device of this invention;
however, when use of the subject devices for drug depot
applications is contemplated, the carrier must be biologically
inert, non-irritating to body tissues and non-allergenic. A
multitude of such carriers are available, including such liquids as
water, alcohols such as ethanol, propylene glycol, glycerine,
polyethylene glycols of various molecular weights, etc., mineral
oil, vegetable oils such as corn oil, peanut oil, cottonseed oil,
etc., and solids which are converted to liquids at the temperature
of the prospective situs of the device, i.e., body temperature in
the case of drug depot applications, such as those disclosed in
copending Nakano, Higuchi and Hussain application Ser. No. 106133,
now abandoned filed Jan. 13, 1971.
The amount of active agent incorporated in the active agent
formulation varies widely depending upon the particular active
agent, the particular vehicle employed and the desired dosage to be
administered by the dispenser. Thus, there is no lower limit on the
amount of active agent to be combined with the carrier, and
likewise, ther is no upper limit save for the physical limitation
of a given carrier material. Accordingly, it is not practical to
define a range for the amount of active agent to be incorporated in
the inert carrier; however, in a typical active agent formulation
the carrier contains from about 5 to about 80 percent by weight of
active agent, preferably from about 35 to about 75 percent.
Typically, a surfactant is advantageously included in the active
agent formulation to enhance its physical stability. The surfactant
must be inert to the active agent as well as biologically inert,
and accordingly non-ionic surfactants are preferred. Exemplary
non-ionic surfactants include sorbitan monostearate, sorbitan
monooleate, polyoxyethylene (20) sorbitan monooleate, and
polyoxyethylene (40) stearate. Several active agent surfactant
combinations have been found to be particularly effective, for
example, sorbitan monostearate has been found effective to
stabilize suspensions of tetracycline, while poloxyethylene
sorbitan monooleate has likewise been found suitable for use with
chloramphenicol. A preferred range for the surfactant is typically
between about 0.1 and 1.0 percent by weight of the total
mixture.
Optionally, the active agent formulations of the invention may
include a anti-oxidant to prevent degradation during prolonged
periods of storage, usually in an amount of from about 0.01 to
about 2 percent by weight of the active agent. Any of the
food-approved anti-oxidants may be employed in this capacity, with
the following being merely illustrative in this regard: tertiary
butyl-4-methoxyphenol (mixture of 2- and 3- isomers),
2,6-ditertiary butyl-p-cresol, propyl gallate,
6-ethoxy-1,2-dihydroxy-2,2,4-trimethylquinoline (ethoxyquin),
nordihydroguaiaretic acid (NDGA) and ascorbyl palmitate. Use of
other preservatives such as methylparaben, propylparaben, sorbic
acid, etc., are likewise contemplated in the active agent
formulations of the invention.
Similarly, there is contemplated the optional inclusion of a
dispersed inert particulate solid to the active agent formulations
of the invention. These particulate solids are included typically
in amounts from about 0.5 to 5 percent by weight of the active
agent to enhance the stability of the product by providing a high
solids content. Thus, when low concentrations of drug or other
active agent are employed as inert solid such as fumed silica,
bentonite, etc., may be added as a gellant to prevent the
formulation from settling out upon prolonged storage of the
device.
To further illustrate the present invention and the advantages
thereof, the following specific examples are given, it being
understood that the same are intended merely as illustrative and in
no wise limitative:
EXAMPLE 1
40 grams of polyethylene glycol 600 containing 8 milligrams of
butylated hydroxytoluene are admixed with 60 grams of tetracycline
hydrochloride. The resulting paste is mixed well and then milled on
an ointment mill to provide a uniform active agent formulation of a
viscous paste or cream-like consistency. 10 cc of the active agent
formulation are then placed in the active agent compartment of an
osmotic dispenser constructed in accordance with FIG. 4 of Higuchi
and Leeper application, Ser. No. 106130, now U.S. Pat. No. 3732865
filed Jan. 13, 1971. In the FIGURE of drawing there is illustrated
the device of this example.
EXAMPLE 2
1200 milligrams of tetracycline hydrochloride and 800 milligrams of
polyethylene glycol 600 - polyethylene glycol 1000 mixture (6:4)
containing 8 milligrams of sorbitan monostearate and 0.16
milligrams of 2,6-ditertiary butyl-p-cresol are mixed at
39.degree.C. whereat the glycol mixture is a clear viscous liquid.
Thereafter, the mixture is milled twice in an Asra mill, reheated
and poured into the active agent compartment of an osmotic
dispenser constructed in accordance with the device of the FIGURE
of drawing. The active agent formulation is then allowed to cool to
room temperature whereupon it solidifies to a storage-stable state.
The osmotic dispenser is then placed in an aqueous solution at
approximately 38.degree.C., and the active agent formulation again
melts to a liquid form and is forced out of the device through the
dispensing head by the osmotic pressure developed in the
osmotically effective solute compartment as a result of water from
the environment permeating by osmosis thereinto.
EXAMPLE 3
6000 milligrams of chloramphenical, 5000 milligrams of cocoa butter
and 44 milligrams of Tween 80 (polyoxyethylene 20 sorbitan
monooleate USP) are mixed at 39.degree.C., milled twice in the Asra
mill, reheated and poured into the active agent compartment of an
osmotic device constructed in accordance with the design
illustrated in FIG. 1 of Higuchi application, Ser. No. 106131, now
U.S. Pat. No. 3760805, filed Jan. 13, 1971. The active agent
formulation is again a solid at room temperature, and is readily
dispensed through the dispensing head of the device in response to
an osmotic pressure developed therein when the device is placed in
an aqueous environment at approximately 36.degree.C.
EXAMPLE 4
An active agent formulation containing 13,000 milligrams
tetracycline base (vacuum dried), 13,000 milligrams of cocoa butter
and 104 milligrams of Span 60 (sorbitan monostearate USP) is
prepared according to the preocedure of Example 3 and poured into
the active agent compartment of an osmotic dispenser constructed in
accordance with FIG. 1 of Higuchi and Leeper application, Ser. No.
106130, now U.S. Pat. No. 3732865 filed Jan. 13, 1971. The
resulting formulation is again solid at room temperature, storage
stable thereat and again an easily dispensible liquid at
approximately 38.degree.C.
EXAMPLE 5
An active agent formulation containing 1000 milligrams of cocoa
butter, 1200 milligrams of sulfisoxazole, 8.8 milligrams of Span 60
(sorbitan monostearate), and 0.2 milligrams of
2,6-ditertiary-butyl-p-cresol is prepared according to the
procedure of Example 3, and poured into the active agent
compartment of a device identical to that employed in Example 3.
Results essentially identical to the foregoing Examples 2 to 4 are
obtained.
The osmotic dispenser can be fabricated in any conventional shape
for either physical insertion or implantation in the body, or for
administration via the gastro-intestinal tract, or for introduction
into any desired environment. Dimensions of the device can 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
active agent to be supplied to the environment to clicit the
desired response, as well as by the form the dosage unit takes, for
example, in cases of specific body uses, implantate, bolus, IUD,
IVD, vaginal ring, uterine capsule for fertility suppression,
artificial gland, pessary, prosthesis, suppository, and the
like.
Thus, the invention provides, in an osmotic dispenser, a reliable
means for releasing effective concentrations of active agent
contained therein to the body of a living organism, or to any other
environment, at an osmotically controlled rate and over a prolonged
period of time. In addition, by providing an active agent
formulation wherein the active agent is formulated in a form other
than wholly in solution, e.g., dispersion, suspension, emulsion,
etc., and preferably in the form of a solid, semi-solid, for
example, a gel, paste, or cream, or a highly viscous liquid, the
active agent formulation will not be decreased in potency by
chemical breakdown and exhibits enhanced storage stability and
handling characteristics as well as advantageous high
concentrations of the active ingredient itself, and the same will
exhibit a decreased tendency to be leached from the device.
While the invention has been described and illustrated with
reference to certain preferred embodiments thereof, those skilled
in the art will appreciate that various modifications, changes,
omissions and substitutions can be made without departing from the
spirit of the invention. It is intended, therefore, that the
invention be limited only by the scope of the following claims.
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