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1 . ..:
1 OSMOTIC DEVICE WITH DELAYED ACTIVATION OF DRUG DELIVERY
2 AND COMPLETE DRUG RELEASE
3
4 FIELD OF THE INVENTION
s The present invention is related to the delayed delivery of an active
agent followed by essentially complete delivery of the active agent. More
s particularly, it is related to osmotically-activated devices for essentially
s complete dispensing of active agents to a biological environment of use
1o following an initial period of delay.
11
12 BACKGROUND OF THE INVENTION
13
14 Oral delivery of therapeutically active agents is a convenient and cost
1s effective method of delivery. The active agent can be released in the mouth
1s or anywhere in the alimentary canal. The delivery can be in a bolus, it can
be
17 intermittent, or it can be continuous.
1s Osmotic dispensing devices for delivery of therapeutically active
1s agents are well known in the art. Such devices use an expansion means to
Zo deliver an agent to an environment of use over a period of hours, days or
z1 months. The expansion means absorbs liquid, expands, and acts to drive
22 out the beneficial agent formulation from the interior of the device in a
z3 controlled, usually constant manner. The osmotic expansion means is
24 used to controllably, usually relatively slowly, and over a period of time,
2s deliver the agent.
zs Osmotic devices have also been described for prolonged and
27 controlled delivery of one or more active agents where an initial delay of
Zs delivery is desired. US Patent No. 5,198,229 is directed to an osmotic
2s device for delivery of an active agent to the upper gastrointestinal tract.
3o The dispensing device comprises concentric housings that are in
31 slidably telescoping arrangement with each other. A first
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2
expansion means imbibes fluid when placed in the stomach environment.
2 This expansion means expands and pushes against a partition layer that in
s turn pushes against an active agent formulation. The active agent is
a delivered to the stomach environment through a small exit port in a
controlled
s and continuous manner. After all the active agent has been delivered,
s the housings separate, the buoyancy chamber is exposed to the stomach
environment, the density of the device increases, and the device sinks and
a exits out of the stomach.
s US Patent No. 5,312,388 describes the use of slidably telescopic
concentric housings in an osmotic device where delivery of more than one
active agent is desired or where separate dosings of one active agent is
desired. In a particular embodiment, initial rapid delivery of a particular
active agent is followed by delayed delivery of the active agent. A loading
~a dose of the active agent is dispensed as soon as the device enters the
~s environment of use. Prolonged delivery is accomplished as a result of arr
is expansion means that imbibes fluid and expands to separate the concentric
housings. Upon separation, the active agent contained within the housings is
~s dispensed.
US Patent No. 5,312,390 describes an osmotic device useful for the
Zo initially delayed delivery of an active agent. Slidably telescoping
concentric
housings separate following absorption of fluid through the housing. A fluid
az passage means is exposed to the fluid environment and the active agent is
2s expelled in a controlled and continuous manner through an exit port at the
za end of the housing opposite the fluid passage means.
is US Patent No. 5,223,285 provides a generally cylindrically shaped
zs delivery device having concentric, slideable housings, which separate upon
27 fluid absorption through one of the housings to provide for an initially
delayed
2a release of active agent. Then an expansion member in the housing
zs containing the active agent expands to deliver the active agent through a
so small opening in the end of the housing over a prolonged period of time.
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,~a . ' . .
~.. .
U.S. Patent No. 5,358,502 describes an osmotic device with a
z semipermeable membrane with an agent that is pH sensitive and thus will
s dissolve at a given pH, thereby releasing the contents of the device.
As can be observed in the above-referenced patents, osmotic devices
s have been described that provide for an initial pulse of an active agent,
AM~N~~ ~EEf
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that provide for prolonged de0ivery of an active agent, and that provide for
z delivery of more than one active agent. However, there remains a continuing
3 need for improved methods and systems for delivering one or more active
a agents in a reliable and reproducible manner.
s
s SUMMARY OF THE INVENTION
s We have observed that devices such as those described above
will
s open in a predictable manner but that the agent contained
in the device may
not always be completely released to the environment of
use following the
desired delay period. Accordingly, the present invention
is directed to a fluid-
imbibing dispensing device and a method for the essentially
complete delivery
of an active agent to a fluid environment of use following
an initially delayed
~a period of delivery of the agent.
15 In one aspect, the invention is directed to a fluid-imbibing
delivery
,s device formed of a first housing and a second housing. The
housings are in
reversibly sliding telescoping arrangement with each other.
The first housing
~s contains an active agent delivery chamber with an active
agent formulation
and a first expansion agent. The active agent formulation
comprises at
zo least one active agent. An open end in the first housing
provides for delivery
a~ of the active agent formulation to the environment of use.
The second
z2 housing contains an expansion chamber for separating apart
the first and
a3 second housings of the device after exposure to the environment
of use.
2a The expansion chamber comprises a second expansion agent
and optionally
is a piston. The first expansion agent within the first housing
ensures
2s essentially complete release of the active agent formulation
to the
' z7 environment of use.
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In another aspect, the invention is directed to a fluid imbibing delivery
2 device formed of a first housing and a closure for the housing. The housing
contains an active agent formulation and a first expansion agent. The active
4 agent formulation comprises at least one active agent. The housing is
s configured to provide a flow path between the interior of the housing and
the
s active agent formulation. The closure comprises a second expansion agent.
The invention is further directed to a device for dispensing an active
s agent formulation to an environment of use following an initial period of
delay,
s that comprises a housing with a closed end and an open end. The housing
~o contains an active agent formulation that comprises at least one active
agent.
11 The housing further contains an expansion agent. The device further
~2 comprises a plug sealing the open end of the housing. The improvement of
13 the invention comprises a fluid flow path between the interior of the
housing
14 and the active agent formulation.
s The invention is also directed to a device for dispensing an active
~s agent formulation to an environment of use following an initial period of
delay,
that comprises a first impermeable housing and a second semipermeable
1s housing. The first and second 'housings are in reversibly sliding
telescoping
~s arrangement with each other. The first housing contains an active agent
2o formulation that comprises at least one active agent. The first housing
further
2~ contains a first expansion agent. The second housing contains a second
22 expansion agent. The first housing is configured to provide a flow path
2s between the interior of the first housing and the active agent formulation.
24
25 DESCRIPTION OF THE D AWINr
2s
2~ The drawings are not drawn to scale, but are set forth to illustrate '
2s various embodiments of the invention. Like numbers refer to like
structures.
2s FIG. 1 is a side cross-sectional view of one embodiment of the
so delivery device of the present invention, the device being in closed or
s~ prepared form prior to placement in the environment of use.
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FIG. 2 shows the device of FIG. 1 in operation after placement
in the
2 environment of use, showing the second expansion means expanded
and the
s first and second housings of tDle device separated to allow
activation of the
a first expansion means to begin delivery of the active agent
formulation to the
J
5 environment.
s FIG. 3 shows the first housing of the device of FIG. 1 in
operation at
7 the end of its useful life, with the first expansion means
expanded and the
s active agent formulation delivered to the environment.
s FIG. 4 is a side cross-sectional view of a further embodiment
of the
~o delivery device of the present invention, the device being
in closed or
11 prepared form prior to placement in the environment of use.
12 FIG. 5 is a side cross-sectional view of yet another embodiment
of the
13 delivery device of the present invention, the device being
in closed or
prepared form prior to placement in the environment of use.
FIG. 6 is a side cross-sectional view of yet another embodiment
of
16 the device of the invention in closed form prior to placement
in the
environment of use.
~s FIG. 7 is a side cross-sectional view of still another embodiment
of
the device of the invention in closed form prior to placement
in the
2o enviroriment of use.
2~ FIG. 8 is a graph showing the release characteristics of
6 inventive
22 devices.
23
2a DETAILED DE~GRIPTION OF THE INVENTION
2s The present invention provides a device which is useful for delivering
' 27 an active agent formulation to a fluid environment of use. There is an
initial
zs delay period to startup or activation of the device, this delay period
lasts a
is predetermined length of time, and is followed by essentially complete
delivery
of the active agent formulation to the environment of use.
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9EFINITIONS
a
s The phrase "initial delay period" intends a period of about a few
a minutes to a period of about a day, preferably between about 1 and 24 hours,
s and in particular between about 2 and 15 hours and usually in the range of
s about 2 to 7 hours. The delivery of the agent formulation from the
dispensing
~ device, once begun, is continued until essentially all of the active agent
a formulation is dispensed. By "essentially all of the active agent
formulation" is
s intended at least about 95% of the active agent formulation, preferably
above
~o about 97% and usually greater than 98% of the active agent is delivered to
the fluid environment of use. The active agent formulation is preferably
2 administered as a bolus, i.e., the dose of active agent in the device is
3 released in a short period of time of one hour or less and usually within
about
4 30 minutes preferably within about 15 minutes of-initiation of delivery of
the
active agent formulation.
s By "semipermeable" is intended a material that is permeable to fluid
7 but impermeable to other ingredients contained in the dispensing device and
~a the environment of use. By "impermeable" is meant that the material is
~s impermeable to fluids as well as to other ingredients contained in the
ao dispensing device such that the migration of such materials into or out of
the
a~ device is so low as to have substantially no adverse impact on the function
of
as the device during the delivery period.
as The term "active agent formulation" intends the active agent optionally
a4 in combination with pharmaceutically acceptable carriers and additional
inert
as ingredients. It is to be understood that more than one active agent may be
zs incorporated into the active agent formulation in a device of this
invention,
z~ and that the use of the term "agent" or "drug" in no way excludes the use
of
a$ two or more such agents or drugs. The agents can be in various forms,
as such as uncharged molecules, components of molecular complexes or
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nonirritating, pharmacologically acceptable salts. Also, simple derivatives of
the agents (such as ethers, esters, amides, etc.) which are easily hydrolyzed
3 by body pH, enzymes, etc., can be employed.
The term "active agent" used herein refers to an agent, drug,
s compound, composition of matter or mixture thereof which provides some
s biological, often beneficial, effect. This includes pesticides, herbicides,
germicides, biocides, algicides, rodenticides, fungicides, insecticides,
s antioxidants, plant growth promoters, plant growth inhibitors,
preservatives,
s antipreservatives, disinfectants, sterilization agents, catalysts, chemical
~o reactants, fermentation agents, foods, food supplements, nutrients,
cosmetics, drugs, vitamins, sex sterilants, fertility inhibitors, fertility
promoters,
microorganism attenuators and other agents that benefit the environment of
~s use. As used herein, the terms further include any physiologically or
~a pharmacologically active substance that produces a localized or systemic
~s effect or effects in animals, including warm blooded mammals, humans and
~s primates; avians; domestic hausehold or farm animals such as cats, dogs,
sheep, goats, cattle, horses and pigs; laboratory animals such as mice, rats
and guinea pigs; fish; reptiles; zoo and wild animals; and the like. The
active
~s agents that can be delivered includes inorganic and organic compounds,
2o including, without limitation, drugs which act on the peripheral nerves,
z~ adrenergic receptors, cholinergic receptors, the skeletal muscles, the
ii cardiovascular system, smooth muscles, the blood circulatory system,
a3 synoptic sites, neuroeffector functional sites, endocrine and hormone
24 systems, the immunological system, the reproductive system, the skeletal
zs system, autacoid systems, the alimentary and excretory systems,
is the histamine system and the central nervous system. Suitable active
z7 agents may be selected from, for example, proteins, enzymes, hormones,
2s polynucleotides, nucleoproteins, polysaccharides, glycoproteins,
lipoproteins,
zs polypeptides, steroids, hypnotics and sedatives, psychic energizers,
so tranquilizers, anticonvulsants, muscle relaxants, antiparkinson agents,
s~ analgesics, anti-inflammatories, local anesthetics, muscle contractants,
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antimicrobials, antimalarials, hormonal agents including contraceptives,
z sympathomimetics, polypeptides and proteins capable of eliciting
s physiological effects, diuretics, lipid regulating agents, antiandrogenic
agents,
antiparasitics, neoplastics, antineoplastics, hypoglycemics, nutritional
agents
s and supplements, growth supplements, fats, ophthalmics, antienteritis
agents,
s electrolytes and diagnostic agents.
Examples of beneficial active agents useful in this invention include
s prochlorperazine edisylate, ferrous sulfate, aminocaproic acid, mecaxylamine
s hydrochloride, procainamide hydrochloride, amphetamine sulfate,
~o methamphetamine hydrochloride, benzphetamine hydrochloride,
~~ isoproteronol sulfate, phenmetrazine hydrochloride, bethanechol chloride,
methacholine chloride, pilocarpine hydrochloride, atropine sulfate,
is scopolamine bromide, isopropamide iodide, tridihexethyl chloride,
phenformin
14 hydrochloride, methylphenidate hydrochloride, theophylline cholinate,
~s cephalexin hydrochloride, diphenidol, meclizine hydrochloride,
~s prochlorperazine maleate, phenoxybenzamine, thiethylperazine maleate,
~~ anisindione, diphenadione erythrityl tetranitrate, digoxin, isoflurophate,
a acetazolamide, methazolamide, bendroflumethiazide, chlorpropamide,
~s tolazamide, chlormadinone acetate, phenaglycodol, allopurinol, aluminum
o aspirin, methotrexate, acetyl sulfisoxazole, hydrocortisone,
~ hydrocorticosterone acetate, cortisone acetate, dexamethasone and its
a2 derivatives such as betamethasone, triamcinolone, methyltestosterone,
is 17-~i-estradiol, ethinyl estradiol, ethinyl estradiol 3-methyl ether,
prednisolone,
2a 17-(3-hydroxyprogesterone acetate, 19-nor-progesterone, norgestrel,
25 norethindrone, norethisterone, norethiederone, progesterone, norgesterone,
is norethynodrel, aspirin, indomethacin, naproxen, fenoprofen, sulindac,
a~ indoprofen, nitroglycerin, isosorbide dinitrate, propranolol, timolol,
atenolol,
za alprenolol, cimetidine, clonidine, imipramine, levodopa, chlorpromazine,
as methyldopa, dihydroxyphenylalanine, theophylline, calcium gluconate,
so ketoprofen, ibuprofen, cephalexin, erythromycin, haloperidol, zomepirac,
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ferrous lactate, vincamine, phenoxybenzamine, diltiazem, milrinone,
2 captropril, mandol, quanbenz, hydrochlorothiazide, ranitidine, flurbiprofen,
s fenbufen, fluprofen, tolmetin, alclofenac, mefenamic, flufenamic, difuninal,
a nimodipine, nitrendipine, nisoidipine, nicardipine, felodipine, lidoflazine,
s .tiapamil, gallopamil, amlodipine, mioflazine, lisinopril, enalapril,
captopril,
s ramipril, enalaprilat, famotidine, nizatidine, sucralfate, etintidine,
tetratolol,
minoxidil, chlordiazepoxide, diazepam, amitriptylin, and imipramine.
s Further examples are proteins and peptides which include, but are not
limited
s to, insulin, colchicine, glucagon, thyroid stimulating hormone, parathyroid
and
,o pituitary hormones, calcitonin, renin, prolactin, corticotrophin,
thyrotropic
11 hormone, follicle stimulating hormone, chorionic gonadotropin, gonadotropin
releasing hormone, bovine somatotropin, porcine somatropin, oxytocin,
~s vasopressin, prolactin, somatostatin, lypressin, pancreozymin, luteinizing
14 hormone, LHRH, interferons, interleukins, growth hormones such as human
~s growth hormone, bovine growth hormone and porcine growth hormone,
fertility inhibitors such as the prostaglandins, fertility promoters, growth
factors, and human pancreas hormone releasing factor.
~s As used herein, the terms "therapeutically effective" amount or rate
refer to the amount or rate of the active agent needed to effect the desired
2o therapeutic, often beneficial, result.
The dispensing devices of the invention find use, for example,
in humans or other animals. Z'he environment of use is a fluid environment
is and can comprise the stomach, the intestinal tract, or a body cavity such
as
Za the peritoneum or vagina. A single dispensing device or several dispensing
25 devices can be administered to a subject during a therapeutic program.
is FIG. 1 depicts, in side cross-sectional view, an embodiment of the
a~ delivery device according to the present invention. The device is shown in
2a closed or prepared form prior 1:o placement in the environment of use.
2s Dispensing device 1 comprises a housing 8 and a closure 10. Housing 8 and
so closure 10 in this particular embodiment are shown to be a first
impermeable
31 housing 12 and a second semipermeable housing 14. First housing 12 and
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a second housing 14 are in slidably telescoping arrangement with each other.
z First housing 12 surrounds and defines an active agent delivery chamber 16
s and contains a first expansion agent 20 and an active agent formulation 22.
Second housing 14 encompasses an expansion chamber 18 and
s contains a second expansion agent 30 and a moveable impermeable
s partition 32. Partition 32 is positioned between second expansion
agent 30 and the open end 36 of first housing 12 which, when exposed to
s the environment, permits delivery of the active agent formulation to the
s environment of use.
First housing 12 and second housing 14 at their ends are close in size
11 SO that a friction fit is formed between the housings. The friction
generated is
~z sufficient to maintain the two housing together prior to activation of the
~s second expansion agent 30 but not so great as to keep the two housings from
~a sliding apart once an expanding driving for is exerted. The end of first
~s housing 12 is adapted to fit within second housing 14. The edge 34 of the
~s end of first housing 12 provides a platform or ridge against which
partition 32
~ abuts to receive the driving force of second expansion agent 30 to separate
is the two housings.
~s In operation, dispensing device 1 is placed in the fluid environment of
zo use and second expansion agent 30 begins to imbibe and absorb fluid
z~ through second housing 14 from the environment. Second expansion agent
zz 30 expands, exerting a driving force via partition 32 against edge 34 of
first
zs housing 12 and the end of formulation 22 to begin to slidably separate
first
z4 housing 12 from second housing 14. Following separation of the first
housing
zs 12 and second housing 14, fluid from the environment of use enters the open
zs end 36 of first housing 12, thus causing first expansion agent 20 to imbibe
z~ fluid. As first expansion agent 20 imbibes fluid, it expands and pushes
za against active agent formulation 22. Agent formulation 22 therefore is
zs expelled from active agent delivery chamber 16 into the environment of use.
so The expansion agent 20 continues to expand and deliver active agent until
31 the expansion agent 20 reaches the open end 36 of the first housing 12.
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At that point, which is within an hour, preferably within about 30 minutes and
z usually within about 15 minutEa of the separation of the two housings,
s essentially all of the active agent formulation 22 has been delivered.
a FIG. 2 shows the dispensing device 1 of FIG. 1 in operation after
s separation of the two housings of the device. First housing 12 has been
s separated from second housing 14 by the expanding driving force of the
z second expansion agent 30, which has expanded in size as a result of
a imbibing fluid from the environment. The open end 36 of the first housing 12
s is now exposed to the environment so that the active agent can be delivered.
FIG. 3 shows first housing 12 and the active agent delivery chamber
11 16 of dispensing device 1 of FIG. 1 after essentially all of the active
agent has
~z been delivered to the environment. First expansion agent 20 has expanded
~s in size as a result of imbibing fluid from the open end 36 of first housing
12 to
~a push active agent formulation 22 out of the first housing 12.
15 FIG.4 shows, in side cross-sectiorial view, a further embodiment of
the delivery device according to the present invention. In this embodiment,
the partition 32 shown in FIGS. 1-3 has been omitted and the expansion
~s agent 30 pushes directly against active agent formulation 22 to accomplish
,s separation of housings 12 and 14.
2o FIG.5 shows, in side cross-sectional view, yet another embodiment of
the delivery device according to the present invention. This embodiment is
2z similar to the devices described above. A third housing 40, comprised of a
zs first section 42 and a second section 44, defines a second active agent
24 delivery chamber 46. The active agent formulation 48 contained within the
2s delivery chamber 46 may be the same,as the active agent formulation 22 or
2s may be different. The active agent itself may be the same or it may be
' 27 different. The housing may be comprised of a dissolvable material such as
a
is gelatin capsule so that when introduced into the fluid environment, the
is housing 40 will dissolve and active agent formulation 48 will be released
as a
so loading dose. Fluid will then be absorbed through housing 14 to effect
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separation of housing 12 and housing 14 and delivery of active agent
z formulation 22 as described above with regard to FIG. 1.
s FIG. 6 shows a further embodiment of the delivery device according to
a the present invention. The device is similar to the device of FIG. 1 in that
it
s comprises a first impermeable housing 12, and a second semipermeable
s housing 14. The first housing contains a first expansion agent 20 and an
active agent formulation 22. In this embodiment, the expansion agent 20 and
s the active agent formulation 22 do not completely fill the first housing 12.
s The housing 12 is configured to provide a fluid flow path 24 between the
inner
wall of housing 12 and the active agent formulation 22 to facilitate rapid
fluid
~ ~ entry into housing 12 after separation of the housings and rapid expansion
of
~z expansion agent 20 and delivery of active agent formulation 22. FIG. 6
~s shows the flow path between the inner wall of housing 12 and both the
active
~a agent formulation 22 and the first expansion agent 20, but the flow path
may
~s be limited to the area between the active agent formulation 22 and the
~s housing 12.
FIG. 7 shows yet another embodiment of the delivery device according '
~s to the present invention. In this embodiment a housing 50 contains an
s expansion agent 54 and an active agent formulation 56. Similar to the device
zo of FIG. 6, the expansion agent 54 and active agent formulation 56 do not
z~ completely fill housing 50. Instead, a fluid flow path 58 that facilitates
fluid
zz entry into the housing 50 and delivery of the active agent formulation 56
is
zs defined between the interior of housing 50 and both the active agent
za formulation 56 and the expansion agent 54. FIG. 7 shows the flow path 58
zs between the inner wall of housing 50 and both the active agent formulation
56
is and the expansion agent 54, but the flow path may be limited to the area
z~ between the active agent formulation 56 and the housing 50. A second '
zs expansion agent in the form of a plug 60 is a closure that seals the open
as end 62 of housing 50. Upon insertion into the fluid environment of use,
so the plug 60 swells and separates from the housing 50, thereby permitting
fluid
~ entry into the chamber.
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.,'
Because first expansion agents 20 and 54 operate by imbibing fluid
that enters the fluid flow paths 24 and 58 via the open ends 36 and 62 of
s housings 12 and 50, respectively, the wall of first housings 12 and 50 are
a preferably comprised of an impermeable material in at least the portion of
the
s housing that is in contact with the first expansion agents 20 and 54. In
this
s way, the first expansion agents 20 and 54 are not prematurely activated.
When an active, agent or an a<aive agent dosage form is sensitive to fluid
s from an exterior fluid present in the environment of use, it is preferred
that
s first housings 12 and 50 be substantially impermeable in their entirety to
the
ingress of the external fluid to serve as a means for substantially protecting
the active agent formulations 22 and 56 as well as the first expansion agents
20 and 54.
13 Because second expansion agent 30 operates by imbibing external
fluid while the housings 12 and 14 remain telescopically connected, the wall
~s of second housing 14 in at least the portion that is adjacent to second
expansion agent 30 must be semipermeable.
The walls of housings 12, 14 and 50 optionally comprise additional
~s ingredients such as, for example, a plasticizer. Impermeable and
semipermeable compositions suitable for use in housings 12, 14, and 50 as
well as suitable additives, are known in the art, examples of which are
disclosed in U.S. Patent 4,874,388.
The delivery devices of the present invention are nontoxic, biologically
2s inert, no!~allergenic and nonirritating to body tissue, and maintain their
24 physical and chemical integrity; that is, the devices do not erode or
degrade
as in the environment of use during the dispensing period. It is within the
scope
is of the invention that the devices be insoluble only during the period of
27 intended use and can thereafter dissolve away in the environment of use.
zs Thus, a dispenser is contemplated which is unaffected by its environment,
is solubility-wise, at the situs of use or which, alternatively, is only
slightly
3o soluble during the period of intended use, such that once its active agent
s~ content has been removed it will then dissolve or erode away.
AMENDED SliEE1'
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. ; : '' 4 .
The first and second expansion agents 20, 30, 56 and 60 are nontoxic,
z nonallergenic and biologically inert. The first and second expansion agents
3 in each device may be the same or they may be different. In one
embodiment, the expansion agents comprise an osmopolymer.
s Osmopolymers interact with water and aqueous biological fluids and swell or
s expand to an equilibrium state. Osmopolymers exhibit the ability to swell in
fluid and to retain a significant portion of the imbibed and absorbed fluid
a within the polymer structure. The expansion agents in another embodiment
s comprise an osmagent. Osmagents are also known as osmotically effective
solutes and compounds. Osmagents that can be used for the purpose of this
invention include inorganic and organic compounds that exhibit an osmotic
,z pressure gradient across a semipermeable, i.e. a fluid-permeable wall. The
expansion agents in yet another embodiment comprise an osmagent
14 dispersed within an osmopolymer. The expansion agents can be in tablet or
layer form, or can be a plurality of tablets or layers. The osmagent or
~s osmopolymer can be in any suitable form such as particles, crystals,
pellets,
granules, porous hydrogels, elastic polymeric sponges and the like.
~a Osmagents and osmopolymers are known to the art and are described in, for
example, U.S. Pat. Nos. 3,865,108, 4,002,173, 4,207,893, 4,327,725 and
20 4,612,008.
z~ Partition 32 may comprise a composition that is substantially
zz impermeable to the passage of fluid and that restricts passage of fluid
23 present in the expansion agent into the first dousing. It operates to
z4 essentially maintain the integrity of the active agent formulation 22 and
the
zs expansion layer. Additionally, partition 32 insures that the expanding
driving
zs force generated by the second expansion agent 30 is applied directly
against
z7 first housing 12 to separate the first and second housings. Thus, partition
32
za must be of sufficient strength, thickness and rigidity to transfer the
driving
is force against first housing 12. Representative impermeable materials useful
so as piston 32 are known to the art and described in, for example, U.S.
Patent
31 No. 4,874,388.
AMENDED SHEEN
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The active agent formulation comprises the active agent to be
delivered, as a liquid, solid, semisolid or thermosensitive composition,
s generally in a carrier substance and with or without additional inert
a ingredients. The active agent formulation may additionally include dosage
s forms comprising the active agent that are capable of maintaining their
s physical configuration and chemical integrity while housed within the
dispenser. These include, without limitation, tablets with or without a
density
s element; matrix tablets; spheres; pellets and elongated tablets; capsules;
s elementary osmotic pumps, such as those described in U.S. Patent
~o No. 3,845,770; mini-osmotic pumps, such as those described in U.S. Patent
» Nos. 3,995,631, 4,034,756 and 4,111,202; and multichamber osmotic
systems referred to as push-pull and push-melt osmotic pumps, such as
13 those described in U.S. Patent Nos. 4,320,759 and 4,449,983.
14 The pharmaceutically acceptable carrier may comprise more than .
~s one ingredient, such as, for example, a buffer, a viscosity regulating
vehicle,
a surfactant, dyes, a permeation enhancer, proteinase inhibitors, or other
formulation ingredients and additives, as are known in the art. The carrier
~s may contain more than one active agent. The active agent formulation can
erode or disintegrate and can be in the form of a wax formulation, solid core
ao or tablet, for example. The formulation can immediately dissolve upon
exposure to fluid or it may erode slowly with or without the presence of
as excipients for controlling erosion.
zs The active agent formulation can be designed in a multitude of ways to
2a provide a specific drug delivery profile. One embodiment may comprise a
2s formulation that contains a biologically acceptable solid surfactant which
is
Zs capable of slow dispersion in the environmental fluid. In another
27 embodiment, the formulation may contain a fluid-insoluble wax and a
Zs surfactant so that the formulation is susceptible to erosion in the
environment.
as In still another embodiment, the formulation may be effervescent and
provide
so drug delivery in a finely dispersed form. This is accomplished by the
addition
AM~~JD~D SHED
CA 02220301 1997-11-OS
2231 CIP 1 ,' ,
. '~ 6
of a solid basic compound capable of evolving carbon dioxide in the presence
2 of an acid in the environment of use. Suitable basic compounds are
s disclosed in U.S. Pat. No. 4,265. In a further embodiment, the formulation
4 may include an .osmotic agent or solute, such as those described above with
s reference to the expansion means, so that when the formulation comes into
s contact with the environmental fluid, it immediately dissolves. In yet
another
embodiment, the agent formulation can be comprised of an agent and a
s thermoresponsive composition. In this manner, the formulation would exhibit
s solid-like properties at room temperature of 21°C and within a few
degrees
~o Celsius thereof, and would have a melting point that approximates
mammalian body temperatures of 37°C and within a few degrees Celsius
thereof. The term "thermoresponsive" as used herein denotes the physical-
s chemical property of an agent carrier composition to exhibit solid, or solid-
like
~a properties at temperatures up to 31 °C and become fluid, semi-solid
or
~s viscous when disturbed by heat at temperatures from 31°C, usually in
the
range of 31 °C to 45°C. Suitable materials useful as active
agent carriers and
excipients are known in the art and are disclosed, for example, in U.S. Patent
~ s Nos. 4, 595, 583 and 4, 874, 388.
~s The amount of active agent employed in the delivery device will be that
zo amount necessary to deliver a therapeutically effective amount of the agent
to
achieve the desired result at the site of delivery. In practice, this will
vary
22 widely depending upon the particular agent, the site of delivery, the
severity
23 bf the condition, and the desired therapeutic effect, but will be between
0.01
ngand 500 mg.
25 . For proper delivery of the active agent, it may be desirable in some
26 instances for the dispensing device to deliver active agent to a particular
27 environment of use. Thus, it may be necessary for the device to remain in a
is particular environment of use until such time as the agent formulation has
29 been delivered or, alternatively, for the device to pass through one
particular
ANtENDED SHEET
CA 02220301 1997-11-OS
2231 CIP 1 _
' ' : ~ i7
environment to another prior to delivering agent formulation. In such cases,
z addition:~l elements are included in the device, or the device is designed
in
such a way to provide for such particular delivery. For example, When the
environment of use is the rumen of a ruminant animal, a density element may
s be included in the dispensing device so that the device is weighted to
remain
s within the rumen during the dispensing period. Density elements are known
in the art and are discussed in, for example, US Patent No. 4,874,388.
s When the environment of use is the human stomach, it may be desirable for
s the device to, for example, have a low initial density or to include air in
that
portion of the internal compartment of the device that also contains the agent
» formulation. In this manner, the device will float on the surface of the
stomach contents and remain in the stomach until the device opens to
~s release the formulation. Where it is desirable, on the other hand, to delay
the
~a release of an active agent which, for example, is inactivated by the
stomach
~s contents or may cause nausea or bleeding by irritating the gastric mucosa
so
~s that delivery in the stomach is not desired, an enteric coating can be
applied
over at least that portion of the housing of the dispensing device that is
comprised of a semipermeable membrane. Enteric coatings will remain intact
in the stomach but will rapidly dissolve once they arrive at the small
intestine,
2o thereafter allowing fluid to be imbibed to activate the dispensing device.
Enteric coatings are well known in the art and are discussed in, for example,
22 "Remington's Pharmaceutical Sciences", Mack Publishing Co., Easton, PA.
as The total delay time prior to separation of the two housings of the
Za dispensing device and the total delivery time of the active agent
formulation
Zs can be controlled by a number of means to provide a sharp start-up of
Zs delivery at a particular time with high accuracy. For example, the rate of
fluid
27 imbibition into each of the expansion agent, and thus the rate of expansion
of
2s the means, can be controlled by the particular choice of semipermeable
2s membrane or microporous screen. The rate of expansion of the expansion
so agent can also be controlled by the choice of composition of the expansion
AMENDED SWEET
CA 02220301 1997-11-OS
WO 96/38130 PCT/US96/07933
18
~ agent. The distance of overlap between the telescoping portions of the first
z and second housings can determine the period of time required for the two
s housings to separate. Combinations of such control means may be used.
a Such control means are known in the art and can be determined without
s undue experimentation.
s The fluid flow path 24 or 58 is formed between the active agent
formulation 22 and the housings 12 or 50 and may extend to the area
s between the first expansion agents 20 and 54 and the housings 12 and 50.
s The space occupied by the fluid flow path is at least 5% of the interior
~o cross-sectional area of the housing, usually between about 5% and 75% of
~ the interior cross-sectional area and often between 20 and 60% of the
interior
~z cross-sectional area.
The delivery device of the present invention can be manufactured by
~a standard manufacturing techniques. For example, in the preparation of
~s devices of the present invention, first housing 12 (the vessel) and second
housing 14 (the cap) may be separately molded or extruded to the desired
shape. Possible semipermeable materials from which the second housing 14
~s may be prepared include, for example, Hytrel~ polyester elastomers
~s (Du Pont), cellulose esters, water flux enhanced ethylene-vinyl acetate
zo copolymers, semipermeable membranes made by blending a rigid polymer
z~ with water-soluble low molecular weight compounds, and other
zz semipermeable materials known to the art. Impermeable materials from
zs which the first housing 12 may be prepared include, for example,
za polyethylene, polystyrene, ethylene-vinyl acetate copolymers, Hytrel~
zs polyester elastomers (Du Pont) and other impermeable materials known to
zs the art. Alternatively, the two portions of a hard gelatin capsule may be
a~ coated, one with an impermeable material and the other with a '
zs semipermeable material such as cellulose ester-based polymer mixtures.
29 In a presently preferred embodiment, the assembled device in closed
3o configuration is about the size and dimensions of a size "3" to size "00"
hard
~ gelatin capsule.
J CA 02220301 1997-11-OS
2231 CIP 1
19 '
In a presently preferred embodiment, the assembled device in closed
a configuration is about the size and dimensions of a size "3" to size "00"
hard
s gelatin capsule.
Expansion agent 20 is prepared from an osmotic material and formed
s into a shape that will fit within vessel 12. The layer is compressed into a
s tablet on a rotary bilayer tablet press. Expansion agent 30 is prepared from
an osmotic material and partition 32 is prepared from an impermeable
s material. Both are formed into a shape that will fit within cap 14, and
s compressed on~a bilayer rotary tablet press.
~o With reference to FIG. 1, the device is assembled as follows.
> > Expansion agent 20 is inserted into the vessel 12 at ifs end opposite its
open
end 36. Active agent formulation 22 is then placed on top of expansion
agent 20. The formulation may be in the from of a liquid, solid, semi-solid,
powder or shaped tablet or tablets, for example. The expansion agent 30 and
~s partition 32 are placed within the cap 14 and the cap assembly is placed
over
the end of the filled vessel 12 so that partition 32 is adjacent to the open
end
of the filled vessel 12.
~s The following examples are illustrative of the present invention.
~s They are not to be construed as a limitation of the scope of the invention.
zo
z~ EXAMPLE 1
za
23 A delivery device according to the present invention for delivering
24 progesterone into the colon for hormone replacement therapy is prepared as
2s follows:
Zs 100 mg of Crosspovidone XL-10 (International Specialty Products,
27 Wayne NJ) powder was compressed in a rotary press into a cylindrical tablet
2a to form the first expanding layer portion of the device. One face of the
tablet
Zs was convex to conform to the shape of the device, while the other face is
flat.
,~NIfNDEO SHEET
CA 02220301 1997-11-OS
WO 96/38130 PCT/US96/07933
1 The second expanding layer portion of the device was formed from an
2 osmotic layer and a barrier layer. The osmotic layer was formed as follows.
s Sodium chloride (NaCI) was sized and screened using a Quardo Mill with
a a 21 mesh screen at the speed set on maximum. This dry component was
s added to a granulator bowl of a Glatt fluid bed granulator with other dry
s components in the following proportions: 58.75 wt% sodium carboxymethyl
7 cellulose (NaCMC), 30 wt% NaCI (prepared as described above), 5.0 wt%
s hydroxypropylmethyl cellulose E-5 (Aqualon), and 1.0 wt% red ferric oxide.
s The dry components were thoroughly mixed for 10 minutes. 5.0 wt% HPC-EF
~o (Aqualon, ~Imington, DE) was dissolved in purified water and sprayed onto
~, the dry components until the components were in granular form. Magnesium
~~ stearate (0.25 wt%) was then added to the granulation and the granulation
~s was thoroughly mixed for 5 min.
~a The barrier layer part of the second expanding layer portion of the
15 device was formed as follows. 95 wt% hydroxypropylmethyl cellulose
~s E-5 (Aqualon) and 5.0 wt% stearic acid were sized and screened using a
~~ 40 mesh screen. The screened materials were added to a mixing vessel
~s of a Hobart mixer and blended for 10 min. Ethanol was then slowly added
19 while mixing until a wet mass was formed. The wet mass was then screened
ao through a 20 mesh screen and the wet granules were allowed to air dry for
2~ 12 hours. After drying, the granules were again passed through a 20 mesh
as screen.
is To form the second expanding layer portion of the device, osmotic
as layer granules (200 mg) and the barrier layer granules (50 mg) were
as compressed together in a rotary press into a cylindrical bilayer tablet
with the
2s osmotic layer face being convex and the barrier layer face being flat.
a~ Tabletting produced a clean, distinct interface between the two layers.
CA 02220301 1997-11-OS
WO 96/38130 PCT/US96/07933
21
The drug layer portion of the device contained 80 wt% progesterone,
2 10 wt% Crosspovidone XL-10 (International Specialty Products, Wayne NJ)
s and 9.5 wt% polyoxyethylene 40 stearate (ICI America International,
a Wilmington, DE). During preparation, each of the components was screened
s through a 40 mesh screen arnd the sized components were added to a mixing
s vessel in the appropriate proportions. The dry components were mixed
thoroughly until a wet mass was formed. The wet mass was then screened
s through a 20 mesh screen and the granules were oven-dried at 40°C for
s 24 hours. After drying, the granules were passed through a 20 mesh screen.
~o Magnesium stearate (0.5 wt%) was then added to the granulation and the
granulation was mixed thoroughly for 5 min. The drug layer granules
(125 mg) comprising 100 mg progesterone were then compressed in a
~s rotary press into a cylindrical tablet with the top and bottom faces being
flat.
The first housing (drug vessel), with one closed end and one open end,
~s and composed of ethylene vimyl acetate copolymer (9 wt% vinyl acetate),
was prepared by placing the palletized ethylene vinyl acetate copolymer
(EVA) in an extruder with a barrel temperature of 130°C and extruding
the
~s material into a mold for the vessel. The EVA was allowed to cool in the
mold,
~s after which the finished vessel was removed.
2o A clear, size O gelatin capsule was used to form the second housing
z~ (engine assembly) of the device. The second expanding layer portion of the
2z device was placed into the shorter segment of the capsule, the convex end
of
2s the tablet pointing into the closed end of the capsule.
Polyvinylpyrrolidone
2a (PVP k29-32, International Specialty Products) was dissolved in methanol
is and sprayed onto the capsule as a 2 mg subcoating. 75 wt% cellulose
zs acetate 398-10 (Eastman Chemical, Kingsport, NJ) and 25 wt% polyethylene
' 27 glycol 3350 (Union Carbide, Danbury, CT) were dissolved in an
is acetone/methanol (80/20 wt/wt) solution to make a 4 wt% solid solution.
is This solution was sprayed onto the subcoating to form a 70 mg
CA 02220301 1997-11-OS
WO 96/38130 PC'TlUS96/07933
22
semipermeable membrane. The second housing was dried at 50°C and
a 50 %RH for 72 hours and then at 50°C and ambient RH for 24 hours to
3 anneal the coating and remove the residue solvents.
a To assemble the delivery device, the first expanding layer portion of
s the device was placed into the first housing with the convex face of the
tablet
s pointing into the closed end of the housing. The drug layer was then placed
on top of the first expanding layer. The open end of this first housing was
a fitted into the open end of the second housing and the two housings were
s compressed together until the first housing, second expanding layer portion
~o and second housing fit together tightly.
The opening times of the devices are shown in Figure 8. The systems
2 were placed in artificial gastric fluid (pH 1.4) for 2 hours, then, in
artificial
3 intestinal fluid for 22 hours. The opening times were determined to be the
~a time interval at which the osmotic caps separated from the drug-containing
s vessels. The progesterone concentration was measured by HPLC following
~s solubilization with ethanol. Figure 8 shows the progesterone release
~ profiles of six devices, indicated that the opening times were between
~s 11 and 14 hours and the delivery was complete within 1 hour of the
s opening time.
ao
z~ EXAMPLE 2
22
2s A tablet containing 100 mg progesterone was encased in a #2 size
2a gelatin capsule and administered with the device according to Example 1.
as The capsule will disintegrate and deliver the initial 100 mg of
progesterone
is immediately upon administration and the remaining 100 mg will be
27 administered 13 hours later.
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WO 96/38130 PCT/US96/07933
23
' EXAMPLE 3
z
s A delivery device according to the present invention for delivering
a human growth hormone into t:he colon is prepared as follows:
f
s 90 mg of Crosspovidone XL-10 (International Specialty Products)
s powder was compressed in a rotary press into a cylindrical tablet to form
the
first expanding layer portion of the device. One face of the tablet was convex
a to conform to the shape of the device, while the other face is flat.
s The second expanding layer portion of the device was formed from an
~o osmotic layer and a barrier layer. The osmotic layer was formed as follows.
11 Sodium chloride (NaCI) was sized and screened using a Quardo Mill with a
~z 21 mesh screen at the speed set on maximum. This dry component was
added to a granulator bowl of a Glatt fluid bed granulator with other dry
components in the following proportions: 58.75 wt% sodium carboxymethyl
~s cellulose (NaCMC), 30 wt% NaCI (prepared as described above), 5.0 wt%
~s hydroxypropylmethyl cellulose E-5 (Aqualon), and 1.0 wt% red ferric oxide.
The dry components were thoroughly mixed for 10 minutes. 5.0 wt% HPC-EF
(Aqualon) was dissolved in purified water and sprayed onto the dry
components until the components were in granular form. Magnesium
zo stearate (0.25 wt%) was then added to the granulation and the granulation
z~ was thoroughly mixed for 5 minutes
zz The barrier layer part of the second expanding layer portion of the
zs device was formed as follows. 95 wt% hydroxypropylmethyl cellulose
za E-5 (Aqualon) and 5.0 wt% stearic acid were sized and screened using a
zs 40 mesh screen. The screened materials were added to a mixing vessel of a
zs Hobart mixer and blended for 10 min. Ethanol was then slowly added while
z7 mixing until a wet mass was formed. The wet mass was then screened
za through a 20 mesh screen and the wet granules were allowed to air dry for
zs 12 hours. After drying, the granules were again passed through a 20 mesh
so screen.
CA 02220301 1997-11-OS
WO 96/38130 PCT/US96/07933
24
To form the second expanding layer portion of the device, osmotic
2 layer granules (250 mg) and the barrier layer granules (50 mg) were
s compressed together in a rotary press into a cylindrical bilayer tablet with
the
4 osmotic layer face being convex and the barrier layer face being flat.
s Tabletting produced a clean, distinct interface between the two layers.
s The drug layer portion of the device contains 6.67 wt% recombinant
z human growth hormone (HGH) CARES-Serono, Norwell, MA), 78.33 wt%
s sodium salicylate (Bryant Lab, Berkeley, CA) and 15 wt% corn oil (Spectrum
..
s Chemical, Gardena, CA). During preparation, the sodium salicylate and HGH
o were each screened through an 80 mesh screen. The sized components
were dry-blended for 15 minutes. The corn oil was added dronwiSC? and
~z mixed until homogeous. The oily mass was then screened through a
~s 40 mesh screen to become granules. The drug layer granules (216 mg)
were then compressed in a rotary press into a cylindrical tablet with the top
~s and bottom faces being flat.
The first housing (drug vessel), with one closed end and one open end
and composed of ethylene vinyl acetate copolymer (9 wt% vinyl acetate),
~a was prepared by placing the pelletized ethylene vinyl acetate copolymer
~s (EVA) in an extruder with a barrel temperature of 130°C and
extruding the
Zo material into a mold for the vessel. The EVA is allowed to cool in the
mold,
after which the finished vessel was removed.
a2 A clear, size O gelatin capsule was used to form the second housing
23 (engine assembly) of the device. The second expanding layer portion of the
24 device was placed into the shorter segment of the capsule, the convex end
of
Zs the tablet pointing into the closed end of the capsule. 90 wt% cellulose
2s acetate 398-10 (Eastman Chemical, Kingsport, NJ) and 10 wt% polyethylene
z7 glycol 3350 (Union Carbide, Danbury, CT) were dissolved in an
Za acetone/methanol (80/20 wt/wt) solution to make a 4 wt% solid solution.
2s This solution was sprayed onto the capsule to form a 29 mg semipermeable
CA 02220301 1997-11-OS
WO 96/38130 PCT/US96/07933
1 membrane. The second housing was dried at 50°C and 50 %RH for 72
hours
2 and then at 50°C and ambient RH for 24 hours to anneal the coating
and
3 remove the residue solvents.
a To assemble the delivery device, the first expanding layer portion of
s the device was placed into the first housing with the convex face of the
tablet
s pointing into the closed end o~f the housing. The drug layer was then placed
z on top of the first expanding layer. The open end of this first housing was
s fitted into the open end of the second housing and the two housings were
a compressed together until the first housing, second expanding layer portion
1o and second housing fit together tightly. The opening time of the system
11 was measured as described in Example 1 and found to be about 6 hours.
1z A dog transit study was conducted in which the devices were fed to dogs.
1s The systems recovered from feces were assayed for the HGH formulation.
14 The results of this study showed that 86% of the HGH formulation on average
1s was delivered as compared to 62% for systems without the first expanding
1s layer portion.
17
.E~CAMPLE 4
19
Zo Delivery devices for delivering 125 mg of a progesterone formulation
i1 into the colon for hormone replacement therapy according to the present
a2 invention were prepared as foUlows.
2s The first housing, with one closed end and one open end was prepared
za by placing pelletized ethylene vinyl acetate copolymer (EVA, 9 wt% vinyl
2s acetate) in an extruder with a barrel temperature of 130°C to form a
vessel
Zs having a 0.762 cm ID and a 0.876 cm OD. An expansion agent tablet was
27 then placed in the first housing. The tablet was prepared from 125 mg of
2s Crosspovidone XL-10 (International Specialty Products, Wayne NJ) powder
i9 which had been compressed in a rotary press to have a diameter of 0.556 cm
so and a length of 0.556 cm. A fluid flow path between the tablet and the
inner
s1 wall of the housing measured 0.206 cm. An active agent formulation tablet
CA 02220301 1997-11-OS
WO 96/38130 PCT/US96/07933
26
~ was placed on top of the expansion agent tablet. The 125 mg active agent
z formulation tablet contained 80 wt% progesterone, 10 wt% Crosspovidone
s XL-10 (International Specialty Products, Wayne NJ) and 10 wt% '
a polyoxyethylene 40 stearate (ICI America International, Wilmington, DE).
s The formulation was prepared by screening the components through a
s 40 mesh screen, mixing with ethanol to form a wet mass, screening through a
~ 20 mesh screen, and oven-drying at 40°C for 24 hours. Magnesium
stearate
a (0.5 wt%) was added. The resultant active agent formulation was
s compressed in a rotary press into cylindrical tablets having a diameter of
~0 0.556 cm and a length of 0.556 cm. The tablet was placed into the first
~ housing leaving a fluid flow path between the active agent formulation
tablet
~z and the inner wall of the first housing of 0.206 cm. The flow path occupied
13 46% of the interior cross-sectional area of the housing.
~a The second housing was formed from a clear, size O gelatin capsule.
~s A second expanding layer of the device v~ias formed from the following dry
~s components: 58.75 wt% sodium carboxymethyl cellulose (NaCMC), 30 wt%
7 NaCI, 5.0 wt% hydroxypropylmethyl cellulose E-5 (Aqualon, Wilmington, DE),
~s and 1.0 wt% red ferric oxide. After mixing for 10 minutes, 5.0 wt% HPC-EF
~s (Aqualon, Wilmington, DE), dissolved in purified water was sprayed onto the
zo dry components to prepare granules. Magnesium stearate (0.25 wt%) was
z1 added and the second expanding layer granules were thoroughly mixed for
zz 5 minutes. An impermeable partition was formed by screening 95 wt%
zs hydroxypropylmethyl cellulose E-5 (Aqualon) and 5.0 wt% stearic acid using
z4 a 40 mesh screen. The screened materials were added to a Hobart mixer
zs and blended for 10 min. Ethanol was added until a wet mass was formed.
zs The wet mass was screened through a 20 mesh screen and allowed to air dry
z7 for 12 hours. The granules were then passed through a 20 mesh screen.
zs 200 mg of the expanding layer granules and 50 mg of the partition layer
zs granules were compressed together into a bilayer tablet in a rotary press.
so The tablet was placed into the gelatin capsule, expanding layer side down.
s~ Polyvinylpyrrolidone (PVP k29-32, International Specialty Products) was
CA 02220301 1997-11-OS
WO 96/38130 PCT/US96/07933
27
1 dissolved in methanol and sprayed onto the capsule as a 2 mg subcoating.
75 wt% cellulose acetate 398-10 (Eastman Chemical, Kingsport, NJ) and
' s 25 wt% polyethylene glycol 3350 (Union Carbide, Danbury, CT) was
dissolved in an acetone/methanol (80/20 wt/wt) solution. This 4 wt% solid
s solution was sprayed onto the subcoating to form a 70 mg semipermeable
s membrane. The second housing was dried at 50°C and 50 %RH for 72
hours
and then at 50°C and ambient RH for 24 hours. The open end of the
second
a housing was fitted over the open end of the first housing and the two
..
s housings were compressed together.
_ 10 -
11 EXAMPLE 5
12
1s Eight devices were prepared as described in Example 1. The systems
1a were orally administered to fasted dogs by placing the systems deeply into
1s the oral pharynx of the dogs so that they were swallowed intact. Water was
1s administered immediately following dosing to ensure passage of the system
17 into the stomach.
1$ The dogs were monitored at regular intervals during the normal work
1s day. At each observation, any fecal material that was found in the cages
was
2o carefully examined for the presence of the system. The time of recovery of
z1 the system was used to estimate the transit time of the device.
CA 02220301 1997-11-OS
WO 96/38130 PCT/US96/07933
28
Table I shows the transit times and amount recovered from these 8 devices.
2
3 TAg~E I
System # Transit time (hr.) Progesterone Residual
1 24.5-24.7 0.9
2 24.5-24.7 0.3
3 24.5-24.7 3.9
4 48.8-50.5 0.0
not recovered N/A
6 26.7-28.2 0.0
7 26.7-28.2 0.7
8 26.7-28.2 0.1
4
s As can be seen from Table I , although transit times vary with the
s individual dogs, the devices delivered greater than 95% of the active agent
formulation in a predictable manner. When similar devices were made with
s no fluid flow path between the housing and the active agent formulation, the
s delivery was not as predictable since the amount of active agent formulation
o remaining in the device varied from 0-82%.
The above description has been given for ease of understanding only.
1~ No unnecessary limitations should be understood therefrom, as modifications
~s will be obvious to those skilled in the art.
