Note: Descriptions are shown in the official language in which they were submitted.
~Z5~7$~8 ARC 1087
CONSTANT RELEASE SYSTEM ~ITH
PULSED RELEASE
FIELD OF THE INVENTION
This invention pertains to an osmotic delivery system. More
particularly, the invention relates to an osmotic system that de1ivers a
beneficial agent (1) at a modulated pulsed rate followed by a substan-
tially constant state~ (2) at a substantially constant rate interrupted by
a time related pulsed delivery of an increased amount of beneficial agent,
(3) at a substantially constant rate followed by a terminal pulsed
- delivery of an increased amount of beneficial agent, or (and) a terminal
pulse followed by a substantially zero order delivery period from the
osmotic system.
BACKGROUND OF THE INVENTION
Osmotic delivery systems, manufactured as an osmotic delivery
device, for delivering usefui agents are becoming increasingly important
articles of commerce and manufacture. These osmotic devices enjoy a wide
application in the pharmaceutical, veterinary, husbandry and agriculture
industries. The osmotic devices used by these industries exhibit a bene-
ficial agent release rate that is substantially constant, once thermo-
dynamic steady state conditions are established by the osmotic device. If
the thermodynamic activity of the beneficial agent is maintained substan-
tially constant in the device, then a steady state will be established with
, ~
~Z5~7~3
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the release rate of agent from the device being constant over a prolonged
period of timeO This is commonly referred to as zero order release, a
phrase suggested by physical-chemical kinetics.
The above described osmotic systems represent an outstanding
advancement in the zero order delivery art for dispensing a beneficial
agent continuously and at a constantly controlled rate. Now, it has been
unexpectedly discovered a therapeutic result can be effected by a pulse
dose of agent delivery. For example, estradiol administered at a low
pulsed dose inhibits gonada-tropin secretion, while at high pulsed doses
estradiol stimulates the ovulating surge of gonadotropin secretion, as
reported in Drugs, Vol. 23, pages 207-226, 1982. Other therapeutic agents
that produce a beneficial medical effect in this manner are pulsed methyl-
prednisolone treatment of collagenic and progressing glomerulonephritis;
pulsed cyclophosphamide-vincristine-adriamycin to patients suffering with
neuroblastoma; pulsed rifampicin therapy in leprosy; pulsed oxytocin in the
induction of labor; and pulsed insulin for the control of hyperglycemia; as
reported in Fertil. and Steril., Vol. 39, pages 695-699, 1983; Vutr. Boles,
Vol 21, pages 65-74, 1982; Br. J. Cancer, Vol 45, pages 86-94, 1982;
Fert. and Steril., Vol. 36, pages 553-5599 1981; Int. J. Radiat. Oncol. Biol.
Phys., Vol. 8, pages 915-919, 1982; J. Clin. Endocrinol. Metab., Vol. 53,
pages 184-91, 1981; and, Diabetes, Vol. 26, pages 571-581~ 1977.
Heretobefore, the prior art lacked a delivery system for
administering a useful agent at a pulsed rate, particularly at a pulsed
rate joined with a zero order rate of delivery. Thus, in the light of the
above presentation, it will be readily appreciated by those versed in the
dispensing art, that a critical need exists for a delivery system that can
deliver a useful agent at a substantially zero order rate which is (a)
~L25~7(3~
preceded by a pulsed delivery of the useful agent, (b) interrupted by a pulsed
delivery of the agent, (c~ terminated by a pulsed delivery of the agent, or (d)
is a terminal pulse followed by a substantially constant delivery from the
osmotic system. It will be further appreciated by those versed in the art, that
it is a novel and useful device made available for delivering an agent at a
constant rate and pulsed rate, such a device would have a positive value and
also represent a valuable contribution to the dispensing art.
Accordingly, in the light of the above presentation, in a first em-
bodiment this invention seeks to provide a novel and useful delivery device
that can deliver a useful agent at a controlled rate accompanied by a timed
pulsed delivery of an increased amount of useful agent.
In a second embodiment this invention seeks to provide an osmotic
delivery system that can deliver a beneficial drug at a controlled and constant
rate with a time dependent pulsed delivery occuring when thermodynamic condi-
tions have been established in the osmotic delivery system for effecting the
pulsed delivery of the useful agent.
In a third embodiment this invention seeks -to provide more effective
drug therapy by making available an osmotic delivery system for achieving
maximum therapeutic action by delivering a drug at controlled rate at a con-
stant concentration for a specific period that is accompanied by a concomitant
pulsed delivery of drug for achieving optimum drug benefits.
In a fourth embodiment this invention seeks to provide an osmotic
drug delivery system that administers a drug concentration within an effective
therapeutic range for the minimum period needed for treatment followed by the
drug released in a pulsed dose needed for the final therapeutic treatment.
In a fifth embodiment this invention seeks to provide an osmotic
~25~7~
delivery system that administers a useful agent at a pulsed rate follo~Jed by a
substantially zero order rate of useful agent delivery over a prolonged period
of time.
In a sixth embodiment this invention seeks to provide an osmotic
delivery system having modes of administration comprising steady drug delivery
with a pulsed frequency of drug delivery, which system can be used in a method
for dispensing a drug as a complete pharmaceutical regimen to a human, the use
of which requires intervention only for initiation, and optionally termination
of the regimen.
In a seventh embodiment this invention seeks to provide an osmotic
delivery system that dispenses a useful agent having terminal pulse followed
by a substantially ~ero order delivery period of useful agent from the osmotic
system.
In an eighth embodiment this invention seeks to provide an osmotic
delivery system characterized by zero order drug release with a late drug
delivery in an amount greater than the amount delivered at zero order release
from the device, for supplying an increased amount of drug to a patient requir-
ing more drug at a particular time of the day or night to maintain proper
therapeutic efficacy.
In a ninth embodiment this invention seeks to provide zero order
delivery of useful agent followed by a useful agent pulse at the end of the
regimen in order to increase the extent of absorption from the dosage form.
Other features and advantages of the invention will be more apparent
to those skilled in the dispensing art from a reading of the detailed descrip-
tion of the specification, taken in conjunction with the claims.
The invention will now be described in detail, including reference
- ~2si~7ai~
to the attached drawings in which:
Figure 1 represents the release rate in a conventional cosolubili- -
zation system;
Figure 2 represents the release rate in a cosolubilization system
according to this invention;
Figure 3 represents a further variation of a cosolubilization system
according to this invention;
Figure 4 represents various aspects of the behaviour of the release
rate of a modulating agent under various conditions;
Figures 5 and 6 represent the product of Example l;
Figure 7 repeats the release rate for the product of Example l;
Figure 8 represents the cumulative amount of active agent released
for the product of Example l;
Figure 9 represents the product of Example 2;
Figure 10 represents the release rate for the product of Example 4;
~igure 11 represents the release rate for the product of Example 5;
Figure 12 represents the release rate for the product of Example 7; and
Figure 13 represents the cumulative amount released by the product
of Example 7.
This invention resides in the unexpected discovery that an osmotic
delivery system can be provided having a modulated release kinetic pattern. The
invention provides an osmotic system that delivers a useful agent at a substan-
tial zero order rate of release for a given period of time, modulated by a time
dependent pulsed delivery of a greater than zero order amount of useful agent
delivered from the osmotic system. The zero order pattern can be modulated
by a pulse that precedes the zero order pattern, or by a zero order pattern
~S~7~3
modulated by a pulsed delivery that interrupts the ~ero order, or a modulated
pulse can occur at the end of the zero order delivery or by a terminal pulse
followed by ~ero order delivery. The unique release kinetics are achieved by
charging the osmotic system with the useful agent and a modulating agent. The
modulating agent is present in an amount such that it is the first o the two
agents to fall below saturation in the osmotic system. When this occurs, the
useful agent solubility increases and concomitantly the amount of useful agent
released increases, giving the pulsed release for the system.
- 5a -
~æ5~7~
ARC 1087
The useful agent and the modulating agenk are delivered by an
osmotic system manufactured as an osmotic device. The osmotic device
comprises a wall that surrounds and defines a compartment. The compartment
contains bo-th a dosage unit amount of a beneficial agent and an effective
amount of a modulating agent. The compartment optionally contains
dispensing ingredients used for easy manufacture and controlled delivery.
A passageway in the wall connects the compartment with the exterior of the
osmotic device for delivering the useful agent from the osmotic device.
The wall of the osmotic delivery device is formed of a semiper-
meable composition that does not adversely affect the useful agent, the
modulating agent, and the environment of use. The wall is formed of a
semipermeable composition that is permeable to the passage of an external
fluid, such as water and biological fluids, and it is impermeable to the
passage of useful agent, the modulating agent and other ingredients present
in the compartment. The selectively permeable polymers useful for manu-
facturing the osmotic device are represented by a member selected from the
group consisting essentially of a cellulose ester, cellulose diester,
cellulose triester, cellulose ether, cellulose ester-ether, cellulose
acylate, cellulose diacylate, cellulose triacylate, cellulose acetate,
cellulose diacetate, cellulose triacetate, cellulose acetate propionate,
and cellulose acetate butyrate. Suitable semipermeable polymers useful for
manufacturing osmotic devices are disclosed in United States Pat. Nos.
3,845,770; 3,916,899; 4,008,719; 4,036,228; and 4,111,210. These patents
are assigned to the ALZA Corporation of Palo Alto, California, the assignee
of this patent application.
In an embodiment, the wall of osmotic device can be a laminate
comprising a semipermeable lamina in laminar arrangement with a microporous
~.25~
AK(, lU~/
lamina. The semipermeable lamina is formed of the above polymers. The
microporous lamina comprises a plurality of micropores and interconnected
micropaths for admitting external fluid into the osmotic device. The
microporous lamina can comprise the above polymers additionally housing a
pore former that is dissolved, or leached from the lamina, when the osmotic
device is in dispensing operation in the biological fluid environment of
use. The pore formers are non-toxic, and they do not react with the
materials forming the microporous lamina. ûn their removal from the
lamina, the paths formed fill with fluid, and these paths become a means
for fluid to enter the osmotic device, acting in cooperation with the
semipermeable lamina. Typical pore formers are represented by sodium
chloride, potassium chloride, sorbitol, mannitol, polyethylene glycol,
hydroxypropyl methylcellulose, and hydroxypropyl butylcellulose. ûsmotic
dispensing devices having a laminated wall comprising a semipermeable
~0
lamina and a microporous lamina are disclosed in United States Pat. No.
4,160,452, assigned to the ALZA Corporation. The osmotic device in another
embodiment can be coated on its exterior surface with a coating containing
a dye. The coating is non-toxic and water soluble, containing a non-toxic
dye. The coating can be on the semipermeable wall~ or it can be on the
laminated wall. For example, the coating can comprise hydroxypropyl
methylcellulose mixed with Food, Drug and Cosmetic pharmaceutically accept-
able lake dye.
The expression passageway as used herein for an osmotic deviceincludes an aperture, orifice, bore, hole and the like embracing osmotic
dimensions through the wall. The expression also includes an erodible
element in the wall, such as a gelatin plug that erodes and forms an
osmotic passageway in the environment of use. A detailed description of
~2~7~3~
ARC 1087
osmotic passageways, and the maximum and minimum dimensions for osmotic
passageways are disclosed in United States Patent Nos. 3,845,770 and
3,916,899. These patents are assigned to the ALZA Corporation.
The compartment of the osmotic device contains the useful agenf
and the modulating agent present in nonequilibrium proportions. Prior to
this invention, the compartment contained9 for example, a useful agent and
an osmo-tic agent present in ratio, which represented the ratio of mutual
solubility between the two components in the compartment. In this inven-
tion, the useful agent and the modulating agent are present in a nonequi-
librium ratio. The modulating agent, which acts as a suppressant optional-
ly termed a desolubilizer for the useful agent, is used initially in an
amcunt sufficient for it to be the first of the two agents to fall below
saturation. Concurrent with this thermodynamic result, the solubility of
the useful agent is enhanced, thereby increasing the amount of useful agent
released at the pulsed moment.
The solubility of the useful agent is lowered when cosolubilized
with a modulating agent. More specifically, the process occurs in the
presence of fluid imbibed through the semipermeable wall into the
compartment, whereby in the presence of the imbibed fluid the modulating
agent diminishes the solubility of the useful agent. In conventional
cosolubilization, the useful agent and the osmotic agent are present in an
equilibrium ratio, and the release rate profile follows the traditional
pattern as seen in Figure la and Figure lb. In Figures la and lb, the
release rate profile for both the useful agent, line a, and the modulating
agent, line b, are linear over time, and then both decline in a like manner
as the concentration of both a and b fall below saturation in the fluid in
the compartment. In this invention, cosolubilization of the useful agent
~ 25170~
and the modulating agent are exemplified by a nonequilibrium ratio, and
the release rate profile is dep,cted in Figure 2a and 2b. In Figure 2a,
the concentration of the modulating agent b, is below the equilibrium ratio
in the compartment, and it is exhausted at an earlier time than the
exhaustion of the useful agent a. Consequently, there is a drastic
increase in the solubility of the useful agent a, in the less than
saturated modulating agent solution, and the release rate for the useful
agent is actually increased as seen by curve a in Figure 2b. A further
reduction of the concentration of the modulating agent will result in the
pair of release rate profiles illustrated in Figure 3a and Figure 3b.
Figure 3a illustrates the release rate profile for the reduced modulating
agent b concentration, and Figure 3b illustrates the delay release
of useful agent a resulting from the reduction of the concentration of the
modulating agent. In the light of this presentation, it becomes evident
this invention provides both an osmotic system and a method for
preprogramming to a desired time of release, a delayed release, or a de-
layed pulsed release of useful agent, that in either instance is achieved
by adjusting the conentration of the modulating agent in the osmotic
system.
2S The timing of the pulsed delivery of useful agent is a function
of the amount of modulating agent and the properties of the osmotic system.
The timing of the pulsed release to start is represented by the following
formula: l~o~h (I-St/p)
SO- ~t-K A
~517~
ARC 1087
wherein T is the time of beginniny of pulsed delivery; Mo is the weight
of the modulating agent present in the osmotic device initially; h is
the thickness of the semipermeable wall; St is the total solubility of both
the modulating agent and the useful agent in the osmotic device; p is the
density of the to-tal mass in the osmotic device; S is the mutual solubil-
ity of the modulating agent in aqueous media; QITtis the total osmoticpressure generated by of both the modulating agent and the useful agent in
the osmotic device; K is the permeability of the senipermeable wall; and A
is the total surface area of the compacted mass present in the compartment
of the osmotic device.
The expression useful agent as used herein denotes an algicide,
air purifier, anti-oxidant, biocide, catalysts, chemical reactant,
cosmetic, drug, disinfectant, fungicide, fermentation agent, food, food
supplement, fertility inhibitor, fertility promotor, germicide, herbicide,
insecticide, micro-organism attenuator, nutrient, pesticide, plant growth
promotor, plant growth inhibitor, preservative, sex sterilant,
sterilization agent, vitamin, and other useful agents that benefit the
~5 environment of use.
In the specification and the accompanying claims, the term drug
includes any physiologically or pharmacologically active substance that
produces a localized or systemic effect in animals, including warm blooded
animals, mammals, humans, primates, avians, reptiles, and pisces. The term
animals also includes domestic household animals, sport and farm animals,
such as sheep, goats, cattle, horses, and pigs, and for administering to
laboratory animals, jungle animals and zoo animals. The active drug can
include inorganic and organic compounds without limitation, those materials
that act on the central nervous system such as hypnotics and sedatives,
-` ~25~7~
psychic energizers, tranquilizers, antidepressants, anticonvulsants, muscle
relaxants, antiparkinson, analgesic, anti-inflammatory, anesthetic, muscle
contractant, anti~infective, anti-microbial, anti-malarial, hormonal
agents, sympathomimetic, metabolic aberration correcting agents, diuretics,
anti-parasitic, neoplastic, hypoglycemic, nutritional, fat, ophthalmic,
elutrolyte, cardiac and diagnostic agents. The drugs act on the peripheral
nerves, adrenergic receptors, cholinergic receptors, nervous system,
skeletal muscles, cardiovascular, smooth muscles, blood circulatory system,
synoptic sites, neuroeffector junctional sites, endocrine and hormone
systems, immunological system, reproductive system, skeletal system,
autocoid system, alimentary and excretory system, inhibitory of autacoids
and histamine systems, and system that acts on all sites of the central
nervous system. The amount of useful agent present in an osmotic system is
generally for a drug dosage unit amount to give the desired therapeutic
effect. Generally, the osmotic system can house from 0.05 ng to 5 g or
more, with individual systems containing for example, 25 ng, 1 mg, 5 mg, 50
mg, 100 mg, 125 mg~ 250 mg, 500 mg, 750 mg, lo5 9 and the like.
The modulating agents useful for the purpose of this invention
are soluble in aqueous and biological fluids, such as ionizing compounds,
inherently polar compounds, inorganic acids, organic acids, bases and
salts, and salts containing a common ion with the drug. In a preferred
embodiment the compounds are solids and they dissolve and form a solution
with fluids imbibed into the osmotic device. Examplary inorganic salts are
represented by a member selected from the group consisting essentially of
lithium chloride, lithium sulfate, magnesium chloride, magnesium sulfate,
potassium chloride, potassium sulfate, potassium acid phosphate, sodium
chloride, sodium sulfate, sodium sulfite, sodium nitrate, sodium nitrite,
and the like. Salts of organic acids are represented by a member selected
~2S~7~3~
from the group consisting essentially of sodium citrate, potassium acid
tartrate, potassium bitartrate, sodium bitartrate, and the like.
Representative of a therapeutically acceptable salt having a common ion
effect with a useful agent or drug is sodium chloride and sodium
indome-thacin; triflupromazine hydrochloride and sodium chloride; or
phenelzine sulfate and.sodium sulfate. The ionizable solid acids useful as
modulating agents are represented by a member selected from the group
consisting essentially of tartaric, citric, maleic, malic, fumaric,
tartronic, itaconic, adipic, succinic, mesaconic acid, and the like. The
basic compounds are represented by a member selected from the group
consisting essentially of potassium carbonate9 sodium carbonate, amnnonium
carbonate, and the like.
The concentration of the modulating agent inside the osmotic system
during its non-zero order period from an osmotic device is given by
equation 1.
Vt s
c
Vt ~ (t-tZ) (l)
wherein CO is the concentration of modulating agent in the osmotic device
during its non-zero order period, Vt is the total internal volume of the
osmotic device, ZO is the zero order release rate of the modulating agent,
SO is the solubility of the modulating agent, t is the time at the start of
the delivery, and tz is the zero order delivery time of the modulating
agent. The release rate pattern for the modulating agent of equation 1 is
depicted in Figure 4a.
12
~2517~8
ARC 1087
Conversely, the solubility of the useful agent increases
with the decrease of the modulating agent concentration such that as the
concentration of the modulating agent C approaches zero, C -~ 0, the
concentration of the useful agent Cd inside the osmotic system equals the
solubility of the useful agent Sd in water, Cd=Sd at large value. Also,
when the concentration of -the modulating agent CO equals the saturated
solubility SO of the modulating agent, the concentration of the useful
agent Cd equals the concentration of the mutual solubility of the useful
agent and the modulating agent, Cd=Sd at small value, as depicted by
Figure 4b. Table I lists experimental data of the solubility of a useful
agent, salbutamol, in different concentrations of modulating agent, NaCl.
The concentration of useful agent decreases nomotonically between
these two lirnits as the modulating agent's concentration is exhausted over
time. The useful agent rate of release from the osmotic device is
represented by equation 2.
(d~d (h) k~'t Cd (2)
wherein (dm/dt)d is the release rate of the useful agent, k is the water
permeability of the semipermeable membrane, A is the surface area of the
osmotic device, h is the thickness of the semipermeable membrane, Cd is the
concentration of useful agent in the osmotic device, and ~t is the osmotic
pressure generated by the formulation consisting of useful agent and modu-
lating agent.
13
- ~2~1L7~
l
:=> 2
~ O
C~: ~ tU_, P~ co o CD ~ C~ ~--O ~
~_ ~ ` E o ~'
J
m I ~ = ~ ~ t
C~~ ~ O - O C~ ~ M~
a c~ , ~ ~ o ~r-- ~ _
o o
o ~ ~
~n .¢ ~: E
~ C3 ~ _
z
a
Z ~ O ~ ~ r~ o
o
- 13a
~S~L7~31 !3
ARC 1087
Thus, as C0 continually diminishes according to equation 1, Cd
increases from a small value Sd to a large value Sd thus resulting in a
large increase in (d-t) according to equation 2, accompanied by a pulse in
the release profile as seen in Figure 4c, wherein (dm/dt)O is the release
rate of the modulating agent. In the osmotic device, the total driving
force for the drug delivery is the product of ~tCd . The ~tCd is maximum
at certain concentration of the modulating agent. In the example given
in Table I, the peak of the pulse occurs at about CO/SO ~ .38 . According-
ly, the ratio of modulating agent to useful agent, R, can be any value
O<R<( SO/Sd ) in which S0 / Sd is the mutual solubility of the useful agent
in the modulating agent.
The useful agent and the modulating agent can be present in the
compartment mixed with a binder, dye, lubricant, dispersant, and lik~
pharmaceutical compounding ingredients. The pharmaceutical compounding
ingredients include binders such as poly(ethylene glycol), gelatin, agar,
carboxycellulose, poly(vinyl alcohol)9 and poly(vinyl pyrrolidone).
Typical lubricants include stearic acid, magnesium stearate, zinc stearate,
aluminum stearate, halogenated vegetable oil, and talc. The compartment
can contain also a disintegrant to effect dissolution and solution forming
of the useful agent and the modulating agent, for enhancing controlled
delivery from the osmotic device. Typical disintegrants include lightly
cross-linkecl poly(vinyl pyrrolidone), corn starch, potato starch, Veegum,
bentonite, and citrus pulp. The coloring agents include Food, ~rug and
Cosmetic approved non-toxic dyes such as blue number 1 in lactose.
14
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ARC 1087
Optionally, the dye in the compartment, and a dye in the wall can be the
same dye or a different dye. The amount of a binder, a lubricant, or a
disintegrant usually is about 0.01% to 20% respectively of the total weight
present in the compartment.
The osmotic systems provided by this invention containing the
useful agent, the modulating agent and other ingredients are manufactured
by standard manufacturing techniques. For example, in one embodiment the
useful agent is mixed in a nonequilibrium ratio with the modulating agent,
and other compartment core ingredients by balling, calendering, stirring,
and pressing the ingredients into a preselected shape corresponding to the
shape of the final osmotic device. The material forming the wall of the
de~ice can be applied by dipping, molding or spraying the pressed blend.
One procedure for applying the semipermeable wall, or the laminated wall is
the air suspension technique. This technique can be used for manufacturing
a wall formed of a single layer, or for forming a laminated wall formed of
two layers. The air suspension procedure is described in llnited Sta~es
Pat. No. 2,799,241; in J. Am. Pharm. Assoc., Vol. 48, pgs. 451 to 459,
1959; and in ibid, Vol. 49, pgs. 82 to 84, 1960. An osmotic passageway is
made by mechanical drilling, laser drilling, punching or cutting with a
die. A procedure for forming the passageway using a laser is described in
United States Pat. Nos. 3,916,899; and in 4,088,864, both assigned to the
ALZA Corporation. The osmotic delivery device designed for oral
administration can embrace various conventional shapes and sizes such as
round with a diameter of 3/16 inches to 9/16 inches, or it can be shaped
like a solid capsule having a range of sizes from triple zero to zero, and
from 1 to 8. In these forms, the osmotic device is sized, shaped,
structured and adapted for administering the useful agent to warm-blooded
animals, which includes humansO Other standard manufacturing procedures
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ARC 1087
are described in Modern Plastic Encyclopedia, Vol. 46, pgs. 62 to 70~ 1969;
in Remington's Pharmaceutical Sciences, 14th Ed., pgs. 1649 to 1698; and in
The Therapy and Practice of K.Industrial Pharmacy, by lackmann et al., pgs.
197 to 225, 1970.
DESCRIPTION OF EXAMPLES
OF THE INVENTION
The following examples are merely illustrative of the present
invention and they should not be considered as limiting the scope of the
invention in any way, as these examples and other equivalents thereof will
become more apparent to those versed in the dispensing art in the light of
the present disclosure and the accompanying claims.
EXAMPLE
An osmotic therapeutic device for the controlled delivery of the
~-adrenergic stimulant and bronchodilator salbutamol, or ~-[(tert- ~
butylamino)methyl]-4-hydroxy-m-xylene-~ ~_diol-hemisulfate, delivered at
a constant rate modulated by a pulsed rate is made as follows: first, the
solubility of salbutamol hemisulfate (hereafter salbutamol) and the
modulating agent sodium chloride were measured in distilled water at 37C
and the measurements indicated the following solubilities: solubility of
salbutamol in water is 275 mg/ml, solubility of salbutamol in saturated
solution of sodium chloride is 16 mg/ml, solubility of sodium chloride in
water is 321 mg/ml, solubility of sodium chloride in saturated solution of
16
~25~7~3
ARC 1087
salbutamol is 320 mg/ml, and, the total solubility of salbutamol in
saturated sodium chloride and sodium chloride in water is 16 plus 320 equal
to 336 mg/ml.
Next, a composition is prepared containing salbutamol and sodium
chloride in a ratio of 1:5 as follows~ first, 14.45 mg of salbutamol,
72.30 mg of sodium chloride, 1.8 mg of cross-linked sodium
carboxymethylcellulose, and 1.8 mg of poly(vinyl pyrrolidone) are passed
through a 60 mesh screen and mixed in a blender for 1 hour. Then, the
blended ingredients are transferred to a larger blender and 8 ml of a
granulating fluid consisting of ethanol:water, 90:10, is added thereto and
all the ingredients blended for about 20 minutes. The homogenously blended
ingredients next are passed through a 20 mesh screen and dried in a forced
air oven at 50C -For 12 hours. After drying~ the granules are mixed with
0.9 mg of magnesium stearate and blended for 10 minutes. The granules are
transferred to a conventional Manesty tablet press and compressed with a
standard round 5/32 inch dye to a hardness of 1.5 to 2 Kp. The area of the
compressed drug core measured 0.41cm and weighed 91.3 mg.
The compressed core is transferred to an Aeromatic~ air
suspension coater, and a wall consisting of cellulose acetate having an
acetyl content is coated around the core. The semipermeable wall is formed
from a composition comprising 42.5% (12.759) of cellulose acetate having an
acetyl content of 39.8%, 42.5% (12.759) of cellulose acetate having an
acetyl content of 32.0%, 15% (4.59) of hydroxypropyl methyl cellulose in a
cosolvent consisting of methylene chloride-methanol~ 80%-20% (588 ml
-256 ml). After the wall is formed around the reservoir, they are trans-
ferred to a forced air oven and air dried for 48 hours at 50C. Next, anosmotic passageway having a diameter of 0.25 mm is laser drilled through
~5~5~7C~
the semipermeable wall. The semipermeable wall ~Jeight is 5.9 mg.
The osmotic useful agent delivery device prepared by the exampie
is illustrated in Figures 5 and 6. In Figure S, the osmotic device 10 is
seen comprising a body 11 with a passageway 12 that connects the exterior
with the interior of osmotic device 10. In Figure 6, osmotic device 10 is
seen in opened section at 13 and it comprises semipermeable wall 14 that
- surrounds and defines internal compartment 15. Compartment 15 contains
useful drug salbutamol 16, modulating agent sodium chloride 17, and other
dispensing ingredients. In Figure 7, the release rate pattern for the
device is seen consisting of an essentially zero order rate of release for
7 hours, modulated by a pulsed release of useful agent from 7 to 9 hours.
Figure 8 depicts the cumulative amount of useful agent salbutamol delivered
over a 12 hour delivery period. In the Figures 7 and 8, the bars represent
the maximum and the minimum rate of release at the time of measurement.
EXAMPLE 2
An oral, osmotic device for the controlled codelivery of
salbutamol and the bronchodilator terbutaline sulfate, 1-(3,5-dihy-
droxyphenyl)-2- (tert-butylamino) ethanol, at a constant rate interrupted
by a pulsed rate delivery is made as follows: first, 9.64 mg of salbutamol
5 mg of terbutaline sulfate, 24 mg of sodium chloride, 0.71 mg of poly
(vinyl pyrrolidone~, and 0.71 mg of cross-linked sodium carboxymethyl
cellulose are blended and passed through a 60 mesh screen. The ratio of
the salbutamol to sodium chloride in the composition is 1 to 3. Next, 8 ml
of a granulating fluid consisting of ethanol:water, 90:109 is added to the
screened blend, and all the ingredients blended for about 15 to 20 minutes.
18
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ARC 1087
The well-blended ingredients are passed through a 30 mesh screen ar,d dried
in a forced air oven for 12 to 15 hours at 50C. After drying, the
granules are mixed with 0.35 mg of stearic acid and blended for 10 minutes.
Then, the blend is compressed into a precompartment forming drug formula-
tion. The compressed drug formulation is placed in an air suspension
machine and coated with a microporous lamina forming composition. The
microporous lamina composition comprises 49% by weight of cellulose acetate
having an acetyl content of 39.8%, 28.5% by weight of hydroxypropyl methyl-
cellulose, and 22.5% by weight of polyethylene glycol 4000. The lamina is
formed from a methylene chloride-ethanol (95%) lamina solvent (80:20
wt:wt). The microporous lamina is 0.12 mm thick.
Next, an exterior semipermeable lamina is laminated onto the
microporous lamina in the conventional air suspension machine. The semi-
permeable lamina forming composition comprises 90% by weight of cellulose20
acetate having an acetyl content of 39.8% and 10% cellulose acetate having
an acetyl content of 32%. The semipermeable lamina is applied in laminar
arrangement from a solvent mixture comprising methylene chloride and
ethanol (80:20 wt:wt). The osmotic devices are dried and a passageway
having a diameter of 0.26 mm is drilled with a laser through the laminated
wall. In Figure 9, osmotic device 10 is seen comprising body 11,
passageway 12, opened section 13, outside semipermeable wall 14, inside
compartment 15, salbutamol 16, sodium chloride 17, inside microporous wall
18 and terbutaline 19.
, 19
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EXAMPLE 3
An oral, osmotic device for the controlled and continuous
delivery of oxprenolol-HCl modulated by a pulsed release of oxprenolol-HCl
is made by following the general procedure described about. In the osmotic
device of this example, the compartment houses a drug formulation
comprising a nonequilibrium formulation of 1 part of oxprenolol-HCl to 6
parts of potassium chloride:sodium chloride (50:50) mixture. The compart-
ment contains also 2 mg of dextrose, 2 mg of potato starch and 3 mg of
magnesium stearate. The formulation after compressing has a diameter of 9
mm. The device has a laminated wall consisting essentially of 60% by
weight of cellulose acetate having an acetyl content of 43.5% and a degree
of substitution of 3 and 407O by weight of cellulose acetate having an
acetyl content of 39.8 and a degree of substitution of 2.4. The semi-
permeable lamina is applied from a solvent consisting cssen~ially of
methylene chloride and methanol, 80:20by weight. The device has an
exterior microporous lamina consisting essentially of 55% by weight of
cellulose acetate having an acetyl content of 39,8%, 35% by weight of
sorbitol, and 10% by weight of polyethylene glycol 400. The lamina is
applied from a solvent comprising methylene chloride-methanol,
90:10 by weight. The semipermeable lamina is 0.12 mm thick, and the
microporous lamina is 0.13 mm thick. The device has a 0.25 mm passageway.
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EXAMPLE 4
The procedure of Example 1 is repeated to yield an osmotic device
wherein the ratio of salbutamol to sodium chloride is 1 to 7, and the
compartment of the osmotic device contained a drug formulation consisting
essentially of 9.6 mg of salbutamol hemisulfate, 56 mg of sodium chloride,
1.4 mg of poly(vinyl pyrrolidone), 1.4 mg of cross-linked sodium
carboxymethyl cellulose and 0,6 mg of magnesium stearate. The device
delivers salbutamol for 12 hours and has a terminal pulsed release of
salbutamol as seen in Figure 10. The osmotic device has a semipermeable
wall 4.9 mils thick (0.13 mm), comprising the semipermeable wall compo-
sition of Example 1.
EXAMPLE 5
The procedure of Example 1 is followed to yield an osmotic device
wherein the ratio of salbutamol to the modulating agent sodium chloride is
1 to 9. The compartment of the osmotic device contains a drug formulation
consisting essentially of 28.9 mg of salbutamol hemisulfate, 216 mg of
sodium chloride, 5.2 mg of poly(vinylpyrrolidone), 5.2 mg of cross-linked
sodium carboxymethyl cellulose, and 2.6 mg of magnesium stearate. The
osmotic device has a semipermeable wall weighing 20.1 mg comprising the
composition of Example 1. The device has a zero order rate of release of
salbutamol for 16 hours followed by an increased pulsed salbutamol for 8
hours. The 24 hour release pattern for the osmotic device is illustrated
in Figure 11.
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~RC 1087
EXAMPLE 6
An oral osmotic device that delivers acebutolol, a ~-adrenergic
blocker, is sized, shaped and manufactured for administration into the
gastrointestional tract as follows: 10 parts of acebutolol hydrochloride
and 90 parts of potassium carbonate, 8.75 mg of noncross-linked poly-
(vinylpyrrolidone) are mixed and passed through a 60 mesh stainless steelscreen and blended for 1 hour at room temperature. Next, the blended
ingredients are transferred to a larger blender and 40 ml of a granulating
fluid consisting of ethanol:water, 90:10 by volume, is added to the
blender, and the ingredients blended for 20 minutes. The thoroughly
blended ingredients are passed through a 30 mesh screen and dried in a
forced di r oven at 50C For 16 to 17 hours.
Then, the dried granules are passed through a 20 mesh screen and
5 mg of magnesium stearate is added to the granules. The ingredients are
blended for 15 minutes, and the blended granules transferred to a
conventional Manesty press. The ingredients are compressed into acebutolol
reservoirs having a diameter of about 6 mm.
The acebutolol precompartment forming compositions are
transferred to an air suspension coater and surrounded with a semipermeable
wall. The semipermeable wall is formed from a wall forming composition
comprising 35 9 of cellulose acetate having an acetyl content of 39.8 from
an organic solvent consisting essentially of 550 ml of methylene chloride
and 110 of methanol. After the semipermeable wall is formed surrounding
the drug reservoir, they are dried in a forced air oven for 50 hours at
50C. Next, a 0.4 mm passageway is laser drilled through the semipermearle
wall connecting the interior compartment with the exterior of the osmotic
device. The semipermeable wall weighed 8.6 mg and the device delivers the
drug for 12 hours time span modulated by a terminal pulsed delivery.
EXAMPLE 7
The procedure of Example 1 is repeated to manufacture an osmotic
device wherein the ratio of useful agent salbutamol to modulating agent is
10 1 to 9 to produce a device wherein the pulsed delivery occurs near the
middle of the release pattern. In Example 77 the osmotic device comprises
9.3% by weight of salbutamol, 1.9% by weight as the hemisulfate, 83.8% by
weight of sodium chloride, 2% by weight of cross-linked sodium
carboxymethyl cellulose, 2~ by weight of polyvinylpyrrolidone, and 1% by
weight of magensium stearate. The device has a semipermeable wall
consisting of 42.5% by weight of cellulose acetate having an acetyl content
of 39.8%, 42.5% by weight of cellulose acetate having an acetyl content of
32%, and 15% by weight of hydroxypropyl methylcellulose. The diameter of
the passageway is 0.25 mm, the semipermeable wall weighs 4~8 mg and the
wall is 0.06 mm thick. The measured release rate pattern for the osmotic
device is depicted in Figure 12 and the cumulative amount released is
25 illustrated in Figure 13.
The invention in one presently preferred embodiment pertains also
to a method for delivering a drug at a constant rate modulated by a pulsed
delivery of the drug, which method comprises the steps of: (A) admitting
orally osmotic device shaped, sized and structured into the gastro-
intestional tract of a patient, the osmotic device comprising: (a) a wall
formed of a nontoxic semipermeable composition that is permeable to the
passage of an exterior fluid and substantially impermeable to the passage
of drug and modulating agent, the wall surrounding and forming; (b) a
~L~25~L7(~3
compartment containing a dosage unit amount of drug and an effective amount
of modulating agent which modulating agent is a means for providing a
pulsed delivery of drug; and (c) a passageway in the wall for communicating
the exterior of the osmotic device with the interior of the osmotic device;
(B) imbibing exterior fluid through the semipermeable wall into the
compartment at a rate determined by the permeability of the semiperrneable
wall and the osmotic pressure gradient across the semipermeable wall to
form a solution comprising drug that is hydrodynamically and osmotically
delivered from the osmotic device; and (C) delivering the drug in a
therpeutically effective amount at a substantially constant rate
accompanied by a pulsed delivery of drug in an effective amount larger than
the constant rate through the passageway to the gastrointestional tract of
the patient to produce the desired beneficial effect of the constant rate
and the pulsed rate of drug delivery over the prolonged period of time.
The osmotic devices also can be used as an implant, or a conduct
can be attached to the passageway for intravenous delivery of drug, or for
subcutaneous delivery of drug. Drugs that can be delivered in a zero order
rate with a pulsed rate comprise a method for the controlled and
substantially constant delivery of salbutamol accompanied by a pulsed
delivery of salbutamol; a method for the controlled and constant delivery
of acebutolol accompanied by a time-dependent pulsed delivery of
acebutolol; a method for the management of asthma which method comprises
administerir,g to a patient suffering with asthma a therapeutically
effective amount of salbutamol at a constant rate interrupted by a pulsed
amount of salbutamol for producing a beneficial effect in said asthmatic
patient. The salbutamol and acebutolol also can be administered in a
method for producing bronchodilation in a patient in need of a
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bronchodilator, particularly for acute and chronic patients. The
beneficial agent is delivered at a controlled and continuous rate over a
period of time from 15 minutes to 24 hours accompanied by an intermittent
pulsed or terminal pulsed delivery of 15 minutes to 24 hours.
The invention provides an osmotic therapeutic system manufac-
tured in the form of an osmotic device for producing an improved drug
delivery program. While there has been described and pointed out the novel
features of the invention as applied to presently preferred embodiments,
those skilled in the art will appreciate that various modifications,
changes and omissions in the invention illustrated and described can be
made withou-t departing from the spirit of the invention.
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