Note: Descriptions are shown in the official language in which they were submitted.
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CONTROLLED DELIVERY OF BISPHOSPHONATES
FIELD OF THE INVENTION
This invention relates generally to the controlled delivery of drugs and more
specifically to the delivery of drugs from long term polymeric implanted
devices.
BACKGROUND OF THE INVENTION
Bisphosphonates are chemical compounds that have C-P bonds, especially P-
CP bonds. Some bisphosphonates that have been commercialized include:
alendronate, clodronate, pamidronate and etidronate. Others such as
cimadronate,
ibandronate, neridronate, olpadronate, tiludronate, risedronate, and
zoledronate are in
different stages of pharmaceutical development.
Due to the affinity that bisphosphonates exhibit in binding to bone, they have
been used to treat bone diseases such as osteoporosis, Paget's disease,
hypercalcemia
and bone cancer. Osteoporosis is a disease where reduction in bone mass takes
place
and specifically when that bone mass is 2.5 standard deviations less than that
of
young adults. This bone-brittling disease affects 20 million Americans, with
only
about 2 million currently being treated.
Bisphosphonates have been used to treat both post-menopausal osteoporosis
as well as corticosteroid-induced osteoporosis and have been shown to increase
both
the mineral density, as well as the mechanical strength of bone. For example,
the
lumbar spine density of patients with osteoporosis was increased by 7% over a
two
year period when patients were treated with 150 mg pamidronate orally, while
the
lumbar spine density of the placebo group decreased by 1 % over the baseline
[L.
Reid, et al., T Clin Endocrinol Metab., Z2: 1595 (1994)]. Etidronate has also
been
used to treat calcification, i.e, deposition of calcium phosphate in areas
that are not
normally calcified (soft tissue). Bisphosphonates therefore may have use in
the
prevention of kidney stones, dental calculi, ectopic bone formation and
calcification
of heart valves. Other applications for bisphosphonates include treatment for
Paget's
disease (localized foci of increased bone turnover), osteolytic tumor bone
diseases
and non-tumor induced hypercalcemia.
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The oral dose bioavailability of bisphosphonates in animals as well as
humans is low, between 1 % and 10% [H. Fleisch., Bisphosphonates in Bone
Disease, The Parthenon Publishing Group, \Tew York, p.57 (1995)]. It is
generally
lower for the more potent bisphosphonates such as amino derivatives which are
delivered in lower amounts. Relative to an intravenous reference dose, the
mean oral
bioavailability of alendronate in women was 0.7% for doses ranging from 5 to
40 mg
when administered after an overnight fast and two hours before a standardized
breakfast [Merck package insert for Fosamax (alendronate sodium tablets)]. The
bioavailability decreases further if the drug is given with meals, especially
when
calcium, iron or other multivalent canons are present. Oral delivery of
bisphosphonates is never administered during mealtimes or with orange juice,
coffee, milk or iron supplements. With alendronate, bioavailability was
reduced by
60% when given with coffee or orange juice. Bioavailability was negligible
when
alendronate was delivered up to two hours after a standardized breakfast
[Fosamax
package insert].
Bisphosphonates can also cause esophageal irritation to the upper
gastrointestinal mucosa. Esophageal adverse reactions such as esophagitis,
esophageal ulcers, and esophageal erosions with bleeding have been reported in
patients receiving treatment with Fosamax [Fosamax package insert].
With Fosamax, rare events of gastric and duodenal ulcers, some severe and
with complications, have also been reported. Additionally, oral
bisphosphonates
have been known to produce other gastrointestinal side effects such as nausea,
dyspepsia, vomiting, gastric pain and diarrhea.
There are also undesirable side effects upon intravenous (i.v.) delivery of
bisphosphonates, including deposition in other organs, mostly the liver and
spleen.
The deposition is proportionally greater when large amounts of the compounds
are
given [H. Fleisch, Bisphosphonates in Bone Disease, The Parthenon Publishing
Group, New York p. 58 ( 1995)]. This extraosseous deposition appears to be due
to
formation of metal complexes or aggregates after too rapid of an intravenous
injection. The formation of aggregates in the blood possibly explains the
renal
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failure that can ensue. When the aggregates are formed with calcium, a
decrease in
ionized calcium can take place resulting in hypocalcemia, an acute toxicity
which
needs to be rapidly corrected. Therefore, when bisphosphonates are
administered
intravenously, the rate of infusion will have to be carefully controlled and
monitored.
In healthy volunteers the bisphosphonates that are not deposited in the bone
are rapidly excreted in the urine. However, when renal insufficience is
present, the
excretion cannot take place efficiently, so increasing amounts of drug are
present in
the plasma, kidney, spleen, and tibia. Thus, bone absorption may increase.
Fosamax
is not recommended for patients with severe renal insufficiency [Fosamax
package
insert].
For some bisphosphonates, e.g., etidronate, the dosage required to decrease
bone absorption is similar to the dose causing inhibition of bone
calcification or
mineralization. This can cause osteomalacia, where the amount of bone is
normal
but the percent of mineral is reduced causing softening of the bones, which
then
allows bones to also fracture. Osteomalacia is distinct from osteoporosis,
because in
osteoporosis the amount of bone is decreased but the percent mineral is
normal.
When large doses of bisphosphonates are delivered (i.v. delivery) they can
form metal aggregates which deposit on non-calcified tissues and can cause
renal
failure and hypocalcemia. In patients with renal insufficiency,
bisphosphonates are
contraindicated because bone absorption can increase in a non-predictable
fashion.
What are needed are methods for delivery of bisphosphonates which avoid
the undesirable side effects associated with current oral medications and also
which
avoid the formation of metal aggregates caused by high dose delivery methods.
SUMMARY OF THE INVENTION
The present invention provides a drug delivery device useful in a method for
controlled delivery of bisphosphonates to a patient over an extended time
period.
This method provides a pharmaceutically effective amount of bisphosphonates,
while avoiding metal aggregation sometimes associated with prior art
intravenous
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administration of bisphosphonates and the undesirable gastrointestinal side
effects
associated with oral delivery.
Thus, in one aspect, the present invention provides an implantable drug
delivery device containing bisphosphonate. Suitably, the device delivers at
least one
bisphosphonate at a daily dose that is less than 50% of its oral dose for an
extended
period of time, e.g., three to twelve months. In one particularly desirable
embodiment, the device is a hydrogel polymer material and the bisphosphonate
is
alendronate.
In another aspect, the present invention provides a method of delivering
bisphosphonate to a patient. This method involves implanting the patient with
a
drug delivery device as described herein. Desirably, the bisphosphonates are
released at zero or near zero order kinetics and the drug delivery device is a
biodegradable polymer.
Other aspects and advantages of the invention will be readily apparent from
the detailed description of the invention.
Detailed Description of the Invention
The invention provides a device useful in a method for treating veterinary
and human patients with bone diseases by delivering bisphosphonates. This
device
is particularly well suited to treatment of such chronic illnesses as
osteoporosis and
Paget's disease, avoids the gastrointestinal problems associated with oral
medications containing bisphosphonates and provides a continuous low dosage
which avoids metal aggregate formation, renal failure and hypocalcemia. The
reduction in dosage provided by the use of the present invention is also
effective in
eliminating the problems associated with inhibition of bone mineralization.
Thus the present invention pertains to the parenteral delivery of low amounts
of bisphosphonates in a continuous, slow and controlled administration. More
specifically, the present invention pertains to an implantable device which
delivers
over an extended period of time from three months to one year, a
bisphosphonate at
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a daily dose which is from 0.5% to 50%, and preferably 0.5% to 25%, and most
preferably, 0.5% to 10%, of current oral doses of these compounds.
Bis~hos~honates
One of skill in the art can readily select the desired bisphosphonate for use
in
the device and method of the invention. Such bisphosphonates may be produced
using conventional methods or may be purchased commercially. For example,
alendronate ((4-amino-1-hydroxybutylidene)-bis-phosphonate) is commercially
available from Gentili and Merck Sharp & Dohme. A suitable daily oral of
alendronate dose for a human or non-human animal of about 80 kg (hereinafter
adult) is in the range of 20 to 40 mg. Cimadronate ([(cycloheptylamino)-
methylene]bis-phosphonate) is available from Yamanouchi. Clodronate
((dichloromethylene)-bis-phosphonate) is available from Astra and Boehringer
Mannheim, among others, and is typically administered in an amount of 400 to
1660
mg/daily adult oral dose. EB-1053 ([1-hydroxy-3-(1-pyrrolidinyl)-
propylidene]bis-
phosphonate is available from Leo. Etidronate, (1-Hydroxyethylidene)-bis-
phosphonate, is available from Procter & Gamble and Gentili and is typically
administered at 400 to 800 mg/ daily adult oral dose. Ibandronate, [1-Hydroxy-
3-
(methylpentylamino)propylidene]bis-phosphonate is available from Boehringer
Mannheim. Neridronate, (6-Amino-1-hydroxyhexylidene)bis-phosphonate, is
available from Gentili. Olpadronate, [3-(Dimethylamino)-1-
hydroxypropylidene]bis-phosphonate, is available from Gador and is typically
administered at 200 mg/daily adult oral dose. Pamidronate, (3-Amino-1-
hydroxypropylidene)bis-phosphonate, is available from Ciba-Geigy and Gador and
is typically administered at a daily adult oral dose of 250 to 300 mg.
Risedronate,
[1-Hydroxy-2-(3-pyridinyl)-ethylidene]bis-phosphonate, is available from
Procter &
Gamble. Tiludronate, [[(4-Chlorophenyl)thin]-methylene]bis-phosphonate, is
available from Sanofi. YH 529, [1-Hydroxy-2-imidazo-(1,2-a)pyridin-3-
ylethylidene]bis-phosphonate is available from Yamanouchi. Zoledronate, [1-
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Hydroxy-2-(1H-imidazol-1-yl)ethyliden]bis-phosphonate, is available from Ciba-
Geigy.
The device and method of the invention are particularly well suited to
extended delivery of bisphosphonates at a level which is lower than the oral
dose.
Thus, doses of the bisphosphonate or combinations thereof, selected for
delivery can
readily be selected by one of skill in the art. Generally, the doses are 0.5%
to 50%,
preferably, 0.5% to 25%, and most preferably 0.5% to 10%, of the oral doses
identified above. However, the dose may be adjusted as needed, depending upon
a
number of factors, including the age, weight, and condition of the veterinary
or
human patient. For example, doses in the range of 1 % to 5% of oral doses, or
other
alternative doses, may be desirable. Typically, the doses delivered by the
method of
the invention are also lower than current intravenous doses of bisphosphonate.
Optionally, the delivery devices may contain more than one bisphosphonate
and/or may contain additional ingredients. For example, it may be desirable to
administer a bisphosphonate in combination with a vitamin compound (e.g.,
Vitamin
D and analogs thereof), calcium, an anti-inflammatory agent (including, but
not
limited to corticosteroids), prostaglandin inhibitors, calcitonin, or another
active
agent.
Drug Delivery Devices
In various embodiments, the novel drug delivery device of the invention is
designed for implantation into the body of the animal to which the
bisphosphonate
formulation is to be delivered. The drug delivery devices of the invention are
desirably implants containing bisphosphonate in a reservoir, optionally
together with
another active agent and/or a pharmaceutically acceptable carrier. Such
reservoir
devices may be composed of hydrophobic or hydrophilic polymers, co-monomers,
metals, or other suitable materials. Alternatively, the drug delivery devices
may be
hydrogels, or other polymeric or co-monomer materials, made up of a matrix
having
the bisphosphonates and any other optional active agents or carriers
interspersed
throughout. Preferably, the bisphosphonates are dispersed homogeneously
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throughout the matrix. Yet other suitable implants are known to those of skill
in the
art and may be readily selected.
The novel implant drug delivery devices of the invention, in a preferred
aspect, are highly useful in the delayed/sustained and the immediate/sustained
release of bisphosphonates to animals, e.g., humans, sheep, dogs, cats,
turkeys,
cattle, etc. "Delayed/sustained release" is defined as delaying the release of
an
active agent until after placement in a delivery environment, followed by a
sustained,
preferably zero-order, release of the agent at a later time. Currently, this
type of
release is preferably achieved using a hydrogel delivery device, which may be
implanted in a dry or partially hydrated state. Thus, the release of an active
agent
may be delayed for several weeks. "Immediate/sustained release" is defined as
the
commencement of the release of bisphosphonate or other active agent
immediately
or soon thereafter after placement in a delivery environment, followed by
sustained
release of the active agent. The bisphosphonates will be present in the
delayed/sustained release compositions in varying amounts, depending upon the
effect desired.
The amount of bisphosphonates and any other agents employed in the drug
delivery devices of the invention will depend not only on the desired daily
dose but
also on the number of days that dose level is to be maintained. While this
amount
can be calculated empirically, the actual dose delivered is also a function of
any
interaction with materials and the carrier, if employed in the device.
Thus, the drug delivery device may contain a pharmaceutically acceptable
carrier which may be in the form of suspending media, solvents, aqueous
systems,
and solid substrates or matrices. These carriers are known to those of skill
in the art
and are not intended to be a limitation on the present invention.
For example, suspending media and solvents useful as the carrier include, for
example, oils such as silicone oil (particularly medical grade), corn oil,
castor oil,
peanut oil and sesame oil; condensation products of castor oil and ethylene
oxide
combining about 30 to 35 moles of ethylene oxide per mole of castor oil;
liquid
glyceryl triesters of a lower molecular weight fatty acid; lower alkanols;
glycols;
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polyalkylene glycols. The aqueous systems include, for example, sterile water,
saline, dextrose, dextrose in water or saline, and the like. The presence of
electrolytes in the aqueous systems may tend to lower the solubility of the
bisphosphonate in them. The solid substrates or matrices include, for example
starch, gelatin, sugars (e.g. glucose), natural gums (e.g. acacia, sodium
alginate,
carboxymethyl cellulose), and the like. The carrier may also contain adjuvants
such
as preserving, stabilizing, wetting and emulsifying agents, and the like.
In one suitable embodiment, hydrogels are suited as implantable delivery
vehicles for use in delivery of bisphosphonates according to the present
invention.
One particularly desirable hydrogel is prepared by mixing about 60 weight
percent to
about 95 weight percent comonomers, at least one of which is hydrophilic, and
sufficient amounts of a crosslinker and a liquid diffusion enhancer which is
miscible
with the comonomers, to yield a homogenous copolymer hydrogel having the
equilibrium water content (EWC) value in the range from about 20% to about
85%.
Most preferably, the polymerizable liquid mixture contains about 1 weight
percent
to about 50 weight percent diffusion enhancer which may be readily selected
from
among C1-C4 alkyl alcohol, allyl alcohol, tetrahydrofuryl alcohol, cyclohexyl
alcohol, diethylene glycol, polyethylene glycols, glycerol, acetone, ethylene
glycol
monomethyl ether, ethylene glycol monoethyl ether, glyceryl isopropylidene
ether
dioxane, tetrahydrofuran; ethyl acetate; dimethyl sulfoxide; water, and
mixtures
thereof. The crosslinker and comonomers may be readily selected by one of
skill in
the art. This hydrogel, as well as details on its preparation, are provided in
preferred
hydrogel is described in co-pending International Patent Application Number
PCT/US00/01664, filed January 26, 2000 for "HYDROGEL COMPOSITIONS
USEFUL FOR THE SUSTAINED RELEASE OF MACROMOLECULES AND
METHODS OF MAKING SAME". Other suitable hydrogels may be readily
selected by one of skill in the art. See, e.g., US 5,266,325; US 4,959,217;
and US
5,292,515.
The hydrating liquid useful in the hydrogels used in the invention is
typically
a liquid simulating the environment in which the active compound will be
released,
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e.g., body fluid, sterile water, tear fluid, physiological saline solution,
phosphate
buffer solution, and the like. While liquids other than water are useful as
the
hydrating liquid, the degree to which a hydrophilic membrane is hydrated is
referred
to as its "water content".
In another suitable embodiment, the implants may be in the form of an
osmotic pump, such as described by Alza [see, e.g., U. S. Patent No. 4,285,987
and
U. S. Patent No. 5,273,752] or Merck [see, e.g., European Patent No. 314,206],
among others. In another example, the implant device may be composed of a
hydrophobic membrane material, such as ethylenemethacrylate (EMA) and
ethylenevinylacetate (EVA). Other suitable implant delivery devices include
bioresorbable polymer systems [see, e.g., International Patent Application No.
W098/44964, Bioxid and Cellomeda; U. S. Patent No. 5,756,127 and U. S. Patent
No. 5,854,382]. Suitable bioresorbable implant devices have been described in
the
literature and may be composed of, for example, polyesters, polyanhydrides, or
lactic
1 S acid/glycolic acid copolymers [see, e.g., U. S. Patent No. 5,817,343
(Alkermes
Inc.)].
Regardless of whether the delivery device is composed of a hydrogel,
EVA/EMA polymer, bioresorbable material, metal or other material, the devices
useful in the inventions) provide sustained release of bisphosphonates over
extended periods of time. This time period may range from a month to a year or
several years, depending on the desired administration regimen. Preferably,
the
bisphosphonates will be released in daily doses, over a period of about 1 week
or
longer, and preferably over a period of about three months to one year, it
being
understood that this time factor is a variable depending on the rate-releasing
membrane of choice, its interconnecting pore structure, the bisphosphonates of
choice, the solubility of the active compounds) in the liquid medium, and
other
considerations well known to those skilled in the art.
Methods for determining the release profile (i.e., delay time, release rate
and
duration) of a bisphosphonate formulation from the delivery device of the
invention
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are well known, and include use of the Fick's First Law of Diffusion. See,
e.g., US
Patent 5,266,325, which is incorporated herein by reference.
Where the delivery device is composed of a hydrogel, it may be prepared
such that the hydrogel forms the walls of a cavity which contain the active
agent. A
predetermined amount of at least one bisphosphonate per se or an admixture
with an
inert, non-toxic material or as a suspension in a non-toxic material or as a
suspension
in a non-toxic medium, e.g., medical grade silicone oil, is introduced into
the cavity
to partially fill the core. The void in the core is thereafter sealed to
prevent leakage
into or out of the vesicle. Preferably this can be accomplished by introducing
sufficient polymerizable material into the void to cover the layer of inert
material or
to substantially or completely fill the void and thereafter effecting a
polymerization
reaction to form a plug of water-swellable, water-insoluble polymer which
seals the
opening of the vesicle. The hydrophilic polymer plug, upon maximum hydration,
will have an equilibrium water content value of the hydrophilic vesicle. Using
polymerizable material comprising ethylenically unsaturated monomers) and
desirably crosslinking agent(s), a polymer plug grafted to the inner surface
of the
vesicle can be obtained.
In a currently desired embodiment, hydrophilic cartridges are prepared by the
rotational casting of polymerizable material in a tubular mold, as described
in US
Patent 5,266,325 and 5,292,515, which are incorporated herein by reference.
Briefly, the internal radius of the tube is approximately 1.2 to 1.3 mm, and
may be
larger. The tube is rotated about its longitudinal axis which is maintained
parallel to
the ground. Rotational speeds are of the order of 2150 rpm, though greater or
lesser
speeds could be used, e.g., 1000 rpm or less to 3000 rpm and more. The tubes
are
fabricated of polyethylene, polypropylene, glass, or other suitable materials.
When
the polymerizable mixture within the spinning tube stabilizes to the
predetermined
shape, U.V. light at a distance of less than one foot is then directed at the
spinning
tube for several minutes, e.g., about 7 minutes, to polymerize the mixture to
the
shaped product. The shaped product is cured and annealed as follows:
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Thermal Cure: 60 minutes at 65 ° C; Postcure: 30 minutes at 95
°C; Annealing: 30
minutes at 115 °C with gradual cooling to about 25 °C.
After shaping and polishing the closed end of the cartridge to a oval-like
cylindrical profile, there is obtained small cylindrically-shaped objects
having
smooth, unscored cylindrical surfaces. The dimensions of the cartridges are as
follows: internal radius 0.98 mm; external radius l.3mm; length 25mm.
Smooth, unscored cylindrically-shaped objects of various lengths, e.g., up to
25 cm and longer, can also be prepared in accordance with the teachings
herein.
Such objects, in a hydrated state or plasticized with a non-toxic,
biocompatible
material, can be formed into desired shapes. A ring shape, for use as
pessaries,
surgical implants, etc. Yet other drug delivery devices and implant shapes may
be
prepared using techniques known to those of skill in the art or purchased from
commercial sources.
Use of Delivery Devices
The invention provides a method of delivering bisphosphonates, alone or in
combination with other active agents, to a veterinary or human patient in need
thereof. Typically, such a patient has a bone disease or condition such as
osteoporosis, Paget's disease, hypercalcemia or bone cancer.
In order to treat a patient, a delivery device as described herein can be
implanted subcutaneously in an animal by perforation. Such devices are
characterized by a length of 10 to 50 mm, or less (e.g., 6 to 9 mm), an
external
diameter of 2 to 5 mm, or less (e.g., 1.5 to 1.9 mm). The dimensions of the
device
(e.g., a cartridge) can vary outside of the limits stated above depending, in
particular,
on the medical application involved. Animals such as sheep, cows, goats,
cattle, and
large animals, in general, can tolerate implantation by perforation of larger
dimensional drug delivery devices. Implantation can be effected by other
means,
e.g., open surgery.
In one embodiment, the drug delivery device is a biodegradable matrix,
which is bioresorbed and eliminated from the body following completion of the
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course of therapy, e.g., three to twelve months, or more. Alternatively, a
selected
delivery device may be removed by surgical means.
Suitably, treatment of bone conditions using the drug delivery devices of the
invention may be readily combined with other therapies administered by routes
other
through the use of an implantable devices. For example, treatment with
bisphosphonates according to the invention may be combined with other
treatments
or therapies, including, for example, calcium supplements, radiation,
chemotherapy.
The following examples are provided to illustrate the invention and do not
limit the scope thereof. One skilled in the art will appreciate that although
specific
reagents and conditions are outlined in the following examples, modifications
can be
made which are meant to be encompassed by the spirit and scope of the
invention.
Examples - Preparation of Delivery Devices for Bisl hosphonates
Monomeric mixtures containing one or more comonomers (listed in Table 1)
and 0.5% trimethylol propane trimethacrylate were prepared. To the resulting
mixtures, 0.2% benzoin methyl ether was added and dissolved. Representative
samples from these formulations were cured and the resulting polymers
evaluated
for their hydration characteristics, expressed as % Equilibrium Water Content
(%
EWC). These results are also shown in Table 1.
Table 1. Polymer compositions and their % EWCs used in examples of drug
delivery devices prepared for the release of bisphosphonates.
Example
Hydroxethyl Hydroxypropyl Methyl Methacrylic EWC
Methacrylate Methacrylate Methacrylate Acid
1 - 49.5 50 - 7.3
2 - 74.5 25 - 13.6
3 99.5 - - - 37.7
4 99.0 - - 0.5 40.4
5 98.7 - - 0.8 46.0
6 97.5 - - 2.0 55.6
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An implant cartridge was prepared essentially as described in US 5,266,325.
More particularly, the mixture was deoxygenated by bubbling nitrogen through
it for
minutes. To avoid premature polymerization the mixture was shielded from
light.
One end of a polypropylene tube (65 mm in length and d; of 2.5 mm) was plugged
5 with a silicone sealant; the other end of the tube was sealed with a plug
made by
injecting a small amount of the above mixture, which was cured under a UV lamp
for 5 minutes. Using a syringe filled with said mixture, the silicone plug was
punctured and the tube was filled with the mixture to a height of about 10 mm
from
the top. The tube was inserted in a spin casting apparatus and spun (spinning
axis
10 parallel to the ground) at about 2200 rpm. The centrifugal force created by
the
spinning tube caused the radially outward displacement of the mixture to
assume a
predetermined hollow cylindrical liquid configuration (i.e., a hollow tube of
polymerizable liquid mixture). The spinning tube was then exposed to UV light
for
7 minutes to polymerize the "liquid tube" to a solid hydrophilic tube
(cartridge).
The cartridge within the polypropylene tube was postcured for 14 hours at 65
° C,
followed with an additional 40 minutes at 1 OS ° C, and annealed at 116
° C for 40
minutes, and then slowly cooled to 22 ° C.
The cartridge was ejected from the tube, inspected for defects, and cut to a
length of 30 mm. There was obtained a precisely dimensional plastic cartridge
fabricated of crosslinked homogeneous polymers characterized by recurring
hydrophilic units. The weight of the cartridge was recorded.
This cartridge is available for filling with alendronate sodium (4-amino-1-
hydroxybutylidene) bisphosphonic acid monosodium salt trihydrate, by tightly
packing it to a 20 mm height. The filled cartridge is weighed again to
determine the
weight of active agent bisphosphonates. The empty space of the cartridge is
filled
with the aforesaid monomeric mixture. Part of the cartridge containing the
active
agent is covered with aluminum foil. The cartridge is then placed in the lathe
and
spun slowly (spinning axis of cartridge parallel to ground) under a UV lamp
for 5
minutes to effect polymerization of the mixture. Postcuring of the polymer
plug was
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effected by maintaining the cartridge at 50° C for 18 hours. The end
product is an
implantable drug delivery device containing bisphosphonates.
The bisphosphonates used for evaluation of these devices were etidronic acid
and pamidronic acid. The solubility of etidronic acid is relatively high,
therefore the
delivery devices for this compound were prepared from lower % EWC polymers as
shown in examples 1 and 2. Pamidronic acid was used in examples 3, 4, 5 and 6.
In vitro release rates were evaluated by placing the implants in individual
glass vials containing 10 ml of physiological saline. The vials and their
contents
were placed in a shaker waterbath maintained at 37°C and agitated at 60
strokes/minute. The elution media were changed weekly, and assayed for their
drug
contents.
Detection of small amounts of bisphosphonates (microgram levels) is
generally very difficult. Visual inspection of samples undergoing the elution
testing
indicates that the etidronic acid is being released. The colorimetric method
adopted
1 S for evaluation of pamidronic acid proved to be more reliable and we were
able to
evaluate the release rates. The results from pamidronic elution study
available to
date are shown in Table 2.
Table 2. Release rates of pamidronic acid from hydrogel implants as a function
of polymer Equilibrium Water Content (% EWC).
Example Implant Pamidronic Acid Release Rate (,ug/day)
Week 1 Week 2 Week 3 Week 4 Week 5
3 37% 0 53 610 1,281 884
4 40% 0 245 377 1,239 4,162
5 46% 0 336 2,051 2,177 4,931
6 55% 0 1,503 3,045 1,101 1,167
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WO 00/64516 PCT/US00/10696
All publications cited in this specification are incorporated herein by
reference herein. While the invention has been described with reference to a
particularly preferred embodiment, it will be appreciated that modifications
can be
made without departing from the spirit of the invention. Such modifications
are
intended to fall within the scope of the appended claims.
