U.S. patent application number 10/327018 was filed with the patent office on 2003-05-22 for formulation for controlled release of drugs by combining hydrophilic and hydrophobic agents.
Invention is credited to Kochinke, Frank, Wong, Vernon.
Application Number | 20030095995 10/327018 |
Document ID | / |
Family ID | 23823541 |
Filed Date | 2003-05-22 |
United States Patent
Application |
20030095995 |
Kind Code |
A1 |
Wong, Vernon ; et
al. |
May 22, 2003 |
Formulation for controlled release of drugs by combining
hydrophilic and hydrophobic agents
Abstract
Combinations of hydrophilic and hydrophobic entities in a
biodegradable sustained release implant are shown to modulate each
other's rate of release. Formulations of a therapeutically active
agent and modulator provide substantially constant rate of release
for an extended period of time.
Inventors: |
Wong, Vernon; (Rockville,
MD) ; Kochinke, Frank; (San Jose, CA) |
Correspondence
Address: |
Mika Mayer
Morrison & Foerster LLP
755 Page Mill Road
Palo Alto
CA
94304-1018
US
|
Family ID: |
23823541 |
Appl. No.: |
10/327018 |
Filed: |
December 20, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10327018 |
Dec 20, 2002 |
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09160635 |
Sep 24, 1998 |
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09160635 |
Sep 24, 1998 |
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08459134 |
Jun 2, 1995 |
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5869079 |
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Current U.S.
Class: |
424/426 |
Current CPC
Class: |
A61P 31/12 20180101;
A61P 29/00 20180101; Y10S 514/953 20130101; A61K 47/34 20130101;
A61F 2210/0004 20130101; A61K 9/0048 20130101; A61K 9/204 20130101;
A61K 9/2054 20130101; A61K 9/0024 20130101; A61P 35/00 20180101;
A61F 9/0017 20130101; A61K 9/2013 20130101; A61K 9/0051 20130101;
A61P 27/02 20180101; A61P 31/04 20180101 |
Class at
Publication: |
424/426 |
International
Class: |
A61K 009/00 |
Claims
What is claimed is:
1. An implant for sustained drug release comprising: a
pharmacologically acceptable biodegradable polymer which is
degraded at the site of implantation, wherein said biodegradable
polymer comprises at least about 20 weight percent of the implant;
a therapeutically active agent at a concentration from 10 to 50
weight percent of the implant; a release modulator at a
concentration from 10 to 50 weight percent of the implant; wherein
said therapeutically active agent is released within a therapeutic
dosage which does not vary by more than about 100% for a period of
at least about 3 days.
2. An implant according to claim 1, wherein said release modulator
is a hydrophilic entity and said therapeutically active agent is a
hydrophobic entity.
3. An implant according to claim 2, wherein said release modulator
is hydroxypropylmethylcellulose.
4. An implant according to claim 1, wherein said release modulator
is a hydrophobic entity and said therapeutically active agent is a
hydrophilic entity.
5. An implant according to claim 1, wherein said release modulator
is a therapeutically active agent.
6. An implant according to claim 5, wherein said active agent is a
steroid and said release modulator is a water soluble
antibiotic.
7. An implant according to claim 5, wherein said active agent is a
non-steroidal antiinflammatory drug and said release modulator is a
water soluble antibiotic.
8. An amplant according to claim 1, wherein said biodegradable
polymer is poly-lactate glycolic acid copolymer.
9. An implant for sustained drug release comprising: poly-lactate
glycolic acid copolymer at a concentration of at least about 20
weight percent of the implant; methotrexate at a concentration from
10 to 50 weight percent of the implant; ciprofloxin at a
concentration from 10 to 50 weight percent of the implant; wherein
said methotrexate is released within a therapeutic dosage which
does not vary by more than about 100% for a period of at least
about 3 days.
Description
TECHNICAL FIELD
[0001] Biodegradable implants formulated for controlled, sustained
drug release.
BACKGROUND OF THE INVENTION
[0002] Solid pharmaceutically active implants that provide
sustained release of an active ingredient are able to provide a
relatively uniform concentration of active ingredients in the body.
Implants are particularly useful for providing a high local
concentration at a particular target site for extended periods of
time. These sustained release forms reduce the number of doses of
the drug to be administered, and avoid the peaks and troughs of
drug concentration found with traditional drug therapies. Use of a
biodegradable drug delivery system has the further benefit that the
spent implant need not be removed from the target site.
[0003] Many of the anticipated benefits of delayed release implants
are dependent upon sustained release at a relatively constant
level. However, formulations of hydrophobic drugs with
biodegradable matrices may have a release profile which shows
little or no release until erosion of the matrix occurs, at which
point there is a dumping of drug.
[0004] The eye is of particular interest when formulating
implantable drugs, because one can reduce the amount of surgical
manipulation required, and provide effective levels of the drug
specifically to the eye. When a solution is injected directly into
the eye, the drug quickly washes out or is depleted from within the
eye into the general circulation. From the therapeutic standpoint,
this may be as useless as giving no drug at all. Because of this
inherent difficulty of delivering drugs into the eye, successful
medical treatment of ocular diseases is inadequate.
[0005] Improved sustained release formulations which allow for a
constant drug release rate are of considerable interest for medical
and veterinary uses.
[0006] Relevant Literature
[0007] U.S. Pat. Nos. 4,997,652 and 5,164,188 disclose
biocompatible implants for introducing into an anterior chamber or
posterior segment of an eye for the treatment of an ocular
condition.
[0008] Heller, Biodegradable Polymers in Controlled Drug Delivery,
in: CRC Critical Reviews in Therapeutic Drug Carrier Systems, Vol.
1, CRC Press, Boca Raton, Fla., 1987, pp 39-90, describes
encapsulation for controlled drug delivery. Heller in: Hydrogels in
Medicine and Pharmacy, N. A. Peppes ed., Vol. III, CRC Press, Boca
Raton, Fla., 1987, pp 137-149, further describes bioerodible
polymers.
[0009] Anderson et al., Contraception (1976) 13:375 and Miller et
al., J. Biomed. Materials Res. (1977) 11:711, describe various
properties of poly(dL-lactic acid). U.S. Pat. No. 5,075,115
discloses sustained release formulations with lactic acid polymers
and co-polymers.
[0010] Di Colo (1992) Biomaterials 13:850-856 describes controlled
drug release from hydrophobic polymers.
SUMMARY OF THE INVENTION
[0011] Compositions and methods are provided for biodegradable
implants formulated to provide a controlled, sustained drug
release. The release rate is modulated by combining in the implant
hydrophobic and hydrophilic agents. The release modulator may act
to accelerate or retard the rate of release. Optionally, the
modulator will be a therapeutically active agent. The invention
provides a sustained release implant having a combination of active
agents with a defined release profile.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] FIG. 1A shows the release profile of a hydrophobic drug from
an extended release drug delivery system. FIG. 1B shows the release
profile of the same drug when formulated in a drug delivery system
with a release modulator.
[0013] FIG. 2A shows the release profile of dexamethasone in the
absence or presence of the release modifier, ciproflaxacin HCl.
FIG. 2B shows the release of ciprofloxacin in the presence of
dexamethasone. FIG. 2C shows the release of ciprofloxacin in the
absence of a release modifier. FIG. 2D shows the releae profile
from a drug delivery system having combined hydrophilic and
hydrophobic drugs, and further having a pharmaceutically inactive
release modifier.
[0014] FIG. 3 shows a cross-sectional view of an eye.
DESCRIPTION OF THE SPECIFIC EMBODIMENTS
[0015] A controlled drug release is achieved by an improved
formulation of slow release biodegradable implants. The release
rate of a drug from an implant is modulated by addition of a
release modulator to the implant. Release of a hydrophobic agent is
increased by inclusion of an accelerator in the implant, while
retardants are included to decrease the release rate of hydrophilic
agents. The release modulator may be physiologically inert, or a
therapeutically active agent.
[0016] The rate of release of the therapeutically active agent will
be controlled by the rate of transport through the polymeric matrix
of the implant, and the action of the modulator. By modulating the
release rate, the agent is released at a substantially constant
rate, or within a therapeutic dosage range, over the desired period
of time. The rate of release will usually not vary by more than
about 100% over the desired period of time, more usually by not
more than about 50%. The agent is made available to the specific
site(s) where the agent is needed, and it is maintained at an
effective dosage. The transport of drug through the polymer barrier
will also be affected by drug solubility, polymer hydrophilicity,
extent of polymer cross-linking, expansion of the polymer upon
water absorption so as to make the polymer barrier more permeable
to the drug, geometry of the implant, and the like.
[0017] The release modulator is an agent that alters the release of
a drug from a biodegradable implant in a defined manner. It may be
an accelerator or a retardant. Accelerators will be hydrophilic
compounds, which are used in combination with hydrophobic agents to
increase the rate of release. Hydrophilic agents are those
compounds which have at least about 100 .mu.g/ml solubility in
water at ambient temperature. Hydrophobic agents are those
compounds which have less than about 100 .mu.g/ml solubility in
water at ambient temperature.
[0018] Therapeutically active hydrophobic agents which benefit from
release modulation include cyclosporines, e.g. cyclosporin A,
cyclosporin G, etc.; vinca alkaloids, e.g. vincristine and
vinblastine; methotrexate; retinoic acid; certain antibiotics, e.g.
ansamycins such as rifampin; nitrofurans such as nifuroxazide;
non-steroidal antiinflammatory drugs, e.g. diclofenac, keterolac,
flurbiprofen, naproxen, suprofen, ibuprofen, aspirin, etc. Steroids
are of particular interest, including hydrocortisone, cortisone,
prednisolone, prednisone, dexamethasone, medrysone,
fluorometholone, estrogens, progesterones, etc.
[0019] Accelerators may be physiologically inert, water soluble
polymers, e.g. low molecular weight methyl cellulose or
hydroxypropyl methyl cellulose (HPMC); sugars, e.g. monosaccharides
such as fructose and glucose, disaccharides such as lactose,
sucrose, or polysaccharides such as cellulose, amylose, dextran,
etc. Alternatively, the accelerator may be a physiologically active
agent, allowing for a combined therapeutic formulation. The choice
of accelerator in such a case will be determined by the desired
combination of therapeutic activities.
[0020] Formulations of particular interest will have a therapeutic
combination of two or more active agents, which provides for a
sustained release of the agents. Combinations may include steroids,
as indicated above, as the hydrophobic agent and water soluble
antibiotics, e.g. aminoglycosides such as gentamycin, kanamycin,
neomycin, and vancomycin; amphenicols such as chloramphenicol;
cephalosporins, such as cefazolin HCl; penicillins such as
ampicillin, penicillin, carbenicillin, oxycillin, methicillin;
lincosamides such as lincomycin; polypeptide antibiotics such as
polymixin and bacitracin; tetracyclines such as tetracycline;
quinolones such as ciproflaxin, etc.; sulfonamides such as
chloramine T; and sulfones such as sulfanilic acid as the
hydrophilic entity. A combination of non-steroidal
anti-inflammatory drugs, as indicated above, with water soluble
antibiotics is also of interest. Combinations of anti-viral drugs,
e.g. acyclovir, gancyclovir, vidarabine, azidothymidine,
dideoxyinosine, dideoxycytosine with steroidal or non-steroidal
anti-inflammatory drugs, as indicated above, are of interest. A
particular combination of interest is dexamethasone and
ciproflaxin.
[0021] Release retardants are hydrophobic compounds which slow the
rate of release of hydrophilic drugs, allowing for a more extended
release profile. Hydrophilic drugs of interest which may benefit
from release modulation include water soluble antibiotics, as
described above, nucleotide analogs, e.g. acyclovir, gancyclovir,
vidarabine, azidothymidine, dideoxyinosine, dideoxycytosine;
epinephrine; isoflurphate; adriamycin; bleomycin; mitomycin; ara-C;
actinomycin D; scopolamine; and the like.
[0022] Agents of interest as release retardants include non-water
soluble polymers, e.g. high molecular weight methylcellulose and
ethylcellulose, etc., low water soluble organic compounds, and
pharmaceutically active hydrophobic agents, as previously
described.
[0023] A combined anti-inflammatory drug, and antibiotic or
antiviral, may be further combined with an additional therapeutic
agent. The additional agent may be an analgesic, e.g. codeine,
morphine, keterolac, naproxen, etc., an anesthetic, e.g. lidocaine;
.beta.-adrenergic blocker or .beta.-adrenergic agonist, e.g.
ephidrine, epinephrine, etc.; aldose reductase inhibitor, e.g.
epalrestat, ponalrestat, sorbinil, tolrestat; antiallergic, e.g.
cromolyn, beclomethasone, dexamethasone, and flunisolide;
colchicine. Anihelminthic agents, e.g. ivermectin and suramin
sodium; antiamebic agents, e.g. chloroquine and chlortetracycline;
and antifungal agents, e.g. amphotericin, etc. may be co-formulated
with an antibiotic and an anti-inflammatory drug. For intra-ocular
use, anti-glaucomas agents, e.g. acetozolamide, befunolol, etc. in
combinations with anti-inflammatory and antimicrobial agents are of
interest. For the treatment of neoplasia, combinations with
anti-neoplastics, particularly vinblastine, vincristine,
interferons .alpha., .beta. and .gamma., antimetabolites, e.g.
folic acid analogs, purine analogs, pyrimidine analogs may be used.
Immunosuppressants such as azathiprine, cyclosporine and mizoribine
are of interest in combinations. Also useful combinations include
miotic agents, e.g. carbachol, mydriatic agents such as atropine,
etc., protease inhibitors such as aprotinin, camostat, gabexate,
vasodilators such as bradykinin, etc., and various growth factors,
such epidermal growth factor, basic fibroblast growth factor, nerve
growth factors, and the like.
[0024] The amount of active agent employed in the implant,
individually or in combination, will vary widely depending on the
effective dosage required and rate of release from the implant.
Usually the agent will be at least about 1, more usually at least
about 10 weight percent of the implant, and usually not more than
about 80, more usually not more than about 40 weight percent of the
implant. The amount of release modulator employed will be dependent
on the desired release profile, the activity of the modulator, and
on the release profile of the active agent in the absence of
modulator. An agent that is released very slowly or very quickly
will require relatively high amounts of modulator. Generally the
modulator will be at least 10, more usually at least about 20
weight percent of the implant, and usually not more than about 50,
more usually not more than about 40 weight percent of the
implant.
[0025] Where a combination of active agents is to be employed, the
desired release profile of each active agent is determined. If
necessary, a physiologically inert modulator is added to precisely
control the release profile. The drug release will provide a
therapeutic level of each active agent.
[0026] The exact proportion of modulator and active agent will be
empirically determined by formulating several implants having
varying amounts of modulator. A USP approved method for dissolution
or release test will be used to measure the rate of release (USP
23; NF 18 (1995) pp. 1790-1798). For example, using the infinite
sink method, a weighed sample of the drug delivery device is added
to a measured volume of a solution containing four parts by weight
of ethanol and six parts by weight of deionized water, where the
solution volume will be such that the drug concentration is after
release is less than 5% of saturation. The mixture is maintained at
37.degree. C. and stirred slowly to maintain the implants in
suspension. The appearance of the dissolved drug as a function of
time may be followed by various methods known in the art, such as
spectrophotometrically, HPLC, mass spectroscopy, etc. until the
absorbance becomes constant or until greater than 90% of the drug
has been released. The drug concentration after 1 h in the medium
is indicative of the amount of free unencapsulated drug in the
dose, while the time required for 90% drug to be released is
related to the expected duration of action of the dose in vivo.
Normally the release will be free of larger fluctuations from some
average value which allows for a relatively uniform release,
usually following a brief initial phase of rapid release of the
drug.
[0027] Normally the implant will be formulated to release the
active agent(s) over a period of at least about 3 days, more
usually at least about one week, and usually not more than about
one year, more usually not more than about three months. For the
most part, the matrix of the implant will have a physiological
lifetime at the site of implantation at least equal to the desired
period of administration, preferably at least twice the desired
period of administration, and may have lifetimes of 5 to 10 times
the desired period of administration. The desired period of release
will vary with the condition that is being treated. For example,
implants designed for post-cataract surgery will have a release
period of from about 3 days to 1 week; treatment of uveitis may
require release over a period of about 4 to 6 weeks; while
treatment for cytomegalovirus infection may require release over 3
to 6 months, or longer.
[0028] The implants are of dimensions commensurate with the size
and shape of the region selected as the site of implantation and
will not migrate from the insertion site following implantation.
The implants will also preferably be at least somewhat flexible so
as to facilitate both insertion of the implant at the target site
and accommodation of the implant. The implants may be particles,
sheets, patches, plaques, fibers, microcapsules and the like and
may be of any size or shape compatible with the selected site of
insertion.
[0029] The implants may be monolithic, i.e. having the active agent
homogenously distributed through the polymeric matrix, or
encapsulated, where a reservoir of active agent is encapsulated by
the polymeric matrix. Due to ease of manufacture, monolithic
implants are usually preferred over encapsulated forms. However,
the greater control afforded by the encapsulated, reservoir-type
may be of benefit in some circumstances, where the therapeutic
level of the drug falls within a narrow window. The selection of
the polymeric composition to be employed will vary with the site of
administration, the desired period of treatment, patient tolerance,
the nature of the disease to be treated and the like.
Characteristics of the polymers will include biodegradability at
the site of implantation, compatibility with the agent of interest,
ease of encapsulation, a half-life in the physiological environment
of at least 7 days, preferably greater than two weeks, water
insoluble, and the like. The polymer will usually comprise at least
about 10, more usually at least about 20 weight percent of the
implant.
[0030] Biodegradable polymeric compositions which may be employed
may be organic esters or ethers, which when degraded result in
physiologically acceptable degradation products, including the
monomers. Anhydrides, amides, orthoesters or the like, by
themselves or in combination with other monomers, may find use. The
polymers will be condensation polymers. The polymers may be
cross-linked or non-cross-linked, usually not more than lightly
cross-linked, generally less than 5%, usually less than 1%. For the
most part, besides carbon and hydrogen, the polymers will include
oxygen and nitrogen, particularly oxygen. The oxygen may be present
as oxy, e.g., hydroxy or ether, carbonyl, e.g., non-oxo-carbonyl,
such as carboxylic acid ester, and the like. The nitrogen may be
present as amide, cyano and amino. The polymers set forth in
Heller, supra, may find use, and that disclosure is specifically
incorporated herein by reference.
[0031] Of particular interest are polymers of hydroxyaliphatic
carboxylic acids, either homo- or copolymers, and polysaccharides.
Included among the polyesters of interest are polymers of D-lactic
acid, L-lactic acid, racemic lactic acid, glycolic acid,
polycaprolactone, and combinations thereof. By employing the
L-lactate or D-lactate, a slowly biodegrading polymer is achieved,
while degradation is substantially enhanced with the racemate.
Copolymers of glycolic and lactic acid are of particular interest,
where the rate of biodegradation is controlled by the ratio of
glycolic to lactic acid. The most rapidly degraded copolymer has
roughly equal amounts of glycolic and lactic acid, where either
homopolymer is more resistant to degradation. The ratio of glycolic
acid to lactic acid will also affect the brittleness of in the
implant, where a more flexible-implant is desirable for larger
geometries.
[0032] Among the polysaccharides will be calcium alginate, and
functionalized celluloses, particularly carboxymethylcellulose
esters characterized by being water insoluble, a molecular weight
of about 5 kD to 500 kD, etc. Biodegradable hydrogels may also be
employed in the implants of the subject invention. Hydrogels are
typically a copolymer material, characterized by the ability to
imbibe a liquid. Exemplary biodegradable hydrogels which may be
employed are described in Heller in: Hydrogels in Medicine and
Pharmacy, N. A. Peppes ed., Vol. III, CRC Press, Boca Raton, Fla.,
1987, pp 137-149.
[0033] Particles can be prepared where the center may be of one
material and the surface have one or more layers of the same or
different composition, where the layers may be cross-linked, of
different molecular weight, different density or porosity, or the
like. For example, the center would comprise a polylactate coated
with a polylactate-polyglycola- te copolymer, so as to enhance the
rate of initial degradation. Most ratios of lactate to glycolate
employed will be in the range of about 1:0.1 to 1:1. Alternatively,
the center could be polyvinyl alcohol coated with polylactate, so
that on degradation of the polylactate the center would dissolve
and be rapidly washed out of the implantation site.
[0034] The formulation of implants for use in the treatment of
ocular conditions, diseases, tumors and disorders are of particular
interest. The biodegradable implants may be implanted at various
sites, depending on the shape and formulation of the implant, the
condition being treated, etc. Suitable sites include the anterior
chamber, posterior chamber, vitreous cavity, suprachoroidal space,
subconjunctiva, episcleral, intracorneal, epicorneal and sclera.
Suitable sites extrinsic to the vitreous comprise the
suprachoroidal space, the pars plana and the like. The suprachoroid
is a potential space lying between the inner scleral wall and the
apposing choroid. Implants that are introduced into the
suprachoroid may deliver drugs to the choroid and to the
anatomically apposed retina, depending upon the diffusion of the
drug from the implant, the concentration of drug comprised in the
implant and the like. Implants may be introduced over or into an
avascular region. The avascular region may be naturally occurring,
such as the pars plana, or a region made to be avascular by
surgical methods. Surgically-induced avascular regions may be
produced in an eye by methods known in the art such as laser
ablation, photocoagulation, cryotherapy, heat coagulation,
cauterization and the like. It may be particularly desirable to
produce such an avascular region over or near the desired site of
treatment, particularly where the desired site of treatment is
distant from the pars plana or placement of the implant at the pars
plana is not possible. Introduction of implants over an avascular
region will allow for diffusion of the drug from the implant and
into the inner eye and avoids diffusion of the drug into the
bloodstream.
[0035] Turning now to FIG. 3, a cross-sectional view of the eye is
shown, illustrating the sites for implantation in accordance with
the subject invention. The eye comprises a lens 16 and encompasses
the vitreous chamber 3. Adjacent to the vitreous chamber 3 is the
optic part of the retina 11. Implantation may be intraretinal 11 or
subretinal 12. The retina is surrounded by the choroid 18.
Implantation may be intrachoroidal or suprachoroidal 4. Between the
optic part of the retina and the lens, adjacent to the vitreous, is
the pars plana 19. Surrounding the choroid 18 is the sclera 8.
Implantation may be intrascleral 8 or episcleral 7. The external
surface of the eye is the cornea 9. Implantation may be epicorneal
9 or intra-corneal 10. The internal surface of the eye is the
conjunctiva 6. Behind the cornea is the anterior chamber 1, behind
which is the lens 16. The posterior chamber 2 surrounds the lens,
as shown in the figure. Opposite from the external surface is the
optic nerves, and the arteries and vein of the retina. Implants
into the meningeal spaces 13, the optic nerve 15 and the intraoptic
nerve 14 allows for drug delivery into the central nervous system,
and provide a mechanism whereby the blood-brain barrier may be
crossed.
[0036] Other sites of implantation include the delivery of
anti-tumor drugs to neoplastic lesions, e.g. tumor, or lesion area,
e.g. surrounding tissues, or in those situations where the tumor
mass has been removed, tissue adjacent to the previously removed
tumor and/or into the cavity remaining after removal of the tumor.
The implants may be administered in a variety of ways, including
surgical means, injection, trocar, etc.
[0037] Other agents may be employed in the formulation for a
variety of purposes. For example, buffering agents and
preservatives may be employed. Water soluble preservatives which
may be employed include sodium bisulfite, sodium bisulfate, sodium
thiosulfate, benzalkonium chloride, chlorobutanol, thimerosal,
phenylmercuric acetate, phenylmercuric nitrate, methylparaben,
polyvinyl alcohol and phenylethyl alcohol. These agents may be
present in individual amounts of from about 0.001 to about 5% by
weight and preferably about 0.01 to about 2%. Suitable water
soluble buffering agents that may be employed are sodium carbonate,
sodium borate, sodium phosphate, sodium acetate, sodium
bicarbonate, etc., as approved by the FDA for the desired route of
administration. These agents may be present in amounts sufficient
to maintain a pH of the system of between 2 to 9 and preferably 4
to 8. As such the buffering agent may be as much as 5% on a weight
to weight basis of the total composition. Where the buffering agent
or enhancer is hydrophilic, it may also act as a release
accelerator, and may replace all or part of the hydrophilic agent.
Similarly, a hydrophilic buffering agent or enhance may replace all
or part of the hydrophobic agent.
[0038] The implants may be of any geometry including fibers,
sheets, films, microspheres, circular discs, plaques and the like.
The upper limit for the implant size will be determined by factors
such as toleration for the implant, size limitations on insertion,
ease of handling, etc. Where sheets or films are employed, the
sheets or films will be in the range of at least about 0.5
mm.times.0.5 mm, usually about 3-10 mm.times.5-10 mm with a
thickness of about 0.25-1.0 mm for ease of handling. Where fibers
are employed, the diameter of the fiber will generally be in the
range of 0.05 to 3 mm. The length of the fiber will generally be in
the range of 0.5-10 mm. Spheres will be in the range of 2 .mu.m to
3 mm in diameter.
[0039] The size and form of the implant can be used to control the
rate of release, period of treatment, and drug concentration at the
site of implantation. Larger implants will deliver a
proportionately larger dose, but depending on the surface to mass
ratio, may have a slower release rate. The particular size and
geometry of an implant will be chosen to best suit the site of
implantation. The chambers, e.g. anterior chamber, posterior
chamber and vitreous chamber, are able to accomodate relatively
large implants of varying geometries, having diameters of 1 to 3
mm. A sheet, or circular disk is preferable for implantation in the
suprachoroidal space. The restricted space for intraretinal
implantation requires relatively small implants, having diameters
from 0.5 to 1 mm.
[0040] In some situations mixtures of implants may be utilized
employing the same or different pharmacological agents. In this
way, a cocktail of release profiles, giving a biphasic or triphasic
release with a single administration is achieved, where the pattern
of release may be greatly varied.
[0041] Various techniques may be employed to produce the implants.
Useful techniques include solvent evaporation methods, phase
separation methods, interfacial methods, extrusion methods, molding
methods, injection molding methods, heat press methods and the
like. Specific methods are discussed in U.S. Pat. No. 4,997,652,
herein incorporated by reference. In a preferred embodiment,
extrusion methods are used to avoid the need for solvents in
manufacturing. When using extrusion methods, the polymer and drug
are chosen so as to be stable at the temperatures required for
manufacturing, usually at least about 85.degree. C.
[0042] The following examples are offered by way of illustration
and not by way of limitation.
EXPERIMENTAL
EXAMPLE 1
Manufacture and Testing of a Drug Delivery System (DDS) without a
Release Modulator
[0043] Release of the hydrophobic drug dexamethasone from an
extended release drug delivery system was measured. The drug
delivery system was made with dexamethasone and polylactic
acid/polyglycolic acid copolymer. Dexamethasone powder and a powder
of polylactic acid polyglycolic acid (PLGA) copolymer were mixed
throughly at a ratio of 50/50. The well mixed powder was filled
into an extruder, and heated for 1 hour at 95.degree. C., then
extruded through a 20 gauge orifice. Six DDS of approximately
100-120 .mu.g were cut from the extruded filaments for drug release
assessment.
[0044] Each individual DDS was placed in a glass vial filled with
receptor medium (9% NaCl in water). To allow for "infinite sink"
conditions, the receptor medium volume was chosen so that the
concentration would never exceed 5% of saturation. To minimize
secondary transport phenomena, e.g. concentration polarization in
the stagnant boundary layer, each of the glass vials was placed
into a shaking water bath at 37.degree. C. Samples were taken for
HPLC analysis from each vial at defined time points. The HPLC
method was as described in USP 23 (1995) pp. 1791-1798. The
concentration values were used to calculate the cumulative relase
profiles. The release profile is shown in FIG. 1A. It is seen that
drug release is very slow with this DDS. Appreciable drug release
begins in the fourth week after initiation, at approximately the
time of polymer disintegration.
Manufacture and Testing of a DDS with HPMC Release Modifier
[0045] A drug delivery system was manufactured as described above,
except that various concentrations of hydrophilic
hydroxypropylmethylcellulose (HPMC) were included as a release
modifier. The combinations of drug, polymer and HPMC shown in Table
1 were used.
1TABLE 1 Lot # PLGA HPMC Dexamethasone Total XT014 3.5 1.5 5 10
XT015 2 2 5 9 XT013 1.5 1.5 5 8
[0046] The release of drug was tested as described above. The data
is shown in FIG. 1B. It is seen that with the addition of HPMC,
there is a pronounced increase in the rate of release. Close to
zero order release is observed for XT014 and XT015, where the ratio
of release modulator to drug is 0.3 to 0.4. By selection of the
appropriate polymer and release modifier, drug release and delivery
interval can be custom-tailored to provide a release profile that
is accelerated or retarded.
EXAMPLE 2
Manufacture and Testing of a DDS with a Pharmaceutically Active
Release Modifier
[0047] A drug delivery system was manufactured as described in
Example 1, except that ciprofloxacin HCl, a pharmaceutically
active, hydrophilic compound, was included as a release modifier.
The combinations of drug, polymer and HPMC shown in Table 2 were
used.
2 TABLE 2 Release Lot # PLGA Modifier Drug XT029 5 -- 5
dexamethasone XT032 4 2 ciprofloxacin 4 dexamethasone XT030 5 -- 5
ciprofloxacin
[0048] The release of dexamethasone is increased with the addition
of ciprofloxacin HCl, as shown by the data in FIG. 2A. The actual
drug release is almost doubled when compared to the DDS without a
modifier. In addition to the benefits of increased drug delivery,
there are therapeutic benefits introduced with the antibiotic
activity of ciprofloxacin. The release of ciprofloxacin from from
the same DDS is shown in FIG. 2B. The release rate is higher than
that of dexamethasone. However, the overall release of
ciprofloxacin is slower when co-formulated with dexamethasone than
it is without dexamethasone, as shown in FIG. 2C.
EXAMPLE 3
Manufacture and Testing of a DDS with Multiple Release
Modifiers
[0049] A drug delivery system was formulated with
hydroxymethylcellulose, cirpofloxacin HCl and dexamethasone,
according to the Table 3.
3TABLE 3 Lot # PLGA HPMC Ciprofloxacin Dexamethasone XT035 3.4 0.4
2.4 3.8
[0050] The data show that after an initial higher release in the
first day, an almost zero-order release there after can be
observed. The overall release characteristic would be
therapeutically acceptable from a therapeutic efficiency
aspect.
[0051] It is evident from the above results that biodegradable
implants formulated with an active agent and release modulator
provide for release kinetics where the drug is released at a
constant rate over long periods of time, avoiding the need of a
patient to administer drugs in much less effective ways, such as
topically. The implants provide an improved method of treating
ocular and other conditions, by avoiding peaks and troughs of drug
release.
[0052] All publications and patent applications mentioned in this
specification are indicative of the level of skill of those skilled
in the art to which this invention pertains. All publications and
patent applications are herein incorporated by reference to the
same extent as if each individual publication or patent application
was specifically and individually indicated to be incorporated by
reference.
[0053] Although the foregoing invention has been described in some
detail by way of illustration and example for purposes of clarity
of understanding, it will be obvious that certain changes and
modifications may be practiced within the scope of the appended
claims.
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