U.S. patent application number 10/016390 was filed with the patent office on 2002-05-30 for body cavity drug delivery with thermo-irreversible polyoxyalkylene and ionic polysaccharide gels.
Invention is credited to Henry, Raymond L., Reeve, Lorraine E., Viegas, Tacey X..
Application Number | 20020064514 10/016390 |
Document ID | / |
Family ID | 46246799 |
Filed Date | 2002-05-30 |
United States Patent
Application |
20020064514 |
Kind Code |
A1 |
Viegas, Tacey X. ; et
al. |
May 30, 2002 |
Body cavity drug delivery with thermo-irreversible polyoxyalkylene
and ionic polysaccharide gels
Abstract
Balanced pH, thermo-irreversible gels are ideal vehicles for
drug delivery to a body cavity of a mammal. The gels contain a
mixture of a polyoxyalkylene block copolymer or polyether together
with an ionic polysaccharide which is thermo-irreversibly gelled in
the presence of a counter-ion.
Inventors: |
Viegas, Tacey X.;
(Birmingham, AL) ; Reeve, Lorraine E.; (Dexter,
MI) ; Henry, Raymond L.; (St. Clair Shores,
MI) |
Correspondence
Address: |
Pillsbury Winthrop LLP
50 Fremont Street
San Francisco
CA
94105
US
|
Family ID: |
46246799 |
Appl. No.: |
10/016390 |
Filed: |
December 10, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10016390 |
Dec 10, 2001 |
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08908747 |
Aug 7, 1997 |
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08908747 |
Aug 7, 1997 |
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08604358 |
Feb 21, 1996 |
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08604358 |
Feb 21, 1996 |
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08207981 |
Mar 8, 1994 |
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08207981 |
Mar 8, 1994 |
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07939475 |
Aug 31, 1992 |
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07939475 |
Aug 31, 1992 |
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07563640 |
Aug 7, 1990 |
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Current U.S.
Class: |
424/78.38 ;
514/54 |
Current CPC
Class: |
Y10S 514/967 20130101;
A61K 47/36 20130101; Y10S 514/944 20130101; A61K 47/10 20130101;
A61K 9/0048 20130101; A61K 47/18 20130101; A61K 9/0014 20130101;
Y10S 514/966 20130101 |
Class at
Publication: |
424/78.38 ;
514/54 |
International
Class: |
A61K 031/77; A61K
031/715 |
Claims
That which is claimed:
1. A method of forming a gel material in situ in contact with at
least one biological tissue, in a body cavity, comprising:
preparing a material which comprises an ionic polysaccharide and a
polymer, said polymer having polyoxyalkylene blocks comprising a
block copolymer of the general formula: Y[(A).sub.n- - - E - - -
H].sub.x where A is a polyoxyalkylene moiety having an
oxygen/carbon atom ratio of less than 0.5, x is at least 2, Y is
derived from water or an organic compound containing x reactive
hydrogen atoms, E is a polyoxyethylene moiety constituting at least
60 percent by weight of the polyoxyalkylene block copolymer, n has
a value such that the minimum molecular weight of A is between
about 500 and about 900, as determined by the hydroxyl number of an
intermediate of general formula: Y[(A).sub.n- - - H].sub.x and the
average molecular weight of the polyoxyalkylene block copolymer is
between about 5000 and about 50,000; placing said material in
contact with at least one biological tissue; and cross-linking said
material in contact with said at least one biological tissue via,
said cross-linking being mediated through a thermal mechanism, a
counter-ion mechanism or a combination thereof wherein the
cross-linking of said material results in an in situ formation of
the gel material.
Description
[0001] This application is a continuation of U.S. Ser. No.
08/908,747 filed Aug. 7, 1997, which is a continuation of U.S. Ser.
No. 08/604,358, filed Feb. 21, 1996, abandoned, which is a
continuation of U.S. Ser. No. 08/207,981, filed Mar. 8, 1994,
abandoned, which is a continuation of U.S. Ser. No. 07/939,475,
filed Aug. 31,1992, now U.S. Pat. No. 5,346,703, issued Sep. 13,
1994, which is a continuation-in-part of U.S. Ser. No. 07/563,640,
filed Aug. 7, 1990, now U.S. Pat. No. 5,143,731, issued Sep. 1,
1992.
FIELD OF THE INVENTION
[0002] This invention relates to body cavity drug delivery systems
and pharmaceutical compositions comprising an aqueous gel.
DESCRIPTION OF THE PRIOR ART
[0003] Over the years, methods have been developed to achieve the
efficient delivery of a therapeutic drug to a mammalian body part
requiring pharmaceutical treatment. Use of an aqueous liquid which
can be applied at room temperature as a liquid but which forms a
semisolid gel when warmed to body temperature has been utilized as
a vehicle for drug delivery since such a system combines ease of
application with greater retention at the site requiring treatment
than would be the case if the aqueous composition were not
converted to a gel as it is warmed to mammalian body temperature.
In U.S. Pat. No. 4,188,373, PLURONIC.RTM. polyols are used in
aqueous compositions to provide thermally gelling aqueous systems.
Adjusting the concentration of the polymer provides the desired
sol-gel transition temperature, that is, the lower the
concentration of polymer, the higher the sol-gel transition
temperature, after crossing a critical concentration below which a
gel will not form.
[0004] In U.S. Pat. Nos. 4,474,751, 4,474,752, 4,474,753, and
4,478,822, drug delivery systems are described which utilize
thermosetting gels; the unique feature of these systems is that
both the gel transition temperature and/or the rigidity of the gel
can be modified by adjustment of the pH and/or the ionic strength,
as well as by the concentration of the polymer.
[0005] Other patents disclosing pharmaceutical compositions which
rely upon an aqueous gel composition as a vehicle for the
application of the drug are U.S. Pat. Nos. 4,883,660, 4,767,619,
4,511,563, and 4,861,760. Thermosetting gel systems are also
disclosed for application to injured mammalian tissues of the
thoracic or peritoneal cavities in U.S. Pat. No. 4,911,926.
[0006] Ionic polysaccharides have been used in the application of
drugs by controlled release. Such ionic polysaccharides as chitosan
or sodium alginate are disclosed as useful in providing spherical
agglomerates of water-insoluble drugs in the Journal of
Pharmaceutical Sciences volume 78, number 11, November 1989,
Bodmeier et al. Alginates have also been used as a depot substance
in active immunization, as disclosed in the Journal of Pathology
and Bacteriology volume 77, (1959), C.R. Amies. Calcium alginate
gel formulations have also found use as a matrix material for the
controlled release of herbicides, as disclosed in the Journal of
Controlled Release, 3 (1986) pages 229-233, Pfister et al.
[0007] In U.S. Pat. No. 3,640,741, a molded plastic mass composed
of the reaction product of a hydrophilic colloid and a
cross-linking agent such as a liquid polyol, also containing an
organic liquid medium such as glycerin, is disclosed as useful in
the controlled release of medication or other additives. The
hydrophilic colloid can be carboxymethyl cellulose gum or a natural
alginate gum which is cross-linked with a polyol. The cross-linking
reaction is accelerated in the presence of aluminum and calcium
salts.
[0008] In U.S. Pat. No. 4,895,724, compositions are disclosed for
the controlled release of pharmacological macromolecular compounds
contained in a matrix of chitosan. Chitosan can be cross-linked
utilizing aldehydes, epichlorohydrin, benzoquinone, etc.
[0009] In U.S. Pat. No. 4,795,642, there are disclosed
gelatin-encapsulated, controlled-release compositions for release
of pharmaceutical compositions, wherein the gelatin encloses a
solid matrix formed by the cation-assisted gelation of a liquid
filling composition incorporating a vegetable gum together with a
pharmaceutically-active compound. The vegetable gums are disclosed
as polysaccharide gums such as alginates which can be gelled
utilizing a cationic gelling agent such as an alkaline earth metal
cation.
[0010] While the prior art is silent with respect to aqueous drug
delivery vehicles and isotonicity thereof, osmotic drug delivery
systems are disclosed in U.S. Pat. No. 4,439,196 which utilize a
multi-chamber compartment for holding osmotic agents, adjuvants,
enzymes, drugs, pro-drugs, pesticides, and the like. These
materials are enclosed by semipermeable membranes so as to allow
the fluids within the chambers to diffuse into the environment into
which the osmotic drug delivery system is in contact. The drug
delivery device can be sized for oral ingestion, implantation,
rectal, vaginal, or ocular insertion for delivery of a drug or
other beneficial substance. Since this drug delivery device relies
on the permeability of the semipermeable membranes to control the
rate of delivery of the drug, the drugs or other pharmaceutical
preparations, by definition, are not isotonic with mammalian
blood.
SUMMARY OF THE INVENTION
[0011] Compositions and a process are disclosed for pharmaceutical
compositions containing pharmacologically active medicaments useful
in providing treatments to various body cavities of the mammalian
body requiring pharmacological treatment. The pharmaceutical
compositions of the invention provide a physiologically acceptable
media having a buffered pH and an osmotically balanced vehicle so
as to, preferably, provide an isotonic mixture which is iso-osmotic
with body fluids and has a similar pH to body fluids, such as blood
plasma, lacrimal tears, and the extracellular fluid of exposed
tissue, such as found in the area of third degree burn tissue. The
pH and osmotic pressure of such bodily fluids is about pH 7.4 and
290 m0sm/kg. In addition, the pharmaceutical compositions are,
optionally, sterilized.
[0012] The compositions of the invention in one embodiment comprise
aqueous mixtures of a polyoxyalkylene polymer, an ionic
polysaccharide, and, optionally, a latent counter-ion useful to gel
the polysaccharide upon release of the counter-ion. The counter-ion
can be microencapsulated in a heat sensitive medium, for instance,
the walls of the microcapsule can be made of mono-, di-, or
tri-glycerides or other natural or synthetic heat sensitive polymer
medium. Alternatively, ion exchange resins can be incorporated in
the compositions of the invention so as to release the desired
counter-ion upon contact with an environment opposite in pH to the
pH of the ion exchange resin. The aqueous mixture can be delivered
to the body cavities of a mammal requiring treatment as a low
viscosity liquid at ambient temperatures which, upon contact with
the mammalian body, forms a semi-solid gel having a very high
viscosity. Alternatively, the counter-ion, instead of being present
in a latent form, can be separately applied in an aqueous solution,
for instance, by aerosol or non-aerosol spray application to the
semi-solid gel formed by the polyoxyalkylene polymer upon contact
with the mammalian body. Because the preferred pharmaceutical
compositions of the invention are low viscosity liquids, at ambient
temperatures, they insure maximum contact between exposed tissue
and the pharmaceutical composition of the invention. The
pharmaceutical gel compositions of the invention can be either
peeled away or allowed to be absorbed over time. The gels are
gradually weakened upon exposure to mammalian body conditions.
[0013] Polyphase systems are also useful and may contain
non-aqueous solutes, non-aqueous solvents, and other non-aqueous
additives. Homogeneous, polyphase systems can contain such
additives as water insoluble high molecular weight fatty acids and
alcohols, fixed oils, volatile oils and waxes, mono-, di-, and
triglycerides, and synthetic, water insoluble polymers without
altering the functionality of the system.
[0014] A wide variety of polyoxyalkylene polymers are suitable for
the preparation of the pharmaceutical compositions of the
invention. Generally, it is necessary to adjust the polymer
concentration in aqueous solution so as to obtain the desired
sol-gel transition temperature in order that the compositions can
be provided as low viscosity liquids at ambient temperature, yet
form semi-solid gels at mammalian body temperatures. In addition to
the concentration of the polymer and the concentration of a water
soluble or dispersible pharmacologically active medicament, other
suitable excipients must be added so as to provide the desired
isotonic, iso-osmotic properties.
[0015] The useful polymers which provide the sol-gel
characteristics of the pharmaceutical compositions of the invention
are, preferably, polyoxyalkylene block copolymers.
[0016] The ionic polysaccharides are natural polymers such as
chitosan or alginates. Aqueous solutions of these ionic
polysaccharides form gels upon contact with aqueous solutions of
counter-ions such as calcium, strontium, aluminum, etc., or an
aqueous solution of a metal tripolyphosphate.
DESCRIPTION OF THE DRAWING
[0017] The drawing provides a curve showing the penetration, as
measured by a Precision Universal Penetrometer, of a 20 mm
thickness aqueous gel formed by combining Poloxamer 407 with sodium
alginate and prepared in accordance with the procedure of Example
1. The scale at the left side of the plot indicates the penetration
while the scale on the bottom of the plot indicates the temperature
of the composition when tested. The arrow in the plot indicates the
point at which an aqueous solution of calcium ions at a
concentration of 0.137 molar is made to contact the gelled
Poloxamer 407 solution so as to gel the polysaccharide component of
the mixture.
DETAILED DESCRIPTION OF THE INVENTION
[0018] It has been found that aqueous pharmaceutical vehicles
containing a polyoxyalkylene block copolymer, which have the unique
feature, in a preferred embodiment, of being liquid at ambient
temperatures and transitioning at mammalian body temperatures to a
semi-solid gel, can be made resistant to shear thinning and the
polyoxyalkylene gel made more resistant to penetration by the
inclusion of a polysaccharide in admixture with the polyoxyalkylene
polymer and contacting the polysaccharide with a counter-ion to gel
the polysaccharide. The compositions can be made isotonic, or
iso-osmotic, and adjusted to the pH of mammalian body fluids, such
as blood plasma, lacrimal tears, and extracellular fluid, such as
found in the area of third degree burns. The pH and osmotic
pressure of such bodily fluids are generally about 7.4.+-.0.2 and
290.+-.20 m0sm/kg, respectively. It is advantageous to deliver a
pharmacologically active medicament to an area of the mammalian
body requiring pharmacological treatment under pH and osmotic
pressure conditions which match those of bodily fluids. Optionally,
the, pharmaceutical compositions of the invention can be provided
in a sterile condition. The pharmaceutical compositions of the
invention can be utilized within bodily cavities such as the
rectal, urethral, nasal, vaginal, otic, peritoneal, pleural, oral
cavities, or cavities created by injury.
[0019] The block copolymer compositions of the invention comprise:
at least one polyoxyalkylene block copolymer of the formula
Y[(A).sub.n- - - E - - - H].sub.x (I)
[0020] wherein A is a polyoxyalkylene moiety having an
oxygen/carbon atom ratio of less than 0.5, x is at least 2, Y is
derived from water or an organic compound containing x reactive
hydrogen atoms, E is a polyoxyalkylene moiety constituting at least
about 60% by weight of the copolymer, n has a value such that the
average molecular weight of A is at least about 500 to about 900,
as determined by the hydroxyl number of a hydrophobe base
intermediate
Y[(A).sub.n- - - H].sub.x (II)
[0021] and the total average molecular weight of the copolymer is
at least about 5000.
[0022] Generally, the polyoxybutylene-based block copolymers useful
in the compositions of the invention are prepared by first
condensing 1, 2-butylene oxide with a water soluble organic
compound initiator containing 1 to about 6 carbon atoms, such as 1,
4-butylene glycol or propylene glycol, and at least 2 reactive
hydrogen atoms to prepare a polyoxyalkylene polymer hydrophobe of
at least about 500, preferably, at least about 1,000, and most
preferably, at least about 1500 average molecular weight.
Subsequently, the hydrophobe is capped with an ethylene oxide
residue. Specific methods for preparing these compounds are
described in U.S. Pat. No. 2,828,345 and British Patent No.
722,746, both of which are hereby incorporated by reference.
[0023] Useful polyoxyethylene-polyoxybutylene based block
copolymers conform to the following generic formula:
HO(C.sub.2H.sub.4O).sub.b(C.sub.4H.sub.8O).sub.a(C.sub.2H.sub.4O).sub.bH
(III)
[0024] wherein a and b are integers such that the hydrophobe base
represented by (C.sub.4H.sub.8O).sub.a has a molecular weight of at
least about 500, preferably, at least about 1000, and most
preferably, at least about 3000, as determined by hydroxyl number,
the polyoxyethylene chain constituting at least about 60%,
preferably, at least about 70% by weight of the copolymer and the
copolymer having a total average molecular weight of at least about
5000, preferably, at least about 10,000, and most preferably, at
least about 15,000.
[0025] The copolymer is characterized in that all the hydrophobic
oxybutylene groups are present in chains bonded to an organic
radical at the former site of a reactive hydrogen atom thereby
constituting a polyoxybutylene base copolymer. The hydrophilic
oxyethylene groups are used to cap the polyoxybutylene base
polymer.
[0026] Polyoxyethylene-polyoxypropylene block copolymers which can
be used to form aqueous gels can be represented by the following
formula:
HO
(C.sub.2H.sub.4O).sub.b(C.sub.3H.sub.6O).sub.a(C.sub.2H.sub.4O).sub.bH
(IV)
[0027] wherein a and b are integers such that the hydrophobe base
represented by (C.sub.3H.sub.6O).sub.a has a molecular weight of at
least about 900, preferably, at least about 2500, and most
preferably, at least about 4000 average molecular weight, as
determined by hydroxyl number; the polyoxyethylene chain
constituting at least about 60%, preferably, at least about 70% by
weight of the copolymer and the copolymer having a total average
molecular weight of at least about 5000, preferably, at least about
10,000, and most preferably, at least about 15,000.
[0028] Polyoxyethylene-polyoxypropylene block copolymer adducts of
ethylene diamine which can be used may be represented by the
following formula: 1
[0029] wherein a and b are integers such that the copolymer may
have (1) a hydrophobe base molecular weight of at least about 2000,
preferably, at least about 3000, and most preferably, at least
about 4500, (2) a hydrophile content of at least about 60%,
preferably, at least about 70% by weight, and (3) a total average
molecular weight of at least about 5000, preferably, at least about
10,000, and most preferably, at least about 15,000.
[0030] The hydrophobe base of the copolymer of formula V is
prepared by adding propylene oxide for reaction at the site of the
four reactive hydrogen atoms on the amine groups of ethylene
diamine. An ethylene oxide residue is used to cap the hydrophobe
base. The hydrophile polyoxyethylene groups are controlled so as to
constitute at least about 60%, preferably, at least about 70% by
weight, and most preferably, at least about 80% by weight of the
copolymer.
[0031] The procedure used to prepare aqueous solutions which form
gels of the polyoxyalkylene block copolymers is well known. Either
a hot or cold process for forming the solutions can be used. A cold
technique involves the steps of dissolving the polyoxyalkylene
block copolymer at a temperature of about 5.degree. C. to about
10.degree. C. in water. When solution is complete the system is
brought to room temperature whereupon it forms a gel. If the hot
process of forming the gel is used, the polymer is added to water
heated to a temperature of about 75.degree. C. to about 85.degree.
C. with slow stirring until a clear homogenous solution is
obtained. Upon cooling, a clear gel is formed. Block copolymer gels
containing polyoxybutylene hydrophobes must be prepared by the
above hot process, since these will not liquify at low
temperatures.
[0032] As used herein, the term "gel" is defined as a solid or
semisolid colloid containing a certain quantity of water. The
colloidal solution with water is often called a "hydrosol".
[0033] The organic compound initiator which is utilized in the
process for the preparation of the polyoxyalkylene block copolymers
generally is water or an organic compound and can contain a
plurality of reactive hydrogen atoms. Preferably, Y in formulas I
and II above is defined as derived from a water soluble organic
compound having 1 to about 6 carbon atoms and containing x reactive
hydrogen atoms where x has a value generally, of at least 1,
preferably, a value of at least 2. Falling within the scope of the
compounds from which Y is derived from water soluble organic
compounds having at least two reactive hydrogen atoms are water
soluble organic compounds such as propylene, glycol, glycerin,
pentaerythritol, trimethylolpropane, ethylene diamine, and mixtures
thereof and the like.
[0034] The oxypropylene-chains can optionally contain small amounts
of at least one of oxyethylene or oxybutylene groups. Oxyethylene
chains can optionally contain small amounts of at least one of
oxypropylene or oxybutylene groups. The physical form of the
polyoxyalkylene block copolymers can be a viscous liquid, a paste,
or a solid granular material depending upon the molecular weight of
the polymer. Useful polyoxyalkylene block copolymers generally have
a total average molecular weight of about 5,000 to about 50,000,
preferably, about 5,000 to about 35,000 and most preferably, about
10,000 to about 25,000.
[0035] In addition to those polyoxyalkylene polymers described
above, which are suitable in the formation of the pharmaceutical
compositions of the invention, other polyoxyalkylene polymers,
which form gels at low concentrations in water are suitable. One
such polymer is described in U.S. Pat. No. 4,810,503, incorporated
herein by reference. These polymers are prepared by capping
conventional polyoxyalkylene polyether polyols with an alpha-olefin
epoxide having an average of about 20 to about 45 carbon atoms, or
mixtures thereof. Aqueous solutions of these polymers gel in
combination with surfactants, which can be ionic or nonionic. The
combination of the capped polyether polymers and the surfactants
provide aqueous gels at low concentrations of the capped polymer
and surfactant, which generally do not exceed 10% by weight total.
Detailed methods of preparing these aqueous gels are disclosed in
U.S. Pat. No. 4,810,503. Preparation of said aqueous gels is
generally described below. Preferred surfactants for use in
preparing these gels are also disclosed in said patent.
[0036] A conventional copolymer polyether polyol is prepared by
preparing block or heteric intermediate polymers of ethylene oxide
and at least one lower alkylene oxide having 3 to 4 carbon atoms as
intermediates. These are then capped with the alpha-olefin epoxide
to prepare the polymers. Ethylene oxide homopolymers capped with
said alpha-olefin oxides are also useful as intermediates.
[0037] The heteric copolymer intermediate is prepared by mixing
ethylene oxide and at least one lower alkylene oxide having 3 to 4
carbon atoms with a low molecular weight active hydrogen-containing
compound initiator having at least two active hydrogens and
preferably, 2 to 6 active hydrogen atoms such as a polyhydric
alcohol, containing from 2 to 10 carbon atoms and from 2 to 6
hydroxyl groups, heating said mixture to a temperature in the range
of about 50.degree. C. to 150.degree. C., preferably from
80.degree. C. to 130.degree. C., under an inert gas pressure
preferably from about 30 psig to 90 psig.
[0038] A block copolymer intermediate in prepared by reacting
either the ethylene oxide or said alkylene oxide having 3 to 4
carbon atoms with said active hydrogen-containing compound followed
by reaction with the other alkylene oxide.
[0039] The ethylene oxide and the alkylene oxides having from 3 to
4 carbon atoms are used in said intermediates in amounts so that
the resulting polyether product will contain at least 10 percent by
weight, preferably about 70 percent to about 90 percent by weight,
ethylene oxide residue. The ethylene oxide homopolymer intermediate
is prepared by reacting ethylene oxide with said active
hydrogen-containing compound. The reaction conditions for preparing
the block copolymer and ethylene oxide homopolymer intermediates
are similar to those for the heteric copolymer intermediate. The
temperature and pressure are maintained in the above ranges for a
period of about one hour to ten hours, preferably one to three
hours.
[0040] The alpha-olefin oxides which are utilized to modify the
conventional polyether intermediate of the prior art are those
oxides and the commercially available mixtures thereof generally
containing an average of about 20 to 45, preferably about 20 to 30,
carbon atoms. The amount of alpha-olefin required to obtain the
more efficient capped polyethers is generally about 0.3 to 10
percent, preferably about 4 to 8 percent, of the total weight of
the polyethers.
[0041] Since the preparation of heteric and block copolymers of
alkylene oxides and ethylene oxide homopolymers are well known in
the art, further description of the preparation of said polymers is
unnecessary. Further details of the preparation of heteric
copolymers of lower alkylene oxide can be obtained in U.S. Pat. No.
3,829,506, incorporated herein by reference. Further information on
the preparation of block copolymers of lower alkylene oxides can be
obtained in U.S. Pat. Nos. 3,535,307, 3,036,118, 2,979,578,
2,677,700, and 2,675,619 incorporated herein by reference.
[0042] The surfactants may be ionic or non-ionic and many
surfactants and types of surfactants may be employed. While all
surfactants may not be effective in the preparation of the isotonic
gels of the instant invention, the fact that many are effective
makes it a simple matter for one skilled in the art to select such
surfactant with a minimum of trial and error.
[0043] The amounts of capped polyether polymer and surfactant may
be as little as 1.0 percent by weight or less of each depending on
the type and amount of the other component. There appears to be no
maximum amount of either component than that dictated by economic
considerations. However, the total amount of capped polymer and
surfactant would generally not exceed 10 percent by weight.
[0044] The ionic polysaccharides found useful in the present
invention are hydrophilic colloidal materials and include the
natural gums such as alginate gums, i.e., the ammonium and alkali
metal salts of alginic acid and mixtures thereof as well as
chitosan, which is a common name for the deacetylated form of
chitin. Chitin is a natural product comprising poly
(N-acetyl-D-glucosamine). The alginates are available as dry
powders from Protan, Inc., Commack, N.Y. and from Kelco Company,
San Diego, Calif.
[0045] The alginates can be any of the water-soluble alginates
including the alkaline metal (sodium, potassium, lithium, rubidium
and cesium) salts of alginic acid, as well as the ammonium salt,
and the soluble alginates of an organic bass such as mono-, di-, or
tri-ethanolamine, aniline, and the like.
[0046] Useful counter-ions for gelling the alginate ionic
polysaccharide in combination with the polyoxyalkylene polymer
compositions of the invention are cationic gelling agents
preferably, comprising a divalent or trivalent cation. Useful
divalent cations include the alkaline earth metals, preferably,
selected from the group consisting of calcium and strontium. Useful
trivalent cations include aluminum, chromium, and iron. The
preferred counter-ions for gelling the alginate ionic
polysaccharide are contained in ionic compounds selected from
pharmaceutically-acceptabl- e gluconates, fluorides, citrates,
phosphates, tartrates, sulfates, acetates, borates, chlorides, and
the like having alkaline earth metal cations such as calcium and
strontium. Especially preferred counter-ion containing inorganic
salts for use as ionic polysaccharide gelling agents include such
inorganic salts as the chloride salts, such as strontium chloride,
calcium chloride, and mixtures thereof.
[0047] While the counter-ion such as calcium or other counter-ions
may be obtained by contact with bodily fluids, it is preferred that
the counter-ion in latent form be added to the ionic polysaccharide
and polyoxyalkylene polymer compositions of the invention.
Alternatively, a counter-ion can be added to the ionic
polysaccharide and polyoxyalkylene polymer compositions of the
invention utilizing a two part system in which the counter-ion is
topically applied to the remaining components of the drug delivery
system subsequent to their topical application to a body cavity. It
is preferred to incorporate the counter-ion in a latent form
together with the ionic polysaccharide and polyoxyalkylene polymer
compositions of the invention. This may be accomplished by either
encapsulating an aqueous solution of one of the counter-ion gelling
agents, previously described above, or by the incorporation of the
counter-ion gelling agent into a matrix which provides for the
controlled, slow-release of the gelling agent. For instance, the
counter-ion can be incorporated into an ion exchange resin or
gelatin-encapsulated controlled-release compositions can be used,
as disclosed in U.S. Pat. No. 4,795,642, incorporated herein by
reference. In this patent there is disclosed the preparation of a
gelatin shell encapsulating a controlled-release formulation in
which the gelatin composition includes calcium chloride as a
gelling agent. Alternatively, the counter-ion can be incorporated
as an aqueous solution of a counter-ion gelling agent encapsulated
in a vesicle composed, for instance, of alpha-tocopherol, as
disclosed in U.S. Pat. No. 4,861,580.
[0048] Generally, aqueous solutions of chitosan can be gelled with
multivalent anion gelling agents, preferably, comprising a metal
polyphosphate, such as an alkali metal or ammonium polyphosphates,
pyrophosphates, sodium and potassium metaphosphates, and sodium and
ammonium (mono-, di-, tri-) phosphates. Generally, a molar ratio of
counter-ion to chitosan or alginate of about 1:1 to about 10:1,
preferably, about 2:1 to about 5:1, and, most preferably, about 3:1
to about 5:1 is used to render the compositions of the invention
thermally-irreversibly gelled.
[0049] With specific reference to the application of the
pharmaceutical drug delivery compositions of the invention to a
body cavity, such as the rectum, urethra, nasal cavity, vagina,
auditory meatis, oral cavity, buccal pouch, peritoneum, or pleura,
each of these areas desirably require, for the avoidance of adverse
physiological effects to the area requiring pharmacological
treatment, that the pH and the osmolality of the pharmaceutical
vehicle be matched to the pH and osmolality of the bodily fluids
present at the area of treatment.
[0050] In general, the preferred drug delivery system of the
present invention will contain from about 0.01% to about 60% by
weight of the medicament or pharmaceutical, from about 10 to about
50% by weight of the polyoxyalkylene polymer, about 0.2 to about
2.5% by weight, preferably, about 0.5 to about 1.5% by weight of
ionic polysaccharide, and from 80% to about 20% water. In special
situations, however, the amounts may be varied to increase or
decrease the dosage schedule.
[0051] If desired, the drug delivery vehicle may also contain
preservatives, co-solvents, suspending agents, viscosity enhancing
agents, ionic strength and osmolality adjusters and other
excipients in addition to the medicament and buffering agents.
Suitable water soluble preservatives which may be employed in the
drug deliver vehicle are sodium bisulfite, sodium thiosulfate,
ascorbate, benzalkonium chloride, chlorobutanol, thimerosal,
phenylmercuric borate, parabens, benzyl alcohol, and phenyl ethanol
and others. These agents may be present, generally, in amounts of
about 0.001% to about 5% by weight and, preferably, in the amount
of about 0.01% to about 2% by weight.
[0052] Suitable water soluble buffering agents are alkali or alkali
earth carbonates, phosphates, bicarbonates, citrates, borates,
acetates, succinates and the like, such as sodium phosphate,
citrate, borate, acetate, bicarbonate, carbonate and trimethamine
(TRIS). These agents are present in amounts sufficient to maintain
the pH of the system at 7.4..+-.0.2 and, preferably, 7.4. As such
the buffering agent can be as much as 5% on a weight basis of the
total composition.
[0053] The pharmaceutical vehicles for drug deliver of the
invention are an improvement over these prior art methods of body
cavity drug delivery in that the preferred compositions are not
only optimized for physiological tolerance in the body cavity
preferably by formulating the drug delivery compositions so as to
have isotonic characteristics but made more resistant to shear
thinning as the result of higher gel strength. These advantages are
obtained by the incorporation of an ionic polysaccharide in
admixture with a polyoxyalkylene polymer. By matching the
osmolality of the drug delivery compositions of the invention to
those of the bodily fluids, it is possible to eliminate burning or
other discomfort upon application of the drug delivery systems of
the invention. The higher gel strength compositions upon contact
with a counter-ion for the ionic polysaccharide allow retention of
the gel at the desired locus for longer intervals, thus, increasing
the efficacy of the delivered drug.
[0054] Many pharmaceutically active materials may be delivered to
body cavities by the drug delivery system of this invention.
Preferably, the drug, or pharmaceutical, is water soluble. Some
drugs will show greater solubility in the aqueous polymer system
than others. Cosolvents can be used to enhance drug solubility.
However, some drugs may be insoluble. These can often be suspended
in the polymer vehicle with the aid of suitable suspending or
viscosity-enhancing agents.
[0055] Suitable classes of drugs which can be administered to a
body cavity by the drug polymer delivery system of the present
invention are antibacterial substances such as B-lactam
antibiotics, such as cefoxitin, n-formamidoyl thienamycin and other
thienamycin derivatives, tetracyclines, chloramphenicol, neomycin,
gramicidin, bacitracin, sulfonamides; aminoglycoside antibiotics
such as gentamycin, kanamycin, amikacin, sisomicin and tobramycin;
nalidixic acids and analogs such as norfloxacin and the
antimicrobial combination of fludalanine/pentizidone/-
nitrofurazones, and the like; antihistaminics and decongestants
such as pyrilamine, cholpheniramine, tetrahydrazoline, antazoline,
and the like; anti-inflammatories such as cortisone,
hydrocortisone, beta-methasone, dexamethasone, fluocortolone,
prednisolone, triamcinolone, indomethacin, sulindac, its salts and
its corresponding sulfide, and the like. Also included are
antiparasitic compounds such as ivermectin; antiviral effective
compounds such as acyclovir and interferon.
[0056] For treatment of vaginal and urethral conditions requiring
antifungal, amoebicidal, trichomonacidal agents or antiprotozoals,
the following agents can be used: polyoxyethylene, nonylphenol,
alkylaryl sulfonate, oxyquinoline sulfate, miconazole nitrate,
sulfanilamide, candicidin, sulfisoxazole, nysatitin, clotrimazole,
metronidazole and the like and antiprotozoals such as
chloramphenicol, chloroquine, trimethoprim, sulfamethoxazole and
the like.
[0057] For use rectally the following suitable drugs can be
administered by the drug polymer deliver system of the present
invention:
[0058] (1) Analgesics such as aspirin, acetaminophen, deflunisal
and the like;
[0059] (2) anesthetics such as lidocaine, procaine, benzocaine,
xylocaine and the like:
[0060] (3) antiarthritics such as phenylbutazone, indomethacin,
sulindac, dexamethasone, ibuprofen, allopurinol, oxyphenbutazone
probenecid and the like;
[0061] (4) antiasthma drugs such as theophylline, ephedrine,
beclomethasone dipropionate, epinephrine and the like;
[0062] (5) urinary tract disinfectives such as sulfamethoxazole,
trimethoprim, nitrofurantoin, norfloxicin and the like;
[0063] (6) anticoagulants such as heparin, bishydroxy coumarin,
warfarin and the like;
[0064] (7) anticonvulsants such as diphenylhydantoin, diazepam and
the like;
[0065] (8) antidepressants such as amitriptyline, chlordiazepoxide,
perphenazine, protriptyline, imipramine, doxepin and the like;
[0066] (9) antidiabetics such as insulin, tolbutamide, tolazamide,
acetohexamide, chlorpropamide and the like;
[0067] (10) antineoplastics such as adriamycin, fluorouracil,
methotrexate, asparaginase and the like;
[0068] (11) antipsychotics such as prochlorperazine, lithium
carbonate, lithium citrate, thioridazine, molindone, fluphenazine,
trifluoperazine, perphenazine, amitriptyline, triflupromazine and
the like;
[0069] (12) antihypertensive such as spironolactone, methyldopa,
hydralazine, clonidine, chlorothiazide, deserpidine, timolol,
propranolol, metoprolol, prazosin hydrochloride, reserpine and the
like;
[0070] (13) muscle relaxants such as mephalan, danbrolene
cyclobenzaprine, methocarbamol, diazepam and the like;
[0071] (14) antiprotozoals such as chloramphenicol, chloroquine,
trimethoprim, sulfamethoxazole, and the like; and
[0072] (15) spermicidals such as nonoxynol.
[0073] Typically as stated previously, the present liquid drug
delivery device can contain from about 0.01% to about 60% of the
medicament, or pharmaceutical, on a weight to weight basis. Thus,
from one gram of the liquid composition containing about 1 ml of
solution, one would obtain about 0.1 mg to about 600 mg of
drug.
[0074] The particular drug used in the pharmaceutical composition
of this invention is the type which a patient would require for
pharmacological treatment of the condition from which said patient
is suffering. For example, if the patient is suffering from pain or
itch of the external auditory canal, the drug of choice would
probably be benzocaine.
[0075] Also included in this invention is the use of the drug
delivery device or pharmaceutical composition minus the active drug
or medicament for restoration or maintenance of vaginal acidity.
All the ratios of components as described above would be
satisfactory for this composition. For this use one would
administer the vehicle as needed at the desired pH.
[0076] Representative buffering agents or salts useful in
maintaining the pH at about 7.4.+-.0.2 are alkali or alkali earth
carbonates, chlorides, sulfates, phosphates, bicarbonates,
citrates, borates, acetates, succinates and tromethamine (TRIS).
Representative preservatives are sodium bisulfate, sodium
thiosulfate, ascorbate, benzalkonium chloride, chlorobutanol,
thimerosal, phenylmercuric borate, parabens, benzylalcohol and
phenylethanol.
[0077] The preparation of the pharmaceutical drug delivery
compositions of the invention are described below. The Examples
which follow were prepared according with the following preparation
procedure. Since the polyoxyalkylenes dissolve more completely at
reduced temperatures, the preferred methods of solubilization are
to add the required amount of polymer to the amount of water to be
used. Generally after wetting the polymer by shaking, the mixture
is capped and placed in a cold chamber or in a thermostatic
container at about 0.degree. C. to 10.degree. C. in order to
dissolve the polymer. The mixture can be stirred or shaken to bring
about a more rapid solution of the polymer. The pharmacologically
active medicaments and various additives such as buffers, salts,
and preservatives can subsequently be added and dissolved. In some
instances the pharmacologically active substance must be suspended
since it is insoluble in water. The pH of 7.4.+-.0.2 is obtained by
the addition of appropriate buffering agents.
[0078] The following Examples illustrate the various aspects of the
invention but are not intended to limit its scope. Where not
otherwise specified throughout this specification and claims,
temperatures are given in degrees centigrade and parts,
percentages, and proportions are by weight.
EXAMPLE 1
[0079] This Example formulation describes a composition of the
invention characterized as iso-osmotic, sterile, and having a pH of
7.4.+-.0.2. An aqueous solution was made of a
polyoxyethylene-polyoxypropylene block copolymer having the
structure generically shown above as Formula IV and having a
polyoxypropylene hydrophobe base average molecular weight of about
4000, a total average molecular weight of about 11,500, and
containing oxyethylene groups in the amount of about 70% by weight
of the total weight of copolymer. This copolymer (Formula VI below)
is sold under the trademark PLURONIC.RTM. F-127 (also known as
Poloxamer 407) by the BASF Corporation, Parsippany, N.J.. A
solution in TRIS hydrochloride buffer was made by dissolving said
polymer and sodium alginate in cold (4.degree. C.) buffer to give a
concentration of 19% by weight polyoxyalkylene and 1% by weight
sodium alginate. More specific solution procedures are described in
"Artificial Skin I Preparation and Properties of PLURONIC F-127
Gels For Treatment of Bums", Journal of Biomedical Material
Research 6, 527, 1972, incorporated herein by reference. The block
copolymer has the formula: 2
[0080] This formulation forms the basis for the FIGURE in which the
curve shows the penetration of a 20 mm thickness aqueous gel at
various temperatures. After contact of the gel with calcium ions,
as indicated by the arrow at 40.degree. C., the gel strength is not
reduced or the composition rendered fluid by lowering the
temperature back to 25.degree. C.
EXAMPLE 2 (Inventive) AND EXAMPLE 3 (Control)
[0081] These examples describe hyperosmotic, pH balanced,
thermo-sensitive systems, in which the active ingredient is
dissolved. The following antibacterial formulations were prepared
to contain 11.2% by weight of mafenide acetate. The antibacterial
formulations were prepared as follows:
1 Percent by Weight Example 3 Ingredient Example 2 (Control)
mafenide acetate 11.2 11.2 sodium alginate 0.5 -- carrageenan --
0.5 Poloxamer 407 (BASF) 19.0 19.0 TRIS hydrochloride 69.3 69.3
buffer (0.1 molar)
[0082] The formulations were prepared by dissolving the drug and
sodium alginate or carrageenan by stirring in the required amount
of TRIS hydrochloride buffer. These ingredients in a glass beaker
were placed in an ice bath and the Poloxamer 407 was added to the
beaker slowly while stirring. After the Poloxamer 407 was
completely dissolved, the formulation was stored at 4.degree. C.
The entire process was carried out under a nitrogen atmosphere. The
produce obtained was characterized as clear, straw colored and
exhibiting gelation at the temperature of mammalian skin
(33.+-.2.degree. C.). In the gelled state, the pH and osmolality of
the preparation would be expected to be 7.5 and over 720 m0sm/Kg,
respectively. Iso-osmotic solutions containing 2.5 to 3% by weight
would be expected to be iso-osmotic but less therapeutically
effective.
[0083] The solutions of Examples 2 and 3 were exposed to an equal
amount of 2% by weight solution of calcium chloride. The solution
of Example 2 formed a thermo-irreversible gel. The solution of
Example 3 remained thermo-reversible. Comparison of these examples
illustrates the importance of utilizing an ionic (sodium alginate)
instead of a non-ionic polysaccharide (carrageenan). In these
examples, the 2% solution of calcium chloride was applied both as a
spray to the solution of Examples 2 and 3 and also the 2% solution
of calcium chloride was used to impregnate a gauze bandage and
subsequently the solutions of Examples 2 and 3 were placed in
contact with the gauze bandage. In both cases, the solution of
Example 2 was rendered thermo-irreversible and the solution of
Example 3 was unaffected.
EXAMPLES 4 (Inventive) AND 5 (Control)
[0084] Examples 2 and 3 are repeated substituting for Poloxamer
407, 2% by weight of polymer #2, as described in U.S. Pat. No.
4,810,503 and 4% by weight of surfactant #1, as described therein.
The balance of the percentage of Poloxamer 407 used in Examples 2
and 3 is made up with TRIS hydrochloride buffer. These formulations
form soft gels at room temperature which are usefully stiffened
upon exposure to a 2% by weight aqueous solution of calcium
chloride, in the case of Example 4, and are unaffected in the case
of control Example 5. Substantially similar pH and osmolality
results are obtained.
EXAMPLE 6
[0085] Ion exchange resin beads sold under the trade name Duolite
were treated so as to incorporate calcium by first treating a 30
gram sample of the ion exchange resin with a solution of 0.1 molar
hydrochloric acid so as to allow for the exchange of protons for
sodium. After three washings with 0.1 molar hydrochloric acid, the
beads were washed with water and then washed twice with a 2%
aqueous solution of calcium chloride. Each of the washing steps
took place over a period of 16 hours (overnight). The beads were
thereafter filtered and washed with water utilizing coarse filter
paper and a Buchner glass filter assembly. The beads were then left
overnight in a desiccator to dry.
[0086] The dried beads of ion exchange resin which were obtained
were utilized in the amount of 2 grams to fill a first compartment
(close to the needle of the syringe) of a glass syringe utilized to
apply liquids and dry materials. The syringe is sold under the
trade name Hypak. Into the second compartment of the syringe, there
was placed the solution of Example 2. Pushing the plunger of the
syringe forward resulted in mixing the solution of Example 2 with
the ion exchange beads. After 5 to 10 minutes subsequent to mixing,
the mixture was expelled from the syringe. After an additional 15
minutes, the expelled material formed a thermo-irreversible film on
the substrate on which it was expelled.
[0087] While this invention has been described with reference to
certain specific embodiments, it will be recognized by those
skilled in the art that many variations are possible without
departing from the scope and spirit of the invention, and it will
be understood that it is intended to cover all changes and
modifications of the invention, disclosed herein for the purpose of
illustration, which do not constitute departures from the spirit
and scope of the invention.
* * * * *