U.S. patent application number 13/693341 was filed with the patent office on 2013-04-18 for sol-gel nanostructured titania reservoirs for use in the controlled release of drugs in the central nervous system and method of synthesis.
This patent application is currently assigned to UNIVERSIDAD AUTONOMA METROPOLITAN. The applicant listed for this patent is UNIVERSIDAD AUTONOMA METROPOLITAN. Invention is credited to Tessy Maria Lopez-Goerne.
Application Number | 20130095164 13/693341 |
Document ID | / |
Family ID | 37835067 |
Filed Date | 2013-04-18 |
United States Patent
Application |
20130095164 |
Kind Code |
A1 |
Lopez-Goerne; Tessy Maria |
April 18, 2013 |
SOL-GEL NANOSTRUCTURED TITANIA RESERVOIRS FOR USE IN THE CONTROLLED
RELEASE OF DRUGS IN THE CENTRAL NERVOUS SYSTEM AND METHOD OF
SYNTHESIS
Abstract
The invention is related to a method of administering a
controlled release central nervous system drug by means of sol-gel
nanostructured titania reservoir comprising silica, titania and
silica-titania, and comprising partially hydrodyzed nano-materials.
This reservoir may be in the form of a xerogel.
Inventors: |
Lopez-Goerne; Tessy Maria;
(Delagacion, MX) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
UNIVERSIDAD AUTONOMA METROPOLITAN; |
Mexico City |
|
MX |
|
|
Assignee: |
UNIVERSIDAD AUTONOMA
METROPOLITAN
Mexico City
MX
|
Family ID: |
37835067 |
Appl. No.: |
13/693341 |
Filed: |
December 4, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12303953 |
Aug 12, 2009 |
8343514 |
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PCT/IB2006/001725 |
Jun 6, 2006 |
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13693341 |
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Current U.S.
Class: |
424/423 ;
514/770; 977/831; 977/906 |
Current CPC
Class: |
A61K 9/0024 20130101;
C01P 2002/82 20130101; C01G 23/053 20130101; C01P 2004/03 20130101;
C01P 2006/12 20130101; C01B 33/14 20130101; A61P 25/00 20180101;
A61P 25/08 20180101; Y10S 977/906 20130101; C01P 2004/04 20130101;
B82Y 5/00 20130101; A61K 9/0085 20130101; A61L 31/026 20130101;
A61K 9/06 20130101; A61K 47/02 20130101; Y10S 977/831 20130101 |
Class at
Publication: |
424/423 ;
514/770; 977/831; 977/906 |
International
Class: |
A61L 31/02 20060101
A61L031/02 |
Claims
1. In a method of administering a controlled release central
nervous system (CNS) drug to a patient in need thereof, the
improvement wherein the drug is carried by a sol-gel nanostructured
titania reservoir comprising silica, titania and silica-titania,
and comprising partially hydrolyzed nano-materials.
2. The method of claim 1, wherein the reservoir is the form of a
xerogel.
3. The method of claim 2, wherein the reservoir comprises a
neurological drug occluded within its interior.
4. The method of claim 2 wherein the reservoir is biocompatible
with a surrounding brain tissue.
Description
FIELD OF THE INVENTION
[0001] This invention is related to the synthesis of a titania
reservoir which is biocompatible with brain tissue. The pore size
distribution, crystallite size and the extant of the crystalline
phase distribution of anatase, brookite and rutile can be fully
controlled. This device will be used to contain neurological drugs.
It will be inserted directly into brain tissue for the purpose of
the controlled time release of drugs over a period of from 6 months
to three years.
BACKGROUND FOR THE INVENTION
[0002] State of the art research in the treatment of chronic
diseases is based on the development of controlled release systems
capable of delivering drugs rapidly and efficiently to where they
are needed. A major requirement is that these devices should insure
delivery and penetration of the drug to the active site. New
naoostructured materials represent an efficient way to administer
medications and biological products in future applications.sup.1-5.
Hydrogels based on N-isopropylacrilimide and metacrilic acids (MAA)
have recently received considerable attention. This is due to their
ability to swell in response to the stimulation of the
medium.sup.6-8. In the solid state, the existence of interpolymeric
complexes in which monomers are linked together through hydrogen
bonds has been observed. These linkages occur under acid conditions
and are stabilized through hydrophobic interactions. This leads to
a marked dependence on the pH of the medium in which swelling
occurs. This swelling is also strongly dependent on the degree of
cross-linking. The use of drug delivery by oral means has received
considerable attention, particularly in cases in which activation
is controlled by variations in the pH. Copolymers having a high
concentration of N-isopropylacrilamide appear to be the most
effective in enabling one to obtain different cut-off curves used
in the drug model..sup.12-15
[0003] In the majority of cases, which involve controlled drug
release, the medication or other biological agent, is introduced
into the interior of the reservoir normally known as the
transporter. The transporter usually consists of a polymeric
material. Under normal conditions the rate of drug release is
controlled by the properties of the polymeric material which
constitutes the transporter. However, other factors may also be
rate determining. When these factors are taken into account, it may
be possible to insure a slow, constant rate of drug delivery over
extended periods of time..sup.16-18 The use of these materials has
lead to considerable advances in drug delivery when compared to
systems currently in use. In conventional drug delivery systems,
drag concentrations reach a maximum value only to decay, finally
reaching a concentration, which requires the administration of
another dose. Additionally, if the maximum drug concentration
exceeds the safe level or if, alternatively it fails below the
required dose, cyclic periods will occur during which the drug is
not producing the desired effect. This is generally known as
"variations in tisular exposure". When controlled drug release is
used, it may be possible to maintain drug concentrations, which
fall between the maximum allowed rate, and the minimum,
concentration at which the rate is effective.sup.19-21.
[0004] In order for the drug to fee delivered to the desired site,
diffusion from the surface of the transporter to the medium
surrounding the transporter must occur. From this point, the drug
must diffuse over an area in which it will be effective. Following
many studies, it has been concluded that there are four general
mechanisms by which controlled drug release can be classified: 1)
diffusion controlled systems, 2) chemically controlled systems, 3)
systems activated by a desolubilizer and, 4) systems which are
magnetically controlled.
[0005] The migration of a drug to a fluid medium for a system such
as that described here, must involve a process in which the drug is
described from the surface of the transporter and is simultaneously
absorbed info the fluid medium. This process is controlled by a
concentration gradient. The fluid might consist of either water or
a biological fluid. The entrance of a solvent into a polymer, which
is in a vitreous state, may produce a considerable increase in the
macromolecular motion. From a thermodynamic point of view, a
solubility parameter d, and the interaction between the material
and the solvent c, can express the compatibility between the
solvent and the reservoir. If the solid is only slightly compatible
with the polymer, it will remain in the vitreous state and under
these conditions the controlled release of any drug will be very
slow and of limited pharmacological use. On the other hand if the
thermodynamics are favorable, the probability that the solute can
diffuse from the transporter to the fluid is very large (Korsmeyer
and Pepas; 1084 and Lee 1985a)..sup.22 In 1871 Yasoda and Lamaze
refined their theory on free volume and noted that they could
predict the diffusion coefficient of a drug across a polymeric
matrix with considerable accuracy.sup.23. In this treatment they
showed that the normalized diffusion coefficient of the solute in
the polymer and the diffusion coefficient of the solute in the pure
solvent are related by the extent of hydration. The external
transport of the drug is caused by the dissolution of the solute at
the interface between the solute and the reservoir followed by
external diffusion under the influence of a concentration gradient,
which obeys Fick's first law (hanger and Peppas, 1983).sup.24.
These systems are capable of drug release at a constant rate.
However, in practice factors exist which may lead to large
deviations. This problem can usually be corrected by adjusting or
changing the geometry of the device. When the system is a monolith,
the active compound is uniformly distributed on the support of the
solid polymer.
[0006] The drug may be dissolved within the polymer matrix or
dispersed depending on whether its concentration is such that its
solubility in the polymer has been exceeded. The migration of the
drug to the fluid medium occurs as a result of molecular surface
diffusion along the support or by pore diffusion through the micro
and meso pores within the matrix of the polymer. In this case,
diffusion can be interpreted using Fick's second law. However, in
any case the migration of the drug to the fluid medium will
decrease as a function of time. This decrease occurs as a result of
an increase in the length of the diffusion path.sup.25 (Rhine et
al., 1980).
[0007] The drug is chemically bound to the polymer chain and is
released as a result of a hydrolytic cleavage. The rate of drug
release can be altered if the hydrolysis can be catalyzed by
enzymes (Kopeck et. al, 1981).sup.26. Other systems of continual
drug release include polymers formed from polylactic acid and its
copolymers.sup.30. These precursors, together with glycolic acid
have been used primarily due to their biodegradabilility and
blocompatibility. The microencapsulation of drugs.sup.31-32 from a
technical point of view can be defined as a process, which involves
the covering of drugs. This may occur as molecules, solid particles
or liquid globules. The materials used in the encapsulation process
will depend on the particular application. However, the process
will give rise to particles having mlcrometrie dimensions. The
products, which are formed as a result of this process, are
referred to as "micropaslides", microcapsules` or
"microspheres".
[0008] These systems differ in their morphology and infernal
structure. However, they are all similar in size which is
approximately 1 mm.sup.33-34. When the particle size is less than 1
.mu.m, the resultant products of the microencapsulation process are
referred to as "nanospberes", "nanoparticles" or
nanocapsules".sup.35-37. An important feature of the
microencapsulation process is that the products are not limited to
drugs or biological materials but are extended to include products
in such areas as agriculture, cosmetics and food.sup.38.
[0009] There are other areas in which controlled drug delivery is
used. These include medications, which are absorbed through the
skin. Creams and gels, which can be applied to the skin, have been
used for many years as sedatives and medications to eradicate
localized infections. They can also be used to treat the entire
body (systemic).sup.39. An increasing number of medications have
recently become available as transdermal patches. They adhere to
the skin through an adhesive ring while a thin film of the
medication.sup.40 covers the center of the patch. The medication is
slowly absorbed through the skin until it is absorbed into the
blood stream. The transdermal patches most frequently used include
testosterone, estrogens, sedatives, birth control and nicotine
patches (used to aid smoking cessation). Other patches such
gabapentin deliver anticonvulsant medications
(Neurontin).sup.41-43. In some cases, the active medication is
mixed with another substance that controls the rate at which it is
absorbed. This means that they can be used continually for longer
periods of time or even for several days.
[0010] Another method by which transdermic administration is
applied makes use of small receptacles, which use air pressure to
inject a small stream of medication through the upper layers of
skin. People who require insulin on a daily basis can make use of
some very small receptacles to administer the medication.sup.44.
Researchers involved in gene therapy to treat HIV have experimented
with this technology to infect genetic materials through the skin
or muscle tissue.sup.46-46. Medications can also be delivered
through mucous membranes. A large number of the drugs are
administered through the lungs or through the nasal passage and are
rapidly absorbed into the blood stream. A large gamut of
medications, including painkillers and vaccinations can be applied
using this technique. In what promises to be a significant advance
in the treatment of diabetes, a new technique, which makes use of
inhalation technology, is being tested. Patches can also be adhered
in the mouth at the interior of the cheek muscles.sup.47-50.
[0011] In order to avoid the formation of a spinel, the sol-gel
technique can be used as a good method by which the various solid
phases can be controlled (T. Lopez et. al, Catalysis Today 35, 283,
1997). A greater degree of control can be achieved in comparison to
other methods of synthesis. One can tailor make the reservoir to
tit specific applications by using this method. Advances
include:
(i) Superior homogeneity and purity (ii) High biocompatibility with
brain tissue (iii) Better nano and microstructural control of the
polymeric reservoir. (iv) Greater BET surface area. (v) Improved
thermal stability of the drugs attached to the reservoir. (vi)
Well-defined pore size distributions. (vii) The ease by which drugs
can be attached and released from the reservoir. (viii) Inorganic
chain structures can be generated in solution (ix) A finer degree
of control over the hydroxylation of the reservoir can be
achieved.
[0012] The process of reservoir fabrication has as an objective the
optimization of the following variables: particle size, mean pore
size, interaction forces and the degree of functionalization. It
may also be desirable to modify the textural and electronic
behavior of the reservoir.
[0013] Titania is a material, which has important applications in
industry. As an example we cite the synthesis of hydrocarbons from
carbon monoxide or synthesis gas (U.S. Pat. No. 4,992,406; U.S.
Pat. No. 4,784,099; U.S. Pat. No. 5,140,050; U.S. Pat. No. 521,563;
U.S. Pat. No. 6,124,367.
[0014] Due to its unique electronic properties it has been used to
modify the electronic properties of a transition metal when it is
used as a reservoir (Klein L. C., Sol-Gel Technology for Thin
Films, Fibers, Perform, Electronics and Shapes, (Noyes: New: New
Jersey 1997)
[0015] Under conditions of normal atmospheric pressure, titania can
have three different crystal phases: brookite, anatase and rutile.
In all three phases, the Ti atoms are centered inside deformed
oxygen octahedra. The number of edges of these ociahedra that are
shared distinguishes the different crystalline phases. Three
octahedral edges are shared in brookite, four in anatase, and two
in futile (L. Pauling, JACS 61 (1929) 1010. This results in a
different mass density for each phase. Pure titania with a large
crystallite size is stoichiometric, dielectric and not useful in
catalysis. It is necessary to change the stoichiometry by creating
oxygen vacancies or other bulk defects.
[0016] The electronic and catalytic properties of titania depend on
the local density and on the type of impurities present in the
crystal structure (R. H. Clark "The chemistry of Titanium and
Vanadium, Elsevier Publishers Co. MY. 1888, Ch 9).
[0017] Sol-gel technology is an important synthesis method by which
the crystalline phases and particle size of titania can be
controlled. A sol is a fluid, colloidal dispersion of solid
particles in a liquid phase where the particles are sufficiently
small to stay suspended in Brownian motion, A "gel" is a solid
consisting of at least two phases wherein a solid phase forms a
network that entraps and immobilizes a liquid phase.
[0018] In the sol-gel process the dissolved or "solution"
precursors can include metal alkoxides, alcohol, water, acid or
basic promoters and on occasion salt solutions. Metal alkoxides are
commonly employed as high purity solution precursors. When they
react with water through a series of hydrolysis and condensation
reactions they yield amorphous metal oxides or oxyhydroxide gels.
When the volatile alcohol's are removed the result is the formation
of crystalline solid compounds.
[0019] The materials that are used as colloid precursors can be
metals, metal oxides, metal oxo-hydroxides or other insoluble
compounds. The degree of aggregation or flocculation in the
colloidal precursor can be adjusted in such a way that the pore
size distribution can be controlled. Dehydration, gelation,
chemical cross-linking and freezing can be used to form the shape
and appearance of the final product. Some advantages using sol-gel
technology include control over the purity of the alkoxide
precursors, control over the homogeneity of the product, control
over the evolution of the desired crystalline phases and most
importantly, the reproducibility of the materials synthesized.
[0020] For H.sub.2O/Ti(OR).sub.4 ratios of between 0 and 0.1, the
titanium alkoxide reacts immediately with wafer and alcohol. During
the hydrolysis, the hexacoordination of the central titanium
remains (T. Boyd, J. Polymer Sci., 7 (1961)591). The hydrolysis
product is not fully hydrolyzed nor can it ever be a pure oxide. It
can only be in the form,
Ti.sub.nO.sub.2n(x+y)/2(OH).sub.xOR).sub.y
[0021] Where n is the number of titanium atoms polymerized in the
polymer molecule and x and y is the number of terminal OH and OR
groups respectively. It is well known that some sol-gel structures
attain their highest coordination state through intermolecular
links (Sanker G., Vasureman S, and Rao C. N. R., J. Phys. Chem, 94,
1879 (1988)). Because there are strong Van der Wall interaction
forces between the drugs and the titania reservoir, it is possible
to encapsulate a large amount of medication within the titania
reservoir.
[0022] Additional Titania Patents Using Sol-Methods
[0023] U.S. Pat. No. 6,124,367. This patent protects reservoirs
used in the Fischer Tropsch reactions from sintering by imparting a
higher degree of mechanical strength to the reservoir. It
incorporates SiO.sub.2 and Al.sub.2O.sub.3 into the reservoir and
claims a rutile-anatase ratio of 1/9. If is a porous reservoir with
either a spherical or a cylindrical shape. It is made by extrusion,
spray drying or tableting.
[0024] U.S. Pat. No. 6,117,814. This patent describes a titania
reservoir which also incorporates silica and alumina as a hinder
into the structure. The purpose of the binder is to impart better
mechanical properties to the reservoir. The size range of this
reservoir is from between 20 to 120 microns. The reservoir is
approximately 50% binder, which is fabricated by a sol-gel
process.
[0025] U.S. Pat. No. 6,087,405. This patent describes a reservoir
to be used in a Fischer Tropsch gas synthesis reaction. The
reservoir incorporates group VII metals into its-structure. The
rutile-anatase ratio in the structure is a distinguishing feature
of this patent.
OBJECTIVES
[0026] 1. The development of nanostructured materials for use in
the time controlled release of drugs in the central nervous system
(CNS)
[0027] 2. Optimization of materials to enable control of the
following parameters: pore size distribution, particle size,
crystalline phase, degree of functionalization, size of reservoir
required to accommodate the drug, and release time for effective
delivery
[0028] 3. Obtain constant drug delivery times to damaged neurons
and to prevent an overdose to the blood stream, liver, intestine
and to the hematoencefalic barrier.
[0029] 4. Construct complex systems, which mimic the central
nervous system in order to obtain specific diffusion and kinetic
delivery rates.
[0030] 5. Due to the nature of the products it is essential to
coordinate preparation times with administration time to patients,
if this is not correctly assessed, drug delivery concentrations may
not be correct. Drug retention times in the reservoirs must be
carefully studied.
[0031] 6. It will be important that a constant rate of drug release
be maintained for periods of between six months and three
years.
[0032] 7. The reservoirs will consist of nanostructured titania
prepared using sol-gel methods.
DETAIL OF THE INVENTION
[0033] The present invention includes a novel nano-material
(silica, titania and silica-titania) obtained by the sol-gel
process. Neurological drugs having an active molecular size of
between 1.5 to 4.0 nm can be occluded within the interior of this
device.
[0034] This nano-material consists of partially hydrolyzed
nano-materials having a Ti:Si range of compositions between (100:0
and 0.0:100). These materials were prepared using a sol-gel
process, which has been used to synthesize ceramic and glass
materials.
[0035] During the drying operation, the temperature was controlled
in order to stabilize the internal stresses and bonds within the
gel. If the material is not given sufficient time to relax, under
controlled vacuum and temperature conditions in the rotavapor,
significant cracking and break-up of the material may occur.
[0036] Following the drying process the hydroxyl groups remain
stable within the matrix. Polymerization continues for a
considerable period of time following gelation. This is referred to
as the aging process, which results in a much more stable get.
[0037] The titania, silica and titania-silica xerogels (100:0,
0:100) materials are found to be biocompatible with surrounding
tissue.
[0038] In a prior article, the slow time release of drugs into the
brain from an implanted device has been described in terms of
months. Release times well in excess of a one-year period are
needed.
[0039] The rate of drug release from an implanted device is
strongly dependent on the strength of the drug-device interaction.
For weak interactions the release time may be too fast. If the
interaction is very strong the drug release time may be too
slow.
[0040] The electronic structure of the device is controlled to
obtain the adequate release of the neurological drug.
[0041] The rate of drug release is described in a previous study.
If the drug is basic an acidic device is preferable. On the other
hand, when the released drug is acidic a basic device should be
used. Drug dispersions within the matrix are between 90 and 100%.
The time release pretties in addition to being dependent on
drug-device interactions, are also dependent on pore diffusion and
consequently, on the porosity of the gel.
[0042] When the synthesis of the pure TiO.sub.2 device was
performed under acid conditions at a pH=2, the BET surface area of
the device was relatively constant at approximately 500 m.sup.2/g
and was found to be independent of the amount of neurological drug
(i.e. anticonvulsant drug) adsorbed. When the loading of the drug
approached 1000 mcg/20 g of the device, there was a slight decrease
in the surface area.
[0043] When the synthesis of the device was performed under basic
conditions at pH=12 the BET surface area was relatively constant at
approximately 680 m.sup.2/g. It was found to be independent of the
loading of neurological drug (i.e. an anticonvulsant drug), for all
drug loadings up to an including 1000 mcg/20 g of the device.
[0044] The results described under 9 and 10 show the remarkable
flexibility of the device. When synthesis is performed under acid
conditions basic drugs are weakly bound to the device.
[0045] Pore volumes and pore diameters are not strongly affected by
drug loadings. However, there is a small decrease in both pore
volume and pore diameter at very low drug loadings.
[0046] The kinetics of the drug release process show a zero order
dependence on the concentration of the encapsulated drug
[0047] The zero order kinetics of the drug release delivery process
ensures a constant rate of delivery.
[0048] Drug-device interactions occur through Van der Waais forces
and hydrogen bonding between hydroxyl groups on the device and
carbonyl groups on the drug.
[0049] The diffusion is controlled by two phenomena: a) a chemical
interaction between the device and the drug, and b) mean pore
size.
[0050] Following the depletion of the neurological medication, a
fresh dose of the drug may be easily replaced using stereotaxic
surgery.
[0051] Drug delivery using devices prepared using Sol-gel chemistry
are currently state of the art. The porosity of the nanomaterial
can be controlled by the pH of the solution. On the other hand an
acid catalyst is not needed when the drug is acidic. Drug
dispersions in the matrix are between 90 to 100%.
[0052] The drugs can be encapsulated during the gelling process. If
can be seen from the release profiles that the drug release is
based on the porosity of the gel.
[0053] The ceramic material in this Invention is completely
biocompatible with the brain tissue surrounding the implant.
Detailed Description of the Synthesis Methods Used
Sol-gel TiO.sub.2, TiO.sub.2-Silica and SiO.sub.2 or (Sol-Gel
TiO.sub.2--SiO.sub.2 0:100 to 100:0).
[0054] In the three-necked flask shown in the figure, a mixture
consisting from 38 ml of dionized wafer, 0 to 50 ml of (EDTA)
ethylene diamine tetraacetic acid and 190 ml of ter-butanol (Baker,
purity 99%) were refluxed. Prior to initiating the reflux, the pH
of the solution was adjusted to 2 using HNO.sub.3 in one case and
12 using ammonium hydroxide in another case. In either case, the
acid or base was added in a dropwise manner until the desired pH
was reached. The pH was continually monitored by means of a
potentiometer throughout the entire process. Using two funnels, 87
ml of titanium n-butoxide (Aldrich, 98% purity) and 21.5 ml of
tetraethoxysilane were added to the solution being refluxed. The
dropwise addition was performed over a four-hour period in order to
enhance the nucleation and the functionalization of the hydroxyl
(OH) and the ammonium groups (NH). Following the addition of the
alkoxides, the colloidal suspension was refluxed for an additional
period of 24 hours. Following this process, the samples were dried
under vacuum conditions in a roto-vapor (10.sup.-3 mm. Hg) in order
to remove excess water and alcohol. Finally, the samples were dried
at 30.degree. C. for 72 hours. In order to reach the final drying
temperature of 30.degree. C., the temperature was increased at a
rate of 0.25.degree. C./min) using a conventional inert atmosphere
furnace.
The Effect of Synthesis Variables on the Physical Properties of the
Products Obtained
(1) The Role of pH.
[0055] An increase in pH from 3 to 9 results in a substantial
decrease in the percentage of Brookite in the crystal structure.
For example, at 300.degree. C. the percentage of Brookite decreases
from 13.6% to 0% when the pH is increased from 3 to 5, while that
of Anatase increases from 84.7 to 100% over the same pH range. The
percentage Rutile also decreases from 8.2 to 0% over the same pH
range. The dominant structure appears to be Anatase at all pH's
from 3 to 9 at 300.degree. C. See Table 1
(2) The Role of Temperature.
[0056] When the calcination temperature is increased from 70 to
900.degree. C., both Brookite and Anatase decrease drastically to
0.degree. C. at 900.degree. C. while Rutile becomes the dominant
crystal phase. Over the same temperature range, Rutile increases
from 1.7 to 100%. See Table 1.
(3) The Role of pH and Temperature on the Average Crystallite Size
of Brookite.
[0057] The average crystallite size increases substantially with
temperature between 70 and 300.degree. C. at a pH of 3. However,
when the pH is increased to 7, there is no noticeable change in the
crystallite size over the same temperature range. Changes in the
lattice parameters of Brookite appear to be more dependent on pH
than on temperature. These results are summarized in Table 2.
(4) The Role of pH and Temperature on the Physical Properties of
Anatase.
[0058] These results are shown in Table 3. An increase in the
calcination temperature at a given pH results in a sharp increase
in crystallite size. This observation holds for all of the pH's
studied. The lattice parameters are less dependent on pH and
calcination temperature. Sintering appears to be considerably more
noticeable at pH 3 than at higher pH's. This is apparent from the
rather large increase in density between 70 and 600.degree. C. The
titanium occupancy increase with temperature at all pH's
(5) The Role of pH and Temperature on the Physical Properties of
Rutile.
[0059] These results are shown in Table 4. An increase in
crystallize size is observed with an increase in temperature.
However, the effect is considerably less than that observed for
Brookite and Anatase. This increase is observed at all the pH's
studied with the exception of pH 5 in which a slight decrease in
crystallite size was observed. The occupancy of titanium is not
strongly dependent on particle size or temperature.
FIGURE CAPTIONS
[0060] FIG. 1. H NMR of: a) TiO2-VPA and b) pure valproic acid.
[0061] FIG. 2. FTIR spectroscopy of TiO2 and TiO2-VPA
reservoir.
[0062] FIG. 3. N2 adsorption isotherms of empty TiO2 reservoir and
TiO2 with VPA occluded.
[0063] FIG. 4. Scanning Electron Microscopy (SEM) images of a TiO2
reservoir implanted in the hipocampus region: (a) Detail of the
tissue mixed with the reservoir nanoparticles (b) Frontier (c)
Panoramic, between hippocampus tissue and reservoir, and (d) Detail
of the implanted tissue.
[0064] FIG. 5. Scanning Electron Microscopy (SEM) images of a
sol-gel TiO2 reservoir obtained at: (a) pH7 (30,000.times.), (b) pH
7 (120,000.times.), (g) pH 9 and (d) pH 3. Note the difference in
structure obtained at pH 7 and pH 3. An increase in acidity results
in a change from a spherical to a more fiber like structure.
[0065] FIG. 6. Scanning Electron Microscopy (SEM) images of a
sol-gel TiO2 reservoir 120000.times.. Detail
[0066] FIG. 7. Transmission Electron Microscopy (TEM) images of the
nanostructured TiO2 reservoir synthesized at pH 3
(200,000.times.).
[0067] FIG. 8. Model of the reservoir and the drug release.
[0068] FIG. 9. This figure shows the technique used to implant a
reservoir into the temporal lobe of the brain of a Winster rat. (a)
The cannula that was used to obtain the cylinders used in the
implant. (b) The biocompatible reservoir and the brain tissue show
there is no damage to the tissue surrounding the implant. (c)
Stereotactic surgery used to implant the reservoir.
[0069] FIG. 10. The local effect of the ordered titania material
implant was studied in the close vicinity of brain tissue. A
well-organized fibrous capsule was formed surrounding the implant
following an implantation period of 6 months or greater. The
implant did not cause necrosis and inflammation was not observed.
The histopathological study surrounding the implant was made. No
pathology was reported. The results show that there was good
biocompatibility with brain tissue.
[0070] FIG. 11. Stereotactic surgery, rat conduct and
histophatological study after one year.
[0071] FIG. 12. The biocompatibility study of the brain was
focussed on the chronic inflammatory response associated with the
reservoir implantation procedure. This absence of alterations in
implanted rats confirms a high degree of biocompatibility of the
materials.
PURPOSE OF THE INVENTION
[0072] When taken orally, the absorption of a drug into the blood
stream results in a considerable loss of the drug due to
elimination through the urine and other organs in the body. As much
as 86% is eliminated through the urine. In order to avoid this
loss, implantation directly info an area adjacent to the affected
region may result in considerable savings in the amount of the drug
actually needed. Additionally, large fluctuations in the
concentration of the drug can be avoided. In order for the
controlled drug release to be effective several conditions need to
be met as follows: [0073] (1) The concentration of the drug
released must be as constant as possible. Because the structure of
the reservoir described in this invention is highly porous,
diffusional processes through the porous structure of the reservoir
are involved. The results obtained in this invention have shown
that the rate of delivery is constant over periods of 6 months to
three years. The rate of delivery is close to zero order in the
concentration of the drug. In other words it is constant. Large
fluctuations in the concentration of the drug during delivery are
avoided. [0074] (2) The implanted canister containing the drug must
be biocompatible with the surrounding tissue. This biocompatibility
is clearly shown in FIG. 11. Little, if any damage to the
surrounding tissue was observed. [0075] (3) The implantation
process is reversible. When the concentration of the drug in the
delivery process fails below that required for effective delivery
the canister may be removed and reinserted with a fresh dose of the
medication. [0076] (4) In addition to the delivery of
anticonvulsants, this device may be used in other applications,
chemotherapy in the treatment of cancer for example. [0077] (5) The
nanoconstruction process using a sol-gel approach, results in a
very small canister, which will decrease the damage induced in the
implantation process. [0078] (6) The mesoporous structure of the
TiO.sub.2 nanoreservoir permits microglial cells to access the
interior of the implant.
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