Language selection

Search

Patent 2662162 Summary

Third-party information liability

Some of the information on this Web page has been provided by external sources. The Government of Canada is not responsible for the accuracy, reliability or currency of the information supplied by external sources. Users wishing to rely upon this information should consult directly with the source of the information. Content provided by external sources is not subject to official languages, privacy and accessibility requirements.

Claims and Abstract availability

Any discrepancies in the text and image of the Claims and Abstract are due to differing posting times. Text of the Claims and Abstract are posted:

  • At the time the application is open to public inspection;
  • At the time of issue of the patent (grant).
(12) Patent Application: (11) CA 2662162
(54) English Title: BIOCERAMIC COMPOSITE COATINGS AND PROCESS FOR MAKING SAME
(54) French Title: REVETEMENTS COMPOSITES BIOCERAMIQUES ET PROCEDES DE FABRICATION
Status: Deemed Abandoned and Beyond the Period of Reinstatement - Pending Response to Notice of Disregarded Communication
Bibliographic Data
(51) International Patent Classification (IPC):
  • A61L 27/32 (2006.01)
  • A61L 27/28 (2006.01)
  • A61L 27/30 (2006.01)
  • A61L 27/34 (2006.01)
  • A61L 27/40 (2006.01)
  • A61L 27/54 (2006.01)
  • A61L 27/56 (2006.01)
  • A61L 27/58 (2006.01)
  • A61L 29/12 (2006.01)
  • C09D 1/00 (2006.01)
(72) Inventors :
  • TROCZYNSKI, TOMASZ (Canada)
  • YANG, QUANZU (Canada)
(73) Owners :
  • THE UNIVERSITY OF BRITISH COLUMBIA
(71) Applicants :
  • THE UNIVERSITY OF BRITISH COLUMBIA (Canada)
(74) Agent: OYEN WIGGS GREEN & MUTALA LLP
(74) Associate agent:
(45) Issued:
(86) PCT Filing Date: 2006-08-30
(87) Open to Public Inspection: 2008-03-06
Availability of licence: N/A
Dedicated to the Public: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): Yes
(86) PCT Filing Number: PCT/CA2006/001442
(87) International Publication Number: WO 2008025122
(85) National Entry: 2009-02-27

(30) Application Priority Data: None

Abstracts

English Abstract

The present invention discloses novel polymer-ceramic matrix composites and processes for making same. The composites can be used in biomedical applications, in particular, coatings of implants and other medical devices, where both the ceramic phase and the polymer phase are bio-compatible. The composites combine a reinforcing polymer phase with a continuous ceramic matrix to create materials with properties that are new and superior to polymer or ceramic phases alone. The composites can incorporate a bioactive agent.


French Abstract

Revêtements composites biocéramiques et procédés de fabrication. Les composites peuvent être utilisés dans des applications médicales, en particuliers comme revêtements d'implants et autres dispositifs médicaux, où à la fois la phase céramique et la phase polymère sont biocompatibles. Dans ces composites, une phase polymère de renforcement se combine avec une matrice céramique continue pour créer des matériaux dotés de propriétés nouvelles et supérieures à celles de la phase poylmère seule ou de la phase céramique seule. Ces composites sont intégrés en tant qu'agent bioactif.

Claims

Note: Claims are shown in the official language in which they were submitted.


-31-
WHAT IS CLAIMED IS:
1. A bio-polymer/bioceramic matrix composite coating comprising: (a) a
porous bioceramic matrix of continuous phase; and (b) at least one
biocompatible
polymer of continuous or discontinuous phase.
2. A bio-polymer/bioceramic matrix composite coating as claimed in claim 1
wherein a bioactive agent is incorporated in the composite coating.
3. A bio-polymer/bioceramic matrix composite coating as claimed in claim 1,
wherein said porous bioceramic matrix is made by a process selected from the
group
consisting of sol-gel coating, thermal spray coating, electro-chemical
deposition,
electrophoretic deposition, biomimetic deposition and shape and sintering.
4. A bio-polymer/bioceramic matrix composite coating as claimed in claim 1,
wherein the coating is porous and the pore size of the coating is in the range
of
0.01µm to 1000µm.
5. A bio-polymer/bioceramic matrix composite coating as claimed in claim 4,
wherein volume of porosity of the coating is in the range of 5vol % to 70vol
%.
6. A bio-polymer/bioceramic matrix composite coating as claimed in claim 4,
wherein the thickness of the porous bioceramic coating is in the range of 0.1
to
1000µm.
7. A bio-polymer/bioceramic matrix composite coating as claimed in claim 4,
wherein the pores are open and interconnecting.
8. A bio-polymer/bioceramic matrix composite coating as claimed in claim 1,
wherein the porous bioceramic matrix (a) is selected from the group consisting
of:
hydroxyapatite, calcium metaphosphate, tricalcium phosphates, dicalcium
phosphate dihydrate, calcium hydrogen phosphate, tetracalcium phosphates,
heptacalcium decaphosphate, calcium pyrophosphate dihydrate, crystalline
hydroxy
apatite, poorly crystalline apatitic calcium phosphate, calcium pyrophosphate,
monetite and octacalcium phosphate.

-32-
9. A bio-polymer/bioceramic matrix composite coating as claimed in claim 1,
wherein the bioceramic matrix is hydroxyapatite.
10. A bio-polymer/bioceramic matrix composite coating for a medical device
comprising: (a) a porous bioceramic matrix;(b) at least one biocompatible
polymer;
and (c) at least one bioactive agent.
11. A bio-polymer/bioceramic matrix composite coating as claimed in claim 10
wherein the bioceramic matrix (a) is continuous phase.
12. A bio-polymer/bioceramic matrix composite coating as claimed in claim 10
wherein the biocompatible polymer is continuous or discontinuous phase.
13. A bio-polymer/bioceramic matrix composite coating as claimed in claim 10,
wherein said porous bioceramic matrix coating is made by a process selected
from
the group consisting of sol-gel coating, thermal spray coating, electro-
chemical
deposition, electrophoretic deposition, chemical vapor deposition, physical
vapor
deposition and biomimetic deposition.
14. A bio-polymer/bioceramic matrix composite coating as claimed in claim 10,
wherein the pore size of the coating is in the range of 0.011µm to
1000µm.
15. A bio-polymer/bioceramic matrix composite coating as claimed in claim 10,
wherein volume of porosity of the coating is in the range of 5vol % to 70vol
%.
16. A bio-polymer/bioceramic matrix composite coating as claimed in claim 14,
wherein the thickness of the porous bioceramic coating is in the range of
0.1µ m to
1000µm.
17. A bio-polymer/bioceramic matrix composite coating as claimed in claim 14,
wherein the pores are open and interconnecting.
18. A bio-polymer/bioceramic matrix composite coating as claimed in claim 10,
wherein the porous bioceramic matrix (a) is selected from the group consisting
of:
hydroxyapatite, amorphous calcium phosphate, calcium metaphosphate,
tricalcium phosphates, dicalcium phosphate dihydrate, calcium hydrogen
phosphate,
tetracalcium phosphates, heptacalcium decaphosphate, calcium pyrophosphate

-33-
dihydrate, crystalline hydroxy apatite, poorly crystalline apatitic calcium
phosphate,
calcium pyrophosphate, monetite and octacalcium phosphate.
19. A bio-polymer/bioceramic matrix composite coating as claimed in claim 10
wherein the bioceramic matrix coating is hydroxyapatite.
20. A bio-polymer/bioceramic matrix composite coating as claimed in claim 10,
wherein the coating is deposited on a medical device and the coating covers at
least
a portion of the medical device.
21. A bio-polymer/bioceramic matrix composite coating as claimed in claim 10,
wherein the polymer is impregnated into the pores of the porous bioceramic
matrix
coating.
22. A bio-polymer/bioceramic matrix composite coating as claimed in claim 10,
wherein the polymer is infiltrated into the pores of the porous bioceramic
matrix
coating.
23. A bio-polymer/bioceramic matrix composite coating as claimed in claim 10,
wherein the biocompatible polymer is a biodegradable polymer.
24. A bio-polymer/bioceramic matrix composite coating as claimed in claim 10,
wherein the biocompatible polymer is a non-biodegradable polymer.
25. A bio-polymer/bioceramic matrix composite coating as claimed in claim 10,
wherein the porous bioceramic matrix coating is impregnated at least once with
a
polymer solution.
26. A bio-polymer/bioceramic matrix composite coating as claimed in claim 10,
wherein the porous bioceramic matrix coating is multi-step impregnated with a
polymer solution.
27. A bio-polymer/bioceramic matrix composite coating as claimed in claim 10,
wherein the porous bioceramic matrix coating is multi-step impregnated with
dissimilar polymer solutions.

-34-
28. A bio-polymer/bioceramic matrix composite coating as claimed in claim 10,
wherein the bioactive agent is selected from the group consisting of:
anti-inflammatory agents, anti-cancer agents, antibiotics, anti-restenosis
drugs, anti-thrombosis agents, antineoplastic agents and therapeutic
combinations
thereof.
29. A bio-polymer/bioceramic matrix composite coating as claimed in claim 10,
wherein the bioactive agent is paclitaxel.
30. A bio-polymer/bioceramic matrix composite coating as claimed in claim 20,
wherein the medical device is a stent.
31. A bio-polymer/bioceramic matrix composite coating as claimed in claim 20,
wherein the medical device is an implantable device or a surgical tool.
32. A bio-polymer/bioceramic matrix coating as claimed in claim 14 wherein the
pores in the coating are created by including a burn-out additive in the
coating and
burning out the additive.
33. A bio-polymer/bioceramic matrix coating as claimed in claim 14 wherein the
pores in the matrix are created by a gas-forming additive.
34. A bio-polymer/bioceramic matrix coating as claimed in claim 10 wherein the
biocompatible polymer is non-biodegradable and is selected from the group
consist-
ing of:
polyether block amides (PEBA), polyoctenamers, polyolefins, ethylenic
copolymers, ethylene vinyl acetate copolymers (EVA) and copolymers of ethylene
with acrylic acid or methacrylic acid; thermoplastic polyurethanes (TPU) and
polyurethane copolymers; metallocene catalyzed polyethylene (mPE), mPE copoly-
mers, ionomers, and mixtures and copolymers thereof; and vinyl aromatic
polymers
and copolymers.
35. A bio-polymer/bioceramic matrix coating as claimed in claim 10 wherein the
biocompatible polymer is biodegradable and is selected from the group
consisting
of:
biodegradable polylactic acid, polyglycolic acid, poly(L-lactide) (PLLA),
poly(D,L-lactide) (PLA); polyglycolic acid [polyglycolide (PGA)],

-35-
poly (L-lactide-co-D, L-lactide) (PLLA/PLA), poly(L-lactide-co-glycolide)
(PLLA/PGA), poly(D, L-lactide-co-glycolide) (PLA/PGA),
poly(glycolide-co-trimethylene carbonate) (PGA/PTMC),
poly(D,L-lactide-co-caprolactone) (PLA/PCL), polyethylene oxide (PEO),
polydioxanone (PDS), polypropylene fumarate, poly(ethyl glutamate-co-glutamic
acid), poly(tert-butyloxy-carbonylmethyl glutamate), poly(carbonate-ester)s,
polycaprolactone (PCL), polycaprolactone co-butylacrylate, polyhydroxybutyrate
(PHBT) and copolymers of polyhydroxybutyrate, poly(phosphazene),
poly(phosphate ester), poly(amino acid) and poly(hydroxy butyrate),
polydepsipeptides, maleic anhydride copolymers, polyphosphazenes,
polyiminocarbonates, cyanoacrylate, polyethylene oxide,
hydroxypropylmethylcellulose, hyaluronic acid, chitosan and regenerate
cellulose,
and proteins such as gelatin and collagen, and mixtures and copolymers
thereof.
36. A method of encapsulating a bioactive agent in a bio-polymer/bioceramic
matrix composite coating comprising:
(a) a porous bioceramic matrix coating;
(b) at least one biocompatible polymer; and
(c) at least one bioactive agent; said method being selected from the
group consisting of:
(i) immersing the composite coating bio-polymer/bioceramic
matrix in a solution containing the bioactive agent;
(ii) impregnating a solution of the biocompatible polymer and the
bioactive agent into the porous bioceramic matrix coating; and
(iii) multi-impregnating the composite coating by employing a
combination of method (i) and method (ii).
37. A method as claimed in claim 36 wherein the matrix composite coating after
encapsulating the bioactive agent in the matrix composite coating is coated
with a
thin polymer film.
38. A method as claimed in claim 36 wherein the composite coating is deposited
on a medical device.
39. A method of preparing a bio-polymer/bioceramic matrix composite compris-
ing: (a) a porous bioceramic matrix of continuous phase; and (b) at least one
biocompatible polymer of continuous or discontinuous phase, wherein the

-36-
bioceramic matrix is made by a process selected from the group consisting of
sol-gel
coating, thermal spray coating, electro-chemical deposition, electrophoretic
deposi-
tion, biomimetic deposition and shape and sintering.
40. A method as claimed in claim 39 wherein the composite incorporates a
bioactive agent and the composite is deposited as a coating on a medical
device and
the coating covers at least a portion of the medical device.
41. A method as claimed in claim 39 wherein the polymer is impregnated into
the pores of the porous bioceramic matrix.
42. A method as claimed in claim 39 wherein the polymer is infiltrated into
the
pores of the porous bioceramic matrix.
43. A method as claimed in claim 39 wherein the porous bioceramic matrix is
impregnated at least once with a polymer solution.
44. A method as claimed n claim 39 wherein the porous bioceramic matrix is
multi-step impregnated with a polymer solution.
45. A method as claimed in claim 39 wherein the porous bioceramic matrix
coating is multi-step impregnated with dissimilar polymer solutions.

Description

Note: Descriptions are shown in the official language in which they were submitted.


CA 02662162 2009-02-27
WO 2008/025122 PCT/CA2006/001442
BIOCERAMIC COMPOSITE COATINGS AND
PROCESS FOR MAKING SAME
FIELD OF THE INVENTION
[0001] The present invention discloses novel polymer-ceramic matrix composites
and processes for making same. The composites can be used in biomedical
applica-
tions, in particular, coatings of implants and other medical devices, where
both the
ceramic phase and the polymer phase are bio-compatible. The composites combine
a reinforcing polymer phase with a continuous ceramic matrix to create
materials
with properties that are new and superior to polymer or ceramic phases alone.
BACKGROUND OF INVENTION
[0002] Bioceramics are ceramic materials used for biomedical applications.
Bioceramics can be used for structural functions, e.g. for joint or tissue
replace-
ment, or can be used as coatings to improve biocompatibility of metal
implants, or
can function as a resorbable vehicle which provides a temporary framework that
is
dissolved and replaced as the body rebuilds tissue. Some bioceramics
additionally
feature drug-delivery capability.
[0003] Calcium phosphate (CP), in particular hydroxyapatite (HAP), are the
most
important inorganic constituents of biological hard tissues. In the form of
carbonated
HAP combined with organic component (e.g. collagen), they are present in bone,
teeth, and tendons to give these organs stability, hardness, and the specific
structural
function. Biologically formed calcium phosphates are often nanocrystals that
are
precipitated under mild conditions, i.e. ambient pressure, and near room
tempera-
ture. The beneficial biocompatible properties of hydroxyapatite (HAP) are well
documented. HAP is rapidly integrated into the human body, e.g. it will bond
to
bone. Hydroxyapatite is used as a coating for implants (e.g. titanium or
stainless
steels). Recent studies have examined the possibility of the use of HAP in
compos-
ite form, namely in materials that combine polymers with ceramic or
metal/ceramic
combinations. Reports of this research are available through several
publications,
e.g. Ritzoulis et al, "Formation of hydroxyapatite/biopolymer biomaterials. I.
Microporous composites from solidified emulsions", in Journal of Biomedical
Materials Research (2004 Dec 15), 71A(4), 675-8; Bigi et al, "Nanocrystalline
hydroxyapatite-polyaspartate composites", in Bio-Medical Materials and
Engineer-
ing (2004), 14(4), 573-579; Furuzono et al, "Nano-scaled hydroxyapatite/
polymer
composite IV. Fabrication and cell adhesion properties of a three-dimensional
scaffold made of composite material with a silk fibroin substrate to develop a
percutaneous device", in Journal of Artificial Organs (2004), 7(3), 137-144.

CA 02662162 2009-02-27
WO 2008/025122 PCT/CA2006/001442
2-
[0004] Considerable research has been also performed on methods of producing
HAP coatings on metal substrate for medical device applications, for example,
WO
2004/024201, US 2002/155144, US 6426114, JP 2003/342113 and US
2003/099762. Another example of inorganic biomaterial is bioglass, an oxide
glass
including silicon dioxide, calcium oxide and phosphorous oxide. Bioglass,
includ-
ing glass and glass-ceramics, is currently used as implant materials, i.e.
refer to
Dubok, "Bioceramics - yesterday, today, tomorrow", in Powder Metallurgy and
Metal Ceramics, Vol.39, Nos. 7-8, 2000 and Kokubo, "Surface chemistry of
bioactive glass ceramics" in Journal of Non-Crystalline Solids (1990), 120(1-
3),
138-51.
[0005] Chemical and morphological similarly between natural bone and the
implant
material tends to promote implant/bone interfacial bonding, thereby providing
high
interface sheer strength. The body of the patient will tend to isolate the
implant if
the body views the implant as foreign material, often by re-absorption of the
surrounding tissue and the subsequent formation of a fibrous tissue membrane
at the
interface between the implant and the natural bone. Such fibrous tissue
formation at
the interface interferes with the development of a strong mechanical interlock
between the implant and the bone material surrounding the defect site. A
better
interface may be achieved when the implant material either allows or even
promotes
bone ingrowth into the defect site, providing a superior mechanical lock with
the
implant or prosthesis. Various synthetic bone substitutes have been proposed,
including poorly crystalline hydroxyapatite (PC-HAP), as described by Lee et
al., in
US Patent No. 6,331,312. Tricalcium phosphate (TCP), PC-HAP and TCP have
been reported to provide implants with bioactive surfaces that promote
ingrowth of
natural bone when implanted into bone. In addition, it has been observed that
both
PC-HAP and TCP are reabsorbed by the host tissue, i.e. see Matsushita et al,
"A
new bone-inducing biodegradable porous tricalcium phosphate", in Journal of
Biomedical Materials Research, Part A (2004), 70A(3), 450-458; and Lu et al,
"The biodegradation mechanism of calcium phosphate biomaterials in bone", in
Journal of Biomedical Materials Research (2002), 63(4), 408-412.
[0006] In addition to bioceramic materials, organic polymers have been used as
bone defect repair materials, including poly(methyl methacrylate) (PMMA),
poly(lactic acid) (PLA), and poly(glycolic acid) PGA, i.e. refer to Kaito et
al,
"Potentiation of the activity of bone morphogenetic protein-2 in bone
regeneration

CA 02662162 2009-02-27
WO 2008/025122 PCT/CA2006/001442
-3-
by a PLA-PEG/hydroxyapatite composite", Biomaterials (2004), Volume Date
2005, 26(1), 73-79.
[0007] PMMA, also commonly used as a bone cement, is not subject to
degradation
by most biological processes in the patient. However, PMMA-based compositions
have been made partially resorbable by including cross-linked poly(propylene
glycol
fumarate) (PPF) and a particulate bioceramic, as described by Gerhart et al.,
in US
5,085,861 and US 4,843,112. However, these cements are primarily designed to
be
used in conjunction with the implantation of other non-resorbable prosthetic
devices.
[0008] Bioceramic-polymer matrix composites are a new generation of
implantation
material based on calcium phosphates. They substantially expanded the
possibility
of restorative and substitutive osteoplastic surgery, mainly in dentistry,
maxillofacial
surgery, and neurosurgery. The composite of HAP and biodegradable polymer
improves the mechanical strength and resistance to impact loading. In
addition,
HAP significantly improves the biocompatibility, bioactivity, bioresorpation
of the
overall composite including biopolymer. The evolution in mechanical properties
due
to biodegradation of the polymer can provide progressive load transfer from
implant
to the bone during healing, thereby eliminating stress shielding.
[0009] These types of composites are expected to be used for defect filling,
augmen-
tation of implant attachment to bone and internal fracture fixation without
the use of
other additional components, e.g. refer to Durucan, et al, "Biodegradable
hydroxyapatite-polymer composites", Advanced Engineering Materials (2001),
3(4), 227-231; Beletskii et al, "Biocomposite calcium-phosphate materials used
in
osteoplastic surgery", in Glass and Ceramics (Translation of Steklo i
Keramika)
(2000), 57(9-10), 322-325.
[0010] Wang et al (Annales de Chimie (Paris, France) (2004), 29(1), 17-28)
reported that hydroxyapatite (HAP) and tricalcium phosphate (TCP) have been
incorporated into polyhydroxybutyrate (PHB) to form new composites for tissue
replacement and regeneration applications. SEM examination showed that the
earliest nucleation of mineral crystals occurred on HA/PHB composites only
after
one day immersion in SBF.
[0011] Cooper (WO 2004/067052) discloses a method of forming a bioabsorbable
implant from a composite of a bioabsorbable polymer and a bioactive ceramic
filler.

CA 02662162 2009-02-27
WO 2008/025122 PCT/CA2006/001442
-4-
The surface of the implant is abraded with a biocompatible abrasive material
such as
a hydroxyapatite grit. A part of the outer surface of the implant is provided
by the
ceramic filler.
[0012] Several disclosures have been made also by W. Bonefield et al (US
Patent
Nos. 5,017,627, 5,728,753, 5,962,549), wherein discontinuous bio-ceramic or
bio-glass particles are dispersed in bio-polymer matrix, to form bulk
composites
suitable for implants. However, properties of all composites wherein the
polymer is
the continuous phase, are controlled by the properties of the polymer phase.
In
particular, resorption of the polymer would lead to degradation of the whole
composite.
[0013] The ideal material for medical applications would not only be
biocompatible,
but would also have physical properties similar to those of the tissue being
replaced
or repaired. Ceramics, though they include good chemical and corrosion-
resistant
properties, are notoriously brittle, e.g. of fracture toughness of the order
of 1
MPa/m. This means that ceramics have a very low tolerance of crack-like flaws.
The absence of energy-dissipating mechanisms, such as generation and movement
of
dislocations in ceramics, causes ceramics to fail in a catastrophic fashion.
Improving
the toughness of ceramics is a current research goal. One of the important ap-
proaches to accomplish this goal is via ceramic matrix composites.
[0014] Several reports describe a combination of bioceramics and biopolymer
phases for increased mechanical properties of the bulk composite. For example,
as
reported by Komlev, et al. in "Strength enhancement of porous hydroxyapatite
ceramics by polymer impregnation", in Journal of Materials Science Letters,
22,
2003, 1215-121, disc samples of 10 mm diameter and about 4 to 6 mm thickness
were uniaxially pressed at 50 MPa pressure at room temperature. The green
bodies
were sintered at 1200 C for 1 h in air. The samples of porous HA ceramics were
immersed in the polymer solution under a vacuum of 1.33 Pa for 10 or 30 min,
and
without vacuum for 30 min. The tensile strength of porous hydroyxapatite
impreg-
nated with polymer solution can be increased by a factor 2 to 6. However, this
process is not suitable for making coatings on any metallic substrate for
medical
applications because of high temperature process for making porous ceramic
body at
1200 C.

CA 02662162 2009-02-27
WO 2008/025122 PCT/CA2006/001442
-5-
[0015] King et al (US Patent Application 2004/0002770) disclose processing of
polymer-bioceramic composite for orthopaedic applications. These composites
are
characterized by a polymer dispersed into a porous bioceramic matrix.
Processes for
preparing the composites by compression molding at elevated temperature are
described, including compression molding to induce orientation of the polymer
in
multiple directions. These composites are also claimed to be useful as drug
delivery
vehicles to facilitate the repair of bone defects. However, there are a number
of
limitations to this process. For example, the molding processing of dispersed
polymer at high temperature is very difficult to control because of melting
polymers
and the need for protecting gas environment. Additionally, the high pressure
and
high temperature required for the process will denature the bioactive agents
if they
are used as drug delivery vehicles, e.g. within the polymer matrix or ceramic
matrix. Also, the high pressure processing will require high mechanical
strength of
porous ceramic matrix to resist the pressure without fracture. Also, this
processing
is not suitable for coating applications. The subject matter of the foregoing
publica-
tions and patents is incorporated herein by reference.
SUMMARY OF THE INVENTION
[0016] The present invention discloses novel polymer-ceramic matrix composites
(PCMC) and processes for making same. The PCMC's are intended primarily for
biomedical applications, in particular, composite coatings for medical
devices. The
PCMC's combine reinforcing bio-polymer phases with a bio-ceramic matrix in a
unique process, to create materials that have new superior properties compared
to
either a polymer phase or a ceramic phase alone.
[0017] The invention is directed to a bio-polymer/bioceramic matrix composite
coating comprising: (a) a porous bioceramic matrix of continuous phase; and
(b) at
least one biocompatible polymer of continuous or discontinuous phase. A
bioactive
agent can be incorporated in the composite coating.
[0018] The porous bioceramic matrix can be made by a process selected from the
group consisting of sol-gel coating, thermal spray coating, electro-chemical
deposi-
tion, electrophoretic deposition, bioinimetic deposition and a shape and
sintering
process, as known in the art.
[0019] The coating can be porous and the pore size of the coating can be in
the
range of 0.01 m to 1000 m. The volume of porosity of the coating can be in the

CA 02662162 2009-02-27
WO 2008/025122 PCT/CA2006/001442
-6-
range of 5vo1% to 70vo1%. The thickness of the porous bioceramic coating can
be
in the range of 0. 1 to 1000 m. The pores of the bio-polymer/bioceramic matrix
composite coating can be open and interconnecting.
[0020] The porous bioceramic matrix (a) can be selected from the group
consisting
of: hydroxyapatite, amorphous calcium phosphate (ACP), calcium metaphosphate,
tricalcium phosphates, dicalcium phosphate dihydrate, calcium hydrogen
phosphate,
tetracalcium phosphates, heptacalcium decaphosphate, calcium pyrophosphate
dihydrate, crystalline hydroxy apatite, poorly crystalline apatitic calcium
phosphate,
calcium pyrophosphate, monetite and octacalcium phosphate.
[0021] The invention is also directed to a bio-polymer/bioceramic matrix
composite
coating for a medical device comprising: (a) a porous bioceramic matrix; (b)
at least
one biocompatible polymer; and (c) at least one bioactive agent.
[0022] The bioceramic matrix (a) can be continuous phase. The biocompatible
polymer can be continuous or discontinuous phase.
[0023] The porous bioceramic matrix coating can be made by a process selected
from the group consisting of sol-gel coating, thermal spray coating, electro-
chemical
deposition, electrophoretic deposition, chemical vapor deposition, physical
vapor
deposition and biomimetic deposition. The pore size of the coating can be in
the
range of 0.01 m to 1000 m. The volume of porosity of the coating can be in the
range of 5vo1% to 70vo1%. The thickness of the porous bioceramic coating is in
the
range of 0.1 to 1000 m. The pores can be open and interconnecting.
[0024] The coating can be deposited on a medical device and the coating can
cover
at least a portion of the medical device.
[0025] The polymer can be impregnated into or infiltrated into the pores of
the
porous bioceramic matrix coating. The biocompatible polymer can be a biodegrad-
able polymer or a non-biodegradable polymer.
[0026] The porous bioceramic matrix coating can be impregnated at least once
with
a polymer solution. The porous bioceramic matrix coating can multi-step impreg-
nated with a polymer solution. The porous bioceramic matrix coating can be
multi-step impregnated with dissimilar polymer solutions.

CA 02662162 2009-02-27
WO 2008/025122 PCT/CA2006/001442
-7-
[0027] The bioactive agent can be selected from the group consisting of:
anti-inflammatory agents, anti-cancer agents, antibiotics, anti-restenosis
drugs,
anti-thrombosis agents, antineoplastic agents and therapeutic combinations
thereof.
The bioactive agent of the bio-polymer/bioceramic matrix composite coating can
be
paclitaxel.
[0028] The medical device can be a stent. The medical device can be an
implantable device or a surgical tool.
[0029] The pores in the coating can be created by including a burn-out
additive in
the coating and burning out the additive or by a gas-forming additive.
[0030] The biocompatible polymer can be non-biodegradable and can be selected
from the group consisting of: polyether block amides (PEBA), polyoctenamers,
polyolefins, ethylenic copolymers, ethylene vinyl acetate copolymers (EVA) and
copolymers of ethylene with acrylic acid or methacrylic acid; thermoplastic
polyurethanes (TPU) and polyurethane copolymers; metallocene catalyzed polyeth-
ylene (mPE), mPE copolymers, ionomers, and mixtures and copolymers thereof;
and vinyl aromatic polymers and copolymers.
[0031] The biocompatible polymer can be biodegradable and can be selected from
the group consisting of: biodegradable polylactic acid, polyglycolic acid,
poly(L-lactide) (PLLA), poly(D,L-lactide) (PLA); polyglycolic acid
[polyglycolide
(PGA)], poly (L-lactide-co-D, L-lactide) (PLLA/PLA), poly(L-lactide-co-
glycolide)
(PLLA/PGA), poly(D, L-lactide-co-glycolide) (PLA/PGA),
poly(glycolide-co-trimethylene carbonate) (PGA/PTMC),
poly (D, L-lactide-co-caprolactone) (PLA/PCL), polyethylene oxide (PEO),
polydioxanone (PDS), polypropylene fumarate, poly(ethyl glutamate-co-glutamic
acid), poly(tert-butyloxy-carbonylmethyl glutamate), poly(carbonate-ester)s,
polycaprolactone (PCL), polycaprolactone co-butylacrylate, polyhydroxybutyrate
(PHBT) and copolymers of polyhydroxybutyrate, poly(phosphazene),
poly(phosphate ester), poly(amino acid) and poly(hydroxy butyrate),
polydepsipeptides, maleic anhydride copolymers, polyphosphazenes,
polyiminocarbonates, cyanoacrylate, polyethylene oxide,
hydroxypropylmethylcellulose, hyaluronic acid, chitosan and regenerate
cellulose,
and proteins such as gelatin and collagen, and mixtures and copolymers
thereof.

CA 02662162 2009-02-27
WO 2008/025122 PCT/CA2006/001442
8-
[0032] The invention is also directed to a method of encapsulating a bioactive
agent
in a bio-polymer/bioceramic matrix composite coating comprising: (a) a porous
bioceramic matrix coating; (b) at least one biocompatible polymer; and (c) at
least
one bioactive agent; said method being selected from the group consisting of:
(i)
immersing the composite bio-polymer/bioceramic matrix coating in a solution
containing the bioactive agent; (ii) impregnating a solution of the
biocompatible
polymer and the bioactive agent into the porous bioceramic matrix coating; and
(iii)
multi-impregnating the composite coating by employing a combination of method
(i)
and method (ii).
[0033] The matrix composite coating after encapsulating the bioactive agent in
the
matrix composite coating can be coated with a thin polymer film. The film
coated
composite can be applied on a medical device.
[0034] The invention is also directed to a method of preparing a bio-poly-
mer/bioceramic matrix composite comprising: (a) a porous bioceramic matrix of
continuous phase; and (b) at least one biocompatible polymer of continuous or
discontinuous phase, wherein the bioceramic matrix is made by a process
selected
from the group consisting of sol-gel coating, thermal spray coating, electro-
chemical
deposition, electrophoretic deposition, biomimetic deposition and shape and
sintering. [0035] The composite can incorporate a bioactive agent and can be
deposited as a
coating on a medical device and the coating can cover at least a portion of
the
medical device.
[0036] The polymer can be impregnated into the pores of the porous bioceramic
matrix or it can be infiltrated into the pores of the porous bioceramic
matrix.
[0037] The porous bioceramic matrix can be impregnated at least once with a
polymer solution or it can be multi-step impregnated with a polymer solution.
The
porous bioceramic matrix coating can be multi-step impregnated with dissimilar
polymer solutions.

CA 02662162 2009-02-27
WO 2008/025122 PCT/CA2006/001442
9-
DRAWINGS
[0038] In drawings which illustrate specific embodiments of the invention, but
which should not be construed as restricting the spirit or scope of the
invention in
any way:
[0039] Figures 1-10 illustrate salient features of the invention, and the
effects of the
application of the inventive PCMC coatings on surface of cardiovascular
stents, in
contrast to the behaviour of ceramic coatings only.
[0040] Figure 1 provides the scllematic comparison of the microstructure of
polymer matrix composite and ceramic matrix composite (PCMC). The bioceramic
fillers (such as fiber, particles, spheres) is a discontinuous phase and
biopolymer is
the continuous matrix of the composite in Figure 1B. The biopolymer fillers
(such
as fiber, particles, spheres) is a continuous or discontinuous phase and
bioceramic is
the continuous matrix phase of the PCMC composite in Figure 1D. The
microstructural differences of two composites have significant impact on the
biological and mechanical properties of materials.
[0041] Figure 2 provides the schematic four (A, B, C, D) mechanisms of drug
encapsulation in polymer-bioceramic matrix PCMC composite. Drug encapsulated
in open pores of bioceramic matrix only (Fig. 2A) will be released through
diffusion
through the open pores, with release rate R1. Drug encapsulated in closed
pores of
bioceramic matrix only (Fig. 2A) will be released through resorption of the
ceramic,
with release rate R2. Drug encapsulated in the biopolymer residing in the open
pores of bioceramic matrix, Fig. 2B, will be released through resorption of
the
polymer and diffusion through the open pores of the bioceramic, with release
rate
R3. Drug encapsulated in open pores and closed pores of bioceramic matrix, and
in
the biopolymer residing in the open pores of bioceramic matrix, Fig. 2C, will
be
released through resorption of the ceramic and the polymer, and diffusion
through
the open pores of the bioceramic, with release rate R4. The release rate R4
may be
decreased to R5 by imposing a surface diffusion barrier of slowly- or non-
resorbing
polymer, Fig. 2D.
[0042] Although the drug release rates will vary with time, the rates
generally can
be ranked as follows: R5 < R2 < R3 < R4 < R1. Generally the drugs residing
in biopolymer matrix are expected to release faster than these residing in the

CA 02662162 2009-02-27
WO 2008/025122 PCT/CA2006/001442
-10-
ceramic matrix. Therefore, the drug release profiles from PCMC can be
engineered
according to the specific clinical requirements, for short, medium and long
term.
[0043] Figure 3 provides the schematic comparison of biological and mechanical
properties of bioceramics, biopolymer, and PCMC composites, in a "radar"
diagram. The bioceramic matrix PCMC composites combine in the balanced fashion
the best features of bioceramics and biopolymers, resulting in excellent
biological
and mechanical properties of PC'MC in biomedical coating applications. These
properties are relatively easy to adjust and optimize for the varying clinical
require-
ments.
[0044] Figure 4 illustrates the morphologies of (A) HAP porous coatings
prepared
using alcohol-based sol-gel solution with porogen agent (combustible polymer)
to
induce large fraction of porosity in HAP upon heat treatment and (B) HAP
matrix
composite coatings PCMC made by impregnating the polymer solution into HAP
porous coating presented in Fig. 4A.
[0045] Figure 5 illustrates the morphologies of (A) HAP porous coatings made
by
water-based sol-gel solution witli porogen agent (combustible polymer) to
induce
large fraction of porosity in HAP upon heat treatment and (B) HAP matrix
compos-
ite coatings made by impregnating the polymer solution into HAP porous coating
shown in Fig. 5A.
[0046] Figure 6 illustrates the morphologies of cross section of (A) HAP
porous
coatings showing with brittle fracture and (B) HAP-based composite PCMC
coatings with ductile fracture as illustrated by arrow in Fig. 6B.
[0047] Figure 7 illustrates the surface morphologies of bioceramic composite
PCMC
coatings produced of ECD-HAP coating impregnated with different concentration
of
PLGA solutions. It is shown that PLGA filled in most of the pores of ECD-HAP
coating for 2wt% PLGA solution and PLGA filled in the all pores of ECD-HAP
coating for 4wt% PLGA solution, however, the features of ECD coating surface
can
still be observed. The 6wt% solution of PLGA filled in the all pores of ECD-
HAP
coating and additionally covered the surface of ECD coating such that the
surface
features of the ECD-HAP coating essentially disappeared.

CA 02662162 2009-02-27
WO 2008/025122 PCT/CA2006/001442
- 11 -
[0048] Figures 8 and 9 illustrate the performance of PCMC coatings during
expan-
sion of coronary stents made of 316 stainless steel, and then coated with the
respective PCMC. These two illustrations (Fig. 8, 9) are included, as
expansion of
coronary stent represents one of the most severe tests for coatings, as the
stent
undergoes strain of up to 10% in some regions. It is well known in the art
that
ceramics fail at strains on the order of 0. 1 %. The behaviour of PCMC during
expansion of coronary stents illustrates the resilience of the coatings. That
means,
even if the ceramic backbone of the PCMC coating undergoes fracture, the
fracture
is contained by the polymeric component, to preserve the overall integrity of
the
coating.
[0049] Figure 8 illustrates the expansion test of biopolymer-bioceramic
composite
PCMC coated stent, based on ECD-HAP impregnated with 2wt% solution of
PLGA. The ceramic component of the coatings was produced to have about 45vo1 %
of open porosity using ECD-HAP process. For the severe over-expansion shown in
both tests, there is no PCMC cracking or separation for these stents.
[0050] Figure 9 illustrates the expansion test of biopolymer-bioceramic
composite
PCMC coated stent, based on ECD-HAP impregnated with 4wt% solution of
PLGA. The ceramic component of the coatings was produced to have about 45vol %
of open porosity using ECD-HAP process. For severe over-expansion shown in
both tests, there is no PCMC cracking or separation for these stents.
[0051] Figure 10 illustrates expansion test of bioceramics only coated stent.
The
coatings were produced to have about 45vo1 % of open porosity using ECD-HAP in
the same process used for deposition of the ceramic component of the composite
PCMC coatings on stents illustrated in Figs. 8, 9. Even for typical expansion
strain
shown in this test, there is severe cracking and coating separation from the
stent
surface.
DETAILED DESCRIPTION OF THE INVENTION
[0052] Throughout the following description, specific details are set forth in
order
to provide a more thorough understanding of the invention. However, the
invention
may be practiced without these particulars. In other instances, well known
elements
have not been shown or described in detail to avoid unnecessarily obscuring
the
invention. Accordingly, the specification and drawings are to be regarded in
an
illustrative, rather than a restrictive, sense.

CA 02662162 2009-02-27
WO 2008/025122 PCT/CA2006/001442
-12-
[0053] In the classical ceramic matrix composites, the primary goal of the
polymer
reinforcement is to provide toughness and to overcome the intrinsic
brittleness and
lack of reliability of the ceramics. 'The novel PCMC's according to the
invention
composites combine the desirable bioceramics with biopolymers to tailor
properties
such as strength, toughness and elasticity to meet structural system
requirements, in
addition to the inherent functional properties of the bio-polymer and bio-
ceramic,
such as biological properties and drug/protein delivery properties.
[0054] Many technologies are available to produce porous ceramics, wherein the
porosity is open (i.e. accessible) porosity. For example, a porous ceramic
matrix
can be made by sol-gel processing with a surfactant, by mixing ceramics
powders
with porogens such as polymer particles or fibers as template and then
sintering the
product at high temperature.
[0055] The porous ceramic matrix can be subsequently infiltrated or
impregnated by
biopolymer solutions at room temperature. The open pores and voids of the
ceram-
ics matrix are filled with polymer solutions and then dried to form a ceramic
matrix
composite. Multi-infiltration processing may be required for increasing
polymer
content. The pore size and/or voids will be in range in 0. l m to 1000 m and
the
polymer content will be 1-80 volume %.
[0056] For drug eluting applications, the drugs are incorporated into the
pores of
the bioceramic matrix and/or polymer solutions. Therefore, the pores and voids
will serve as a drug carrying vehicle, and the drugs are encapsulated inside a
bioceramic matrix. The drugs will release from the composite by diffusion
and/or
degradation of the biopolymer phase. The drugs releasing profile will be
controlled
by the porous structure and pore size of the matrix, polymer degradation rate,
and
interaction of bioceramics with the drugs.
[0057] For ceramics coating applications, the porous coatings can be
fabricated by
sol-gel processing with surfactants, i.e. see to Lu et al, "Continuous
formation of
supported cubic and hexagonal mesoporous films by sol-gel dip-coating", in
Nature
(London) (1997), 389(6649), 364-368, Electro-Chemical Deposition (ECD) [i.e.
Cheng et al, "Electrochemically assisted co-precipitation of protein with
calcium
phosphate coatings on titanium alloy", in Biomaterials 25 (2004) 5395-5403],
Electro-Phoretic Deposition (EPD) [i.e. Sridhar et al, "Preparation and
character-

CA 02662162 2009-02-27
WO 2008/025122 PCT/CA2006/001442
- 13 -
ization of electrophoretically deposited hydroxyapatite coatings on type 316L
stainless steel", in Corrosion Science (2003) 45(2), 237-252], and biomimetic
coatings deposition [i.e. Costantini et al, "Hydroxyapatite coating of
titanium by
biomimetic method", in Journal of Materials Science: Materials in Medicine
(2002), 13(9), 891-894]. These publications are incorporated herein by
reference.
In order to increase the flexibility and reliability of the coatings, the
porous coatings
were impregnated with biopolymer solution to form biopolymer/ceramic matrix
composites, at room or near-room temperatures. As the drug delivery vehicle,
the
drugs can be loaded and encapsulated inside the pores of ceramics matrix by
impregnating with drug solution and polymer solution, individually, to control
drug
release profiles.
[0058] Beneficial drugs, proteins and therapeutic agents for the practice of
the
present invention include anti-thrombotic agents, anti-proliferative agents,
anti-inflammatory agents, anti-migratory agents, agents affecting
extracellular
matrix production and organization, antineoplastic agents, anti-mitotic
agents,
anesthetic agents, anti-coagulants, vascular cell growth promoters, vascular
cell
growth inhibitors, cholesterol-lowering agents, vasodilating agents, proteins,
DNA,
and agents that interfere with endogenous vasoactive mechanisms.
[0059] The novel polymer-ceramic matrix composite (PCMC) with multi-functional
properties can be used for a number of biomedical applications, such as, but
not
limited to, implantable devices, drug eluting stents, scaffolds, and tissue
engineer-
ing.
[0060] The present invention is directed to a polymer-ceramic matrix composite
material that comprises (a) a continuous bioceramic matrix (b) a biocompatible
polymer and (c) a therapeutic bioactive agent.
[0061] A key inventive feature of the subject invention is that although the
reinforc-
ing polymer phase may be either continuous or discontinuous phase, the
reinforced
ceramic phase must be a continuous phase. The ceramic phase must be a
continuous
phase in order to provide a structural support in terms of stiffness and
strength to
the polymer filler phase. The primary goal of the reinforcement polymer phase
is to
provide toughness and to overcome the intrinsic brittleness and lack of
reliability of
the continuous ceramic phase. The PCMC composite is processed at room or
near-room (37 C) temperatures through impregnating a diluted solution of a

CA 02662162 2009-02-27
WO 2008/025122 PCT/CA2006/001442
-14-
polymer phase into the open pores of the ceramic phase. Both the polymer phase
and ceramic phase of PCMC are bio-compatible. The novel PCMC composites
therefore combine desirable bioceramics with biopolymers to tailor properties
such
as strength and elasticity, while maintaining desirable biological properties
of the
system, such as bio-degradability in biological environments. The new PCMC
composite coatings can be used for biological and structural applications, as
well as
a vehicle for controlled release of biologically-active species such as drugs
and
proteins.
[0062] The bioceramic matrix composite (PCMC) provides structural support to
the
biopolymer filler phase the role of which is to provide toughness and to
overcome
the intrinsic brittleness and lack of reliability of the ceramic phase. The
key feature
of the invention is that the ceramic phase is a continuous phase. Therefore
disinte-
gration of the polymer phase, which takes place rapidly for bio-degradable
polymers
and less rapidly for other organic polymers, does not affect the integrity of
the
whole composite. Therefore, a variety of bio-polymer phases may be selected as
fillers of the ceramic phase without substantially affecting the structural
performance
of the composite. This has significant impact on selection of the polymers for
controlled drug delivery, e.g. rapidly dissolving polymers for rapid delivery
of
drugs may be selected without affecting composite integrity.
[0063] The PCMC material may be applied to deposit films, and coatings
function-
ing in biological environments, e.g. films and coatings for implants. The
bioceramic matrix composites can be used to improve the biocompatibility of
metal
implants and for better drug deliver vehicles, and can also function as fully
resorbable scaffolds which provide temporary structures which are replaced as
the
body rebuilds tissue.
[0064] Materials for medical implants devices must be non-toxic. As many
materi-
als will chemically interact when exposed to tissue or body fluids, the
products of
such chemical interaction must also be non-toxic. This in many cases is
difficult to
avoid entirely because it is well known that metallic implants will release
harmful
metal ions to body fluids. Irrespective of this disadvantage, metals are used
because
of their irreplaceable structural properties such as strength and stiffness.
[0065] Although almost every living organism requires certain structural
support
from the tissue to maintain the functionality of the organism (the larger the
organ-

CA 02662162 2009-02-27
WO 2008/025122 PCT/CA2006/001442
- 15-
ism, the more critical the structural support becomes), nature never
"selected"
metals to provide that necessary support. This is because the chemical
functionality
of metals, in particular the toxicity towards living tissue, overrides their
potential
benefits as structural materials. Instead, by selection, organo-ceramic
composites
largely constitute what is known as "hard tissue", e.g. bone or tooth. This is
the
combination of calcium phosphate ceramic with the natural tissue such as
collagen,
provides an excellent structural material, which is at the same time an
entirely
bio-compatible material, bio-resorbable without any adverse effects towards
the host
tissue.
[0066] The present invention follows this basic lesson from nature and
inventively
proposes the use of a porous, continuous ceramic matrix of calcium phosphate,
in
particular HAP, as a carrier of bio-polymer, both components being entirely
bio-compatible and bio-resorbable without any adverse effects towards the host
tissue. Thus the whole composite is entirely bio-compatible and bio-resorbable
without any adverse effects towards the host tissue.
[0067) Many polymers will degrade and the products of degradation will be
toxic or
trigger allergic/inflammatory reaction of the tissue. However, researchers are
frequently forced to select such polymers for implants because of a number of
reasons, such as structural properties. The present invention enables the
selection
of polymers which do not produce adverse reaction of tissue upon resorption,
even
if the polymer phase lacks the required structural properties such as
strength. This
is because the bio-ceramic phase, such as calcium phosphate (in particular
HAP)
provides sufficient structural support, whereas the organic polymer phase may
be
selected entirely for its biological/chemical advantages. It is well known
that
calcium phosphate (in particular HAP) is entirely bio-compatible and provides
no
adverse reaction from living tissue upon resorption.
[0068] According to another aspect of the present invention, a therapeu-
tic-agent-releasing medium is provided, which comprises: (a) an implantable or
insertable medical device; (b) a release or drug or biological agent over at
least a
portion of the implantable or insertable medical device; and (c) a therapeutic
agent.
Upon implantation or insertion of the device into a patient, the rate of
release of the
therapeutic agent is controlled by microstructure of the bioceramic matrix,
the
ceramic matrix degradation rate, the biopolymer degradation rate, and the
diffusion
rate of the degradation products and the biologically active agents (drugs,
proteins)

CA 02662162 2009-02-27
WO 2008/025122 PCT/CA2006/001442
- 16-
through the porosity channels of the ceramic matrix. This is in contrast to
the drug
delivery systems based on (i) bio-polymer only, or (ii) biopolymer combined
with
ceramic wherein the ceramic is a discontinuous phase. In both cases (i) and
(ii) the
drug release is controlled by degradation of the polymer, without the
additional
factors of controlling the release of the therapeutic agent by bioceramic
matrix, the
ceramic matrix degradation rate, and the diffusion rate of the degradation
products
and the biologically active agents (drugs, proteins) through the porosity
channels of
the ceramic matrix.
[0069] In a preferred embodiment of the invention, the biodegradation rate of
biopolymer phase will be faster than that of a bioceramic matrix.
Consequently, the
products of degradation, and biologically active agents, will be released from
the
PCMC body only after diffusion through the network of open porosity in the
bio-ceramic matrix. This diffusion process allows for long-time delivery of
steady
level dosage of the agents. Additionally, in the initial period after
implantation of
the composite bio-material, the polymer phase increases the composite
toughness
and reliability, and only at a later stage contributes to the release of the
biological
agents from pores or voids of porous ceramic matrix through the biodegradation
and
diffusion of bioactive agents. The porous ceramic matrix provides a
biocompatible
surface and structure for drug delivery.
[0070] An important aspect of the subject invention is the possibility of
using such
composite materials as coatings for implants. The novel PCMC bioceramic matrix
composite coatings overcome the disadvantages of brittleness of entirely
ceramic
materials and increase flexibility and reliability, which is especially useful
for
flexible substrates, such as stents. During stent implanation, the deformation
and
stresses due to stent expansion may cause serious damage to the bioceramic
coatings
on the stent because of their brittleness. Thus the fully ceramic coating may
suffer
defects such as cracks, delamination, and debris release. Also, biologically
active
agents such as drugs or proteins, are difficult to retain or otherwise
encapsulate
within a fully ceramic matrix. The bioceramics matrix composite increases the
flexibility and bonding strength of coatings, allowing for controlled
encapsulation
and release of the biological agents. Suitable ceramic matrix calcium
phosphates
include, but are not limited to, hydroxyapatite, amorphous calcium phosphate,
calcium metaphosphate, tricalciuin phosphates, dicalcium phosphate dihydrate,
calcium hydrogen phosphate, tetracalcium phosphates, heptacalcium
decaphosphate,
calcium pyrophosphate dihydrate, crystalline hydroxy apatite, poorly
crystalline

CA 02662162 2009-02-27
WO 2008/025122 PCT/CA2006/001442
- 17-
apatitic calcium phosphate, calcium pyrophosphate, monetite and octacalcium
phosphate. All these phosphates may have partially crystalline, or amorphous
calcium phosphate structures. The degree of crystallinity allows additional
control
of the resorption rate of the composite, i.e. less crystalline ceramics will
resorb
faster.
[0071] Ceramics in a number of forms and compositions are currently in use or
under consideration for use as bioinaterials. Titinia, mullite, silica,
alumina and
zirconia are among the bioinert ceramics used for prosthetic devices. Porous
ceramics such as calcium phosphate-based materials are used for filling bone
defects. The ability to control porosity and solubility of some ceramic
materials
offers the possibility of their use as drug delivery systems.
[0072] In the subject invention, the PCMC is directed to overcoming the main
drawback of monolithic and films ceramics, namely their brittleness. The
PCMC's
are referred to as inverse composites, which is to say that the failure strain
of the
matrix is lower than the failure strain of the ceramics, whereas it is the
reverse in
most polymer matrix composites. In order to prevent an early failure of the
brittle
ceramics when the matrix starts to microcrack, ceramic matrix bonding will be
controlled during processing. PCMC's according to the invention are tough
materials and display a high failure stress when the bonding between polymers
and
ceramic matrix is not too strong or too weak.
[0073] In the subject invention, porous bioceramic coatings can be made by
burn-
ing-out additives, which can be represented by any combustible material that
is
economically justifiable. Bioceraniic slurry or sol-gel mixed with burning-out
additives are coated on substrates by dipping, spinning, and spraying. The
porosity
of coatings with burning-out additives depends on their type, content, and the
grain
size. A maximum content of such additives is limited by the fact of loosening
and
abrupt decrease in strength of material. Such ceramics should be fired in an
oxidiz-
ing medium until complete burning-out of the additive. The method of
introducing
burn-out additives makes it possible to produce bioceramic coatings with
porosity up
to 20vo1 % - 65vo1 %.
[0074] In this invention, several methods of chemical formation of pores in
suspen-
sions to achieve porous coatings, are used. For example, gas-forming additives
can
be used to ensure formation of a large volume of gases, and a uniform release
of gas

CA 02662162 2009-02-27
WO 2008/025122 PCT/CA2006/001442
-18-
within a prescribed temperature interval. The additives should not be toxic.
Among
numerous potential chemical reactions involving gas formation, the ones
practically
used are reactions between carbonates and acids. The process of formation of a
cellular mixture in chemical formation of pores depends on many factors: the
suspension viscosity, the temperature, type, content, and dispersion of the
solid
gas-forming agent, the type of acid and its content, and the presence and
content of
a stabilizer for the swelled mixture. This method provides for production of
ceramics with high and super high porosity based on various initial materials,
which
is used in thermal insulation and heat-shielding. However, the porosity formed
this
way is frequently a closed porosity, which does not allow impregnation of
second-
ary phases such as bio-polymer phase into the pores.
[0075] According to one aspect of this invention, porous bioceramic matrix
coatings
are deposited on the surface of implantable medical devices by sol-gel
processing
with polymer surfactant porogen, electro-chemical deposition, electrophoresis
deposition, biomimetic deposition, composite sol-gel processing, spray
coating,
spin coating, dip coating, or plasma spray coatings. In this invention, all
commer-
cial available porous ceramic coatings can be used as composite ceramic
matrixes.
[0076] The porous matrices of bioceramics may be macroporous or microporous.
Microporous matrices typically have pores in the range from about 0. l m to
about
100 microns in size, while macroporous matrices typically have pores in the
range
from about 100 to about 1000 microns in size. In certain embodiments the pore
size
in a given range is substantially uniform. The pores in the matrix account for
the
void volume. Such void volume may be from about 10% to about 90%. The pores
are typically interconnecting, and in some cases to a substantial degree. The
pores
may form an open-cell configuration in some embodiments. In embodiments where
the void volume constitutes a substantial portion of the matrix volume, the
pores are
typically close together.
[0077] In this invention, the mechanisms for drug encapsulation and controlled
release include, but are not limited to, the following:
[0078] (1) The bioactive agents are encapsulated into the bioceramic matrix
compos-
ite coatings PCMC through dipping a porous bioceramic matrix coating into a
drug
solution, then removing the excess of drug solution by spinning. Subsequently,
biopolymers are impregnated into the micropores of the bioceramic coating in
the

CA 02662162 2009-02-27
WO 2008/025122 PCT/CA2006/001442
- 19-
composite PCMC structure. The drug is immobilized inside the mesopores of the
porous bioceramic coatings, and may be released by diffusion through the
bioceramic matrix and biopolymer barrier, degradation of biopolymer and
bioceramic matrix. The drug eluting rate is slow and persists in long term. In
this
variant of the invention, the drug material is not combined with the polymer
material.
[0079] (2) The bioactive agents are encapsulated by impregnating a biopolymer
and
drug mixture solution into a bioceramic matrix to form bioceramic matrix
composite
PCMC. Extra solution is removed by spinning. The drug is released by diffusion
and degradation of biopolymer. By comparison with conventional drug and
biopolymer coatings, there is no biopolymer debris released during the
biopolymer
degradation, of a size that is larger than the pores of the ceramic matrix.
This is
because the biopolymer and drug are immobilized inside microporous and
mesoporous structures. Also, the drug eluting rate is much slower that that of
normal biopolymer coatings.
[0080] (3) The bioactive agents are encapsulated through multi-drug
encapsulation,
with different release rates and fi.inctions by a combination of the two
processing
methods 1, 2 above. For example, paclitaxel can be encapsulated into a porous
bioceramic matrix by dipping porous coatings into a paclitaxel-alcohol
solution.
Such drug-loaded paclitaxel porous bioceramic coatings are then impregnated by
a
mixture solution of biopolymer and rapamycin to form a bioceramic matrix
compos-
ite. The release rate of paclitaxel inside the ceramic matrix is much slower
that that
of a drug in biopolymer phase.
[0081] (4) In order to meet the special requirements of long term drug release
(e.g.
up to one year), the thin polymer film as the drug diffusion barrier can be
deposited
on the surface of the bioceramic matrix composite coatings. The drugs in both
of the
ceramic matrix and biopolymer phase must go though the barrier and slow the
release rate.
[0082] The above example methods for use of PCMC for drug delivery illustrate
the
multiple possibilities of the PCMC system, which are impossible to achieve
through
use of polymer only, or ceramic only, or a composite in which the ceramic is a
dispersed phase within the polymer phase.

CA 02662162 2009-02-27
WO 2008/025122 PCT/CA2006/001442
-20-
[0083] The polymeric materials used for making PCMC composite coatings may
comprise any biocompatible polymer suitable for use in implantable or
insertable
medical devices. The biocompatible polymer may be substantially
non-biodegradable or biodegradable. The term "biocompatible" describes a
material
that is not substantially toxic to the human body, and that does not
significantly
induce inflammation or other adverse response in body tissues. Biocompatible
polymers include essentially any polymer that is approved or capable of being
approved by Food and Drug Administration (FDA) for use in humans or animals
when incorporated in or on an implantable or insertable medical device.
[0084] Non-biodegradable polymers include, but are not limited to, polyether
block
amides (PEBA), polyoctenamers, polyolefins, ethylenic copolymers, ethylene
vinyl
acetate copolymers (EVA) and copolymers of ethylene with acrylic acid or
methacrylic acid; thermoplastic polyurethanes (TPU) and polyurethane
copolymers;
metallocene catalyzed polyethylene (mPE), mPE copolymers, ionomers, and
mixtures and copolymers thereof; and vinyl aromatic polymers and copolymers.
[0085] Biodegradable polymers include, but are not limited to, polylactic
acid,
polyglycolic acid, poly(L-lactide) (PLLA), poly(D,L-lactide) (PLA);
polyglycolic
acid [polyglycolide (PGA)], poly(L-lactide-co-D,L-lactide) (PLLA/PLA),
poly (L-lactide-co-glycolide) (PLLA/PGA), poly(D, L-lactide-co-glycolide)
(PLA/PGA), poly(glycolide-co-trimethylene carbonate) (PGA/PTMC),
poly(D,L-lactide-co-caprolactone) (PLA/PCL), polyethylene oxide (PEO),
polydioxanone (PDS), polypropylene fumarate, poly(ethyl glutamate-co-glutamic
acid), poly(tert-butyloxy-carbonylmethyl glutamate), poly(carbonate-ester)s,
polycaprolactone (PCL), polycaprolactone co-butylacrylate, polyhydroxybutyrate
(PHBT) and copolymers of polyhydroxybutyrate, poly(phosphazene),
poly(phosphate ester), poly(amino acid) and poly(hydroxy butyrate),
polydepsipeptides, maleic anhydride copolymers, polyphosphazenes,
polyiminocarbonates, cyanoacrylate, polyethylene oxide,
hydroxypropylmethylcellulose, hyaluronic acid, chitosan and regenerate
cellulose,
and proteins such as gelatin and collagen, and mixtures and copolymers
thereof,
among others.
[0086] The therapeutic agent for use in composite coatings of the present
invention
can be any pharmaceutically acceptable therapeutic agent which is approved or
capable of being approved by Food and Drug Administration (FDA) for use in

CA 02662162 2009-02-27
WO 2008/025122 PCT/CA2006/001442
-21-
humans or animals when incorporated in or on an implantable or insertable
medical
device. As noted above, preferred therapeutic agents include anti-
inflanvnatory
agents, anti-cancer agents, antibiotics; anti-restenosis drugs anti-thrombosis
agents,
antineoplastic agents and combinations thereof.
[0087] The bioactive agents include, but are not limited to, phenylbutazone,
gentomycin, vancomycin, indomethacin, naproxen, ibuprofen, flubiprofen,
diclofenac, dexmethasone, prednisone and prednisolone, gentomycin, vancomycin,
rapamicin, paclitaxel, actinomycin, sirolimus, everolimus, tacrolimus,
dexametha-
sone, mycophenolic acid, and heparin.
[0088] In this invention, the amount of therapeutic agent present in
bioceramic
matrix will depend upon the efficacy of the therapeutic agent employed, the
length
of time during which the medical device is to remain implanted, as well as the
rate
at which the bioceramic matrix or barrier layer releases the therapeutic agent
in the
environment of the implanted medical device. Thus, a device that is intended
to
remain implanted for a longer period will generally require a higher
percentage of
the therapeutic agent. Similarly, a bioceramic matrix that provides faster
rate of
release of the therapeutic agent may require a higher percentage of the
therapeutic
agent. One skilled in the art can readily determine an appropriate therapeutic
agent
content to achieve the desired outcome.
EXAMPLES
General Example of PCMC Processing
[0089] This example presents the general processing steps, the processing
variants,
and the resulting properties of PCMC. The coatings microstructures and perfor-
mance is illustrated through Figures 1-10. The specific details of the
specific
processes to achieve the specific desired properties of PCMC coatings are
provided
in Examples 1-10 below.
[0090] In the general PCMC process, a porous ceramic coating is deposited on a
substrate. There are may well known techniques for depositing porous ceramic
coatings, and some of these techniques are presented in more details in the
exam-
ples 1-10 below. The coating open porosity (i.e. porosity accessible to
outside
gases or liquids) is generally in the range of 1-80vol%, more desirably in the
range
10-50vo1 %. The coating thickness is in the range of about 0.1-1000 m, more
desirably in the range 0.5-10 m. The coating phase is bio-ceramic or bio-
glass,

CA 02662162 2009-02-27
WO 2008/025122 PCT/CA2006/001442
-22-
more desirably calcium phosphate such as HAP. The distinctive feature of the
current invention is that the ceramic phase is a continuous phase, as
illustrated in
Fig. 1C. As such, the ceramic phase acts as a back-bone of the coating system
and
thus during dissolution of the organic polymer phase the structural integrity
of the
coating is retained.
[0091] In general Process 1, the bio-polymer is dissolved in a suitable
Solvent A
such as water or alcohol. The polymer concentration in the solvent depends on
the
type of the polymer/solvent system. The general requirement is that the system
viscosity and wettability of the ceramic at room or near-room temperature is
low
enough to allow polymer penetration of the pores in the ceramic down to 0.1 m
range, preferably down to 0.05 m range. The concentration of the polymer in
the
solvent can be in the range of 0.1-50wt%, preferably in the range 1-10wt%.
[0092] The bio-polymer solution is impregnated into the porous ceramic phase
through simple immersion, or through vacuum-assisted or pressure-assisted
impreg-
nation. Sufficient time is allowed for the solution to penetrate the 0.1 m
pores in
the ceramic, the time and the required pressure depending on the solution
viscosity,
wettability of the ceramic, and pore size distribution in the ceramic.
Afterwards,
the sample is removed from the solution, excess solution is removed, e.g.
through
spinning, and the solvent is removed by evaporation at room or near-room
tempera-
ture. The resulting PCMC resembles the microstructure illustrated in Fig. 1D.
In a
variant of this general Process 1, a molten thermoplastic polymer may be used
instead of the polymer solution. This variant however precludes use of any
temper-
ature-sensitive additives in the process, such as drugs. Processes 2 and 3
below are
preferred for such temperature-sensitive additives.
[0093] In a variant of the above pi-ocess herein named Process 2, a drug D 1
or
protein Pl is dissolved in Solvent A together with the polymer, and
impregnated
into the porous ceramic matrix, followed by excess solution removal and
solvent
removal as described above. The resulting microstructure is typically like the
one
illustrated in Fig. 2B.
[0094] In a variant of the above process herein named Process 3, a drug D2 or
protein P2 is dissolved in Solvent B, and impregnated into the porous ceramic
matrix, followed by excess solution removal and solvent removal as described
above. Subsequently, the polymer is dissolved in Solvent A, and this solution
is

CA 02662162 2009-02-27
WO 2008/025122 PCT/CA2006/001442
-23-
impregnated into the remaining porosity within the ceramic. If the drug Dl or
protein Pl is not soluble in Solvent A, there is no carry-over of D1 or P1
into the
polymer phase during the impregnation process, and the resulting
microstructure is
like the one illustrated in Fig. 2A.
[0095] Processes 2 and 3 may be combined to result in encapsulation of various
drugs and proteins both in the polymer phase and the ceramic phase, as
illustrated in
Fig. 2C. The excess polymer film may be left on the PCMC to further enhance
mechanical properties of the composite, and add further control to the
delivery of
drug from the PCMC vehicle, as illustrated in Fig. 2D.
Specific Illustrative Examples of PCMC Processing
Example 1. Poly(lactic acid) - Hydroxyapatite (HAP) Matrix PCMC compos-
ite coatings by sol-gel processing
[0096] The porous HAP coatings were fabricated through a sol-gel route. There
are
a number of sol-gel routes to HAP, as disclosed in the scientific and patent
litera-
ture. In this particular example, the inventors have followed the route
disclosed
previously by one of the co-authors (TT) in US Patent No. 6,426,114, issued
July
30, 2002, the contents of which are incorporated herein by reference. In this
route,
as quoted from US Patent No. 6,426,114, "phosphite sol was hydrolysed in a
water-ethanol mixture (a concentration of 3M) in a sealed beaker until the
phosphite
was completely hydrolysed (which is easily recognized by loss of a
characteristic
phosphite odour), at ambient environment. A Ca salt (2M) was then dissolved in
anhydrous ethanol, and the solution was then rapidly added into the hydrolysed
phosphite sol. The sol was left at ambient environment for 8 hours, followed
by
drying in an oven at 60 C. As a result of this process, a white gel was
obtained. For
the sol containing Ca/P ratio required to produce HA, the gel showed a pure
(single
phase) apatitic structure with a Ca/P ratio of 1.666, identical to
stoichiometric HA,
after calcining at a temperature as low as 350 C. Varying the Ca/P ratio
allows
other calcium phosphates, such as dicalcium phosphate (Ca/P=1) or tricalcium
phosphate (Ca/P=1.5), to be obtained. A coating produced using this process,
and
applied to Ti substrate, showed sufficient adhesive strength after curing at a
temper-
ature <450 C. The coating was crack-free and porous."
[0097] There are many other known sol-gel routes to porous HAP. The sol-gel
coatings may also be deposited on substrates through numerous routes, such as

CA 02662162 2009-02-27
WO 2008/025122 PCT/CA2006/001442
-24-
dip-coating, spin-coating, spray-coating, aerosol-coating, and others. For the
purpose of the current example, spray coating processing was selected. The
coatings
were dried at 100 C for 20 min, and fired at 500 C for 30 min. The firing
process
decomposes all the precursors used in sol preparation, aids in formation of
HAP
structure (either crystalline or anlorphous, depending on temperature of heat
treatment), partially removes porosity in the structure, and as well, removes
other
organic additives which may be used, such as polymer surfactants.
[0098] The thickness of the resulting porous sol-gel HAP coatings is typically
in
range of 0.2-21tm with porosity in range 10-30vo1%, majority of which (> 90%)
is
open porosity, e.g. accessible to impregnation. The pore size is typically in
range of
0.01 to 0.l m. The coating processed in this particular example had thickness
of
0.4 m and porosity of about 25vo1%.
[0099] The porous sol-gel HAP coating was impregnated by bio-polymer through
the following route. lg of poly (lactic acid) was dissolved into lOg
methylcholine.
The porous HAP coatings on stents were impregnated with polymer solution for 4
hours, in which time the solution will have reached all the pores of the
coating and
interface of substrate and coatings. The extra solution was removed by
centrifuge
(spin) processing, followed by drying at 37 C for 60 minutes. This process
resulted
in deposition of the polymer within the pores of the ceramic matrix. As
diluted
solution of polymer was used, the pores were only partially filled with the
polymer.
In this particular example, about 20% of the available volume within the pores
was
filled. In order to increase the polymer content, multi-step impregnation is
neces-
sary.
[0100] The resulting Poly(lactic acid) Hydroxyapatite (HAP) Matrix PCMC
composite coatings have advantageous properties resulting from combination of
the
properties of the biopolymer and the properties of the continuous network of
porous
bioceramics, as illustrated in Fig. 3. These include (i) mechanical
properties, such
as mechanical flexibility (i.e. enhanced strain to failure), strong
interfacial bonding,
high fracture toughness; and (ii) biological properties, such as high
biocompatibility
and no toxic products of bio-degradation.
[0101] The resulting Poly(lactic acid) Hydroxyapatite (HAP) Matrix PCMC
composite coatings are suitable for coating implants such as hip implant,
dental
implants, stents, and many other implants. The particular combination of

CA 02662162 2009-02-27
WO 2008/025122 PCT/CA2006/001442
-25-
biocompatibility and strain tolerance makes the PCMC composites particularly
suitable for implants undergoing strain and deformation during implantation,
such as
stents.
Example 2. Poly(lactic acid) - Drug - Hydroxyapatite (HAP) Matrix PCMC
composite coatings by sol-gel processing
[0102] The porous HAP coatings were fabricated and deposited on implant
surface
through sol-gel route, as described in Example 1. The porous sol-gel HAP
coating
was impregnated by bio-polymer-drug mix through the following route. lg of
poly
(lactic acid) and 0.2 g Rapamycin were co-dissolved into 10 g methylcholine.
The
porous HAP coatings were impregnated with polymer and drug solution for 4
hours,
in which time the solution will have reached all the pores of the coating and
inter-
face of substrate and coatings. The extra solution was removed by centrifuge
(spin)
processing, followed by drying at 37 C for 60 minutes. This process resulted
in
deposition of the drug and polymer within the pores of the ceramic matrix.
About
20-50 g of drug can be deposited within the pores of such processed PCMC, per
1cm~ of the coating. In this particular example, 34 g of drug was deposited
within
the PCMC per 1cm2 of the coating.
[0103] The resulting Poly(lactic acid)-drug-Hydroxyapatite (HAP) Matrix PCMC
composite coatings have advantageous properties resulting from combination of
the
properties of the biopolymer, the drug and the properties of the continuous
network
of porous bioceramics, as illustrated in Fig. 3. These include (i) mechanical
properties, such as mechanical flexibility (i.e. enhanced strain to failure),
strong
interfacial bonding, high fracture toughness; (ii) biological properties, such
as high
biocompatibility and no toxic products of bio-degradation; and (iii) drug
delivery
properties, such as long term drug eluting profile controlled by degradation
rate of
the polymer AND transport through porosity network in the ceramic.
[0104] The resulting Poly(lactic acid)-Drug-Hydroxyapatite (HAP) Matrix PCMC
composite coatings are suitable for coating implants such as hip implant,
dental
implants, stents, and many other implants. The particular combination of
biocompatibility, drug delivery and strain tolerance makes the PCMC composites
particularly suitable for implants undergoing strain and deformation during
implan-
tation, such as stents.

CA 02662162 2009-02-27
WO 2008/025122 PCT/CA2006/001442
-26-
[0105] However, as the sol-gel coatings thickness typically does not exceed
about
l m, similarly the PCMC coatings thickness also typically does not exceed
about
l m (unless additional polymer membrane is deposited as illustrated in Fig.
2D),
and therefore the overall volume of the pores available to carry drugs or
proteins is
relatively small. Alternative processing routes to achieve thicker PCMC
coatings
suitable for carrying larger amounts of drugs are described in Examples 3-7.
Example 3. Poly(lactic acid) - Drug - Hydroxyapatite (HAP) Matrix PCMC
composite coatings by plasma spray processing
[0106] Deposition of porous HAP coatings by plasma spraying is well known and
documented in literature. We have used one of the standard processing routes
to
deposit 110 m thick, 30vo1% porous (including 8 vol % closed porosity and
22vo1 % open porosity) HAP coating. The ceramic HAP matrix was a continuous
matrix used for impregnation to produce PCMC. The coating was impregnated with
drug-biopolymer as described in Example 2. The resulting 110 m thick PCMC was
suitable for implants of relatively simple surface features or pattern, such
as hip
implants or dental implants, and unsuitable for complex deforming implants
such as
stents. The coatings were advantageous over the pure ceramic HAP coatings
typically used for hip or dental implants because of advantageous (i)
biological
properties, such as high biocompatibility and no toxic products of bio-
degradation;
and (ii) drug delivery properties, such as and long term drug eluting profile
controlled by degradation rate of the polymer AND transport through porosity
network in the ceramic. About 200-1000 g of drug can be deposited within the
pores of such processed PCMC, per lcm2 of the coating. In this particular
example
we have deposited 330 g of drug within Poly(lactic acid) -drug-Hydroxyapatite
(HAP) Matrix PCMC composite coating.
Example 4. Poly(lactic acid) -Drug-Hydroxyapatite (HAP) Matrix PCMC
composite coatings by Electro-Chemical Deposition
[0107] Porous HAP coatings were fabricated through Electro-Chemical Deposition
(ECD). The electrolyte solution used for the electrochemically assisted
precipitation
of calcium phosphate consisted of 0.042 mol Ca(N03)2 and 0.025 mol NH4H2PO4
prepared using distilled water. The pH of the solution was approximately 4.2,
and
the solution temperature was maintained at 65 C. The precipitation was carried
out
galvanostatically at a cathodic current of 0.6mA/cm2 for 0.5 - 10 min.
Following
precipitation, the specimen was rinsed with distilled water and air dried for
use.
Thickness of the coatings was in range of 0.2 - 10 m, typically 0.5-31Am, and

CA 02662162 2009-02-27
WO 2008/025122 PCT/CA2006/001442
-27-
porosity in range 30 - 70vol%. The distribution of pore size was typically in
range
of 0.1 to lOgm. In this particular example, the coating was 0.7 m thick, with
45vo1 % of pores in the range of 0.05-0. 3 m. Although good absorbents of
drugs
and polymers, the porous ECD-HAP coatings have relatively poor mechanical
performance. This is illustrated in Fig. 10 wherein the ECD-HAP coating only
was
deposited on stent surface, and then the stent expanded. Significal mechanical
damage to the coating, including separation of the coating from the stent
surface,
results.
[0108] The porous ECD-HAP coating was impregnated by bio-polymer-drug mix
through the route of Example 2. As the coating is thicker and more porous as
compared to the sol-gel coating (presented in Examples 1, 2), about 100-300 g
of
drug can be deposited within the pores of such processed PCMC, per lcm2 of the
coating. In this particular example, we have deposited 60 g of drug per 1cm2
of the
PCMC coating. As the ECD route to HAP coating provides good control of the
coating uniformity and thickness on complex substrates, the technology is
suitable
for stents (as opposed to the plasma spray route in Example 3). Figures 8 and
9
illustrate the expansion test of such biopolymer-bioceramic composite PCMC
coated
stent, based on ECD-HAP impregnated with 2wt% (Fig. 8) and 4wt% (Fig. 9)
solution of PLGA. Dramatic difference of the PCMC coatings behaviour, as
compared to ECD-HAP coating only, is evident upon comparison of Figs. 8, 9 and
10. For the severe over-expansion shown in both tests shown in Figs. 8 and 9,
there
is no PCMC cracking or separation for these stents.
Example 5. Poly(lactic acid) -Drug-Hydroxyapatite (HAP) Matrix PCMC
composite coatings by Electro-Phoretic Deposition
[0109] Porous HAP coatings were fabricated through Electro-Phoretic Deposition
EPD. The suspensions of nano-HAP particles were prepared adding 5 g of HAP
powders to 400 ml of ethanol. The suspensions were dispersed ultrasonically
during
30 min with an ultrasonic vibrator. The suspension was rested during 24h to
eliminate, by sedimentation, the bigger particles. Voltage of lOV was applied
for
depositing the coatings at 10 second. The EPD coatings was sintered at 550 C
for
20 min. As the EPD route to HAP coating provides good control of the coating
uniformity and thickness on complex substrates, the technology is suitable for
stents
(as opposed to the plasma spray route in Example 3). Thickness of the coatings
was
in range of 0.5 - 5 m, typically 1.0 - 3 m, and porosity in range 20 - 50vol
%. The
distribution of pore size was typically in range of 0.1 - 2 m. In this
particular

CA 02662162 2009-02-27
WO 2008/025122 PCT/CA2006/001442
-28-
example the coating was 1.21tm thick, with 35vo1% of pores in the range of 0.
1 -
0.31tm. The porous EPD-HAP coating was impregnated by bio-polymer-drug mix
through the route of Example 2. As the coating is thicker and more porous as
compared to the sol-gel coating (presented in Examples 1 and 2), about 100-200
g
of drug can be deposited within the pores of such processed PCMC, per 1cm2 of
the
coating. In this particular example, we have deposited 55 g of drug per lcm~
of the
PCMC coating.
Example 6. Natural polymer-Hydroxyapatite (HAP) Matrix PCMC composite
coatings by Electro-Chemical Deposition
[0110] Porous HAP coatings were fabricated through Electro-Chemical Deposition
ECD, as in Example 4. 1 g of chitosan, a bio-polymer derived from natural
sources
(chitin) was dissolved into 10 g of water. The porous sol-gel HAP coating was
impregnated by bio-polymer through the route of Example 1. The resulting
Chitosan (Collagen) -Hydroxyapatite (HAP) Matrix PCMC composite coatings have
advantageous properties resulting from combination of the properties of the
natural
polymer and the properties of the continuous network of porous bioceramics.
These
include (i) mechanical properties, such as mechanical flexibility (i.e.
enhanced strain
to failure), strong interfacial bonding, high fracture toughness; and (ii)
biological
properties, such as high biocompatibility and no toxic products of bio-
degradation.
In a variant of this process, collagen was used instead of chitosan, leading
to similar
properties of PCMC coating.
[0111] The resulting PCMC composite coatings are suitable for coating implants
such as hip implant, dental implants, stents, and many other implants. The
particu-
lar combination of biocompatibility and strain tolerance makes the PCMC compos-
ites particularly suitable for implants undergoing strain and deformation
during
implantation, such as stents.
Example 7. Drug Encapsulated in Bioceramics Matrix Only as illustrated in
Figure 2A
[0112] Porous HAP coating was deposited on stent as described in the above
Example 1. The HAP porous coating stents was impregnated with 2wt%
paclitaxel-methanol solution for 20 min and then extra solution was removed by
high speed spinning, and then the solvent dried in oven for 2 hours. The
paclitaxel
filled mostly the mesopores (<0.l m) and partially the larger micropores
(> 0. l m) of the coating. Subsequently the paclitaxel loaded stents were
impreg-

CA 02662162 2009-02-27
WO 2008/025122 PCT/CA2006/001442
-29-
nated by lOwt% PLGA acetone solution, primarily into the larger (still
accessible
micropores) and then the extra solution removed by spinning. The biopolymer
PLGA inside the pores of the ceramic coating is free of drug and results in a
PCMC composite with flexibility and strain tolerance, similarly as illustrated
in
Figs. 8 and 9. The polymer filler provided additionally the diffusion barrier
for
controlling drug release profiles.
Example 8. Drug Encapsulated in Biopolymer Filler Only as illustrated in
Fig. 2B
[0113] Porous HAP coating was deposited on a stent as in the above Example 2.
lg
PLGA was dissolved into lOg methylcholine together with 0.1g paclitaxel. The
porous HAP coatings on stents were impregnated with polymer and drug solution
for 2 hours, in which time the solution will have reached and filled all the
pores in
the ceramic coating, and also the interface between the substrate and the
coatings.
The extra solution was then removed by spinning and then the solvent dried in
an
oven for 2 hours. The PLGA/HAP Matrix composite coatings on stents have
advance properties of combination of biopolymer and bioceramics, such as
mechani-
cal flexibility of coatings, strong interfacial bonding, high
biocompatibility, and
long term drug eluting characteristics.
Example 9. Drug Encapsulated in both Bioceramics Matrix and Biopolymer
Filler - Fig. 2C
[0114] Porous HAP coating was deposited on stent as in the above Example 2.
The
HAP porous coating stents was impregnated into 2wt % paclitaxel methanol
solution
for 20 min and then removed extra solution by high speed spinning, then dried
in an
oven for 2 hours. The paclitaxel was filled into mesopores and partial into
large
pore micropores. The paclitaxel loaded stents were subsequently impregnated
with
l Owt % PLGA acetone solution containing 2wt % Rapamycin and then the extra
solution removed by spinning. The biopolymer PLGA filled inside pores provides
extra flexibility for HAP coatings and diffusion barrier for controlling drug
release
profiles. Rapamycin in the polynler phase will release much faster than that
of
paclitaxel only in the HAP phase.
Example 10. Drug Encapsulated in Bioceramic Composite with Biopolymer
Diffusion Barrier as illustrated in Fig. 2D.
[0115] As illustrated in the above Example 9, different drugs were
encapsulated into
the polymer and HAP phases. In order to add further controls for drug release

CA 02662162 2009-02-27
WO 2008/025122 PCT/CA2006/001442
-30-
profile, e.g. to further slow down the drug release rate, a functional
diffusion
barrier was deposited on the surface of the composite PCMC coating. In this
particular example, a 2 m thick PLGA (85:15) layer was deposited on the PCMC
surface by spin-coating. Rapamycin release from such modified PCMC coating was
sustained for 3-5 months and paclitaxel for 6 - 12 months.
[0116] As will be apparent to those skilled in the art in the light of the
foregoing
disclosure, many alterations and modifications are possible in the practice of
this
invention without departing from the spirit or scope thereof. Accordingly, the
scope
of the invention is to be construed in accordance with the substance defined
by the
following claims.

Representative Drawing
A single figure which represents the drawing illustrating the invention.
Administrative Status

2024-08-01:As part of the Next Generation Patents (NGP) transition, the Canadian Patents Database (CPD) now contains a more detailed Event History, which replicates the Event Log of our new back-office solution.

Please note that "Inactive:" events refers to events no longer in use in our new back-office solution.

For a clearer understanding of the status of the application/patent presented on this page, the site Disclaimer , as well as the definitions for Patent , Event History , Maintenance Fee  and Payment History  should be consulted.

Event History

Description Date
Inactive: IPC expired 2013-01-01
Inactive: IPC removed 2012-12-17
Inactive: IPC removed 2012-12-17
Time Limit for Reversal Expired 2011-08-30
Application Not Reinstated by Deadline 2011-08-30
Deemed Abandoned - Failure to Respond to Maintenance Fee Notice 2010-08-30
Inactive: Cover page published 2009-07-03
Letter Sent 2009-06-08
Inactive: Office letter 2009-06-03
Inactive: Inventor deleted 2009-06-03
Inactive: Inventor deleted 2009-06-03
Inactive: Notice - National entry - No RFE 2009-06-03
Letter Sent 2009-06-03
Inactive: First IPC assigned 2009-05-08
Application Received - PCT 2009-05-07
National Entry Requirements Determined Compliant 2009-02-27
Application Published (Open to Public Inspection) 2008-03-06

Abandonment History

Abandonment Date Reason Reinstatement Date
2010-08-30

Maintenance Fee

The last payment was received on 2009-02-27

Note : If the full payment has not been received on or before the date indicated, a further fee may be required which may be one of the following

  • the reinstatement fee;
  • the late payment fee; or
  • additional fee to reverse deemed expiry.

Please refer to the CIPO Patent Fees web page to see all current fee amounts.

Fee History

Fee Type Anniversary Year Due Date Paid Date
MF (application, 3rd anniv.) - standard 03 2009-08-31 2009-02-27
Registration of a document 2009-02-27
Basic national fee - standard 2009-02-27
MF (application, 2nd anniv.) - standard 02 2008-09-02 2009-02-27
Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
THE UNIVERSITY OF BRITISH COLUMBIA
Past Owners on Record
QUANZU YANG
TOMASZ TROCZYNSKI
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
Documents

To view selected files, please enter reCAPTCHA code :



To view images, click a link in the Document Description column. To download the documents, select one or more checkboxes in the first column and then click the "Download Selected in PDF format (Zip Archive)" or the "Download Selected as Single PDF" button.

List of published and non-published patent-specific documents on the CPD .

If you have any difficulty accessing content, you can call the Client Service Centre at 1-866-997-1936 or send them an e-mail at CIPO Client Service Centre.


Document
Description 
Date
(yyyy-mm-dd) 
Number of pages   Size of Image (KB) 
Drawings 2009-02-27 10 3,058
Description 2009-02-27 30 1,667
Abstract 2009-02-27 1 99
Claims 2009-02-27 6 245
Representative drawing 2009-02-27 1 57
Cover Page 2009-07-03 2 91
Notice of National Entry 2009-06-03 1 193
Courtesy - Certificate of registration (related document(s)) 2009-06-08 1 102
Courtesy - Abandonment Letter (Maintenance Fee) 2010-10-25 1 175
Reminder - Request for Examination 2011-05-03 1 119
PCT 2009-02-27 4 111
Correspondence 2009-06-08 1 17