Field of the invention:
This invention is related to fields of biomedical engineering, medical implants and coatings
suitable for the implants. It concerns advancement in implants, especially in cardiac implants
aiming increased benefit to diabetic patients.
Background of the invention:
Medical devices and medical implants those are deployed in human body typically coated with
polymers, and drugs to enhance biocompatibility. Inclusion of anti-inflammatory or antiproliferative
or anti-microbial or anti-neoplastic or tissue absorption enhancer or antibiotic agent
in the coating ensures a better adaptation of the implant in the body. The drug coatings are of
critical importance for especially cardiac implants i.e. coronary and peripheral stents. This
invention concerns the .implant coatings while focusing on the coronary stent coatings .
1
........... ··- _ .. ,.... ....... ·"""-- .......... Ut:LM.L UJ.-u"::::J-.::::U.::::.l .. - . - ~ J./ .u.::::
-Q)
C)
Ill
D..
Q) -1--N
E ...
0
LL. -M
N
Lt) en
M
0 .... .... ....
N
0
~ en
N
CIO
CIO
CIO -....
N
0
~ c..
Q) en I ....
0
Neointimal proliferation and vascular injury remodeling occurs after vascular interventions like
stents deployment. Remodeling in the heart, and in vulnerable peripheral blood vessels like the
carotid artery, iliac artery, femoral and popliteal arteries is a consequence of vascular
intervention. Restenosis in a treated vessel lumen occurs if the vascular injuries aren't treated.
Restenosis is result of several simultaneous processes such as inflammation, cell proliferation,
luminal thrombosis, fibrin activation, thrombin polymerization and platelet deposition,
calcineurin activation, growth factor and cytokine release, cell migration and extracellular matrix
synthesis etc. To prohibit the restenosis and thrombosis after the vascular interventions, the stents are provided
with a coating to slowly elute anti-proliferative or such drug for sufficient time. The prolonged
drug elution significantly reduces chances of restenosis to occur. In practice, the drug eluting
coating comprises of a polymer and an appropriate therapeutic agent. The polymer can be
permanent or degradable.
The polymer in the coating has prime function to provide pnmary stent adhesion for the
therapeutic agent. Further, appropriate choice of the polymer can lead to desired drug release
dynamics i.e. providing drug encapsulation. Thus polymer content is decided on basis of the drug
carrier and drug encapsulation characteristics desired.
A method of making a drug eluting stent is disclosed in US patent US5599352A. Drugs like
sirolimus or rapamycin, paclitaxel, everolimus, zotarolimus are designed to be eluted in order to
provide thrombosis after stent deployment. German patent DE 19744135C 1 had disclosed coating
of epothilone for inhibiting restenosis. PCT patent W02007111925A2 disclosed zotarolimuscontaining
drug delivery systems for implantation into a body lumen of a subject. Medicated
stent having multi-layer polymer coating is disclosed in US8287590B2. Coated medical devices
are disclosed by US20020133183Al.
Coating of polymers and therapeutics on medical devices is now a typical practice. Further, the
liquid and low melting coatings for stents are disclosed by US20030083740Al. Polymer free
rapid drug releasing coatings comprising oils, fatty acids and/or lipids are disclosed in
US9757351B2. A Japanese patent JP2017170252A discloses biological material including
crosslinked fatty acid as substrate. Cross-linked fatty acid-based biomaterials are disclosed in
US10814043B2 .
2 .. - .. -·"'- .L I . t:J .C:::
-Q)
C)
Ill
D..
Q) -1--N
E ....
0
LL. -M
N
1.1') en
M
0 ..... ..... .....
N
0
~ en
N
CIO
CIO
CIO ................. -- ..... J.t-'U
N
0
~ c.
Q) en I .....
0
Yet there is no coating formulation comprising of fatty acids and polymers. The polymer free
coating formulations aren't suitable where sustained release of the drug is desired. Further, such
coatings have lesser stability.
Objective of the invention
It is objective of the invention to provide a coating on implantable devices consisting of certain
therapeutic agent and polymer which offers better uptake of the agent in heart of diabetic or
obese patients.
It is another objective of the invention to provide a coating on implantable devices consisting of
certain therapeutic agent and polymer which offers benefits to the common patients needing the
implantation.
It is yet another objective of the invention to provide a method of manufacturing of the
implantable devices with said coating.
It is also an objective of the invention to provide an implantable devices coating which reduces
chances of the adverse events due to the implantation.
Varieties of coating formulations are used for the implants with varying choices and quantities of
polymer, therapeutic agent, drug etc. Diabetic patients have higher vulnerability against any
invasive interventions. This invention claims an advanced implant coating which offers increased
potential uptake of the encapsulated therapeutic agent in diabetic patients, thereby increasing
efficacy of the therapeutic agent in such patients and reducing the vulnerability against the
implantation.
Summary of the invention:
Core of the invention is to use fatty acids for the drug encapsulation along with appropriate
polymer. Fatty acids are good carriers for therapeutic agents as they are consumed well by body
metabolism. The fatty acid uptake in diabetic persons is higher. The inventor found that it is
advantageous to encapsulate therapeutic agents in fatty acids while coating on medical implants,
so that they are absorbed with higher efficacy. For sustained release and for primary adhesion
3 _ .... ··- .- .. ,.... ...... ·"'~.-..... .. -. -·-...
ut:LHJ. uJ.--u~-.::::u.::::J. J.t -u.::::
-Q)
C)
Ill
D..
Q) -1--N
E ....
0
LL. -M
N
1.1') en
M
0 ..... ..... .....
N
0
~ en
N
CIO
CIO
CIO
........ -~- ..... .L t-" u
N
0
~
c.
Q) en I .....
0
with the implant, a suitable polymer is needed to be adopted as main encapsulation or matrix for
the therapeutic agents and fatty acids. Thus this invention claims to coat the implant with
composite coating of polymer, fatty acid and therapeutic agents. The polymer slowly releases the
therapeutic agents as well as fatty acids after the implantation; and the released fatty acids carry
the released therapeutic agents. Uptake of the therapeutic agents gets increased due to higher
uptake of fatty acids in diabetic patients.
Preferred embodiment of the invention is coating comprising of stearic acid, PLGA and drug.
The coat is given by common solvent/solution methods.
Detailed description of the invention:
The vascular interventions lead to injuries if left untreated, thereby leading to proliferative
responses. The sustained nature of the proliferative, thrombotic and inflammatory responses to
injury requires a coating that is able to reduce the incidence of such responses after implantation.
It is preferable to release more than one therapeutic agent over a period of time in order to
minimize such cell activated responses. Fatty acids including especially polyunsaturated fatty
acids are known to have therapeutic value rather than being mere drug carrier. Using appropriate
fatty acids in specific formulation efficiently reduce chances of the undesired responses.
The fatty acids not only enhance stability of therapeutic agents, but also increase bioavailability
of them. The free fatty acids maintain sustained drug delivery when incorporated with a drug.
They are also reported to improve the transdermal delivery of drugs [1]. Fatty acid molecules can
integrate into cellular membranes and enhance the solubility of encapsulated drugs into cellular
membranes.
The fatty acids aren't toxic or foreign biomaterials to human body. Thus by employing them
along with the encapsulating polymer, the body metabolism indeed gets benefit. Polymeric
materials have shown toxic effects after the implantation, though acceptably negligible. It is
preferable if a coating component gets metabolized via a bioabsorption mechanism.
Due to the metabolic advantage and drug delivery characteristics of fatty acids, they offer a
desirable component for the implant drug coatings. Going ahead, they offer more advantage for
cardiac and diabetes patients. Fatty acids play an important role in diabetes mellitus; cardiac cells
4
·-. -· -- ~----...........-~'-----
-Q)
C)
Ill
D..
Q) -1--N
E ....
0
LL. -M
N
1.1') en
M
0 ..... ..... .....
N
0
~ en
N
CIO
CIO
CIO
........ --- ..... .L II-" u
N
0
~
c.
Q) en I .....
0
cannot use glucose for energy generation as they are forced to utilise fatty acids. Therefore there
is overexpression of cell membrane transporters and increased fatty acid uptake [3]. It is evident
that the cardiac uptake of fatty acids is double in diabetic mice model [ 4]. Hence the fatty acid
carrier can deliver the therapeutic agents in heart of diabetic patients with higher efficiency.
To utilize efficacy of fatty acids for cardiac drug delivery, implant coatings comprising oils, fatty
acids, and/or lipids are developed [4]. But those are rapid drug releasing coatings; sustained or
slow drug release is often desirable and advantageous for better resistance to undesirable
responses and restenosis.
Polymer free coatings of cross-linked fatty acids are also reported/claimed [5]. But the fatty acids
alone don't provide the sustained release drug encapsulation, as efficient as appropriate polymer.
Importantly, polymers provide a firm seal and good adhesion to the implant surface; such
characteristics aren't offered by fatty acids so qualitatively. Therefore this invention is related to
a better fatty acid-polymer encapsulated therapeutic agent coating. Typical embodiment of the
invention is the coating comprising of fatty acid, polymer and therapeutic agent.
The polymer is durable or degradable or absorbable. However, durable polymers have distinct
advantage over degradable. In a sense, degradation products of many degradable polymers are
either toxic or lack in vivo toxicity data. However, PLA, PGA, PLGA etc. have degradation
products-which are natural human metabolites. The implant surface gets exposed to surrounding
tissues after complete degradation of the coated polymer. The bare metals release ions causing
typical toxic effects; hence the degradable polymer coated metallic implant surfaces have
chances to cause some toxicity after several years of the implantation. In general, the polymer
can be selected from PLA, PGA, PLGA, PHB, PHBV, PMMA, PC etc.
Fatty acids is wider class of materials, thus this component can be used in coating method by
variety of ways. Higher advantage is expected from unsaturated and polyunsaturated fatty acids
than the saturated acids. Simple approach is to prepare a solution of such acids, therapeutic
agents and appropriate polymer, and to coat the composite on the implant surface by solvent
removal. The coating application is done by one of spraying, dipping, ultrasonic atomizing,
electrospraying, electronanospraying etc.
While using saturated fatty acids in order to achieve firm solid coat, the adverse metabolic
I
effects caused by such molecules are needed to be concerned with priority. Saturated fats are
5
P"b.~ll ··- ........ --- ·--·- 4 <'II- • .-...-... Ut::LM.l. U.i-!..:.Ji'::ll-i:.UL.JL J./ ·Ut:.
-Q)
C)
Ill
D..
Q) -1--N
E ....
0
LL. -M
N
1.1') en
M
0 ..... ..... .....
N
0
~ en
N
CIO
CIO
co .......... ,pq..
;:: .A. t-" u
N
0
~ c.
Q) en I .....
0
culprits of increasing LDL (low density lipoprotein) cholesterol in human blood after their
uptake. However, one saturated fatty acid, stearic acid (C18:0), does not raise serum LDL
cholesterol concentrations [6]. Stearic acid is less likely to be incorporated into cholesterol esters.
According to a study about cardiovascular disease risk of fatty acids, in comparison with other
saturated fatty acids, stearic acid fat lowered LDL cholesterol, was neutral with respect to HDL
(high density lipoprotein) cholesterol, and directionally lowered the ratio of total to HDL
cholesterol [7]. Thus stearic acid is a good choice for the coating component. In some
embodiments, unsaturated fatty acids are blended with stearic acid in amounts such that the solid
consistency of the coating is maintained.
Specification of the fatty acid/s to be used is done according to physical and biochemical
requirements. The implant coating shouldn't be liquid or loose, it is needed to be firm. Hence the
fatty acid composition is selected such that the final coating is firm and solid. Thus the blend of
saturated and unsaturated fatty acids is used.
For coating application, a solvent is selected wherein the therapeutic agents, the fatty acids and
the selected polymer all have sufficient solubility. As the fatty acids are desirable drug carriers,
the therapeutic agents and fatty acids are dissolved first. This solution is mixed for some time;
and then sufficient and dissolvable amount of the polymer is added to it. After complete
dissolution, the implant coating solution gets prepared. This solution is then applied on the
implantable surfaces.
In a different embodiment of the invention, top coat of a polymer such as PLGA is given to the
coating on the implantable surface after complete solvent removal/evaporation.
Some of the embodiments are presented with examples of the invention as below.
Example 1
For the coating of the drug sirolimus on coronary stents, we chosen dichloromethane as the
suitable common solvent. To start, 3.6 grams of sirolimus was mixed with 1 gram of oleic acid
and the mixture was added to 200 milliliters dichloromethane. Then 1.5 grams stearic acid was
added to the solution. It was continuously stirred; after 10 minutes, 1 gram poly(lactic acid)
(PLA) and 3. 7 grams of poly(glycolic acid) (PGA) were added to the solution under stirring. The
6
-Q)
C)
Ill
D..
Q) -1--N
E ....
0
LL. -M
N
1.1') en
M
0 ..... ..... .....
N
0
~ en
N
CIO
CIO
CIO ........ -lP'"'b- ..... .l t-" u
N
0
~
c.
Q) en I .....
0
stirring was stopped after 5 minutes, and the solution was used for coating on laser cut stent by
spraying method. Uniform and firm coating was achieved after evaporation of dichloromethane.
Example 2
360 milligrams of sirolimus mixed with 300 milligrams Conjugated linoleic acid, and 640
milligrams Poly(3-hydroxybutyrate-co-3-hydroxyvalerate). All this was added to 20 milliliters
dichloromethane. The clear solution obtained after complete dissolution is the coating solution.
Example 3
300 milligrams everolimus, 200 milligrams stearic acid, 100 milligrams of Conjugated linoleic
acid, 300 milligrams PGA and 200 milligrams PLA were added to 20 milliliters
dichloromethane. The solution obtained after complete dissolution was the coating solution used
for coronary and peripheral stents.
While the present invention has been described in conjunction with various examples, it is not
intended that the invention be limited to such examples. On the contrary, the present invention
encompasses various alternatives, modifications, and equivalents, as will be appreciated by those
of skill in the art. To specifically cover the scope of the invention, the claims are to be stated
exclusively.
Citations
[1] Kim MJ, Doh HJ, Choi MK et al. Drug Delivery. 2008;15:373-379.
[2] Glatz JF, Luiken JJ, Bonen A. Physiological Reviews. 2010;90:367-417 .
[3] Chabowski A, Gorski J, Glatz JF et al. Current Cardiology Reviews. 2008;4(1):12-21.
[4] US Patent: US8414526B2. Medical device rapid drug releasing coatings comprising oils,
fatty acids, and/or lipids
7
-Q)
C)
Ill
D..
Q) -1--N
E ....
0
LL. -M
N
1.1') en
M
0 ..... ..... .....
N
0
~ en
N
CIO
CIO co cop 11""!1 ..-..
;:: ..l t-' lJ
N
0
~
c.
Q) en I .....
0
[5] PCT Patent: PCT/US2009/037364. Cross- linked fatty acid-based biomaterials
[6] Grundy SM, CHOLESTEROL I Factors Determining Blood Cholesterol Levels,
Encyclopedia of Food Sciences and Nutrition (Second Edition), Academic Press, 2003: 1237-
1243
[7] Hunter JE, Zhang J, Kris-Etherton PM. The American Journal of Clinical Nutrition.
201 0;91 ( 1 ):46-63.

We claim
I. A coating for the implantable devices, comprising therapeutic agents, fatty acids, and
polymers.
2. A method for preparation of the coating of claim I, wherein the therapeutic agents, the
fatty acids, and the polymers are dissolved in a common solvent and the solution is used
for the coating application.
3. A medical device having coating as prepared by claim 2.
4. A coating prepared by claim 2 wherein a fat soluble antioxidant such as vitamin E or
butylated hydroxyanisole is added to the coating solution priot to coating operation.
5. A coating prepared by claim 2 wherein the therapeutic agent is anti-proliferative drug like
sirolimus or everolimus or zotarolimus or paclitaxel or mixture thereof, and the
implantable device is vascular stent.
6. A coating of claim I wherein the fatty acids are composed of 40-I 00% C I8 (stearic acid).
7. A coating of claim I wherein the fatty acids are from linoleic acid, conjugated linoleic
acid, Stearic acid, oleic acid etc.
8. A coating of claim I wherein therapeutic agent is antibacterial or anti-inflammatory or
anti-neoplastic or tissue absorption enhancer.
9. A coating of claim 1 wherein the polymer is PLA or PGA or PLGA or PMMA or PHB or
PHBV or PV A or PVC or PTFE or PES or PE or PS or PP or mixture thereof.
10. A coating prepared by claim 2 wherein the therapeutic agent is sirolimus, fatty acid id
stearic acid, and polymers are I 0-20% PLA and 80-90% PGA having the proportion by
weight as sirolimus is 33-38 parts, PLA is 6-I4 parts, PGA is 50-60 parts, all dissolved in
more than I 0 ml dichloromethane.