U.S. patent application number 10/782412 was filed with the patent office on 2004-08-26 for process for producing stents and corresponding stents.
Invention is credited to Cassolaro, Vincenzo, Curcio, Maria, Grignani, Andrea.
Application Number | 20040167612 10/782412 |
Document ID | / |
Family ID | 32731650 |
Filed Date | 2004-08-26 |
United States Patent
Application |
20040167612 |
Kind Code |
A1 |
Grignani, Andrea ; et
al. |
August 26, 2004 |
Process for producing stents and corresponding stents
Abstract
A process for depositing an active substance on selected regions
of the surface of a stent, comprising: (i) providing the active
substance in at least one form selected from the group consisting
of a powder and a paste; and (ii) depositing the active substance
on the selected regions of the surface of the stent. Preferably,
the active substance comprises or consists essentially of FK506,
such as FK506 in the form of a powder with a grain size smaller
than 15 micron or a paste with a base of FK506 with a viscosity not
lower than 100,000 to 120,000 cps.
Inventors: |
Grignani, Andrea; (Chieri
(Torino), IT) ; Curcio, Maria; (Saluggia (Vercelli),
IT) ; Cassolaro, Vincenzo; (Saluggia (Vercelli),
IT) |
Correspondence
Address: |
POPOVICH, WILES & O'CONNELL, PA
650 THIRD AVENUE SOUTH
SUITE 600
MINNEAPOLIS
MN
55402
US
|
Family ID: |
32731650 |
Appl. No.: |
10/782412 |
Filed: |
February 19, 2004 |
Current U.S.
Class: |
623/1.15 |
Current CPC
Class: |
A61L 2300/416 20130101;
A61F 2250/0068 20130101; A61L 31/16 20130101; A61L 31/084 20130101;
A61F 2/91 20130101; A61L 2300/606 20130101 |
Class at
Publication: |
623/001.15 |
International
Class: |
A61F 002/06 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 21, 2003 |
EP |
03425106.6 |
Claims
What is claimed is:
1. A process for depositing an active substance on selected regions
of the surface of a stent, comprising: (i) providing the active
substance in at least one form selected from the group consisting
of a powder and a paste; and (ii) depositing the active substance
on the selected regions of the surface of the stent.
2. The process according to claim 1, wherein the process comprises:
(i) coating the active substance on the selected regions and other
regions of the surface of the stent; and (ii) removing the active
substance from the other regions of the surface of the stent.
3. The process according to claim 1, wherein the active substance
is applied only on the selected regions of the surface of the
stent.
4. The process according to claim 3, wherein the active substance
is applied by a dispensing nozzle.
5. The process according to claim 4, wherein a numerical control
machine for fine positioning imparts on the dispensing nozzle
and/or on the stent a relative movement to apply the active
substance.
6. The process according to claim 2, wherein the active substance
is removed from the other regions of the surface of the stent by
jets of fluid.
7. The process according to claim 2, wherein the active substance
is removed from the other regions of the surface of the stent by
fitting the stent on a nozzle comprising a perforated tube and
emitting jets of fluid from the nozzle and through the inside of
the stent.
8. The process according to claim 6, wherein the jets of fluid
comprise jets of liquid interspersed with puffs of air.
9. The process according to claim 7, wherein the jets of fluid
comprise jets of liquid interspersed with puffs of air.
10. The process according to claim 6, wherein the jets of fluid
comprise jets of water.
11. The process according to claim 7, wherein the jets of fluid
comprise jets of water.
12. The process according to claim 6, wherein the jets of fluid
comprise puffs of nitrogen.
13. The process according to claim 7, wherein the jets of fluid
comprise puffs of nitrogen.
14. The process according to claim 2, wherein the active substance
is removed from the other regions of the surface of the stent by
rubbing the surface of the stent with respect to a support.
15. The process according to claim 14, wherein the rubbing support
has a compliant surface.
16. The process according to claim 1, wherein the process
comprises: (i) making a bed or mat of the active substance; and
(ii) exposing the stent to the bed or mat of active substance so
that the active substance is transferred at least in part onto the
surface of the stent.
17. The process according to claim 16, wherein the stent is exposed
to the bed or mat of active substance with application of
pressure.
18. The process according to claim 16, wherein the process
comprises: (i) exposing the stent to the bed or mat of active
substance in such a way that the active substance coats a surface
of the stent, the surface coated comprising the selected regions
and the other regions of the surface of the stents; and (ii)
removing the active substance from the other regions of the surface
of the stent.
19. The process according to claim 16, wherein the process
comprises: (i) applying on the stent a mask with openings which
leave uncovered the selected regions; (ii) exposing the stent with
the mask applied thereto to the bed or mat of active substance, so
that the active substance coats the mask and the selected regions
left uncovered by the openings of the mask; and (iii) removing the
mask from the stent.
20. The process according to claim 18, wherein the process
comprises: (i) applying on the stent a first mask with first
openings, which leave uncovered first selected regions of the
stent; (ii) exposing the stent, with the first mask applied
thereto, to the bed or mat of active substance so that the active
substance coats the mask and the first selected regions left
uncovered by the first openings of the first mask; (iii) removing
the first mask from the stent; (iv) applying on the stent a second
mask with second openings which leave uncovered second selected
regions of the stent; (v) exposing the stent, with the second mask
applied thereto, to a bed or mat of a second active substance, so
that the second active substance will coat the second mask and the
second selected regions left uncovered by the second openings of
the second mask; and (vi) removing the second mask from the
stent.
21. The process according to claim 1, wherein the process
comprises: (i) subjecting the stent to an electrostatic charging
treatment designed for charging electrostatically at least the
selected regions of the surface of the stent; and (ii) exposing the
stent, with at least the selected regions electrostatically
charged, to the active substance, the electrostatic charge causing
the transfer of the active substance onto the surface of the
stent.
22. The process according to claim 21, wherein the process
comprises: (i) subjecting the stent to an electrostatic charging
treatment designed for electrostatically charging a surface
comprising the selected regions and other regions of the surface of
the stent, so that the electrostatic charge causes the transfer of
the active substance onto a surface comprising the selected regions
and other regions of the surface of the stent; and (ii) removing
the active substance from the other regions of the surface of the
stent.
23. The process according to claim 21, wherein the electrostatic
charging treatment is by corona effect.
24. The process according to claim 22, wherein the electrostatic
charging treatment is by corona effect.
25. The process according to claim 1, wherein the process
comprises: (i) providing a transfer support for the active
substance; (ii) subjecting the transfer support to a charging
treatment designed for electrostatically charging respective
regions of the transfer support homologous with respect to the
selected regions of the surface of the stent; (iii) exposing the
transfer support, with the respective electrostatically charged
regions, to the active substance, the electrostatic charge
determining the transfer of the active substance onto the
respective electrostatically charged regions from the transfer
support; and (iv) exposing the transfer support, with the active
substance transferred onto the respective electrostatically charged
regions, to the surface of the stent, the exposure determining the
transfer of the active substance onto the selected regions of the
stent.
26. The process according to claim 25, wherein steps (ii), (iii),
and (iv) are repeated, employing active substances that each time
are different, with the respective electrostatically charged
regions of the transfer support being either identical or different
for the active substances used.
27. The process according to claim 21, wherein before the
electrostatic charge treatment, the stent is coated with a layer of
biocompatible carbon material.
28. The process according to claim 22, wherein before the
electrostatic charge treatment, the stent is coated with a layer of
biocompatible carbon material.
29. The process according to claim 25, wherein before the
electrostatic charge treatment, the stent is coated with a layer of
biocompatible carbon material.
30. The process according to claim 26, wherein before the
electrostatic charge treatment, the stent is coated with a layer of
biocompatible carbon material.
31. The process according to claim 1, wherein the stent, with the
active substance deposited on the selected regions of the surface
of the stent, is subjected to a treatment for stabilizing the
active substance.
32. The process according to claim 31, wherein the treatment for
stabilizing the active substance is chosen from the group
consisting of: (i) exposure to temperature or thermal cycles; (ii)
dipping in solvent for controlled lengths of time; (iii) exposure
to solvent spray; (iv) exposure to solvent vapors; (v) selective
treatment with a laser; (vi) selective or integral application of a
protective adhesive coating; and (vii) lyophilization.
33. The process according to claim 2, wherein the stent, with the
active substance deposited on the selected regions of the surface
of the stent, is subjected to a treatment for stabilizing the
active substance, and wherein the treatment for stabilizing the
active substance is performed after the removal of the active
substance from the other regions of the surface of the stent.
34. The process according to claim 1, wherein the process is
performed on the stent when the stent is in a radially contracted
condition.
35. The process according to claim 1, wherein the process is
performed on the stent when the stent is in a radially expanded
condition, and then subjecting the stent to radial contraction.
36. The process according to claim 1, wherein least some of the
selected regions are cavities or recesses in the surface of the
stent.
37. The process according to claim 1, wherein the active substance
comprises FK506.
38. The process according to claim 1, wherein the active substance
consists essentially of FK506.
39. The process according to claim 37, wherein the active substance
consists essentially of FK506 in the form of powder with a grain
size not greater than 15 micron.
40. The process according to claim 37, wherein the active substance
consists essentially of a paste with a base of FK506 with a
viscosity having a value not less than 100,000 to 120,000 cps.
41. A stent loaded with at least one active substance, the stent
having been made according to the process of claim 1.
42. The process according to claim 36, wherein the active substance
deposited in the cavities or recesses is subjected to a treatment
for stabilizing the active substance selected from the group
consisting of: (i) exposing the cavities or recesses that contain
the active substance to a laser; and (ii) selective or integral
application of a protective adhesive coating in the form of a plug
to close the cavities or recesses that contain the active
substance.
Description
[0001] The present invention relates to stents. Stents are
expandable endoprostheses that can be implanted in a lumen of the
human body or animal body, such as a blood vessel, for
re-establishing and/or maintaining the patency thereof. Stents are
usually configured as devices of a tubular shape which operate so
as to maintain open a segment of a blood vessel or of another
anatomic lumen. Stents have become widely used over the last few
years for the treatment of stenosis of an arteriosclerotic nature
in blood vessels such as coronary arteries. Stents are now being
used in other regions of the body such as the peripheral
regions.
[0002] The scientific and technical literature, including the
patent literature, regarding stents is quite extensive. For
example, the following documents relate to stents: EP0 806 190 A1,
EP 0 850 604 A2, EP 0 875 215 A1, EP 0 895 759 A1, EP 0 895 760 A1,
EP 1 080 738 A1, EP 1 088 528 A1, EP 1 103 234 A1, EP 1 174 098 A2,
EP 1 212 986 A1, and EP 1 277 449 A1.
[0003] The activities of research, development and
industrialization of stents were directed, in the early years,
principally to the geometrical structure and to the corresponding
techniques of fabrication (winding of a wire, cutting from a
microtube, use of superelastic materials, etc.). The research
activity regarding stents then gradually extended to other specific
embodiments, and in particular to the possibility of applying on
stents or of associating to stents pharmacological agents. Such
pharmacological agents are able to perform a specific activity at
the implantation site of the stent. Drugs that have a
restenosis-antagonist action are of particular interest.
[0004] For example, EP 0 850 604 A2 describes the possibility of
providing the stent with a sculpture that comprises, for instance,
recesses that may receive one or more drugs that are useful in the
prevention or treatment of restenosis and/or other substances that
are expedient for ensuring proper use of the stent (adhesion, mode
of release, kinetics, etc.). The surface sculptures are
characterized both by the outline and the surface of the recess,
and by the depth profile. For example, the recesses may be cavities
having circular or else ovoidal or again elongated openings.
Alternatively, they can assume the form of an appropriate
alternation of cavities with openings of different types according
to the needs of release. The depth profile may be U-shaped or
V-shaped, or shaped like a vessel with or without a surface part
completely dedicated to the reception of the substances in question
referred to above. The surface part may assume the appearance of a
sort of continuous layer on just the outer surface of the
stent.
[0005] In the course of the last few years, extremely extensive
activity has been dedicated to developing materials, particularly
pharmacological agents, to be loaded on the stent. The material to
be loaded on the stent may consist of just one drug, of a pair of
drugs, or of an ensemble of drugs with similar, synergetic, or
different actions. In addition to pharmacologically active
molecules, the stent can serve as a vehicle for substances having
the function of adjuvant of pharmacologically active substances,
such as polymers or excipients of various natures. The function may
be of stabilization of the active substance or active substances,
or else be aimed at regulating the kinetics of release
(deceleration or acceleration of release). The polymers/excipients
can be mixed with the drug or drugs or else are in separate layers
with respect to the pharmacologically active substances. For
example, a recess in the stent could contain a sort of
bioerodible-polymer plug or the material on the stent could have a
stratified structure with successive layers of drug and
polymer.
[0006] Even though in scientific circles this type of application
is not considered at the moment particularly attractive, the
character of activity of the substances loaded on the stent may
include substances that are of a radioactive nature.
[0007] The scientific and patent literature relating to materials
to be loaded on the stent is extremely extensive, as is witnessed,
not only by some of the documents already cited previously, but
also by documents such as, for example: EP 0 551 182 A1, EP 0 747
069 A2, EP 0 950 386 A2, EP 0 970 711 A2, EP 1 254 673 A1, EP 1 254
674 A1, WO 01/87368 A1, WO 02/26280 A1, WO 02/26281 A1, WO 02/47739
A2, WO 02/056790 A2 and WO 02/065947 A2, as well as by the
literature cited in these documents. These documents and
literature, it may be added, by no means exhaust the field.
[0008] As regards the choice of drug having restenosis-antagonist
function, the drugs known as rapamycin (sirolimus) and FK506
(tacrolimus) have assumed particular importance.
[0009] The problems linked to the use of drugs on the stent are not
moreover limited to the choice alone, i.e., to the identification
of the substance or substances used, but involve various other
aspects. Among these further aspects are: (i) the physical form of
the substances to be loaded; (ii) the technique of loading of the
material; (iii) the technique of cleaning of the excess material
deposited; and (iv) the stabilization of the material itself.
[0010] The techniques of loading should take into account the
nature (i.e., the physical form) of the substance or substances
loaded on the stent. Some techniques of loading of a known type
basically operate in an indirect way in so far as they
substantially envisage the formation of a coating on the stent,
typically one of polymeric material (for example polymers of
methacrylate, polyurethane, PTFE, hydrogel or hydrogel/polyurethane
mixture, especially PTFE), to which the drug to be applied on the
stent is linked and/or in which it is dissolved before application
of the coating, subsequently designed to be stabilized by
polymerization. Other techniques substantially envisage, instead,
starting from agents in liquid form or low-viscosity solutions or
dispersions. This method is used because in the majority of cases
considered because the drugs in question are available in the
market in the form of a powder (of different grain size).
[0011] The simplest solution envisages loading the stent by dipping
it in a carrier, typically a liquid, in which is dissolved,
suspended or anyway present the substance or substances to be
loaded on the stent. This technique, which may possibly be
conducted in vacuum conditions, is referred to in the art as
"dipping". For example, the document WO 02/065947 A2 describes a
solution in which the stent is brought into contact with a solution
of FK506 in aqueous or organic solvent (typically in an alcohol,
such as ethanol, in a concentration of 3.3 mg of FK506 in 1 ml of
ethanol). This takes place, for example, by dripping, spraying or
dipping, preferably in vacuum conditions. The stent is then dried,
preferably enough to remove the solvent. The drug coating operation
preferably is then repeated from one to five times. Subsequently,
the stent is possibly washed one or more times with water or
isotonic saline solution, and may then possibly be dried.
[0012] The known methods described above, albeit satisfactory, come
up against a wide range of drawbacks. Among these are: (i) the
complexity of the operation of loading; (ii) the need, in the case
where a coating is made on the stent, in which the drug to be
applied on the stent is bound and/or dissolved, to take into
account the characteristics of the coating and the possible
subsequent elimination thereof; (iii) the difficulty of obtaining
selective coatings, i.e., ones limited to well-confined areas of
the stent; (iv) the difficulty of loading, with a limited number of
steps, a plurality of different agents; and (v) the difficulties
that are intrinsically linked to the simultaneous loading of a
number of agents and possible excipients or other substances that
may contribute to the control of the kinetics of release.
[0013] The purpose of the present invention is to overcome the
drawbacks pointed out above, paying particular attention to its
possible use for making stents with associated biologically active
substances, i.e., the so-called "bioactive stents". The above mode
of use regards in particular the possible presence on the stent of
at least one drug which may perform a restenosis-antagonist
function, such as for example FK506. According to the present
invention, the above purpose is achieved thanks to a process having
the characteristics described below. The invention also regards the
corresponding stent.
[0014] In summary, the invention envisages carrying out the loading
operation starting from a powder or from a paste obtained from the
powder itself. It will be appreciated that the term "paste" is here
understood to indicate any plastic mass having a degree of
viscosity such as to ensure that the mass will substantially
preserve its shape if exposed only to the force of gravity. This
definition is in evident contrast with a liquid or cream, which do
not demonstrate these characteristic of preservation of shape. The
existence or else absence of this characteristic may be determined
in a simple way by depositing on a surface a mass of substance in
an amount corresponding to the quantity required for the
applications here considered and verifying whether the mass
preserves or else modifies its shape as a result of the force of
gravity.
[0015] The powder or paste here considered may consist of: (i) a
pure drug; (ii) a mixture of two or more drugs in appropriate
proportions; and (iii) a mixture of drugs, excipients and/or
substances (such as polymers) that contribute to the control of the
kinetics of release.
[0016] Preferably, the drug is FK506, i.e., the macrolide
antibiotic FK506 (tacrolimus,
[3S-[3R*[AND(1S*,3S*,4S*)],4S*,5R*,-8S*,9E,12R*,14R*,
15S*,16R*,18S*,19S*,26aR*]]-5,6,8,11,12,13,14,15,
16,17,18,19,24,25,25,26-
a-hexadecahydro-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl)-1-meth-
ylentenyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-15,19-epo-
xy-3H-pyrido[2,1-c][1,4]oxa-azacyclotricosin-1,7,20,21(4H,23H)-tetrone;
Merck index No. 9000). This drug is an active substance originally
developed for the medicine of transplants and the immunosuppressive
action of which extends evidently also to the restenosis-antagonist
mechanism.
[0017] Drugs presenting characteristics that are on the whole
similar, which can be used in association with, or alternatively
to, FK506, are: cyclosporine, leflunomide, mycophenolate,
brequinar, rapamycin, everolimus, ABT-574 or other derivatives of
rapamycin; PDGF antagonists; paclitaxel or 7-hexanoyl-taxol;
cisplatin; vinblastin; mitoxantrone; combretastatin A4; topotecan;
methotrexate; flavopyridol; actinomycin D; rheopro/abciximab or
probucol, and drugs capable of mitigating or preventing reactions
underlying the process of restenosis, such as: rapamycin, heparin
and the like, actinomycin D, batimastat, paclitaxel, resten NG
(oligonucleotide), and dexamethasone.
[0018] Drugs that can be advantageously combined with FK506 and/or
other drugs with restenosis-antagonist action, or else, in general,
drugs that can be loaded on a stent according to the modalities
herein described include the following.
[0019] Drugs with anti-inflammatory action, such as:
[0020] Corticosteroids,
[0021] Cortisol Betamethasone Fluocinolone,
[0022] Cortisone Dexamethasone Fluocinonide,
[0023] Corticosterol Flunisolide Fluoromethalone,
[0024] Tetrahydrocortisol Alclomethasone Flurandrenolide,
[0025] Prednisone Amcinonide Alcinonide,
[0026] Prednisolone Clobetasol Medrisone,
[0027] Methylprednisolone Clocortolone Momethasone,
[0028] Fluodrocortisone Desonide Rofleponide,
[0029] Triamcinolone Desoxymethasone,
[0030] Paramethasone Diflorasone,
[0031] as well as all the corresponding esters, salts and
derivatives.
[0032] Non-steroidal anti-inflammatory drugs (NSAIDs):
[0033] Salicylates: Acetylsalicylic acid,
[0034] Diflunisal,
[0035] Salsalate,
[0036] Pyrazolones: Phenylbutazone,
[0037] Oxyphenbutazone,
[0038] Apazone,
[0039] Indomethacin,
[0040] Sulindac,
[0041] Mephenamic acid and phenamates,
[0042] Tolmetin,
[0043] Derivatives of propionic acid: Ibuprofen,
[0044] Naproxen,
[0045] Fenoprofen,
[0046] Ketoprofen,
[0047] Flurbiprofen,
[0048] Pyroxicam and derivatives,
[0049] Diclofenac and derivatives,
[0050] Etodolac and derivatives,
[0051] Drugs with anti-neoplastic action:
[0052] Alkylating agents:
[0053] Nitrogenated mustards: Cyclophosphamide,
[0054] Melfalan,
[0055] Chlorambucyl,
[0056] Ethylenimin and methylmelamine,
[0057] Alkyl sulphonates,
[0058] Nitrosureas: Carmustin,
[0059] Triazenes,
[0060] Antimetabolites:
[0061] Analogues of Folic acid: Methotrexate
[0062] Analogues of Pyrimidines: Fluorouracyl
[0063] Analogues of Purines and derivatives: Mercaptopurine,
[0064] Thioguadinine.
[0065] Natural Products:
[0066] Vinca alkaloids: Vinblastine,
[0067] Vincristine,
[0068] Epipodofillotoxines: Ethoposide,
[0069] Antibiotics: Actinomycin D,
[0070] Doxorubicin,
[0071] Various:
[0072] Complexes of Platinum: Cisplatinum,
[0073] Mitoxantrone and derivatives,
[0074] Hydroxyurea and derivatives,
[0075] Procarbazine and derivatives,
[0076] Mitotanes,
[0077] Aminoglutetimide,
[0078] Derivatives having a naphthopyranic structure,
[0079] Derivatives of butyric acid,
[0080] Taxanes: Taxol,
[0081] Docetaxel,
[0082] Epotilones,
[0083] Batimastat and analogues,
[0084] Drugs with action promoting processes for repairing the
vessel wall,
[0085] Endothelial/angiogenetic growth factors: e.g., VEGF or
antisense oligonucleotides,
[0086] Antisense oligonucleotides: e.g., antisense c-myb,
[0087] Prostacyclin and analogues: Ciprostene,
[0088] Dipyridamol,
[0089] Calcium blockers,
[0090] Arylalkylamines: Diltiazem, Verapamyl, Fendiline,
Gallopamyl, etc.,
[0091] Dihydropyridines: Amlodipine, Nicardipine, etc.,
[0092] Piperazines: Cinnarizine, Lidoflazine, etc.,
[0093] Colchicines,
[0094] Drugs that act on c-AMP:
[0095] Aminofilline, IBMX (bronchodilators),
[0096] Amrinone (cardiotonic),
[0097] 8-Bromo-c-AMP and c-AMP analogues,
[0098] Drugs that act on the lipid metabolism:
[0099] Statins: simvastatin, fluvastatin, etc.,
[0100] Unsaturated .omega.-3 fatty acids,
[0101] Somatostatin and analogues: Sandostatin, Angiopeptin,
etc.
[0102] Cytocalasines,
[0103] Etretinate and derivatives of retinoic acid,
[0104] Anticoagulants: Irudin, Heparin and derivatives,
[0105] Trapidyl: vasodilator,
[0106] Nitrogen monoxide and its generators: Molsidomin,
[0107] Antiplatelet agents: Ticlopidin, Dipyrimidamol, etc.,
[0108] Agents that can act on the activity of the cell and on the
regulation of the
[0109] cell matrix:
[0110] protein (elafin),
[0111] oligonucleotides,
[0112] genes,
[0113] RNA, DNA and fragments,
[0114] RNA, DNA and antisense fragments,
[0115] Monoclonal antibodies.
[0116] For each active substance cited herein, including the active
substance FK506, the concept of "active substance" also covers
direct derivatives of the active substance, and the active
substance also in all the types of salts, enantiomers, racemic
forms, bases, or free acids of the active substance, and their
mixtures.
[0117] It will moreover be appreciated that, rather than to the
identification of the specific substance applied on the stent, the
present invention directs its main attention to the technique
(rheology) of application thereof. The application in the form of a
powder or of a paste formed from the powder manages to reconcile
the need for making a selective application (an important factor
both for the purposes that it is intended to pursue and for the
costs of the substances applied, which are usually rather high),
with the need of ensuring the firm retention of the substances
applied on the stent.
[0118] The above result has been obtained without complex
operations of loading, and avoids the need to make on the stent a
coating in which the drug to be applied on the stent is bound
and/or dissolved. The invention provides a method of obtaining with
relative ease selective coatings, i.e., coatings limited to
well-confined areas of the stent, and/or of loading a plurality of
different agents, while avoiding the difficulties that are
intrinsically linked to the simultaneous loading of a number of
agents and possible excipients or other substances that may
contribute to controlling the kinetics of release.
[0119] Usually, the result of the process of loading must be
selective, in the sense that it must load only those areas of the
stent that actually have to carry the drug or drugs, as well as the
possible additives (excipients). Of course, this result can be
achieved also passing through a generalized loading, which
initially loads also areas of the stent that are designed to be
subsequently cleaned to remove the excess substances loaded.
[0120] Once the substances chosen have been deposited on the stent
(before or after cleaning, according to the operative choices or
techniques adopted), the next step is fixation of the drug or
drugs, as well as of the additives. The purpose of this is to
ensure that the substances can be effectively transported by the
stent onto an implantation site and not be dispersed elsewhere, in
particular during advance towards the implantation site or even
before the stent is inserted in the body in which it is to be
implanted. The operations of stabilization can be conducted in a
selective way on the sole parts where the presence of the
substances deposited is required or else in a generalized way over
the entire stent, at least as regards the outer surface
thereof.
[0121] In a specific way, in the case where the starting part is a
powder, the main methods of loading that can be adopted are: (i)
recourse to a non-selective corona effect (electrostatic effect),
i.e., coating the entire surface with powder and then cleaning the
areas that require cleaning; (ii) recourse to a selective
electrostatic process (such as photocopier or laser printer), for
example through an intermediate roll that collects the powder only
in areas corresponding to the recesses, in which it deposits it
subsequently; if they are stents with the entire outer surface
porous, selectivity is in general not required, and, in both of the
cases so far considered, no specific cleaning operation is called
for; (iii) rolling on a bed or mat of powder, with subsequent
cleaning; and (iv) rolling on a bed or mat of powder with a mask of
a serigraphic type so as to load the recesses alone; no cleaning is
required.
[0122] In the case where the starting point is paste, the main
methods of loading usable are: (i) rolling on a bed or mat of
paste, with subsequent cleaning; (ii) rolling on a bed or mat of
paste with a protective mask (serigraphy); cleaning is not
required; and (iii) application with a dispensing nozzle, typically
moved by a numerical control machine for fine positioning.
[0123] It will moreover be appreciated that whatever the loading
procedure adopted, either for paste or for powder, it is then
preferable to proceed to a stabilization operation, where by
"stabilization" gives the content of the cavity a mechanical
quality and a degree of adhesion to the recesses themselves
adequate for the mechanical stress exerted on the stent in the
steps of transportation, storage, procedure, and expansion.
[0124] To achieve the desired effect of stabilization, it is
possible to resort to techniques, such as: (i) exposure to
temperature or thermal cycles; (ii) dipping in solvent for
controlled lengths of time; (iii) exposure to solvent spray; (iv)
exposure to solvent vapors; (v) selective treatment with laser
(exposure of the recesses to the laser beam); (vi) selective or
integral application of a protective adhesive coating (in the form
of a plug for closing the recesses); and (vii) lyophilization.
[0125] The invention will now be described, purely by way of
non-limiting example, with reference to the annexed drawings.
[0126] FIGS. 1 to 3 illustrate, in general terms, the operation of
loading of a drug or of another substance in the form of powder or
paste on a stent.
[0127] FIGS. 4 to 6 are schematic illustrations of the loading
operation performed with an electrostatic process (corona effect)
of a non-selective type.
[0128] FIGS. 7 and 8 are schematic illustrations of the loading
operation performed with an electrostatic process of a selective
type.
[0129] FIGS. 9 to 11 are schematic illustrations of the loading
operation performed with a process of rolling on a bed or mat.
[0130] FIG. 12 illustrates the implementation of the loading
operation by a device for dispensing a paste.
[0131] The present description is provided, purely by way of
non-limiting example, with reference to a stent 1 substantially
corresponding to the stent described in U.S. Pat. No. 6,325,821 B1,
the contents of which are hereby incorporated by reference herein.
Such a stent consists of a tubular body made of metal material,
which may be dilated, starting from a radially contracted condition
to a radially expanded condition. The body of the stent comprises a
plurality of structural elements or struts 10, which define a
structure with openings presenting an on the whole reticular
character.
[0132] In particular, in the solution described in U.S. Pat. No.
6,325,821 B1 the structure in question comprises a plurality of
annular segments arranged in succession along the longitudinal axis
of the stent. The segments in question present a serpentine pattern
with loop-like parts arranged in opposite sequence, connected
together by connection elements (commonly referred to as "links").
The serpentine sequences of the successive segments are usually in
phase opposition, i.e., with a concavity of each serpentine
opposite to a concavity of an adjacent segment. The connection
elements present a substantially V-shaped pattern with a profile
characterized by an alternation of concave portions and convex
portions. The aforesaid connectors connect the various annular
segments of the stent at the "0" points or nodes of the serpentine
paths of the segments.
[0133] In the view presented in the attached drawings, the stent 1
is represented in cross section, so that in the drawings only the
circular trace of the cross section is perceptible, which is
defined by a certain number of struts traversed by the
cross-sectional plane. The stent in question is provided, on its
outer surface, with a sculpture formed by a pattern with recesses
12 of the type described in U.S. Pat. No. 6,638,302 B1 or U.S.
patent application Publication No. 2003/0028242 A1, the contents of
each of which are hereby incorporated by reference herein. The
recesses 12 can receive within them respective masses 14 of a
material comprising an active substance, such as FK 506 and/or any
one of the other substances or combinations of substances to which
ample reference has been made previously.
[0134] In a particularly advantageous way, the stent in question is
coated, on its outer surface, with a layer of biocompatible carbon
material deposited thereon by resorting to the technique described,
for example, in U.S. Pat. Nos. 5,084,151, 5,133,845, 5,370,684,
5,387,247, and 5,423,886, the contents of each of which are hereby
incorporated by reference herein. The presence of the coating of
biocompatible carbon material proves advantageous for the purposes
of use of the stent, in particular as regards the minimization of
the effects resulting from the implantation of the stent. The
presence of the coating of biocompatible carbon material proves
likewise advantageous for the purposes of loading of the stent,
which is performed with the processes of an electrostatic type
described in greater detail in what follows.
[0135] General Loading Technique
[0136] FIGS. 1 to 3 of the annexed drawings illustrate the
technique here described in its more general terms. The stent 1 is
usually mounted on a support or spindle 16 designed to enable its
manipulation (also by means of a mechanical manipulator, which may
possibly be automatic) without risks of damage. The stent can be
treated both in a radially expanded condition, and in a radially
contracted condition. The treatment in a radially contracted
condition is, however, preferred in that it facilitates the
operations of manipulation and cleaning. Tests show that the radial
contraction of a stent loaded in a radially expanded condition
leads to a modest compacting of the substance loaded in the
recesses 12, which acts in a synergetic way with the stabilization
of the substance itself.
[0137] FIG. 2 illustrates the operation whereby (according to
different modalities, described in greater detail in what follows)
the substance M designed to be loaded in the recesses 12 is
applied, in the form of a powder or a paste, on the surface of the
stent 1. In particular, FIG. 2 refers to an operation of
application performed in a non-selective way, i.e., ensuring that
the substance M not only fills the recesses 12, but covers instead
the surface of the stent 1 in a practically complete way.
[0138] FIG. 3 illustrates the subsequent cleaning operation, in
which the substance M in excess is removed. For example the
substance M can be removed by using a localized jet of fluid coming
from one or more nozzles 17 so as to leave only the specific dose
14 inside the recesses 12.
Example 1
[0139] Non-Selective Electrostatic Loading with Powder
[0140] A very fine powder, with a typical grain size of less than
15 micron, of drug FK 506 (tacrolimus) is laid in a thin and level
layer inside a tray V. The stent 1 is positioned on a support 16
capable of being charged electrostatically, for example as a result
of a corona treatment of the type currently performed on the
printing rolls of photocopier machines (FIG. 4). The support 16 is
electrostatically charged, and the support 16/stent 1 ensemble is
made to rotate (FIG. 5) at a distance of a few tenths of a
millimeter from the surface of the powder that is in the tray V.
The drug M is attracted over the entire surface of the
support/stent ensemble and adheres in a uniform way to the stent,
also filling its cavities 12. The next step is to remove the excess
of drug M from the areas other than the recesses 12. For this
purpose, the stent 1 still fitted on its support 16 is cleaned by a
sequence of jets of cold water and of nitrogen under pressure shot
from one or more nozzles 17 appropriately positioned around the
stent (FIG. 6). Alternatively, the stent 1 is fitted on a nozzle
comprising a perforated tube and is impinged upon by a short
sequence of jets of cold water, emitted under pressure from inside
the stent. The jets of water are interspersed with puffs of
nitrogen under pressure. The remaining residue is removed from the
outer surface of the stent thanks to the rubbing of the latter
against a second support, e.g., a cylinder with a compliant, i.e.,
soft surface.
[0141] To stabilize the drug in the sculptures (recesses) 12, the
stent that has been loaded is subjected to a spray of solvent
effective on FK506, such as for example acetonitrile, from a
distance of 15 cm, or else exposed to acetonitrile vapors in a
chamber for thin-layer chromatography for 5 minutes.
Example 2
[0142] Selective Electrostatic Loading with Powder
[0143] As in the case of the previous example, a very fine powder
of the drug FK506 (tacrolimus), with the same grain size as in
Example 1, is laid in a thin and level layer inside a tray V. A
roll 18 coated with photosensitive material capable of being
charged electrostatically is exposed to a light source 20 capable
of activating or de-activating in a selective way (from the
standpoint of electrostatic charging) areas of the surface of the
photosensitive roll 18 according to a geometry corresponding to the
geometry of the recesses 12 (FIG. 7). The final result is the
presence, on the surface of the roll 18, of a distribution of
electrostatic charges that reproduces the distribution of the
recesses 12 on the surface of the stent.
[0144] Then, by passing over the bed of powder that is in the tray
V, the roll 18 carries away with it masses 14 of drug M, the
distribution and shape of which correspond to those of the recesses
12 (FIG. 8). The roll 18 is then used (like an offset roll in a
similar printing process) for transferring the masses 14 into the
recesses 12 of the stent 1 mounted on the support 16 (this also
usually being charged electrostatically) (FIG. 8).
[0145] The drug M is deposited on the stent 1, which turns in an
opposite direction alongside the roll 18, in areas corresponding to
the sculptures or recesses 12. When all the recesses or sculptures
of the stent are loaded with the drug, the next step of the process
is the fixation of the substance according to the procedure already
described previously (acetonitrile vapors in a thin-layer
chromatography chamber for 5 minutes).
[0146] It will be appreciated that the process just described, in
addition to not requiring the step of cleaning of the excess drug,
lends itself also to being repeated with different substances, for
example so as to fill different recesses with different drugs. In
particular the operations of: (i) subjecting the roll 18,
functioning as support for transfer of the active substance M, to a
charging treatment designed to obtain electrostatic charging of
respective regions that are homologous with respect to the recesses
12 of the surface of the stent 1, (ii) exposing the roll 18, with
the aforesaid respective electrostatically charged regions, to the
active substance M that is in the tray V, ensuring that the
electrostatic charge will cause transfer of the active substance
onto the electrostatically charged regions of the roll 18, and
(iii) exposing the roll with the active substance M, transferred
onto said respective electrostatically charged regions, to the
surface of the stent 1, said exposure determining the transfer of
the active substance M into the recesses 12 of the stent 1, each
can be repeated by employing active substances M that are each time
different, with the respective electrostatically charged regions of
the roll 18 chosen so that they are either identical or different
for the various active substances used.
[0147] As has been mentioned previously, the presence, at least on
the outer surface of the stent 1, of a coating of biocompatible
carbon material proves advantageous for the purposes of loading the
stent performed according to the processes of an electrostatic type
described in Examples 1 and 2.
[0148] Examples 1 and 2 set forth previously can also be
implemented using a paste and not a powder. In this case, the
transfer of the substance M onto the electrostatically charged
areas of the stent 1 or of the roll 18 usually presupposes an at
least marginal contact and not only the close proximity between the
substance M and the stent 1 or the roll 18.
Example 3
[0149] Rolling on a Bed or Mat of Paste
[0150] A mixture of drug FK506 (tacrolimus) with glycerine is
prepared by amalgamating the powder of Example 1 with a few drops
of glycerine. The paste thus obtained, indicated by M, has a
viscosity that is hard to determine but can be estimated to have a
lower limit of 100,000 to 120,000 cps.
[0151] The paste M is then deposited and spread out over a surface
P, such as for example the bottom of a tray (not illustrated), so
as to form a uniform bed or mat. The support 16 for the stent is
mounted so as to be able to rotate with respect to its longitudinal
axis and an axis to translate along the tray itself on a track. By
means of the movement of rotation and translation, accompanied by a
certain pressure, the outer surface of the stent comes into contact
with the paste M, and a layer of paste P is deposited on the outer
surface of the stent and fills the recesses 12 (FIG. 9).
[0152] Tests show that, at least for some ranges of viscosity and
of adhesiveness of the paste (parameters that depend of course upon
the nature and upon the quantity of components), the phenomenon of
transfer of the paste on the stent 1 involves, in a practically
exclusive way, the recesses 12, which evidently exert a sort of
action of "capture" on the paste. After having possibly removed the
fractions of paste M that have remained adherent to the regions of
the surface of the stent other than the recesses 12 (FIG. 10), the
stent 1 itself is then removed from the support 16 and left to rest
at room temperature (e.g., for a period not shorter than 6
hours).
[0153] To render homogeneous and intimately adherent, i.e., to
stabilize, the drug-glycerine mixture on the surface of the
sculptures, the stent is subsequently exposed to vapors of ethyl
alcohol in a thin-layer chromatography chamber. Exposure is
performed for 5 minutes at 30.degree. C. The stent is then left to
dry for 6 hours, dipped for 15 seconds in water, and again left to
dry for 24 hours. In a less preferred way, the operation of removal
of the fractions of paste M that remain adherent to the regions of
the surface of the stent other than the recesses 12 may possibly
follow the operation of stabilization, instead of preceding it.
Example 4
[0154] Rolling on a Bed or Mat of Paste
[0155] A mixture of drug FK506 (tacrolimus) and of polycaprolactone
in the form of powder (in a ratio of 6:4) is prepared by
amalgamating the powder with a few drops of ethyl acetate. Also in
this case, the paste thus obtained, designated by M, has a
viscosity that is hard to determine but can be estimated to have a
lower limit of 100,000 to 120,000 cps.
[0156] As in the case of Example 3, the paste M is then deposited
and spread out over a surface P, such as for example the bottom of
a tray (not illustrated), so as to form a uniform bed or mat. Once
again in a way similar to what was seen in the case of Example 3,
the support 16 for the stent is mounted so as to be able to rotate
with respect to its longitudinal axis and translate along the tray
itself on a track, applying to the stent a certain pressure in the
direction of the bed of paste M.
[0157] Applied on the stent, mounted on the support 16, is a mask
22 consisting of a metal cylinder with slits 24 the geometry of
which corresponds to the geometry (number, shape and position) of
the sculptures or recesses 12 present on the outer surface of the
stent (FIG. 11). The diameter of the mask 22 is chosen so that,
once fitted on the stent 1, the mask 22 will adhere perfectly to
the outer surface thereof, leaving free only the required recesses
12. Also in this case, the movement of rotation and translation of
the support 16/stent 1/mask 24 ensemble on the tray containing the
paste M enables deposition of a layer of paste M on the outer
surface of the mask 24 and in the recesses 12 of the stent 1 that
are left free by the openings 24 of the mask 22.
[0158] At this point, the next step is the fixation of the
drug-polymer mixture to the surface of the stent 1/mask 22
ensemble, for example by putting everything in a stove at
65.degree. C. for 15 minutes. Once cooled, the stent 1 is released
from the mask 22 and slid out of the support 16.
[0159] It will be appreciated that this technique lends itself to
repetition with different masks and different substances, so as to
fill different recesses with different drugs. Specifically, the
process of Example 4 seen previously can be conveniently
implemented, as follows: (i) applying on the stent 1 a first mask
22 with first openings 24 that leave uncovered first regions or
recesses 12 of the stent 1; (ii) exposing the stent 1, with the
first mask applied thereto, to the bed of active substance M, so
that the active substance M will coat the mask 22 and the first
regions 12 left uncovered by the openings 24 of the first mask 22;
(iii) removing the first mask 22 from the stent 1, which is covered
with the active substance in areas corresponding to the (first)
regions or recesses 12 seen previously; (iv) applying on the stent
1 a second mask 22 with second openings 24, which leave uncovered
second regions 12 of the stent (these may coincide at least in part
with the regions 12 already coated); (v) exposing the stent 1, with
the second mask applied thereto, to a bed of further active
substance M (usually different from the one seen previously), so
that said further active substance will coat the second mask 22 and
the second regions or recesses 12 left uncovered by the openings 24
of the second mask 22; and (vi) removing the second mask 22 from
the stent 1, which has thus been loaded with different substances
in regions that are different or coincide with one another,
according to the needs.
[0160] Examples 3 and 4 described previously are suited to being
implemented with a bed or mat of substance M in the form of powder
and not in the form of paste.
Example 5
[0161] Finally, FIG. 12 refers to the possibility of applying
selectively only inside the recesses 12, respective masses 14 of
material in the form of paste. This is achieved by means of a
dispensing nozzle 25 which may be brought into a position facing
the recesses 12, then imparting on the recess 12 each time involved
and on the nozzle 25 a relative movement that leads the nozzle to
"scan" the recess 12, depositing inside it the substance M. This
solution may be achieved with a high degree of precision by
resorting to a numerical control machine for controlling the
relative movement (usually of translation and rotation) of the
support 16 that carries the stent 1 and of the dispensing nozzle
25.
[0162] The unexpected aspect of this solution, which is apparently
very simple, lies in the fact that, contrary to the reasonable
expectation of the sector, the pure and simple deposition of the
substance M in the form of paste, followed by a treatment of
stabilization conducted according to the criteria described
previously (and, in a preferred way, by the subsequent contraction
of the stent, treated in a radially expanded condition, into a
radially contracted condition required, for example, for mounting
on the balloon of an insertion catheter), is sufficient to ensure
the firm retention of the masses 14 inside the recesses 12. This
retention occurs without any risk of dispersion, for example, in
the steps of packaging, transportation, manipulation and insertion
of the stent in the implantation site.
[0163] From the foregoing, it clearly emerges that the individual
steps of treatment set forth with reference to the examples seen
previously are freely transposable from one context of application
to another among the ones previously considered. Furthermore, it is
evident that the examples documented above do not exhaust the range
of application, nor the variants of embodiment of the solution here
described. This applies in particular to the treatments of
stabilization which, as has already been mentioned previously, may
envisage operations such as: (i) exposure to temperature or to
thermal cycles; (ii) dipping in solvent for controlled lengths of
time; (iii) exposure to solvent spray; (iv) exposure to solvent
vapors; (v) selective treatment with laser beam (exposure of the
recesses to laser beams); (vi) selective or integral application of
a protective adhesive coating (in the form of a plug for closing
the recesses); and (vii) lyophilization.
[0164] It will likewise be appreciated that the final result
achieved is the location of the active substance M on the surface
of the stent 1, in a position directly exposed to the outside, even
though usually at least slightly set back in the recesses 12,
without the need for providing coatings or sheaths of any sort on
the surface of the stent. The surface of the stent thus remains
free, with the coating of biocompatible carbon material preferably
provided thereon, with consequent beneficial effects both in the
implantation site of the stent, and in the steps subsequent to
implantation.
[0165] Consequently, without prejudice to the principle of the
invention, the details of implementation and embodiments may vary
with respect to what is described and illustrated herein, without
thereby departing from the scope of the present invention.
* * * * *