U.S. patent application number 10/060146 was filed with the patent office on 2002-08-15 for device for local administration of solid or semi-solid formulations and delayed-release formulations for proposal parental administration and preparation process.
This patent application is currently assigned to SOCIETE DE CONSEILS DE RECHERCHES ET D'APPLICATION. Invention is credited to Cheikh, Roland Cherif.
Application Number | 20020111603 10/060146 |
Document ID | / |
Family ID | 26233135 |
Filed Date | 2002-08-15 |
United States Patent
Application |
20020111603 |
Kind Code |
A1 |
Cheikh, Roland Cherif |
August 15, 2002 |
Device for local administration of solid or semi-solid formulations
and delayed-release formulations for proposal parental
administration and preparation process
Abstract
A method for implanting or inserting a solid or semisolid
formulation containing at least one active principle uses a device
comprising one part set inside the body of the patient and which
conditions the solid or semisolid form, brings these conditioning
action to the deposit site, injects or inserts in this deposit
site, and withdraws after injection or insertion, with one part
remaining outside and activating the functions of the device. The
invention also concerns a sustained-release solid formulation for
parenteral administration comprising a homogeneous mixture of an
active principle in non-dispersed state and of a biologically
compatible and biodegradable excipient, in which the amount of
active principle is at least 50% by weight.
Inventors: |
Cheikh, Roland Cherif; (Issy
Les Moulineaux, FR) |
Correspondence
Address: |
YOUNG & THOMPSON
745 SOUTH 23RD STREET 2ND FLOOR
ARLINGTON
VA
22202
|
Assignee: |
SOCIETE DE CONSEILS DE RECHERCHES
ET D'APPLICATION
51/53 Rue Du Docteur Blanche
PARIS
FR
75016
|
Family ID: |
26233135 |
Appl. No.: |
10/060146 |
Filed: |
February 1, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10060146 |
Feb 1, 2002 |
|
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|
09319159 |
Jul 21, 1999 |
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Current U.S.
Class: |
604/891.1 ;
424/422 |
Current CPC
Class: |
A61M 37/0069 20130101;
A61K 38/09 20130101; A23L 33/40 20160801; A61D 7/00 20130101; A61M
25/0084 20130101; A61K 9/0024 20130101; A61K 38/31 20130101 |
Class at
Publication: |
604/891.1 ;
424/422 |
International
Class: |
A61F 013/00; A61K
009/22 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 2, 1996 |
FR |
96/14755 |
Claims
1. Use, for the implantation or insertion of a solid (1, 9) or
semi-solid (18) formulation, intended to be placed in a precise
depot site (T) of a body, containing at least one active principle,
the said formulation being of solid or semi-solid consistency such
that it is able to persist for a certain period in the site, and
containing a limited dose of active principle for a treatment in a
targeted zone of the body, of a device comprising a part placed
inside the body of the patient with means of packaging of the solid
or semi-solid form, means of positioning allowing these means of
packaging to be led to the site of deposition, means of injection
or of insertion at this depot site, and means of withdrawal after
injection or insertion, and a part left outside with means of
operation of the functions of the device.
2. Use according to claim 1, characterized in that the said means
of packaging of the solid or semi-solid form are placed from the
outset at the end of the device intended to be led to the site of
deposition.
3. Use according to one of claims 1 and 2, characterized in that
the said means of packaging are arranged to allow the solid or
semi-solid formulation to have a thin and elongated, especially
cylindrical, form.
4. Use according to claim 3, in which the said form of the
formulation is approximately cylindrical, characterized in that the
diameter of the means of packaging is such that the form of the
formulation has a diameter of between 0.1 and 2 to 3
millimetres.
5. Use according to claim 4, characterized in that the said means
of packaging are arranged to allow the solid or semi-solid
formulation to have a minimum length/diameter ratio of 10.
6. Use according to one of claims 1 to 5, characterized in that the
means of packaging of the solid or semi-solid forms are also the
means of positioning and of injection.
7. Use according to one of claims 3 to 6, characterized in that the
said device comprises a piston (14) inside a needle (13) which can
be operated in a trocar (9) and/or a catheter (12).
8. Use according to one of claims 3 to 6, characterized in that the
means of conditioning, positioning and injection comprises a needle
(13).
9. Use according to claim 8, characterized in that the said needle
(13), once operated, can be orientated with respect to the device
by elastic preshaping or preconstraint or by mechanical means.
10. Use according to claim 8, characterized in that the external
means of operation of the device allow, in a sequential fashion,
the injection of the needle (13), the advancement of the piston
(14) as far as the bevel (13b) of the needle, to deposit the solid
or semi-solid form, the withdrawal of the needle around the piston
(14) and the combined withdrawal of the needle and of the
piston.
11. Use according to claim 10, characterized in that the sequential
operations of the device starting from external means are
controlled remotely and in order with the aid of two movable stops
of which the first (10) is arranged on a push button (20) coaxial
to the piston (14), and the second (15) is a tubular piece inserted
between the guide (12) and the push button (20).
12. Formulation intended to be placed in a precise site of
deposition in a body, containing at least one active principle, the
said formulation being of solid or semi-solid consistency such that
it is able to persist for a certain period in the site, and
containing a limited dose of active principle for a treatment in a
targeted zone of the body, and having a form making it capable of
being placed by a device according to one of claims 1 to 11.
13. Formulation according to claim 12, characterized in that it is
a delayed-release formulation.
14. Formulation according to one of claims 12 and 13, characterized
in that it contains a low dose of active principle with respect to
the customary dose, for a treatment by the systemic route, of the
active principle considered.
15. Formulation according to one of claims 12 to 14, characterized
in that it has a thin and elongated, especially cylindrical,
form.
16. Formulation according to claim 15, characterized in that it has
a diameter of between 0.1 and 2 to 3 mm.
17. Formulation according to one of claims 15 and 16, characterized
in that the form has a minimum length/diameter ratio of 10.
18. Formulation according to one of claims 12 to 17, of solid
nature, capable of being deformed by being preconstrained in a
device according to one of claims 1 to 11 to regain its shape in
situ.
19. Formulation according to one of claims 12 to 18, characterized
in that it is arranged in order that the release of the active
principle takes place in an anatomical cavity into which it has
been introduced.
20. Formulation according to claim 19, characterized in that it has
a form designed to be able to be imprisoned in an anatomical cavity
of the body while avoiding the displacement or the elimination of
the formulation.
21. Formulation according to claim 20, characterized in that it is
preconstrained in the said means of packaging and regains a
non-rectinilear shape once placed in its depot site.
22. Formulation according to claim 20, in which the length and the
diameter of the formulation are arranged to avoid its elimination
or its displacement.
23. Formulation according to one of claims 12 to 22, characterized
in that the said formulation and the active principle which it
contains are arranged in order that the release of the active
principle takes place in the secretions of a mucous membrane.
24. Formulation according to one of claims 19 to 23, in which the
said cavity or mucous membrane is a cavity or mucous membrane of
the facial or ORL sphere.
25. Formulation according to claim 23, in which the said mucous
membrane is a tracheopulmonary mucous membrane.
26. Formulation according to claim 23, in which the said mucous
membrane is the buco-oesophageal mucous membrane.
27. Formulation according to one of claims 23 to 26, in which the
said formulation is arranged in order to be placed on the surface
of the said mucous membrane such that the active principle is
transported by the mucus.
28. Formulation according to one of claims 23 to 26, in which the
said formulation is arranged to be placed inside the mucous
membrane.
29. Formulation according to claim 28, characterized in that the
said formulation and the active principle which it contains are
arranged for injection into the sub-palpebral mucous membrane.
30. Formulation according to one of claims 19 to 29, characterized
in that it comprises a corticoid suited to the treatment, in a
cavity, cavity wall or mucous membrane, of naso-sinusoid polyposis,
of allergic or non-allergic rhinitis, of types of non-infectious
otitis or sinusitis, by introduction into the maxillary, phenoidal
or frontal sinus, the nasal mucous membrane, the ethmoidal cells or
the cavum tympani.
31. Formulation according to one of claims 12 to 18, characterized
in that the said formulation and the active principle which it
contains are arranged for introduction into or around the vascular
wall by intra- or transluminal injection.
32. Formulation according to claim 31, which can be used especially
after transluminal percutaneous angioplasty, comprising an active
principle for the prevention or the treatment of restenosis.
33. Formulation according to claim 32, containing angiopeptin on
its own or combined with another active principle, especially
heparin.
34. Formulation according to one of claims 12 to 18, characterized
in that the said formulation and the active principle which it
contains are arranged to be introduced into or under a tumour
tissue for an antitumour action.
35. Formulation according to claim 34, in which the active
principle comprises a photosensitive product.
36. Formulation according to one of claims 12 to 18, characterized
in that the said formulation and the active principle which it
contains are arranged for an intra- or peri-articular
injection.
37. Formulation according to one of claims 12 to 37, characterized
in that it contains an anti-inflammatory active principle.
38. Formulation according to one of claims 12 to 36, characterized
in that it contains a high concentration of active principle of
between 20 and 100%.
39. Formulation according to claim 38, characterized by a
concentration of active principle of between 40 and 100%.
40. Formulation according to claim 39, characterized by a
concentration of active principle of between 50 and 100%.
41. Delayed-release formulation according to one of claims 12 to
40, characterized in that the active principle is combined with a
polylactide-glycolide (PLGA) copolymer excipient.
42. Solid formulation according to claim 41, produced in implant
form.
43. Formulation according to one of claims 12 to 42, characterized
in that it contains an active principle of peptide or protein
nature.
44. Solid delayed-release formulation, intended to be placed in a
body, containing at least one active principle and a biodegradable
excipient, characterized in that the excipient is a
polylactide-glycolide (PLGA) copolymer, and in that the
concentration of active principle is between 40 and 100%.
45. Delayed-release formulation according to claim 44,
characterized in that the concentration of active principle is
between 50 and 100%.
46. Delayed-release formulation according to one of claims 44 and
45, characterized in that it has a thin and elongated form with a
diameter not exceeding 3 mm.
47. Delayed-release formulation according to claim 46,
characterized by a diameter not exceeding 2 mm.
48. Delayed-release formulation according to claim 46,
characterized by a diameter of the order of 0.1 mm.
49. Delayed-release formulation according to one of claims 44 to
48, characterized by a minimum length/diameter ratio of 10.
50. Delayed-release formulation according to one of claims 44 to
49, characterized in that it contains an active principle of
peptide or protein nature.
51. Assembly for the implantation and insertion of a solid (1, 9)
or semi-solid (18) formulation containing an active principle,
according to one of claims 12 to 50, in a precise depot site of the
body, characterized in that it comprises a device defined in any
one of claims 1 to 11 and, in the said device, a formulation (1, 9,
18) to be delivered, contained in the said means of packaging.
52. Assembly according to claim 51, characterized in that it is
arranged to be inserted inside a trocar.
53. Assembly according to claim 51, characterized in that it is
arranged to be inserted inside a catheter.
54. Assembly according to claim 51, characterized in that it is
arranged to be inserted inside an endoscope.
55. Assembly according to claim 51, characterized in that it is
arranged to be inserted inside a instrument adapted for a surgical
route of approach.
56. Use of an active principle for the production of a formulation
according to any one of claims 12 to 50.
57. Solid delayed-release formulation for parenteral administration
comprising a homogeneous mixture of an active principle in the
non-dispersed state forming a continuous phase of which at least
one part is in direct contact with the exchange surface of the
formulation and of the exterior biological medium, and of a
biodegradable biocompatible excipient, in which the quantity of
active principle is at least 50% by weight with respect to the
total weight of the formulation, and having a release profile which
is independent of the composition of the excipient, of the
molecular weight of the excipient or of the active
principle/excipient weight ratio, the release profile being
essentially exclusively dependent on the total quantity of active
principle present in the formulation.
58. Delayed-release formulation according to claim 57,
characterized in that the biodegradable biocompatible excipient is
a polymer or copolymer of lactic and/or glycolic acid or a mixture
of polymers and/or copolymers of lactic and/or glycolic acid.
59. Delayed-release formulation according to claim 58,
characterized in that the said biodegradable biocompatible polymer
is a copolymer of lactic acid and glycolic acid (PLGA).
60. Delayed-release formulation according to any one of claims 57
to 59, characterized in that the said biodegradable biocompatible
polymer is a copolymer of lactic and glycolic acid having an
intrinsic viscosity in chloroform at 1 g per 100 ml of greater than
0.6 dl/g.
61. Delayed-release formulation according to claim 59 or claim 60,
characterized in that the copolymer of lactic acid and glycolic
acid is of hydrophilic nature.
62. Delayed-release formulation according to one of claims 57 to
60, characterized in that, when it is placed in vitro in a
physiological liquid medium, it liberates almost the whole of the
active principle in less than a week, and, when it is placed in
vivo subcutaneously or intramuscularly, has a release of active
principle over a period substantially greater than one week.
63. Delayed-release formulation according to one of claims 57 to
62, characterized in that it comprises a mixture of the active
principle and the excipient which is homogeneous at all points.
64. Delayed-release formulation according to any one of claims 57
to 63, characterized in that the release takes place in a single
diffusion phase of the active principle.
65. Delayed-release formulation according to any one of claims 57
to 64, characterized in that the active principle represents at
least 51%, advantageously at least 60%, preferably at least 70% and
up to 99.999% by weight with respect to the total weight of the
formulation, the excipient representing less than 50%, preferably
less than 49%, and more advantageously less than 30% by weight with
respect to the total weight of the formulation.
66. Delayed-release formulation according to any one of claims 57
to 65, characterized in that the active principle is a peptide, a
peptide analogue or a protein, especially LHRH or an analogue of
LHRH, especially Triptoreline.
67. Delayed-release formulation according to any one of claims 57
to 66, characterized in that it is in cylindrical form and has a
diameter less than or equal to 3 mm, preferably less than 1 mm.
68. Delayed-release formulation according to any one of claims 57
to 67 for injection by the intramuscular or subcutaneous route.
69. Delayed-release formulation according to any one of claims 57
to 68, characterized in that it is in the form of an implant.
70. Use of a delayed-release formulation according to any one of
claims 57 to 69 for the preparation of a medicament intended for a
parenteral injection in dry form.
71. Process for preparation of a delayed-release formulation
according to any one of claims 57 to 69, comprising the steps
consisting in: producing a homogeneous mixture of the active
principle and the excipient, containing at least 50% of active
principle; compacting the said mixture; and extruding the said
compacted mixture in the molten state.
72. Process for preparation of a formulation according to any one
of claims 12 to 50 and 57 to 69, comprising the steps consisting
in: producing a homogeneous mixture of the active principle and the
excipient, containing at least 50% of active principle; subjecting
the homogeneous mixture to a high compression; grinding the
compressed articles obtained; and putting into a form suitable for
administration.
Description
[0001] The present invention relates to a therapeutic process for
allowing the targeted treatment of non-liquid pharmaceutical
formulations as well as the preparation and the device designed for
carrying out the process.
[0002] The advantages of the use of a local treatment or
administration when the active principle (AP) is in this way
preferentially directed towards its site of action are known. It is
proved, on the other hand, that oral or parenteral administration
of a medicament and its systemic diffusion can, in certain cases,
not give a satisfactory result. In addition, even in the case where
a general or systemic treatment is aimed at, especially in the case
of delayed-release formulations, it is of interest to insert the
formulation into a suitable site.
[0003] Apart from the improvements in the local efficacy, the local
treatment with respect to a general treatment above all allows the
doses and the secondary effects, especially linked to the AP, to be
decreased in the sites of the body where its presence is either
useless or harmful.
[0004] The local administration of a medicament thus allows the
therapeutic index of the product to be improved while decreasing,
if need be, its general toxicity and the risk of systemic
effects.
[0005] The cutaneous, ocular, naso-sinusal, pulmonary or even
gastric or rectal topical forms were the first non-parenteral forms
to use local administration. When the depot site of the formulation
is accessible with relative difficulty or necessitates an invasive
form and when the treatment must be repeated, or even more,
chronic, even if the advantage of targeting is known, in practice
its use comes up against the difficulty or even the discomfort of a
repeated therapeutic action.
[0006] On the other hand, the advantages of the use of a
sustained-release or delayed-release formulation which allows, in a
single administration, the sick person to be given his/her
medicament for several days, several weeks or several months, is
known.
[0007] This delayed-release form improves compliance when the
observance of the treatment does not depend on the sick person or
the care personnel but on the preparation. This sustained-release
in fact thus improves the comfort of the patient who is no longer
constrained by his/her treatment and who thus continuously receives
a regular and non-variable dose as a function of taking the
medication.
[0008] The development of delayed-release forms has led the
specialists to consider their local use, especially in the case
mentioned above where the depot site is accessible with relative
difficulty. The delayed-release form thus avoids having to repeat
the administrations or, even more, surgery. In this way, it is
possible to hope for significant local concentrations of medicament
over a prolonged period without significant systemic doses, thus
with fewer secondary effects. This solution is more particularly
useful for products which are rapidly metabolized or have a short
half-life when they are administered by the systemic route.
[0009] Inside the body, targeted and prolonged treatments such as
intra- or peri-articular injections of delayed-released corticoids
are thus envisaged. Cancers and especially solid tumours are
candidates of choice for these local forms which allow the total
injected doses of cytotoxic or antineoplastic compound to be
decreased, whilst increasing the concentration in the tumour zone
to be treated. This is thus capable of avoiding the serious
secondary effects of this type of treatment.
[0010] Matrix Pharmaceutical proposes a delayed-release preparation
based on collagen which will be able to be injected intra-tumorally
(IntraDose CDDP-Cisplatin). This formulation is administered in
cancers or cutaneous lesions with the aid of a 3 cc syringe and
possibly a biopsy needle for the less accessible zones. In a
viscous liquid volume which can reach 2 ml, it is thus limited to
the initially relatively easy (peripheral) sites or to
post-surgical treatments.
[0011] It is also possible to mention the MITSUI Patent (FR 2 497
661; JP 562 737) which describes a small rod or needle
polylactide-polyglycolide (PLGA) form for local activity, allowing
its direct implantation into a zone or an organ inside the body,
and, for example, a tumour zone before or after exeresis.
[0012] The Gliadel form (Guildford) for its part describes a
formulation based on polyanhydride in host form containing
carmustine and which can, for example, be deposited at the time of
surgery on a cerebral tumour (glioblastoma).
[0013] In the present state of medical technology, these targeted
treatments inside the body are more often linked to serious
surgical operations. They benefit from the prolonged effect of the
formulation but cannot be easily repeated.
[0014] Chemo-embolization operations are also carried out which
consist in injecting, into vessels, suspensions (microspheres),
gels or glues with their solvent, which will be able to obstruct a
nutrient vascular tract and liberate an AP in a tumour. The
occlusion is obtained by deposition-after the injection vehicle has
left. This technique uses transluminal percutaneous angioplasty
catheters to introduce the fluid into the vessel.
[0015] The local use of delayed-release forms is also envisaged in
certain body cavities and in more accessible sites of the body.
[0016] The .RTM.Ocusert system (Alza) is a flexible and oval ocular
insert which forms a delayed-release reservoir device comprising an
ethylene/vinyl acetate copolymer membrane and which can contain,
for example, pilocarpine.
[0017] This device is placed in the conjunctival sac and liberates
its product according to a zero-order profile. The delayed-release
form allows the dose necessary for the same effect on the
intraocular pressure to be decreased significantly. The therapeutic
efficacy of pilocarpine in the treatment of glaucoma is thus 8 to
10 times better owing to the use of a delayed-release form compared
with local drops.
[0018] U.S. Pat. No. 3,545,439 whose contents are incorporated by
reference describes an intravaginal delayed-release form formed of
a ring made using a silicone elastomer and which liberates a
medicament for several weeks.
[0019] In this case, the local delayed-release administration on
the vaginal mucous membrane also allows, according to the AP, a
general effect (contraception) to be obtained.
[0020] The medical device described by Bukh Meditee (International
Patent Application PCT No. WO 89/03232 whose contents are
incorporated by reference) allows the introduction into a body
cavity of a matrix delayed-release form made of a substance which
is poorly penetrable by water and containing an AP
[0021] The delayed-release form combined with the device thus
delivers the AP at the local level and during the period of the
insertion of the said device. It describes, for example, a catheter
for the urethra opening into the bladder combined with an
antibiotic delayed-release form capable of preventing infections of
the urinary tracts.
[0022] For large-volume liquid forms, certain existing processes of
local injection could be used. Starting from intraurethral
techniques, C.R. BARD, for example, has developed a formulation
(Transurethral delivery Kit) which is a syringe containing a
solution of collagen in glutaraldehyde which can be easily injected
submucosally in volumes of 2.5 to 7.5 ml which form implants
without active principle in the context of plastic surgery against
incontinence.
[0023] The development of intraluminal vascular systems has led to
the production of catheters allowing an AP to be liberated locally
at their end. Contrary to the catheter which is simply open for
liberating fluid, local administration can be obtained with a
double-balloon or porous catheter with multiple perforations. This
local solution, however, is limited by the time of insertion of the
catheter. The pressure of the solution necessary to penetrate the
wall also poses a tolerance problem.
[0024] For liquid solutions, a true local injection can be obtained
in the wall with the aid of an injection system combined with a
balloon (Interventional Technologies) or a catheter with a
retractable needle (Bavarian Medical Technologies). The
administration of the medicament, however, is not prolonged much
with these immediate liquid forms.
[0025] A part of the device can sometimes be left locally and thus
be associated with a delayed-release form. This is the case of the
"stents" used, for example, in angioplasty to avoid restenosis,
which can be covered by a layer containing an active principle,
sometimes with a delayed-release effect. Two essential problems are
then posed, the first is the suitability of the released medicament
for the specific process of "coating". The second is the limitation
of the total dose by the space and the surface offered by the
stent.
[0026] With heparin, for example, certain studies mention the
significance of local treatment to avoid the systemic secondary
effects. According to these studies, heparin inhibits the
proliferation of smooth muscle cells after endothelial damage. Its
systemic administration, in adjacent subcutaneous or local
delayed-release form external to the vessel, always leads to a
decrease in the neointimal proliferation but the local form is the
only one not to involve systemic perturbations of coagulation.
[0027] It would even be possible to cite osmotic pumps which are
used to validate prolonged local administrations with, as a major
disadvantage, their surgical implantation. For this reason, they
are not presently used in man.
[0028] All these examples indeed show the interest and the
advantages brought by a targeted treatment, above all if it can be
prolonged.
[0029] These technical solutions, however, all have certain
disadvantages amongst which the most important are the lack of
versatility of the solution retained, the association with a
specific device which remains totally or partially inserted over
the period of release of the medicament and, finally, the limits
of. the injectable volume, thus, of the dose of AP
[0030] Each of these solutions allows only one or several
particular cases in a well-defined site of the body to be
treated.
[0031] Vectorization by local administration is sometimes described
as first generation with respect to the "prodrug" and vector
(liposomes . . . ) formulations called second generation or to
macromolecular recognition systems or "site-specific" activation
called third-generation. These solutions, even more than the
present local administration techniques, however, are very
specific, not always applicable and sometimes not very precise.
[0032] The aim of the invention is to propose a process solving the
present major disadvantages of local administration or
vectorization by flexible endoscopic surgical techniques
(fibroscopy) or rigid endoscopic surgical techniques (endoscopy)
and of interventional radiology (active or non-active
catheter).
[0033] The non-dispersed solid and semi-solid formulations have the
advantage of offering a minimal volume for a quantity of AP
corresponding to a treatment dose. The solid and semi-solid
delayed-release forms can thus allow several days of treatment in a
volume of a few microlitres.
[0034] The local administration of a treatment allows the total
therapeutic dose for the same effect to be decreased
significantly.
[0035] The combination of a solid or semi-solid delayed-release
form and of a local administration thus leads to the production of
micro-dosages particularly adapted to local deposition at spaced
intervals of time.
[0036] The present development of imaging, optical and
micro-mechanical techniques applied to medicine in the field of
intravascular or cavitary instrumentation and of minimally invasive
surgery has led to the design of more and more fine and more and
more precise tools allowing very deep local intervention in the
body with minimal trauma and thus of multiplying the accessible
sites.
[0037] The invention thus proposes a process, a device and a
formulation suited to the progress and to the miniaturization of
pharmaceutical and medical technologies.
[0038] The process aimed at by the invention for the implantation
or the insertion of an active principle contained in a solid or
semi-solid formulation in a precise administration site of the body
is characterized in that it consists in obtaining the solid or
semi-solid formulation, in loading this formulation into a device
which can be operated outside the body, in bringing the said device
to the said depot site inside conventional tools of intervention at
this level, and in inserting or implanting the said formulation by
operating the said device.
[0039] According to other features of the invention:
[0040] the said depot site is not accessible with a syringe or a
conventional hypodermic trocar,
[0041] the said solid or semi-solid formulation has a thin and
elongated shape once filled into the said device,
[0042] the said device is thin and elongated to be able to move in
the said conventional tools of intervention,
[0043] the said solid or semi-solid formulation is a
delayed-release formulation,
[0044] the said thin and elongated shape gives a minimum length to
diameter ratio of 10,
[0045] the said device is that containing the said formulation
exactly fitted to the said shape,
[0046] the said shape and the said device are cylindrical,
[0047] the said implantation takes place in a tissue, in a mucous
membrane or an internal wall of the body by the cavitary route,
[0048] the said implantation takes place in a tissue, in a mucous
membrane or an internal wall of the body by the vascular, arterial
or venous route,
[0049] the said implantation takes place in a tissue, in a tumour
or a pathogenic zone by the surgical route,
[0050] the said insertion takes place in a body cavity or in an
organ by the cavitary route,
[0051] the said insertion takes place in a body cavity or in an
organ or a tissue by the invasive or surgical route,
[0052] the said active principle is an anti-inflammatory,
[0053] the said active principle is a peptide or a peptide
analogue,
[0054] the said active principle is an anticancer product,
[0055] the said active principle is a mixture of 2 or more active
principles.
[0056] The invention also relates to:
[0057] the said device is thin and elongated to be able to move in
the said conventional tools of intervention,
[0058] the said solid or semi-solid formulation is a
delayed-release formulation,
[0059] the said thin and elongated shape gives a minimum length to
diameter ratio of 10,
[0060] the said device is that containing the said formulation
exactly fitted to the said shape,
[0061] the said shape and the said device are cylindrical,
[0062] the said implantation takes place in a tissue, in a mucous
membrane or an internal wall of the body by the cavitary route,
[0063] the said implantation takes place in a tissue, in a mucous
membrane or an internal wall of the body by the vascular, arterial
or venous route,
[0064] the said implantation takes place in a tissue, in a tumour
or a pathogenic zone by the surgical route,
[0065] the said insertion takes place in a body cavity or in an
organ by the cavitary route,
[0066] the said insertion takes place in a body cavity or in an
organ or a tissue by the invasive or surgical route,
[0067] the said active principle is an anti-inflammatory,
[0068] the said active principle is a peptide or a peptide
analogue,
[0069] the said active principle is an anticancer product,
[0070] the said active principle is a mixture of 2 or more active
principles.
[0071] The invention also relates to:
[0072] a method of therapeutic treatment in which an active
principle in a solid or semi-solid formulation is inserted into a
body cavity so that the active principle is liberated in the fluids
at the surface of the said cavity and should be able to act locally
towards the sites of drainage of the said body fluids,
[0073] a method of therapeutic treatment in which an active
principle in a solid or semi-solid formulation is implanted into a
mucous membrane or an internal secretory tissue of the body such
that the said active principle is liberated and excreted with the
natural fluids and should be able to act locally or towards the
sites of drainage,
[0074] a method of treatment in which the said active principle has
a local and/or systemic action from the administration site of the
implant,
[0075] a method of therapeutic treatment of ORL pathologies in
which the active principle in a solid or semi-solid formulation is
introduced into a cavity of the face or into the mucous membrane
which covers it,
[0076] a method of therapeutic treatment in which the said active
principle is a corticoid,
[0077] a method of therapeutic treatment of conditions or vascular,
venous or arterial treatments in which the active principle in the
solid or semi-solid formulation is introduced into, or around, the
vascular wall by intraluminal injection.
[0078] The pharmaceutical and medical aspects of the invention join
in the search for a fine and miniaturized system which can be
easily positioned and operated in any of the zones of the body from
transluminal percutaneous angioplasty catheters, endoscopes or any
other invasive device which is sufficiently thin and long to reach
the zone of administration. The shape (thin and long) of the
formulation in the administration device facilitates its local
administration. This characteristic of the system under its
pharmaceutical and medical aspect will allow its general use.
[0079] If insertion is understood as meaning a form deposited in
the surface and by implantation or an injection into a tissue, the
targeted, even prolonged, treatment will be able to be inserted
inside a natural cavity of the body if this is capable of acting as
a natural reservoir, that is to say if the form of the
administration of medicament allows it to stay in the body cavity
at least over the time of its release. It will be possible for this
form to be the elongated form studied to facilitate its deposition
with the device, or its production once deposited.
[0080] The shape of the device and of the formulation is thus not
adapted a priori to the zone of insertion as the Ocusert, vaginal
ring or the stents can be. The shape of the formulation, however,
can develop after administration to facilitate its local
maintenance. After its administration, the formulation is not
combined with all or part of the deposition device but left on its
own at the depot site.
[0081] If, for a specific need and therapeutic period, insertion
into a natural cavity of the body is not desirable, the targeted,
or even prolonged, treatment will also be able to be implanted
inside a target tissue of the body to allow its administration over
the release period.
[0082] It will be possible to carry out this implantation with the
device combined with conventional tools, by the transcutaneous
route or by the vascular or cavitary route in a mucous membrane or
a wall of the body or by the surgical route in a target tissue.
[0083] The insertion of the delayed-release form will allow a
local, superficial or external treatment, but also targeting for a
deep effect, or even for a systemic effect, for example with a
deposition to the mucous membranes.
[0084] In the same way, the implantation of the delayed-release
form will allow general treatment but also targeted treatment by
local hyperconcentration or by excretion.
[0085] Thus, according to the therapeutic applications and the
zone, insertion, like implantation, will be able to be a systemic
solution, an internal local solution or, finally, an external
targeting solution.
[0086] It will be possible for the immediate or delayed-release
solid or semi-solid formulations used in the process of the
invention to be any solid or semi-solid formulations whatsoever
capable of being able to be made or packaged in the form and the
volume compatible with the process and the injection device.
[0087] Thus, it will be possible for the solid or semi-solid
formulations preferentially to be formulations produced from
biodegradable excipients such as, for example, inorganic salts
(calcium, magnesium, bismuth, zinc); lipids; carbohydrates
(polysaccharides, sucrose, glucose, agarose, dextrin, cyclodextrin
and mixtures); proteins (gelatin, modified collagen, albumin,
casein, derivatives and mixtures); natural and synthetic polymers
(polyisobutyric acid, polylactic acid, polyglycolic acid,
polylactide-polyglycolide copolymer (PLGA), polyester,
polycaprolactam, polyethylene glycol, polypropylene glycol,
.RTM.Pluronics, polyanhydrides and their mixtures).
[0088] It will be possible to produce the solid or semi-solid
formulations without excipient or structured with small quantities
of injectable excipient of manitol, hyaluronic acid, cellulose
derivatives type etc.
[0089] It will be possible to produce the semi-solid formulations
by mixing the AP with or without excipient, with water, an organic
solvent, oil or any other injectable liquid capable of giving the
semi-solid form.
[0090] The solid or semi-solid formulations will be either
immediate formulations or delayed-release formulations.
[0091] It will be possible to produce the solid immediate
formulations as indicated in the SCRAS patent (Delivery of Solid
Drug Compositions WO 96/07397). It may be possible to produce the
delayed-release semi-solid and solid formulations according to the
formulation and the process claimed by the SCRAS patent (Sustained
Release of Peptides from Solid and Semi-solid pharmaceutical
compositions WO 96/07398 whose contents are incorporated by
reference).
[0092] The solid or semi-solid formulations will advantageously be
produced according to processes allowing a high concentration of
active principle of greater than 20% or even greater than 40%,
preferably of greater than 50% and up to 100% of AP
[0093] Before their deposition, the non-dispersed solid
formulations according to the invention will have a thin and
elongated shape: rod, implant, pellet, stick or needle, so as to be
able to be introduced inside the implantation device which will
itself be able, if necessary as a function of the depth of the
injection into the body, to be inside an endoscope or a catheter.
The dispersed solid formulations (powders, spheres) will have to be
able to be arranged longitudinally in the device.
[0094] The solid formulations in the device will thus
preferentially have a maximum diameter of 3 mm and advantageously a
diameter of less than 2.5 mm or even a diameter of less than 2 mm,
preferably of less than 1 mm. As a function of the total dose and
above all for the immediate forms or the short-duration or low-dose
forms (less than 0.1 mg/day), it will be possible for the diameter
of the solid forms to be even smaller and down to 0.1 mm.
[0095] It will be possible for the smallest diameters, in certain
cases, to have a technical advantage to facilitate deep local
implantation; however, with catheters and endoscopes, a greater
diameter will not have the same disadvantages (especially in terms
of comfort of the sick person) as in the case of trocar-type
superficial injections (Zoladex, trademark registered by Zeneca) or
mini-trocars (Auto-injector, Retro-injector Needle-less Parenteral
Introduction Device WO 96/08289 whose contents are incorporated by
reference) or because the use of medical devices necessitates, in
addition, local or general anaesthesia, or alternatively because
the deep implantation zone is less sensitive than the skin.
[0096] It will be possible for the solid forms to have a length of
a few centimetres, in general of less than 3 cm and preferentially
of less than 2 cm and suited to the space in the depot zone.
[0097] The solid forms will preferentially be cylindrical and
obtained by extrusion techniques.
[0098] The semi-solid forms according to the invention will have a
sufficiently high viscosity to contain a high concentration of AP
(preferentially greater than 20%) and to remain homogeneous while
allowing deep injections through the needle of the device of the
invention.
[0099] It will be possible for the semi-solid forms to be gels,
oils, pastes or any other semi-solid dispersion of an AP in a
liquid vehicle.
[0100] The semi-solid forms will have a low total volume, in
general of less than 300 .mu.l and preferentially of less than 100
.mu.l or even less than 50 .mu.l.
[0101] The process and the devices according to the invention will
preferentially use injectable excipients which are biodegradable or
normally eliminated or solubilized in the body fluids.
[0102] However, it will be possible for the process to use devices
or formulations based on non-biodegradable biocompatible
biomaterials when the site and the deposition tools will easily
allow the withdrawal of the said device or of the said formulation
after its action, that is to say rather for inserts than for
implants. The device or the formulation will have to have a thin
and elongated shape, like the other solid forms compatible with
deep local administration like, for example, Norplant silicone
implants, PHEMA reservoir systems from Hydromed, or even Duros
osmotic pumps from Alza.
[0103] The devices according to the invention correspond to the
solid or semi-solid formulations combined with the localized deep
insertion or implantation device.
[0104] The device according to the invention for the implantation
or the insertion of an active principle in a solid or semi-solid
formulation into a precise administration site of the body is
characterized in that it comprises a part placed inside the body of
the patient with means of packaging of the solid or semi-solid
form, means of positioning to the depot site, means of injection or
of insertion at this depot site and means of withdrawal after
injection or insertion, and a part left outside with means of
operation of the functions of the device.
[0105] According to other characteristics:
[0106] the means of packaging of the solid or semi-solid forms are
also the means of positioning and of injection,
[0107] the said device comprises a piston inside a guide which can
be operated in a trocar or a catheter,
[0108] the means of packaging, positioning and injection is a
needle,
[0109] the said needle once operated can be orientated with respect
to the device by elastic preshaping or preconstraint or by
mechanical means,
[0110] the external means of operation of the device allow, in a
sequential fashion, the injection of the needle, the advancement of
the piston as far as the bevel of the needle to deposit the solid
or semi-solid form, the withdrawal of the needle around the piston
and the combined withdrawal of the needle and of the piston,
[0111] the sequential operations of the device from external means
are controlled remotely and in order with the aid of two movable
stops of which the first is arranged on a push button coaxial to
the piston, and the second is a tubular piece inserted between the
guide and the push button.
[0112] It will be possible for the devices to be used directly or
combined with the medical instruments for local therapy (endoscope,
fibroscope, tube, catheter, spike, aerator, cannula, perforator,
trocar . . . )
[0113] The devices will be introduced at the local level and will
allow the insertion or the implantation of the semi-solid or solid
forms. They will be withdrawn immediately after this
deposition.
[0114] Like the formulations, the devices used according to the
process of the invention for deep local administration of solid or
semi-solid formulations will be versatile and of low volume with a
suited thin and elongated shape.
[0115] The devices will thus preferentially have a maximum diameter
of 3 mm and advantageously a diameter of less than 2.5 mm or even
of less than 2 mm. As a function of the formulation, it will be
possible for the diameter of the device to be even smaller and down
to 0.3 mm.
[0116] In a fibroscope or an endoscope comprising, for example, 4
channels (video, instruments, introduction and withdrawal of fluid,
illuminated optical fibres), it will be possible for the insertion
or implantation device, like a conventional tool (biopsy forceps
style) to occupy the channel of the instruments, which frees the
channel for introduction of fluids or even allows its elimination.
In this case, it will be possible for the devices to have a
diameter of less than 2 mm and, for example, of 1.7 mm like certain
instruments.
[0117] In a catheter, it will be possible for the insertion or
implantation device, like the device for insertion of stents, to
occupy the channel and to be operated from the exterior in situ. In
this case, it will be possible for the device to have a diameter of
less than 2.5 mm and, for example, of 2 mm like certain stents.
[0118] In a trocar, it will be possible for the insertion or
implantation device, like the perforation device, to occupy the
lumen of the trocar. It will be possible for the device to have a
diameter of less than 3 mm and, for example, of 2.5 mm like certain
perforators.
[0119] Other characteristics and advantages of the invention will
become clear from the description which will follow, made with
reference to the annexed drawings which illustrate several
embodiments by way of non-limiting examples.
[0120] FIG. 1 is a view in longitudinal elevation of a first
embodiment of the administration device of solid formulations
according to the invention in the case of the administration of the
formulation inside a natural cavity of the body, used as a
reservoir for release of the formulation.
[0121] FIGS. 2, 3 and 4 illustrate a sequence of employing the
device of FIG. 1 to administer a solid formulation locally in the
body.
[0122] FIG. 5 is a half-longitudinal section half-elevation view of
a second embodiment of the device for administration of
formulations according to the invention, shown partially introduced
into the body of a patient ready for the administration of the
solid formulation.
[0123] FIG. 6 is a transverse sectional view along 6/6 of FIG.
5.
[0124] FIG. 7 is a view analogous to FIG. 5 showing the device
after pushing of the solid form outside a guide of the device,
ready to be deposited in the body of a patient.
[0125] FIG. 8 is a transverse sectional view along 8/8 of FIG.
7.
[0126] FIG. 9 is a view in elevation analogous to FIGS. 5 and 7,
showing the device after partial withdrawal of the needle, the
solid form remaining in place in the body.
[0127] FIG. 10 is a view analogous to FIG. 9 showing the needle and
the piston inside this completely returned.
[0128] FIGS. 11 to 16 are views similar to FIGS. 5 to 10
respectively but in which the device is used to administer a
semi-solid form.
[0129] FIGS. 17, 18 and 19 show the release in vitro of inserts of
dexamethasone at a respective concentration of 10, 15 and 20%.
[0130] FIGS. 20, 21 and 22 show the results of pharmacokinetic
studies on rats of inserts of dexamethasone at a respective
concentration of 10, 15 and 20% injected subcutaneously (A) and
intraperitoneally (B).
[0131] FIGS. 23 and 24 show results of pharmacokinetic studies of
the solid form 12.8 mg of lanreotide acetate respectively on the
dog injected intramuscularly and on the healthy volunteer injected
subcutaneously (A) and intramuscularly (B).
[0132] FIG. 25 shows the pharmacokinetic study on healthy
volunteers of the semi-solid form of 40 mg of lanreotide injected
intramuscularly.
[0133] FIG. 26 shows the in vitro release profile of a Triptoreline
acetate/PLGA (75:25) matrix formulation with 20% of active
principle.
[0134] FIG. 27 shows the in vitro release profile of a Triptoreline
acetate/PLGA (75:25) formulation according to the invention with
52% of active principle.
[0135] FIG. 28 shows the in vitro release profile of a Triptorelin
pamoate (active principle) and PLGA (50:50) formulation with 40% of
active principle.
[0136] FIG. 29 shows the in vitro release profile of a Triptoreline
pamoate (active principle) and PLGA (50:50) formulation with 52% of
active principle.
[0137] FIG. 30 shows photographs of Triptoreline acetate PLGA
(75:25) formulations with 20% of active principle placed in a
physiological medium in vitro after one hour, 1 d, 2 d, 3 d, 7 d
and 10 d.
[0138] FIG. 31 shows photographs of Triptoreline acetate PLGA
(75:25) formulations with 52% of active principle placed in a
physiological medium in vitro after one hour, 1 d, 2 d, 3 d, 7 d
and 10 d.
[0139] FIG. 32 shows the in vitro release profiles of three forms
according to the invention with 52%, 70% and 80% of active
principle (Triptoreline acetate) at a dose of 9 mg.
[0140] FIG. 33 shows the in vitro release profiles of two forms
according to the invention with 52% of active principle
(Triptoreline acetate) at doses of 9 mg and 6 mg.
[0141] FIG. 34 shows the development in the course of time of
amounts of active principle remaining in implants injected into
rats for formulations with 52%, 70% and 80% of active principle
(Triptoreline acetate).
[0142] FIG. 35 shows the development in the course of time of the
absolute residual quantity of active principle remaining in
implants injected into rats for formulations with 52%, 70% and 80%
of active principle (Triptoreline acetate).
[0143] FIG. 36 shows the kinetics in dogs of plasma concentrations
for a Triptoreline acetate/PLGA (75:25) formulation with 20% of
active principle and at a dose of 3 mg and the monitoring of the
pharmaceutical effect by the level of testosterone.
[0144] FIG. 37 shows the kinetics in dogs of plasma concentrations
for a Triptoreline acetate/PLGA (75:25) formulation with 52% of
active principle and at a dose of 6 mg and the monitoring of the
pharmaceutical effect by the level of testosterone.
[0145] FIG. 38 shows the in vivo release profiles in dogs of a
Triptoreline acetate/PLGA (75:25) formulation with 70% of active
principle and at a dose of 9 mg (A) and the monitoring of the
pharmaceutical effect by the amount of testosterone (B).
[0146] FIG. 39 shows the in vivo release profiles in dogs of a
Triptoreline acetate/PLGA formulation with 52% of active principle
and at a dose of 6 mg and with 70% of active principle and at a
dose of 9 mg.
[0147] The administration device of a solid form 1 represented in
FIG. 1 comprises a tubular guide 2 containing a piston 3 which is
able to push outside the guide 2 the solid form 1 contained at the
end of the latter. The guide 2 and the piston 3 are provided, at
their opposite ends, with respective manual handling collars 4,
5.
[0148] FIG. 2 illustrates a possible example of the invasive system
in the body of a patient for the employment of the device for
administration of the solid form 1 of FIG. 1. The invasive system
is, in the example of FIG. 2, a trocar 6 containing a perforator
mandrel 7, if the access to the natural cavity of the body used as
a reservoir for release of the solid formulation 1 necessitates a
perforation of internal tissues. In FIG. 2, the invasive system is
shown partially introduced inside the body in its part situated to
the right of the plane L, while its part situated to the left
remains external.
[0149] If the access to the natural cavity of the body does not
necessitate a perforation of internal tissues, the invasive system
can be an endoscope, a fibroscope or a catheter (not shown). The
invasive system used is introduced into the body cavity (sinus of
the face, oesophagus, trachea, vessel, etc.), with the aid of the
perforator mandrel 7 in the case of a system such as that of FIG.
2. The mandrel 7 is then withdrawn from the trocar 6 (or from the
endoscope, from the catheter, etc.) and the administration device
of FIG. 1 is introduced inside the trocar 6 (FIG. 3), until the
collar 4 of the guide 2 comes up against the bent annular end 8 of
the trocar 6.
[0150] It is then sufficient to push the piston 3 to eject the
solid form 1 outside the guide 2, because no tissue resistance
opposes its movement (FIG. 4).
[0151] In the second embodiment of the device for administration of
a solid form 9, illustrated in FIGS. 5 to 10, this device is
intended for the case of an injection of the said device inside a
tissue, a wall or a mucous membrane from an internal invasive
system already inserted into a cavity as shown in the drawings, but
also from an invasive system inserted in an internal tissue.
[0152] The invasive system comprises a tubular piece 50 partially
inserted in the tissue through the surface P' of the latter, and a
tubular guide 11 which can be a fibroscope or an endoscope, in
which a catheter 12 can be mounted. The latter forms a guide for
the administration device formed by a needle 13 and a piston 14 for
extraction of the solid form 9 in the tissue 17.
[0153] The device has two movable stops (10, 15) of which the first
10 is a sleeve arranged in a push button 20 coaxial to the piston
14, this stop 10 and the push button being longitudinally truncated
(FIG. 8); the second is a tubular piece 15, likewise truncated
(FIG. 6), interposed between the catheter 12 and the push button
20.
[0154] The injection of the administration device 13, 14, 9, can be
obtained by moving the guide backwards, but is preferably carried
out as illustrated in FIGS. 7 to 10, in the following manner. The
stop 15 is withdrawn; the needle 13 is moved with the aid of the
push button 20 containing the stop 10 (FIG. 7). If necessary and as
illustrated in FIG. 7, especially in the case of vessels, the
needle 13 can have at its end a bent shape 13a obtained by
liberation of an elastic preconstraint of the needle 13 in the
guide. Once the constraint of the guide is liberated, the bent end
13a facilitates the oblique injection of the solid form 9 into the
wall or the mucous membrane 17. It will be possible to obtain or
set this angle between the needle and the guide by any other
mechanism customarily used by these devices.
[0155] Once the solid form 9 and the bent end 13a have been
injected, the stop 10 of the push button 20 is removed, and the
needle 13 is withdrawn by traction on the lugs 16 without moving
the piston 14 in order to deposit the solid form 9 in the tissue 17
(FIG. 9). When the bevel 13b of the needle 13 reaches the end of
the piston 14, the latter is withdrawn with the needle 13, leaving
the solid form 9 in place, this movement being obtained by traction
on the push button 20 and the lugs 16 (FIG. 10).
[0156] The device of FIGS. 5 to 10 can likewise allow the
administration of a semi-solid.
[0157] The administration device illustrated in FIGS. 11 to 16 is
similar to that of FIGS. 5 to 10 and only differs from it by the
fact that the piston 14 acts on a non-solid form 18, in
appertaining to a microsyringe up to the point of the injection
device.
[0158] Here also, the invasive system 9, 11, 12 can be inserted in
an internal tissue 17.
[0159] The administration process here consists in injecting by
pushing it outside the guide 9, 11, 12 the administration device
formed of the needle 13, the piston 14 and the semi-solid form 18.
The needle 13 can possibly be bent as in the embodiment of FIGS. 5
to 10. The piston 14 is moved in the needle 13 to inject the
semi-solid 18 (FIG. 14) in the same manner as in the preceding
embodiment.
[0160] The piston 14 and the needle 13 are finally withdrawn
together by reintroduction into the guide 11, 12 by traction on the
lugs 16 and on the push button 20 (FIGS. 15 and 16), the semi-solid
form 18 left in place in the tissue 17 then being able to assume a
spherical or ellipsoidal form.
[0161] The drawings of FIGS. 1 to 16 are to allow the
administration processes for different specific treatments
described further on to be illustrated. These different specific
treatments according to the process of the invention of solid or
semi-solid local administration involve the employment of the
process in order that it can be carried out and thus offer certain
novel therapeutic solutions which are part of the invention. These
different examples illustrate the possible field of application of
the invention, but do not form an exhaustive list of applications
of the process and are thus not limiting.
[0162] Of the number of possible treatments, according to the
process of the invention, it is possible to mention anaesthetic,
analgesic, anti-inflammatory, cancerological, cardiological,
endocrinological, rheumatological etc . . . treatments as well as
the combined treatments. Of the number of endoscopic or
radiological techniques capable of allowing this local treatment
process, it is possible to mention urology, gynaecology,
arthroscopy, ORL, bronchoscopy, gastrology, minimal invasion or
even cardiovascular surgery.
[0163] These processes are novel because they use a low volume
(microlitres) solid or semi-solid, delayed-release or
non-delayed-release pharmaceutical formulation. This formulation
differs from existing local treatments which use large-volume
specific solid forms or liquid or suspension forms.
[0164] According to this process and with these non-liquid
formulations, the formulation is not studied in its composition or
in its form for precise vectorization. On the contrary, the
formulation is studied for a tool or device suited to internal
local administration and which allows remote injection or in-situ
insertion.
[0165] It would be possible for the process to use, in this
pharmaceutical form and with these tools, conventional APs and
especially those having already demonstrated their local
administration interest, or whose local interest can be deduced
from the mode of action of the AP, even if its use in this form
does not yet exist, especially when it could not easily be employed
without the contribution of the invention. The different examples
which follow illustrate the possibilities of this process.
[0166] The process, the formulations and devices allow
administration into body cavities and intratissue administration.
Whatever the cavity or tissue, the advantage is to be able to lead
the formulation to the depot site while avoiding or while
decreasing the tissue lesions.
[0167] It will be possible for these natural cavities to be used as
therapeutic product reservoirs, especially if their anatomy allows
the "imprisonment" of the formulation. The process allows, for
example, administration into natural cavities of the face and into
its tissues. With certain APs, the whole of the objectives stated
above are found with this treatment (better local efficacy,
decrease in dose, increase in the duration of action, improvement
in comfort and compliance, decrease in the secondary effects).
[0168] It will be possible for the intra or perisinusal inserts or
implants to transport the AP into the mucus owing to the ciliary
flows of the mucous membranes or to allow its local systemic
diffusion by contact. It will likewise be possible to envisage a
general action by progressive diffusion towards the digestive
tracts for medicaments necessitating taking low doses daily.
[0169] The local corticoids are a good example of a local action
product having disadvantages by the general route. However, the
existing local treatments (drops, spray etc.) run up against
anatomical arrangements to reach a precise target zone such as the
meatus medius (monocellular sulcus). In addition, with these
existing treatments, the necessary persistence of the AP locally
involves frequent applications.
[0170] This therapeutic process according to the invention allows
this key zone of naso-sinusoid pathology to be reached. In addition
to the maxillary sinuses, according to needs, it will be possible
to treat locally the ethmoidal cells, the sphenoidal and frontal
sinuses, and the cavum tympani. The implanted or inserted solid or
semi-solid delayed-release form will be in contact with this mucous
membrane which secretes and is covered by mucus circulating on the
meatus towards the nasal fossae, and emptied towards the cavum by
passing in contact with the tubal splenium and the Eustachian
tube.
[0171] The process will allow, for example, the concentration of
therapeutic product in the monocellular sulcus which is the seat of
pathologies, in particular inflammatory, to be increased and
maintained. If the delayed-release non-liquid form is deposited in
the interior of the sinuses, it will be possible to use a device
according to the drawing of FIG. 1 which will be able to be
positioned with the aid of conventional otorhinolaryngology
drainage tools (ORL; trocars, tubes). It will likewise be possible
to inject the formulation into the mucous membrane of the nasal
fossae, into the turbinate bones or into the tubal splenium with
the aid of the device shown in FIGS. 5 to 16. According to the zone
of deposition and the formulation, the action will thus
preferentially be external, intratissue or systemic.
[0172] In ORL, it will thus be possible to treat, for example, by
corticoid therapy, naso-sinusoid polyposis, allergic or
non-allergic rhinitis, certain types of otitis or non-infectious
sinusitis etc. In addition to anti-inflammatory treatments, it will
be possible to practice antibiotic, anti-allergic, immunostimulant,
etc. treatments. It will likewise be possible to combine the
treatments. These treatments will have a local aim.
[0173] It is possible, for example, to make rods of dexamethasone
phosphate matrixed to a level of 15% in PLGA 50-50 according to the
following steps: weighing of the raw materials, mixing of the two
powders, extrusion, dosage, packaging and sterilization. It will be
possible for the implant obtained to have an average diameter of
2.4 mm for a length of 12.5 mm. It will be able to be introduced
inside the maxillary sinuses with the aid of the device shown
diagrammatically by FIG. 1. It will likewise be able to be
implanted in the mucous membrane of the turbinate bone with the aid
of the device shown diagrammatically in FIGS. 5 to 10.
[0174] This solid formulation is a 1-month delayed-release
formulation which contains 7.5 mg of dexamethasone and which
releases on average 0.5 mg/day with an implant in each sinus. For
chronic treatment, it would be possible to imagine the
intrasinusoid use of a polymeric form (PLGA 75-25) of three months'
duration of action, or even a reservoir form (Hydromed type) of 1
year's duration of action.
[0175] It will be possible for these delayed-release preparations
to be used in the ambulatory case on patients suffering, for
example, from chronic nasal obstruction. The medical action for the
intrasinusal administration will appertain to the current ORL
actions which can be practised in the doctor's surgery: trocar
puncture with or without anaesthesia. It will or will not be
possible to prepare the route first (meatotomy, spikes, drains or
others).
[0176] Deep injection localized in the turbinate bone or the mucous
membranes of the nasal fossae will also be easy with the aid of the
device which is or is not combined with the customary tools of
endoscopic exploration. In the nasal fossae, local administration
is not very deep. According to the body cavities or the site of
endoscopic surgery, it will be possible for the distance between
the external zone and the internal depot to be even shorter or much
larger.
[0177] Delayed-release corticoids are already used in rheumatology.
It is possible, for example according to the process, to imagine an
intra- or periarticular local injection with delayed-release form
deposition in low volume (corticoids, anti-inflammatories) at the
site of inflammation (tendinitis, bursitis, noninfectious
arthritis, arthrosis, etc.).
[0178] It is also possible, according to the process, to imagine an
ocular treatment by depot injection into the mucous membrane under
the eyelid. The small volume of solid or semi-solid forms will make
this depot insensitive and the injection will at the same time
favour the delayed-release effect and the local maintenance of the
treatment in a more efficacious manner than the depot in the
conjunctival cul-de-sac which is amply drained. Above all, this
approach is advantageous for a chronic treatment such as, for
example, glaucoma, with pilocarpine.
[0179] Here, the injection is virtually superficial and does not
necessitate tools apart from the administration device for the
microvolume semi-solids or solids.
[0180] In the same way, it is possible according to the process of
the invention to treat certain superficial tumours or cutaneous
problems by local, intradermal or hypodermic deposition.
[0181] For example, it will be possible to use dermopeptin (BIM
23014C) in a 20% semi-solid delayed-release form in water and under
a volume of 20 microlitres or a total dose of 4 mg of Somatuline.
It will be possible to inject the formation at the cheloid or
melanoma level, thus creating a high and sustained local
concentration from a diffusion gradient zone at the site of
injection.
[0182] In the case of certain solid tumours, it will be possible to
combine the treatment with a cytotoxic agent (5FU or cisplatin
type) whose diffusion will be regulated by the same local form and
whose local concentration will thus be very high with a very low
total dose.
[0183] It will likewise be possible to use the same formulations in
much deeper applications and, in that case, combined with SMA
(Shape Memory Alloy) active catheter type or fibroscope tools, and
with specialities such as interventional radiology or endoscopic or
robotic surgery.
[0184] It will be possible, for example, to implant intracerebrally
a BIM23014C delayed-release form which is more cytotoxic owing to
access into the cranium.
[0185] The solid or semi-solid forms according to the invention
have the advantage, with respect to the Gliadel-type local
treatment, of being able to be administered without trepanation at
the superficial level, but likewise deeply with the aid of
stereotactic, endoscopic and robotic neurosurgery.
[0186] The solid tumours treated, for example, with the collagen
forms of Matrix will be able to be treated in the same way with
these microdosages. Whatever the solid or semi-solid form, the
advantage of the volume allows vectorization into all the sites and
avoids the risk of spreading caused by the injection of a liquid
volume of a few millilitres.
[0187] It is always possible with a solid or semi-solid form
localized more deeply in the body, after transluminal percutaneous
angioplasty, to treat local intravascular restenosis. With respect
to local treatment combined with the stent, the advantage of a
treatment according to the process is to not be confronted with the
dose limit of the vascular space and of the surface of the device,
and of not entering into direct contact with the damaged vascular
wall, while allowing a high local concentration in all the layers
of the vessel and around, and a systemic effect if necessary.
[0188] It will be possible, for example, to inject angiopeptin
alone or combined with heparin according to the diagram of FIGS. 5
to 16. It will be possible, of course, to inject any other single
or combined AP capable of avoiding the risks of restenosis and of
favouring the result.
[0189] With respect to this perivascular therapy, it is likewise
possible to mention the possible use of semi-solid intravascular
forms with the same objective as chemo-embolization by suspension,
glue or gel. The advantage here is to use a delayed-release form
whose volume (thus the depot zone) is pre-established; this allows
a better localization of the occlusion in the vessel.
[0190] The process and the devices according to the invention
combined with the fibroscope or with any other direct or indirect
imaging solution allow administration in the organic walls.
[0191] For example, when an intervention is made at the level of
the bladder by the urethral route, it is possible to imagine the
implantation of a treatment (prophylaxis, antibiotic, etc.) in the
thickness of the urethra.
[0192] It is possible to reach the trachea and the bronchi
(stents). According to the process, it is thus possible to envisage
a pulmonary treatment either by administration of a solid or
semi-solid form to the lung or by implantation in the mucous
membrane of the bronchi or of the trachea, according to the needs
of local intrapulmonary tolerance, it will be possible for the
solid form to be dispersed (powder or sphere).
[0193] For example, to replace the preventive treatment by inhaled
glucocorticosteroids in slight or moderate asthma of recent
diagnosis, it will be possible to administer to the lung, via the
bronchi, or in the wall which covers them or to cells of the
trachea, a delayed-release form of 0.4 mg of budesonide daily which
will be secreted in the flow if the form is implanted, and which
will be transported by the moisture to the bottom of the pulmonary
alveoli. This low-dose preventive treatment, without secondary
effect, does not thus pose any observance problem, especially in
children. It will be possible for such a form to have a duration of
1 to 3 months, or even more if necessary.
[0194] In the digestive tract, devices allowing the local
administration of treatment according to the invention are likewise
available.
[0195] In the oesophagus and in the stomach, it will be possible
for the treatment of varices to be envisaged with a form which is
local and injected into the wall. In the same way, the tumours at
this level which are well individualized and are presently treated,
for example, by PCT (photochemotherapy), necessitate, after
injection of the photosensitive product, illumination by controlled
introduction of a light diffuser at the local level. It is thus
likewise possible to inject the anticancer agents directly at this
level in solid or semi-solid form with the devices of the
invention. It is possible, then, to target even more the zone to be
treated and to avoid uselessly damaging the peripheral tissues.
[0196] The process of local administration of solid or semi-solid
forms involves the sustained presence of a local depot of AP. It is
possible, if necessary, to envisage adding to the formulation
products favouring local tolerance at the administration site. It
is possible, for example, to add very low percentages of
dexamethasone, indomethacin, heparin or any other AP capable of
avoiding an undesirable local effect.
[0197] The mucous membranes or the walls are more permeable than
the skin and patch or bioadhesive systems exist which are applied
to the mucous membranes (especially buccal or nasal) and which
allow a systemic passage of the AP. The disadvantage is sometimes
the non-persistence of the formulation in contact with the mucous
membrane. It will thus be possible for the sustained presence of
the administration according to the process at the local level of
mucous membranes or of internal walls to have an advantage in the
search for a topical form with systemic activity. It is thus
possible, according to the local treatment, to add to the
formulation in a small quantity any excipient capable of being a
vector of tissue penetration suited to the APs (organic solvents,
surfactants, etc.). Thus, it will be possible for a deep local form
advantageously to be the site of a systemic diffusion with respect
to the buccal or nasal mucous membrane, for example, which would
not allow a sustained topical administration.
[0198] The process according to the invention will likewise find
its application during endoscopic (laparoscopic, arthroscopic,
etc.) minimal invasion surgical interventions. The APs used (local
anaesthetics, anticoagulants, etc.) can be administered in a solid
or semi-solid form with here, again, the advantage of an
appropriate microvolume with the reduced intervention space, and
the possibility of administration by the instrumental access
route.
[0199] It will of course be possible to implant with the aid of the
process any other solid or semi-solid delayed-release form and
especially PLGA implants. It is possible to use them with other
peptides, recombinant proteins (interferon), polyclonal or
monoclonal antibodies, antisense oligonucleotides or
polynucleotides, etc.
[0200] The solid formulations or implants which can be used for
local administration of the active principle as described above are
likewise suitable, through their long and thin shape and their
small diameter, for other types of conventional administration, for
example for systemic treatment by cutaneous or intramuscular
injection.
[0201] It has also been very unexpectedly noted that the said solid
formulations or implants, especially with a PLGA excipient, having
a very significant concentration of active principle, such as
described above, whether they are soluble or insoluble, and
especially those having a concentration of active principle of
between 40 and 100%, and preferably greater than 50%, allow
extremely long release times of one month to three months and more,
and very regular, or even constant, release rates to be obtained in
vivo, in being produced in thin elongated form, of diameter or
transverse size of less than or equal to 3 mm, for example 2.5 or 2
mm, or even 1 mm or less, although they dissolve very rapidly in
vitro, including when they are used for a local or non-local
action.
[0202] Conventionally, such rates of active principle were intended
for formulations with instantaneous or rapid liberation.
[0203] The inventors have additionally discovered that, in a
certain form, in homogeneous distribution of excipient, especially
of PLGA, it was possible to obtain a delayed-release formulation
according to a non-matrix method in which the role played by the
excipient was different; this leads to more advantageous
formulations whose characteristics are different, which
distinguishes them clearly from existing matrix forms.
[0204] These non-matrix forms can be described as matrix forms of
active principle in which the excipient is dispersed.
[0205] The matrix forms employing the PLGA used to date can be
either dispersed forms (microparticles) or non-dispersed forms
(implants).
[0206] Generally speaking, among the delayed-release formulations
which have been developed, forms called reservoir forms and matrix
forms are found.
[0207] The "reservoir" forms use a diffusion barrier or membrane
between the active principle and the medium which will serve to
control the release of this active principle. The medicament can be
inside the reservoir in a solid, semi-solid or liquid form. It can
be in solution or dispersed in an excipient. By its porosity, the
membrane ensures the controlled passage of the active principle
towards the exterior. Among the "reservoir" systems for soluble
active principles, it is possible to mention the hydrophilic
crosslinked hydroxyethyl polymethacrylate membranes (pHEMA, Hydro
Med Sciences). The "reservoir" forms allow a relatively constant
level of release of 0 order to be obtained. The principal
disadvantage of these reservoir techniques is the necessity of
withdrawing the biocompatible but non-biodegradable implant after
liberation of the active principle.
[0208] The matrix forms use a polymer matrix or system in which the
active principle is trapped to be liberated by diffusion, by
erosion or by combination of the two phenomena.
[0209] The non-biodegradable matrix forms, such as, for example the
hydrophobic polymer implants of PDMS silicone type (Norplant,
progestational hormones) function only by diffusion. This method of
functioning can cause a decreasing release of 1st order when the
distance of diffusion increases. The disadvantage is here again the
necessity of withdrawing the silicone implant once the active
principle has been liberated.
[0210] On the other hand, the biodegradable matrix forms do not
have this disadvantage since the polymer matrix is eliminated by
the body. In addition, this elimination or erosion can participate
in the control of the release of the active principle to obtain a
constant release.
[0211] The most common biodegradable matrix forms currently use
polymers of lactic acid or of glycolic acid, copolymers of lactic
acid and of glycolic acid (PLGA) or their mixtures.
[0212] Thus, EP 52510 whose contents are incorporated by reference
describes a PLGA formulation with encapsulation of LHRH or the like
which can be a dispersed form of microcapsules produced by
coacervation of which the feature is the distribution of the active
principle at the centre of the microcapsule with a peripheral PLGA
layer.
[0213] From EP 58481, whose contents are incorporated by reference,
dispersed or non-dispersed formulations of peptides and of PLGA are
known, such as implants, in which the active principle is uniformly
distributed up to the surface and using a specific PLGA in such a
way that the two phases of release (diffusion and degradation)
overlap without there being interruption in the release of the
active principle.
[0214] Numerous other documents relate to the use of PLGA in
delayed-release formulations for peptides but also proteins and
genes. The patent WO 96/40072 whose contents are incorporated by
reference thus describes a preparation of human growth hormone
whose stability in the matrix and in the organic solvents used for
the microencapsulation is favoured and whose release is ensured by
the PLGA matrix. The control process is based on the degradation of
the polymer and the opening of pores in the structure which causes
it.
[0215] All the studies carried out to date agree in saying that the
delayed-release control process with the PLGA can cause up to three
liberation phases. An initial phase which liberates the active
principle by diffusion, a latent phase where no release takes
place, and a phase of release of the bound forms correlated with
the loss of mass of the polymer.
[0216] In all the formulations using PLGA, the control of the
delayed-release effect is obtained by matrix mixing of the PLGA and
of the active principle so as to allow the polymer matrix to play
its role of barrier to the release of the active principle, or even
a role in the physicochemical interactions between the active
principle and the polymer matrix.
[0217] In all cases, this method of release requires a dispersion
of the active principle in the biodegradable polymer matrix so as
to isolate the loading zones of active principle to the exterior
medium and to retain them within the matrix until the
biodegradation of this liberates the active principle which is then
able to diffuse towards the exterior.
[0218] This type of delayed-release matrix form can be easily
characterized by making water penetrate it which will hydrate the
dispersed zones of active principle and cause a swelling of the
formulation under the effects of hydration by the osmotic forces
due to the impossibility of the active principle escaping from the
matrix structure.
[0219] These phases intermix to a greater or lesser extent
according to the PLGA formulation, the degradation of the polymer
allowing, for example, the increase in the size of the cavities by
which the active principle can diffuse.
[0220] Apart from PLGA and polylactic acids mentioned above, very
few injectable delayed-release excipients exist. However, it is
possible to mention, for example, certain polymers, gels and fatty
substances. The polyanhydrides are, for example, polymers whose
surface erosion process gibes a release profile distinct from that
of PLGA and more dependent on the form of the depot than the PLGA
which undergoes a global degradation.
[0221] Certain delayed-release formulations are likewise found
which use collagen or gelatin to obtain a release over time. Other
formulations use gels or hydrogels. Matrix Pharmaceutical, for
example, uses a viscous injectable gel (AccuSite.RTM.,
Intradose.RTM.).
[0222] These formulations formed of a matrix which is less
susceptible to isolate the active principle from the medium or more
rapidly eliminated in general contain a small percentage of active
principle.
[0223] Other injectable excipients such as mannitol, polyethylene
glycols and hyaluronic acid are likewise used, more often as
additives to adjust the delayed-release profile.
[0224] Apart from matrix or reservoir techniques, few other
approaches today allow a sufficiently long, regular and precise
release to be obtained.
[0225] It is possible to mention, however, the case of implants
which are totally or partially covered by a coating serving as a
barrier to the diffusion of the active principle.
[0226] In the dispersed or non-dispersed matrix formulations, a
certain quantity of active principle is found on the surface of the
formulation and is not included in the polymer matrix.
[0227] In the dispersed matrix forms, for a given quantity of
active principle, the surface active principle represents a high
relative quantity with respect to the total of the active principle
because of the significance of the surface with respect to the
total volume.
[0228] To increase the charge or "core-loading" (C.L.) of active
principle, there is thus a constraint to inject a large volume of
polymer matrix for a given volume of active principle.
[0229] This constraint is even more penalizing for the
non-dispersed forms or implants because the volume of these for a
high quantity of charge necessitates the use of a trocar for the
injection of the formulation.
[0230] There has indeed obviously been a search to design
formulations having a higher C.L., but the experiment has
demonstrated the existence of a phenomenon known under the name of
percolation which is manifested by a rapid release of almost the
whole of the active principle due to the fact that in the polymer
matrix the charge zones are found to be in contact with one
another, the polymer (PLGA) no longer ensuring its matrix
function.
[0231] Visually, this phenomenon is manifested after hydration of
the formulation by liberation of active principle in a very short
delay without swelling of the formulation, the active principle
being entrained outside the formulation by the water which
circulates in the polymer matrix.
[0232] In the delayed-release matrix forms, the type of PLGA and
its physicochemical characteristics are clearly specified and
determine an area of feasibility. The direct influence of the PLGA
on the release by its role of matrix barrier, its role in the
relations (hydrophobic, hydrophilic, etc.) with the active
principle and the influence of its degradation involve a precise
choice of PLGA.
[0233] This relation between the PLGA and the release appears
clearly, for example, in the duration of action of a matrix
formulation.
[0234] In such a formulation, the duration of release depends
directly on the time of degradation of the PLGA (second phase or
rebound). Thus, the PLGAs will be selected as a function of the
duration sought. For example, the 50:50 PLGAs, depolymerized in one
month, will be used to produce a one-month formulation although
necessarily formulations over three months will involve PLGAs whose
hydrolysis is slower, for example 75:25 PLGAs.
[0235] In the non-matrix formulations of the invention, the
excipient, especially the PLGA, does not influence the release and
it is, for example, possible to obtain releases over three months
with a single 50:50 PLGA which disappears totally from the body in
60 days or even one-month forms with a 75:25PLGA which will not
even have commenced its hydrolysis although all the active
principle will be liberated. This is made possible by the fact that
the proportion of PLGA is always lower in weight than the
proportion of active principle; this signifies that the continuous
matrix is no longer the PLGA but the active principle which will
thus undergo for the whole of the charge the exterior and
especially aqueous influence. It is thus the active principle,
especially by the total quantity, which will determine the duration
of action.
[0236] The invention thus also especially relates to such
formulations, whether they are with a systemic aim or for a local
treatment, with a conventional dosage or dosage decreased for a
local action.
[0237] The invention more particularly relates to a delayed-release
formulation for parenteral administration comprising a homogeneous
mixture of an active principle in the non-dispersed state forming a
continuous phase of which at least one part is in direct contact
with the exchange surface of the formulation and the exterior
biological medium, and of a biodegradable biocompatible excipient,
in which the quantity of active principle is at least 50% by weight
with respect to the total weight of the formulation, and having a
release profile which is independent of the composition of the
excipient, of the molecular weight of the excipient or of the
active principle/excipient weight ratio, the release profile
essentially being exclusively dependent on the total quantity of
active principle present in the formulation.
[0238] Conversely to known matrix forms permitting a "charge of
active principle" in an upper limit of 30% of active principle in
order to avoid the phenomena of percolation, the formulations of
the invention contain more than 50% of active principle, which
represents a decrease in volume of the depot of the order of 3 to
10 times with respect to the volume of the matrix forms.
[0239] Thus, in solid form, the formulations of the invention
advantageously contain, before as well as after administration, at
least 50%, preferably at least 51%, advantageously at least 60% and
more advantageously at least 70% and up to 99.999% by weight with
respect to the total weight of the formulation, the excipient
representing less than 50%, preferably less than 49% and more
advantageously less than 30% by weight with respect to the total
weight of the formulation.
[0240] The excipients are those traditionally used in the solid
forms with delayed-release liberation, especially the biodegradable
polymers.
[0241] It is possible to mention, by way of example, the polymers
of polylactic or polyglycolic acid type, or the copolymers of
polylactic/polyglycolic acid type, or mixtures of these polymers
and/or copolymers.
[0242] The choice of biodegradable biocompatible polymer forming
the excipient is immaterial, this not having an influence on the
diffusion capacity of the active principle in the polymer.
[0243] It will be possible, for example, to use an injectable fatty
substance as excipient of formulations of the invention, such as a
polymerized or saturated fatty acid such as .RTM.Compritol or even
excipients such as polyvinylpyrrolidone (PVP) or polyethylene
glycol (PEG).
[0244] The viscosity of the polymers can vary considerably. It has
been shown that polymers of low viscosity can be suitable for a
method of release of active principle called monophasic. The
abovementioned patents EP 58481 and 52510 but also the patents EP
21234 and EP 26599 whose contents are incorporated by reference,
for example, put emphasis on low viscosity polymers. These polymers
can be suitable for the present invention (for example, viscosity
lower than 0.5 dl/g in chloroform). The Applicant has additionally
shown in an already filed patent application FR 97 04 837 and in
the examples below that unexpectedly, high viscosity polymers,
especially higher than 0.5 or even 0.6 and being able to range up
to 1.2 dl/g can be preferentially suitable for obtaining a
monophase liberation.
[0245] It is possible to use DL-PLGAs or L-PLGAs, more
preferentially a DL-PLGA produced from 70 to 80% of DL-lactide and
from 20 to 30% of glycolide. A PLGA synthesized from 75% of
DL-lactide with 25% of glycolide is particularly suitable but other
copolymers including 50-50 PLGAs can also be used. It is also
possible to use D- or DL-lactide polymers.
[0246] The PLGAs can be hydrophilic or hydrophobic. It is possible
to produce the formulations of the invention with hydrophilic
polymers.
[0247] As the biodegradable biocompatible polymer, however, PLGA is
preferred, especially a hydrophilic PLGA advantageously having a
viscosity in chloroform at 1 g/100 ml of greater than 0.6 dl/g.
[0248] The duration of action of the delayed-release formulation
will be determined exclusively by the total quantity of active
principle which it contains.
[0249] Active principle in the non-dispersed state is understood as
meaning that the different particles of active principle present in
the formulation are mainly physically in contact with one another
and up to the surface of the formulation.
[0250] It is thus understood that continuous phase is understood as
meaning a distribution such that all or the majority of the
internal parts of the active principle are only separated from the
surface by active principle or a mixture of active principle and a
substance not opposing the diffusion or the dissolution of the
active principle.
[0251] Advantageously, the mixture formed by the active principle
and the excipient is homogeneous at all points.
[0252] The delayed-release formulations according to the invention
are additionally characterized by their difference of duration of
release in vitro and in vivo.
[0253] Thus, the formulations according to the invention placed in
a physiological aqueous medium release the active principle over a
period of less than seven days although the duration of action in
vivo is substantially greater than this period, advantageously one
month at least, and preferably at least three months.
[0254] The matrix formulations comprising the same quantity of
active principle conversely had a longer release in vitro, of the
same order of size as the duration of release in vivo.
[0255] Surprisingly, despite an in vitro release of a limited
duration, the formulations according to the invention allow a
considerably greater duration of release to be obtained in vivo
without relation to the duration of release in vitro.
[0256] In addition, the release profile in vivo is clearly
different from that of the two-phase matrix forms and will be of
pseudo order 0, corresponding to a constant diffusion of the active
principle in the course of time.
[0257] This release profile constitutes another advantage since it
allows a liberation of active principle of a constant level in the
body.
[0258] The formulations according to the invention are injected
directly in their solid form in the absence of any liquid
excipient; the high proportion of active principle thus constitutes
a determining advantage, by allowing the volume to be reduced
significantly.
[0259] Thus, with respect to a matrix form with 20% of active
principle, the novel formulations according to the invention with,
for example, 70% of active principle allow the volume to be reduced
by a factor of 3.5 or even the dose to be multiplied by 3.5 for an
identical volume.
[0260] This signifies that where, for a given active principle with
a non-dispersed matrix formulation, a trocar was necessary to
inject an implant of a diameter of greater than 1.8 mm, a standard
intramuscular needle suffices to deposit a microimplant of a
formulation according to the invention having a diameter of less
than 1 mm.
[0261] In addition, the method of release of the formulation of the
invention, without absorption of fluids, nor initial swelling of a
matrix, constitutes a stability advantage for the active principle
which is preserved in a controlled environment. The delayed-release
forms according to the invention are thus particularly advantageous
for fragile active principles such as recombinant proteins.
[0262] To the extent where no limitation exists for the active
principle taking account of the nature of the biodegradable
biocompatible polymer forming the excipient, it is possible to
incorporate into the formulations according to the invention active
principles of high molecular weight which were not capable of
diffusing in the matrix forms of the prior art, especially
synthetic or natural macromolecules, especially proteins, or their
analogues.
[0263] The invention thus allows liberation over a sustained period
of fragile molecules, especially peptides and-proteins, or their
analogues.
[0264] Among the active substances which can be used for the
invention, it is especially possible to mention proteins, peptides
chosen, for example, in the group formed of Triptoreline acetate,
lanreotide acetate, of a compound having an LH-RH activity such as
Triptoreline, goserelin, leuprorelin, buserelin or their salts, an
LH-RH antagonist, a GPIIb/IIIa antagonist, a compound having an
activity similar to a GPIIb/IIIa antagonist, erythropoietin (EPO)
or one of its analogues, the different .alpha. interferons,
interferon .beta. or .gamma., somatostatin, a derivative of
somatostatin such as described in the European patent EP 215171
whose contents are incorporated by reference, an analogue of
somatostatin such as described in the American patent U.S. Pat. No.
5,552,520 (this patent itself contains a list of other patents
describing analogues of somatostatin which are incorporated by
reference in the present application), insulin, a growth hormone, a
growth hormone release factor (GRF), an epidermal growth factor
(EGF), a melanocyte-stimulating hormone (MSH), a thyrotropin
release hormone (TRH) or one of its salts or derivatives, a
thyroid-stimulating hormone (TSH), a luteinizing hormone (LH), a
follicle-stimulating hormone (FSH), a parathyroid hormone (PTH) or
one of its derivatives, a hydrochloride of lysozyme, a peptide
fragment at the N-terminal end (position 1.fwdarw.34) of human PTH
hormone, vasopressin or one of its derivatives, oxytocin,
calcitonin, a derivative of calcitonin having an activity similar
to that of calcitonin, glucagon, gastrin, secretin, pancreozymin,
cholecystokinin, angiotensin, human placenta lactogen, human
chorionic gonadotropin (HCG), enkephalin, colony-stimulating
factor, an enkephalin derivative, endorphin, kyotorphin, the
interleukins, for example interleukin 2, tuftsin, thymopoietin,
thymosthymine, thymic humoral factor (THF), thymic serum factor
(TSF), a derivative of thymic serum factor (TSF), thymosin, thymic
factor X, tumour necrosis factor (TNF), motilin, bombesin or one of
its derivatives such as described in the American patent U.S. Pat.
No. 5,552,520 (this patent itself contains a list of other patents
describing derivatives of bombesin which are incorporated by
reference in the present application), prolactin, neurotensin,
dynorphin, caerulein, substance P, urokinase, asparaginase,
bradykinin, kallikrein, nerve growth factor, a blood coagulation
factor, polymixin B, colistin, gramicin, bacitracin, a peptide
stimulating protein synthesis, an antagonist of endothelin or one
of its salts or derivatives, a vaso-active intestinal polypeptide
(VIP), adrenocorticotropic hormone (ACTH), a platelet-derived
growth factor (PDGF), a bone morphogenetic protein (BMP) and a
gastric inhibitor polypeptide (GIP). Any other water-soluble active
substance, or one of its salts or precursors, will likewise be able
to be used by the persons skilled in the art if he judges it
useful.
[0265] Preferably, a water-soluble product obtained by salification
in cation form will be used, with, for example, acetic acid.
However, it is possible to use an insoluble salt, such as the
pamoate.
[0266] Peptide and/or protein are/is understood as meaning as well
as the peptide and/or the protein themselves, pharmacologically
active fragments of these peptides or proteins.
[0267] The water-soluble active substance such as used to
manufacture the formulations or implants according to the invention
can in particular be Triptoreline acetate, lanreotide acetate,
goserelin, leuprorelin, buserelin or their salts.
[0268] These formulations additionally have the advantage of being
able to be administered with the aid of the use of the above device
for the process according to the invention.
[0269] The manufacturing processes of formulations according to the
invention depend on mixing techniques, compression techniques,
techniques of extrusion in the molten state and grinding
techniques, conventionally used in the field of the manufacture of
delayed-release pharmaceutical forms.
[0270] The invention likewise relates to a process for preparation
of a delayed-release formulation according to the invention having
the steps consisting in:
[0271] producing a homogeneous mixture of the active principle and
of the excipient, containing at least 50% of active principle;
[0272] compacting the said mixture; and
[0273] extruding the said compacted mixture in the molten
state.
[0274] An alternative process applying generally to the matrix and
non-matrix compositions, whatever the content of active principle
and of excipient, especially of PLGA, and intended for local as
well as for non-local application and necessitating neither
solvent, nor heating of the mixture, comprises the steps consisting
in:
[0275] producing a homogeneous mixture of the active principle and
of the excipient;
[0276] subjecting the homogeneous mixture to high compression,
preferably with a force of greater than 1000 kg;
[0277] grinding the compressed articles obtained; and
[0278] putting into a form suitable for administration.
[0279] According to the first process, the process is carried out,
for example, in the following manner:
[0280] The active principle (AP) and the PLGA are weighed in the
proportions by weight of the mixture (for example 70% AP and 30%
PLGA).
[0281] Mixing is carried out to obtain a homogeneous mixture, for
example with the aid of a .RTM.Turbula mixer. The mixture is then
loaded into a compression die.
[0282] A compaction is carried out which corresponds, in fact, to a
"gentle" compression which allows briquettes to be formed of, for
example, 13 mm diameter by 5 mm thickness. This is advantageously
carried out with a knuckle-joint press.
[0283] The briquettes are pulverized, which can be carried out, for
example, by screening, cryopulverization with balls or with a knife
mill.
[0284] The object of this operation is to improve the quality of
the powder mixture flow during the extrusion necessary in this
particular situation where the molten parts represents less than
50% of the total.
[0285] The mixture is extruded through a die of the same diameter
as the desired microimplants. The extrudate is recovered after
control of the diameter by laser beams (Keyence) on a light drawing
tractor.
[0286] Preferentially, the microimplants are calibrated by the
extrusion nozzle and not by drawing.
[0287] The extrudate is cut to the desired length as a function of
the analytical control to obtain the microimplants which are then
loaded into the injection devices before gamma-irradiation (25
kGy).
[0288] According to the second process, the process is carried out,
for example, as follows:
[0289] Starting from a mixture of AP and PLGA, the process is no
longer a simple compaction but a very high compression of the
mixture starting with the same constituents (excipients and active
principle).
[0290] It will be possible to obtain this hypercompression with a
minimum force of one ton.
[0291] The consequence of this hypercompression carried out at a
significant diameter, for example 13 mm or greater, is the
transformation of this thermoplastic excipient (capable of melting
at temperature) into a structure similar to that obtained under hot
conditions, that is to say transparent or vitreous, very different
from the former obtained after simple compaction.
[0292] This operation takes place at ambient temperature, in cold
conditions or even below 0.degree. C. During this hypercompression,
at a low temperature, the vitreous transition to the plastic state
of the excipient within the mixture is obtained.
[0293] It will be possible to recompact these hypercompressed
articles then pulverized as above in the form of micro-compressed
articles equivalent to the preceding microimplants.
[0294] This technique particularly suited to the delayed-release
forms of PLGA allows without temperature, or solvent, or
manufacturing vehicles, the obtainment of pharmaceutical forms
which are of particular interest for preserving the integrity of
the active principle, especially for fragile molecules such as, for
example, recombinant proteins.
[0295] This process is likewise of interest for the manufacture of
matrix forms (not comprising more than 50% of active principle)
whether these are dispersed or non-dispersed. For the matrix forms,
the compression of the PLGA leads to a matrix structure equivalent
to that obtained by making the excipient melt on heating.
[0296] The hyper-compressed articles after pulverization can be
used directly in a dispersed microparticles form.
[0297] It will be possible to inject the dispersed form directly
after loading into a needle of a device such as that described
above or to inject it in suspension in a liquid medium (such as for
the microspheres, for example).
[0298] One of the possible aspects for the solid form is that of an
elongated cylinder.
[0299] The formulation such as defined above can, preferably, have
the forms and dimensions defined above in relation to the described
local administration device.
[0300] Advantageously, the formulation is in the form of a cylinder
of diameter less than 3 mm, preferably less than 1 mm and of length
less than 50 mm, preferably less than 30 mm, the total volume being
less than 50 mm.sup.3, preferably 20 mm.sup.3.
[0301] The invention likewise relates to a method of therapeutic
treatment comprising injection into a patient necessitating a
treatment involving the liberation of an active principle of a
formulation according to the invention over a sustained period.
[0302] The formulation can be advantageously injected by the
subcutaneous or intramuscular route.
[0303] This can be carried out by any suitable means, especially a
standard injection needle having a diameter of less than 1 mm.
[0304] The invention likewise relates to the use of a solid
formulation such as defined above for the obtainment of a
delayed-release effect.
[0305] The examples below illustrate the invention:
EXAMPLE 1
[0306] Intrasinusoid Insert of Dexamethasone Phosphate, PLGA
Form
[0307] The manufacture of the inserts of dexamethasone phosphate
take place according to the following phases:
[0308] weighing of the raw materials, mixing, first extrusion,
grinding and screening, dosage and packaging, all under class A
laminar flow in a class D clean room, and finally
sterilization.
[0309] For a batch, it will be possible, for example, to weigh
38.25 g of PLGA lactide-coglycolide copolymer (50:50) and to
incorporate 6.75 g of disodium dexamethasone-21-phosphate
pulverized to less than 100 micrometres.
[0310] The powder will be mixed with the aid of the
three-dimensional movement mixer and on the first extrusion, the
quality of the mixture will be controlled (% of AP).
[0311] After extrusion, the mixture is pulverized and extruded
again in canes of diameter 2 to 2.5 whose homogeneity is verified
(% AP, AP content/length). The weight of the insert necessary for
obtaining a dose equivalent to 7.5 mg of dexamethasone phosphate is
thus calculated. The cylinders are cut to lengths corresponding to
the necessary weight and they are packaged individually in the
containing devices which will be gamma-irradiated (25 kGy).
[0312] It will be possible to use the device directly inside a
trocar of diameter 3 mm and length 10 cm according to the diagrams
of FIGS. 5 to 10.
[0313] Before testing the efficacy of these inserts, for example in
chronic nasal occlusion, on the maxillary sinus, the in-vitro and
in-vivo release are verified on a model capable of being predictive
of the life of the insert.
[0314] In vitro, the release is followed by determination of the AP
by HPLC in an isotonic medium inside which the insert is immersed.
FIGS. 17, 18 and 19 show these in-vitro releases for three
different concentrations of AP of 10, 15 and 20% respectively.
[0315] In vivo, a rat model is used. The insert is administered
either subcutaneously or intraperitoneally and the release is
evaluated over a month to the nearest decimal point by determining
the quantity of AP remaining in the insert after sacrifice of the
animals and sampling at determined times.
[0316] FIGS. 20, 21 and 22 show the results of this in-vivo control
at three percentages subcutaneously (A) and intraperitoneally
(B).
EXAMPLE 2
[0317] Transluminal Implant of Lanreotide Acetate, Solid Form
[0318] Implants or cylinders of diameter 0.75 mm and length 30 mm
were manufactured. They contain 12.80 mg of lanreotide (BIM23014C)
for a composition with 90% of lanreotide acetate and 10% of
mannitol.
[0319] For a batch size of 200 units or 4.5 g of solid (lanreotide
acetate/mannitol), the manufacture comprises the following steps:
weighing, connection, evacuation, hydration, mixing, extrusion,
drying, arrangement and irradiation.
[0320] Weighing corresponds to the volume of the water/mannitol
solution, on the one hand, in a syringe and to the somatulin
acetate powder in the other syringe.
[0321] Connection is the combination of the two syringes via a
3-way ball valve.
[0322] Evacuation is then carried out inside the AP powder.
[0323] Hydration is obtained by contacting the powder under vacuum
with the mannitol solution. Mixing is carried out by to and fro
movements by operating the pistons of the two syringes. After
checking the HPLC homogeneity, extrusion corresponds to the
production of a cane through a die suited to the desired diameter.
This extrusion is likewise obtained by operating the piston of the
syringe with a motor.
[0324] Drying is carried out after or before the cutting of the
cylinders. It consists in evaporating the water from the pasty
mixture to obtain the dry cylinder.
[0325] Arrangement consists in introducing the cylinder inside the
injection needle in a device of diameter 1 mm such as is shown in
FIG. 5.
[0326] Irradiation by sterilization, after packaging of the device,
is carried out with 25 kGy.
[0327] It will be possible to inject this device at the local level
to deposit the cylinder of lanreotide before or after angioplasty,
like a stent, through the lumen of the catheter.
[0328] The local delayed-release effect of this formulation has
previously been evaluated intramuscularly (i.m.) on dogs, and i.m.
and subcutaneously (s.c.) in man.
[0329] FIG. 23 shows the result of pharmacokinetics on dogs of the
12.8 mg solid form of lanreotide intramuscularly.
[0330] FIG. 24 shows the results of kinetics in healthy volunteers
subcutaneously (A) and intra-muscularly (B).
[0331] The results obtained allow a sustained delayed-release
effect to be considered at the local level of angioplasty with a
high local concentration over this period.
EXAMPLE 3
[0332] Semi-solid Depot of Lanreotide Acetate
[0333] Lanreotide acetate forms an injectable delayed-release paste
or a semi-solid with water.
[0334] The delayed-release effect is obtained by deposition,
directly from the active principle. This delayed-release effect is
modulable as a function of the percentage. The duration of action
is thus directly proportional to the erosion or elimination of this
semi-solid depot. It is thus possible to combine any other active
principle, for which the combined local effect will be sought, with
lanreotide. It will be possible to evaluate the duration of action
of the AP(s) by the pharmacokinetics of the lanreotide alone.
[0335] The semi-solid is manufactured according to a process close
to that of the solid of Example 2 without mannitol. Extrusion,
drying and rearrangement are replaced by distribution. For example,
for 200 units 40 g of lanreotide acetate will be prepared in the
case of the 35% lanreotide acetate, 65% water one-month form and
for injected doses of 40 mg of AP.
[0336] The manufacturing steps are weighing, connection,
evacuation, hydration, mixing, distribution and irradiation.
[0337] Distribution consists in a volumetric filling of the
injection device (FIGS. 11 to 16), for example, by rotary piston
from the mixture syringe. This semi-solid formulation has been the
subject of a clinical trial in healthy volunteers intramuscularly
(FIG. 25).
[0338] It will thus be possible to then obtain a form which is
local over one month. The concentration and the quantity of paste
will determine the duration and the intensity of the local
diffusion.
EXAMPLE 4
[0339] Comparison of a 20% Matrix Form of Active Principle with a
52% Non-matrix Form
[0340] A very soluble Triptoreline acetate (TA) salt is mixed with
a PLGA (75:25) of molecular weight more than 100,000 and of
inherent viscosity equal to 1 dl/g in chloroform which only
undergoes hydrolysis by loss of mass capable of controlling a
matrix liberation after one month.
[0341] 20% (before percolation) and 52% by weight mixtures of
active principle in PLGA are thus prepared. These mixtures are
extruded so as to form implants whose release is verified in vitro
at 37.degree. C. in 10 ml of physiological serum and without
stirring.
[0342] The 20% implants of active principle only liberate 4% of the
total dose in two days and only 6.7% in 36 days before the loss of
mass of the polymer takes place which involves the liberation of
the active principle between d36 and d60 (FIG. 26). The 52%
implants of active principle liberate 66% of the total dose in two
days and more than 90% in one week (FIG. 27).
EXAMPLE 5
[0343] Comparison of a Matrix and Non-matrix Form With an Insoluble
Salt of Triptoreline (Triptoreline pamoate)
[0344] Two formulations of Triptoreline pamoate and PLGA (50:50)
are prepared, the first with 40% and the second with 52% of active
principle.
[0345] The liberation of these two formulations is compared in an
in-vitro release model (the low solubility of the active principles
necessitates a suspending volume of 100 ml).
[0346] Despite the insolubility of the active principle, a
matrix-type release with 40% is observed (FIG. 28). At 52% (FIG.
29), the release is already essentially independent of the
matrix.
[0347] The in-vitro functioning of the active principle with
respect to the PLGA in matrix and non-matrix mode thus does not
depend on the solubility of its salt.
EXAMPLE 6
[0348] Macroscopic Difference in Mode of Action Between Matrix
Formulation and Non-matrix Form
[0349] The matrix preparation of Example 4, 75:25 PLGA/Triptoreline
acetate (80%-20%) in a non-disperse form after ten days in a
physiological medium in vitro contains virtually all its active
principle; it has a translucent appearance with an increase in
diameter and a decrease in length with respect to time 0 (FIG. 30),
which demonstrates a constraint of the PLGA matrix.
[0350] The 75:25 PLGA/Triptoreline acetate (48%-52%) non-matrix
preparation under the same conditions after ten days is virtually
totally devoid of active principle. It has not undergone a change
in diameter or in length (FIG. 31).
[0351] The active principle has thus escaped from the PLGA
non-matrix skeleton. In this case, the active principle is free of
any physicochemical constraint with the polymer. The PLGA remains
unchanged in the course of the release of the active principle.
EXAMPLE 7
[0352] Comparison Between Non-matrix Form (52% of Triptoreline
Acetate) and Non-matrix Forms with 70% and 80% of Triptoreline
Acetate
[0353] In the same in-vitro release model as in Example 4, three
non-matrix forms were compared at the same dose of 9 mg. The
release results over one day (FIG. 32) demonstrate a similarity of
action of these three formulations. The release value obtained in
vitro is thus not proportional to the C.L. This demonstrates the
role of the active principle and of its total quantity in the
action of the non-matrix forms.
EXAMPLE 8
[0354] Comparison of the In-vitro Liberation of the 52% Non-matrix
Forms in a Dose of 6 mg and 9 mg
[0355] Two formulations using the same 75:25 PLGA of MW greater
than 100,000 were produced with a C.L. of 52% of Triptoreline
acetate (TA). These two formulations were checked in vitro, the
first at a dose of 9 mg (52% of TA in 9 mg) and the second at a
dose of 6 mg (52% of TA in 6 mg). The results (FIG. 33) demonstrate
a difference in release kinetics linked to the difference in dose
of active principle.
EXAMPLE 9
[0356] Comparison of Matrix Forms with 52%, 70% and 80% of Active
Principle (Triptoreline acetate) in an In-vivo Trial in Rats
[0357] Two batches of implants with 52% of active principle, one
batch of implant with 70% of active principle and one batch of
implant with 80% of active principle were injected subcutaneously
in four groups of 12 rats: 4 animals from each group were
sacrificed on d1, d4 and d19. The implants were recovered and
determined by HPLC in order to know the residual quantities of
active principle.
[0358] The results of FIG. 34 express the residual level of the
implants as a percentage between d0 and d19.
[0359] An obvious parallelism is noted in the decrease of this
percentage between the 52%, 70% or 80% forms.
[0360] FIG. 35 represents the development of the residual quantity
of pure active principle in mg. It is noted that contrary to the
results in vitro after 19 days, on average there remains a quantity
of active principle which is significant and equivalent in the 52%
implants and in the 70% and 80% implants.
[0361] Plasma samples were taken on these animals before sacrifice
and this result was confirmed by an RIA analysis.
EXAMPLE 10
[0362] Pharmacokinetic Result of a Matrix Formulation (20% of
active principle) and of a Non-matrix Formulation (52% of active
principle) in Dogs
[0363] The 20% and 52% formulations of Triptoreline acetate were
injected i.m. into two series of six dogs in respective total doses
of 3 and 6 mg of pure Triptoreline and the kinetics were followed
by RIA analysis of the plasma samples as well as the dynamic
efficacy of the active principle with the testosterone levels
(FIGS. 36 and 37).
[0364] The results demonstrate a release activity over three months
at least in the two cases.
[0365] The kinetics of the 20% form show a conventional profile
(with peak and rebound). The kinetics of the 52%. form are not
comparable to those of the conventional PLGA forms but are of
pseudo 0 order without peak or rebound.
EXAMPLE 11
[0366] Pharmacokinetic Results of a Non-matrix Formulation with 70%
of Active Principle in Dogs
[0367] A formulation using the same PLGA and the same active
principle as the 52% formulation of active principle (Example 10)
was produced with 70% and 30% of PLGA.
[0368] This formulation was injected i.m. in the dog at a total
dose of 9 mg of pure Triptoreline. The kinetics were followed by
RIA analysis of plasma samples (FIG. 38A) as well as the dynamic
efficacy of the active principle with testosterone levels (FIG.
38B).
[0369] The results indeed show a release activity over at least
three months as for the 52% form of active principle with, as the
only difference, a higher release level on making the total dose
vary.
[0370] The variation of the loading between 52% and 70% does not
influence either the duration or the profile and the release level
indeed depends on the total dose injected (FIG. 39).
* * * * *