Title of Invention

A COMPOSITION FOR TOPICAL USE

Abstract New pharmaceutical compositions containing hyaluronic acid and collagenase for the topical treatment of wounds, burns and ulcers The present invention concerns new compositions containing hyaluronic acid or the derivatives thereof in association with the proteolytic enzyme collagenase (and relative pharmaceutical formulations) for the preparation of a dressing for topical treatment of various kinds of wounds, burns of varying depth, pressure sores, vascular ulcers and diabetic foot ulcers as well as for the treatment of hypertrophic and keloid scars.
Full Text

''New pharmaceutical compositions containing hyaluronic acid and col 1 agenase for the topical treatment of wounds, burns and ulcers"
SUBJECT OF THE INVENTION The present invention concerns new compositions containing hyaluronic acid or the derivatives thereof in association with the proteolytic enzyme collagenase (and relative pharmaceutical formulations) for the preparation of a dressing for topical treatment of various kinds of wounds, burns of varying depth, pressure sores, vascular ulcers and diabetic foot ulcers as well as for the treatment of hypertrophic and keloid scars.
BACKGROUND OF THE INVENTION Enzyrnatic debridetnent of necrotic tissue involves the removal of such tissue by means of the action of non-toxic, enzymes that are able to degrade denaturated collagen, fibrin and elastin present in the devitalised tissue, preserving the viable tissue.
This technique is preferable to mechanical/surgical debridement because it is more selective towards granulation tissue and is especially suitable in non-infected lesions such as skin ulcers of diverse etiology and of varying depth.
The enzymatic formulations available on the market today contain the proteolytic enzyme collagenase _[Noruxol and

Iruxol®) or are constituted by an association of f ibrinolysin and desoxyribonuclease (Elase ) , all of which are effective (albeit with different results) in removing necrotic tissue, purulent exudate and fibrin (Mekkes J. R., Arch Dermatol Rese, 1998, 290:152-157).
Of great interest from the point of view of application are collagenases produced from bacteria of the Clostridium species, although collagenase produced from Vibrio Alginolyticus (Achromobacter collagenase EC 3.4.24 . 08 ; Borivoj k. , Matrix Supplement, 1992, 1: 127-133; EP0115974 Bl) produced from a non-pathogenic strain with a specific activity that is markedly superior to that of the enzyme produced from Clostridium, has been widely described and characterised (albeit not yet marketed).
Collagenase is a protein that is very unstable in aqueous solutions even at lov; temperatures. Moreover, it can easily be denaturated by chelating agents and various metal ions that can interact with the calcium ion that is essential for the enzymatic activity of the molecule.
It is an enzyme that is extremely sensitive to chemical-physical procedures such as freezing, thawing, freeze-drying and drying, processes that are often necessary in the course of preparing final pharmaceutical formulations. Various different formulations have therefore been tested to find a final composition that contains a stable, and therefore active, collagenase (EP0543521B1, patent application WO96/41870, WO93/00807, W094/24273) .

Albeit still at an experimental stage, the enzyme is used in injectable form to treat Dupuytren's contracture, a deforming condition of the fingers, while the use of collagenase is particularly important in reducing glaucoma, a disorder that causes excessive pressure in the eye with possible damage to the optic nerve, linked with an abnormal deposit of collagen within the duct that drains biological fluids from the anterior chamber of the eye.
The collagenase enzyme is mainly indicated in debridement of burns of varying depth, pressure sores, vascular ulcers and diabetic foot ulcers. Moreover, it is used to treat hypertrophic and keloid scars.
Proper wound healing requires a proper reepithelialisation phase, which follows the phase involving removing the eschar, possibly by surgical and/or enzymatic debridement. Collagen is the chief component of necrotic tissue and, consequently, it is fundamentally important to remove it in order to favour reepithelialisation of the wound. However, in the course of this operation it is necessary to protect the surrounding skin to avoid painful irritative phenomena resulting from the use of collagenase, as the enzyme is capable of degrading both denaturated and natural collagen, hydrolysing the peptide bonds of the amino acid chain. During enzymatic debridement the wound area being treated does not decrease in size, it may even increase. Therefore, when the eschar has been removed, the newly-forming granulation tissue is exposed and consequently open to

dangerous bacterial infections that may jeopardise complete
healing of the lesion.
The wound healing process is a complex phenomenon involving
many types of cellular and humoral factors/ and many phases
that can favour the formation of pathological scarring,
such as hypertrophic and keloid scars.
Proper healing therefore requires the application of drugs
to guide (and accelerate) the wound healing process.
Scientific and patent literature contains ample
descriptions and claims naming hyaluronic acid (HA) as the
chief factor in the tissue regeneration processes (European
patent application EP1196179).
Indeed, thanks to its special chemical-physical and
biological features, hyaluronic acid participates in and
modulates all the main sequential phases of wound healing:
m inflammationl;•
• formation of granulation tissue;
• reepithelialisation;
• scar remodelling.
Owing to its chemical-physical properties, said polysaccharide controls tissue hydration, creating the correct microclimate necessary to fast healing; moreover, its high viscosity protects the wound from possible bacterial and/or viral infections.
Thanks . to its biological properties, hyaluronic acid has proved effective in protecting against free radicals, in controlling inflammatory processes and stimulating

angiogenesis. Its role in controlling the expression of
cytokines and trophic factors has been demonstrated, and in
stabilising the granulation tissue by favouring and
regulating the flow of fibroblasts and endothelial cells
into the wound during reepithelialisation.
Lastly, experimental data have demonstrated an involvement
of hyaluronic acid in controlling keratinocyte
proliferation and the deposit of collagen in the wound,
thus reducing the formation of fibrotic tissue and,
therefore, of pathological scarring (John Chen W. Y. et
al.. Wound Repair and Regeneration, 1999, 7:79-89).
HA is a hetero-polysaccharide composed of alternating
residues of D-glucuronic acid and N-acetyl-D-glucosamine.
It is a straight-chained polymer with a molecular weight in
the range of 50,000 to 13 x 10^ Da, according to the source
from which it is obtained and the methods used to prepare
it.
It is present in nature in the pericellular gels, the
fundamental substance of the connective tissue in
vertebrate organisms (of which it represents one of the
chief components), in the synovial fluid of joints, in the
vitreous humor and umbilical cord.
HA therefore plays an important role in the biological
organism (besides those described above), as a mechanical
support for the cells of many tissues, such as the skin,
tendons, muscles and cartilage.
Said polysaccharide is known to be used as a vehicle for

drugs of various kinds, in simple associations or salified with hyaluronic acid, since its special properties of biocompatibility, biodegradability, non-immunogenicity, viscosity and hydratability make it particularly suitable as a release system for drugs and molecules both at a topical and systemic level (EP0197718B1, EP0445255B1) . Indeed, preclinical experiments with HA associated with anti-inflammatories (such as Diclofenac) for topical use have demonstrated that HA significantly increases (compared to controls) absorption of the drug into the skin where, thanks to the specific action of hyaluronic acid, it is compartmented to form a 'reservoir", minimising further absorption through the skin. The drug's action (and efficacy) is thus significantly increased (Brown M.B. et al., JEADV, 2005, 19:3 09-318).
The Applicant, contrary to the above description of KA as a delivery system, has surprisingly discovered that an association between HA and/or the derivatives thereof with the enzyme collagenase determines a clear reduction in the enzyme's activity, thus enabling the degradation/removal of the eschar with simultaneous formation of granulation tissue, thanks to the specific action of HA. Moreover, said polysaccharide protects the healthy tissue ■surrounding the lesion from the digestive action of collagenase, thus increasing patient compliance with the product. By slowing down the proteolytic activity of collagenase,

hyaluronic acid manifests properties that prove to be the absolute opposite of those of the delivery system described above, as known to an expert in the current state of the art.
A further subject of the present invention is represented by pharmaceutical formulations of a lipophilic nature, containing collagenase in association with HA, that enable the complete stabilisation of the enzyme and, therefore, its maintenance in an active form, at room temperature for prolonged periods of time.
DETAILED DESCRIPTION OF THE INVENTION The present invention describes and claims the association of HA and/or the derivatives thereof with the enzyme collagenase in pharmaceutical formulations of a lipophilic nature which, thanks to the presence of special excipients/stabilisers, allow the proteolytic enzyme to remain stable at room temperature for prolonged periods of time.
Thanks to HA's special properties in tissue regeneration, enzymatic debridement by the new enzyme/HA composition substantially modifies the phases of eschar removal and new tissue regeneration that normally follow treatment with collagenase alone, permitting the establishment of new phases that determine proper wound healing without the formation of pathological scarring:

• the degradation/removal of eschar occurs at the same time as the formation of granulation tissue;
• the formation of new connective tissue determines a reduction in wound size after eschar removal (for the reasons given above) and, hence, a signif icant decrease in the risk of bacterial and/or viral infections;
• the healthy surrounding tissue is protected from the digestive action of collagenase thanks to HA;
• eschar removal can be performed painlessly.
The claims of the new collagenase/HA formulations described above are possible because HA has proved capable of modulating the proteolytic activity of collagenase significantly slowing down its action during enzymatic debridement of the necrotic tissue, as demonstrated hereafter.
The formulation of enzyme/HA is particularly indicated in the debridement of burns of varying depth, pressure sores, vascular ulcers and diabetic foot ulcers, wounds of various nature and of different sizes and depth and, moreover, in the treatment of hypertrophic and keloid scars with final patient compliance with the product that is decidedly greater than that with the enzyme alone.
Furthermore, said composition is also claimed in the treatment of Dupuytren's contracture and glaucoma.

The HA derivatives that can be used in the new formulations that are the subject of the present invention are listed below:
1. HA salified with organic and/or inorganic bases with a molecular weight of 50-730KDa (EP0138572 Bl) or with a high molecular weight of 750-1230 KDa, (EP 535200 Bl) ;
2. Hyaff®: esters of HA with alcohols of the aliphatic, araliphatic, cycloaliphatic, aromatic, cyclic or heterocyclic series, with a percentage of esterification that may vary according to the type and length of the alcohol used, between 1 and 100%, preferably between 50 and 75% (EP 216453 Bl);
3. HyaddTM: amides of HA with amines of the aliphatic, araliphatic, cycloaliphatic, aromatic, cyclic and heterocyclic series, with a percentage of amidation of between 1 and 10%, preferably 4% (EP 1055064 Bl) ;
4. 0-sulphatated derivatives of HA up to the 4th degree of sulphatation (EP 0702699 Bl) ;
5. ACP®: inner esters of HA with a percentage of inner esterification between 0.5 and 10% and preferably 5% (EP 0341745 Bl);
6. Peacetylated HA derivatives: derived from the deacetylation of the N-acetyl-glucosamine fraction with a percentage of deacetylation preferably between 0.1 and 30%, while all the carboxy groups of HA can be salified with organic and/or inorganic bases (EP1313772 Bl);

7. HYOXX™: percarboxylated derivatives of HA obtained
from the oxidation of the primary hydroxyl of the N-
acetyl-glucosamine fraction with a degree of
percarboxylation of between 0.land 100% and preferably
between 25 and 75%. All the carboxy groups of HA can
be salified with organic and/or inorganic bases
(patent application No, EP1339753).
The HA used in the present invention as such or in the
preparation of its derivatives may be derived from any
source, for example it may be obtained by extraction from
rooster combs (EP0138572 Bl) , by fermentation, or by
technological means and its molecular weight may vary
between 400 and 3xlO6Da, in particular between Ix lO5Da and
Ix lO6Da, and more particularly still between 50,000 and
200,000 Da.
The concentration of the collagenase enzyme to be used in association with HA or the derivatives thereof may vary between 0,01U and lOOU/milligram of HA, preferably between 0,1 and 20U and more preferably still between 0,2 and lOU/mg of HA.
The final concentration of HA or the derivatives thereof in the final pharmaceutical composition may vary between 0.01 and 5% weight/weight of the final product, ranging preferably between 0.1 and 2% w/w, and more preferably still between 0.2 and 0.4% w/w.
One unit of collagenase is defined as the quantity of enzyme that hydrolyses 1 nraole of PZ-Pro-Leu-Gly-Pro-D-Arg

in one second at pH equal to 7.1 and at 37°C (PZ=4-phenyl-
azobenzyloxycarbonyl) (Wunsch E. et al, Physiol Chem, 1963,
333:149-151) .
The collagenase preferably used or to be used in the
compositions that are the subject of the present invention
is that produced from the non-pathogenic micro-organism
belonging to the Vibrio Alginolyticus sub. lophagus strain,
NCIMB (National Collection of Industrial and Marine
Bacteria), strain number 11038, equivalent strain: LMG
3418.
It is a gram negative micro-organism that produces a
collagenase with a molecular weight of from 90,000 to
110,000 Daltons, (lUBMB nomenclature: EC 3 .4 .24.3), stable
in a pH range of 4.0 and 11.0 but with an optimal pH of
between 6.0 and 8.0, stable at temperatures varying between
4 and 40°C with an optimal temperature of 37 °C.
The enzyme is defined as a metalloendopeptidase because it
breaks up the collagen into peptide fragments, acting
directly on its triple-chain protein structure. The
specific activity of the enzyme is inhibited hy the silver
and copper salts and also by chelating agents such as EDTA,
which bind the calcium ion necessary to collagenase
activity.
Collagenolytic activity of collagenase from Vibrio
Alginolyticus versus the activity of the same enzyme
associated with hyaluronic acid

The aim of the study was to compare the activity of the enzyme as such with that of the new composition of collagenase/HA, to observe the influence of hyaluronic acid on the proteolytic activity of the same enzyme. Material:
• collagen extracted from bovine skin at a concentration of Img/ml (of buffer prepared as described hereafter) as a substrate for enzymatic activity;
• collagenase extracted from Vibrio Alglnolytxcus tested at three different concentrations of 0,33, 0,66 and 1,32 enzyme units;
• collagenase extracted from Vibrio Alginolyticus tested at the same three concentrations of 0,33, 0,66 and 1,32 U but in association with hyaluronic acid at the following ratios; 0,16 U/mg of HA, 0,33 U or 0,66 U/mg of HA (hence, 0,33, 0,66 and 1,32 U are associated with 2 mg of HA) . In all three cases, the concentration of the polysaccharide was kept constant.
Method of enzymatic digestion:
the collagen degradation process was performed at 37 ^C for
a time period initially set at 90 minutes. Subsequently,
the process was repeated at the same concentrations and at
the same temperature, but the reaction was halted 4 and 12
hours after it was begun.
The digestion reaction occurred in Tris-HCL buffer, 0,05 M,
containing CaCl2 0,01M at pH=7,4 to which the reaction
substrate had been added, either collagenase itself or the

enzyme associated with set concentrations of HA as described above. Results:
the enzymatic digestion mixture obtained (enzyme and relative collagen degradation products) was analysed on 7% polyacrylamide gel (electrophoresis: SDS-PAGE; Laemmli U. K., Nature, 1970, 680-685), to map the various protein fragments separated according to their molecular weight, (MW) and stained with Comassie blue.
After the electrophoresis run, the collagen separates into subunits with a MW of about 100,000 Daltons with further peptide fragments with a MW of about 33,000 Daltons, All the gels were loaded with molecular weight standards, with undigested collagen as positive control, with collagen degraded by collagenase as such and relative enzyme separately loaded and, lastly, with collagen degraded by collagenase associated with HA and enzyme alone. Figure 1 clearly shows that 0,33 U enzymes only partially degrade collagen in 90 minutes but, above all, that the presence of HA in the collagenase/HA composition (at the same concentration of enzyme) modifies the collagenolytic action of the enzyme, reducing its activity.
Figures 2 and 3 further show the modulatory action exercised by hyaluronic acid on the enzyme: after 90 minutes 0,66 and 1,32 U of collagenase completely degrade the collagen while, especially at 0,66 U, HA slows down the collagenolytic action of the enzyme. The influence of said

polysaccharide on the enzyme is even more evident with 1,32
U of collagenase.
Figures4 and 5 show the situation after 4 and 12 hours:
after 4 hours of incubation of the enzyme (0,66 U) with
collagen it is still possible to observe the action of HA
on collagenase because the undigested protein fractions of
collagen are visible, albeit faintly; after 12 hours (again
with 0,66 U of enzyme) the modulatory action of the
polysaccharide is no longer evident and the collagen is
completely degraded.
For purely descriptive purposes, and without being limited
by the same, we report hereafter some examples of how the
new formulations that are the subject of the present
invention can be prepared:
Method of producing collagenase/HA llpogel
An initial aqueous solution or a buffer solution at pH 7,1 (TrisHCL 25 mM, CaCl2 10 mM) is prepared with 82,7 U/ml of collagenase; 45 ml of this solution is freeze-dried with the following excipients: Maltose (18 g) as diluent/stabiliser, Carrageenan, possibly purified (0,54 g) as stabiliser and water 45 g. 18.6 g of f reeze-dried product is obtained (dry product) , composed as follows:
• maltose 95% w/w
• carrageenan 2,8% w/w
• collagenase 0,9% w/w
The freeze-dried product is then micronised.

At the same time, HA obtained by fermentation and with a MW
of 160KDS is also micronised.
Dispersion of the functional components in the lipophilic
base:
Examples 1 and 2
The enzyme collagenase and HA prepared as described above
are evenly dispersed in a lipophilic base constituted by
the following excipients:
• hydrogenated castor oil in powder form {with gelling action)
• cetylstearylic alcohol (as agent of consistence)
• stringy Vaseline (as lipophilic phase)
• light Vaseline oil (as lipophilic phase)
Preparation of the lipophilic base:
dissolve and solubilise at about 88-90 °C the stringy
vaseline and cetylsterylic alcohol in the vaseline oil..
Once a smooth, melted mass has been obtained, dissolve and solubilise the hydrogenated castor oil powder in the newly formed lipophilic phase. Once the mass is evenly melted, cool to 25-30 ^C.








Dispersion of the functional components in the lipophilic base: Example 3
Incorporate and solubilise light Vaseline oil in Jojoba Glaze while slowly stirring at 70-75°C (lipophilic gelling system based on styrene copolymers - propylene - butylene in Jojoba oil) until a smooth mass is obtained. Cool to room temperature and then add, while stirring, Micronised HA and micronised, lipophilic Collagenase as previously described, until the powders have been completely amalgamated in the lipogel.



Said formulations may contain pharmacologically and/or biologically active substances such as, for example, antibiotics, antivirals, wound healers, cytostatic/cytotoxic agents, anticancer drugs, hormones, steroid and non-steroid anti-inflammatory drugs, trophic factors and cytokines of various nature.
The invention being thus described, it is clear that these methods can be modified in various ways. Such modifications are not to be considered as divergences from the spirit and purpose of the invention and any modification that would be

evident to an expert in the field comes within the scope of the following claims.

Explanations of the figures
Figure 1: Collagen digestion time of 90 minutes
MWS = molecular weight standards represented by 6 bands: 205KDs, 116KDs, 97KDs, 66KDs, 45KDs, 29KDs; CP = Collagen as such, Positive control; Coll. 1 = Collagenase at a concentration of 0,33U + collagen; Coll. 2 = Collagenase at a concentration of 0,33U; Coll./HA 1 = Collagenase at a concentration of 0,33U + collagen in the presence of HA; Coll./HA 2 Collagenase at a concentration of 0,33U in the presence of HA.
Figure 2: Collagen digestion time of 90 minutes MWS = molecular weight standards represented by 6 bands: 205KDS, 116KDs, 97KDs, 66KDs, 45KDs, 29KDs; CP = Collagen as such. Positive control; Coll. 1 = Collagenase at a concentration of 0,66U + collagen; Coll. 2 = Collagenase at a concentration of 0/66U; Coll,/HA 1 = Collagenase at a concentration of 0,66U + collagen in the presence of HA; Coll. /HA 2 = Collagenase at a concentration of 0/66U in the presence of HA.
Figure 3: Collagen digestion time of 90 minutes
MWS = molecular weight standards represented by 6 bands: 205KDS, llSKDs, 97KDS, 66KDS, 45KDs, 2 9KDs; CP = Collagen as such. Positive control; Coll. 1 = Collagenase at a concentration of 1,32U + collagen; Coll. 2 = Collagenase at a concentration of 1,32U; Coll./HA 1 = Collagenase at a concentration of 1,32U +

collagen in the presence of HA; Coll./HA 2 Collagenase at a concentration of 1,32U in the presence of HA.
Figure 4: Collagen digestion time of 4 hours
MWS = molecular weight standards represented by 6 bands: 2 05KDs, ll6KDs, 97KDs, 66KDs, 45KDs, 29KDs; CP = Collagen as such, Positive control; Coll. 1 = Collagenase at a concentration of 0,66U + collagen; Coll. 2 = Collagenase at a concentration of 0,66U; Coll./HA 1 = Collagenase at a concentration of Q,66\3 + collagen in the presence of HA; Coll./HA 2 Collagenase at a concentration of 0,66U in the presence of HA
Figure 5: Collagen digestion time of 12 hours
MWS = molecular weight standards represented by 6 bands: 205KDs, 116KDs, 97KDs, 66KDs, 45KDs, 29KDs; CP = Collagen as such, Positive control; Coll. 1 = Collagenase at a concentration of 0,66U + collagen; Coll. 2 = Collagenase at a concentration of 0,66U; Coll./HA 1 = Collagenase at a concentration of 0,66U + collagen in the presence of HA; Coll. /HA 2 = Collagenase at a concentration of 0,66U in the presence of HA.












CLAIMS
1) Medicament for topical use containing hyaluronic acid and/or the derivatives thereof in association with the proteolytic enzyme collagenase.
2) Medicament containing hyaluronic acid and/or the derivatives thereof in association with the proteolytic enzyme collagenase for the treatment of Dupuytren's contracture and glaucoma.
3) Medicament according to claims 1 and 2 wherein the collagenase is produced from the non-pathogenic microorganism belonging to the strain ViJbrio Alginolyticus sub. lophagus.
4) Medicament according to claims 1-3 wherein the hyaluronic acid derivatives are its salts with organic and/or inorganic bases, esters, amides, sulphatated derivatives, inner esters, deacetylated and percarboxylated derivatives.
5) Medicament according to claims 1-4 containing pharmacologically and/or biologically active substances.
6) Medicament according to claims 1, 3-5 in the treatment of burns of varying depth, pressure sores, vascular ulcers and diabetic foot ulcers and in the treatment of hypertrophic and keloid scars.
7) Medicament according to claims 1-6 wherein the concentration of the proteolytic enzyme collagenase may vary between 0,01U and lOOU/milligrams of HA.

8) Medicament according to claim 7 wherein the concentration of the enzyme collagenase ranges between 0,1 and 20U/milligrams of HA.
9) Medicament according to claim 8 wherein the concentration of the enzyme collagenase ranges between 0,2 and lOU/milligrams of HA.

10) Medicament according to claims 1-9 wherein the final concentration of HA may range between 0.01 and 5% weight/weight of the finished product.
11) Medicament according to claim 10 wherein the final concentration of HA ranges between 0.1 and 2% w/w.
12) Medicament according to claim 10 wherein the final concentration of HA ranges between 0.2 and 0.4% w/w.
13) Pharmaceutical compositions according to claims 2-5 and 7-12 for the treatment of Dupuytren's contracture and glaucoma.
14) Lipophilic pharmaceutical compositions containing hyaluronic acid and/or the derivatives thereof in association with the proteolytic enzyme collagenase and further containing maltose and carrageenan as stabilising agents.
15) Lipophilic pharmaceutical compositions
according to claims 2-5, 7-12 containing maltose and
carrageenan as stabilising agents.

16) Pharmaceutical compositions according to
claims 14 or 15 in the treatment of burns of varying
depth, pressure sores, vascular ulcers and diabetic
foot ulcers and in the treatment of hypertrophic and
keloid scars.
17) Use of medicaments according to claims 1,
3-5, 7-12 in the treatment of burns of varying depth,
pressure sores, vascular ulcers and diabetic foot
ulcers and in the treatment of hypertrophic and keloid
scars.
18) Use of medicaments according to claims 2-
5, 7-12 for the treatment of Dupuytren's contracture
and glaucoma.
19) Use of lipophilic pharmaceutical
compositions according to claims 14 or 15 the
treatment of burns of varying depth, pressure sores,
vascular ulcers and diabetic foot ulcers and in the
treatment of hypertrophic and keloid scars.
20) Use of lipophilic pharmaceutical
compositions according to claims 14 or 15 for the
treatment of Dupuytren's contracture and glaucoma.
21) Process for the preparation of a lipogel
containing hyaluronic acid and/or the derivatives
thereof in association with the proteolytic enzyme
collagenase, involving the following steps:
I) preparation of freeze-dried collagenase with set quantities of maltose and carrageenan;

II) micronisation of said freeze-dried collagenase;
III) micronisation of HA;
IV) preparation of the lipophilic base of the lipogel;
V) smooth dispersion of the micronised components in
the lipogel base.


Documents:

095-chenp-2008-abstract.pdf

095-chenp-2008-claims.pdf

095-chenp-2008-correspondnece-others.pdf

095-chenp-2008-description(complete).pdf

095-chenp-2008-drawings.pdf

095-chenp-2008-form 1.pdf

095-chenp-2008-form 18.pdf

095-chenp-2008-form 3.pdf

095-chenp-2008-form 5.pdf

095-chenp-2008-pct.pdf

95-CHENP-2008 AMENDED PAGES OF SPECIFICATION 10-08-2011.pdf

95-CHENP-2008 AMENDED CLAIMS 10-08-2011.pdf

95-chenp-2008 correspondence others 18-08-2011.pdf

95-chenp-2008 form-1 10-08-2011.pdf

95-CHENP-2008 OTHER PATENT DOCUMENT 02-09-2011.pdf

95-chenp-2008 power of attorney 18-08-2011.pdf

95-CHENP-2008 AMENDED CLAIMS 04-05-2012.pdf

95-CHENP-2008 AMENDED PAGES OF SPECIFICATION 04-05-2012.pdf

95-CHENP-2008 CORRESPONDENCE OTHERS 04-05-2012.pdf

95-CHENP-2008 EXAMINATION REPORT REPLY RECEIVED 10-08-2011.pdf

95-CHENP-2008 FORM-3 02-09-2011.pdf

95-CHENP-2008 CORRESPONDENCE OTHERS 02-09-2011.pdf

95-CHENP-2008 CORRESPONDENCE 30-05-2011.pdf


Patent Number 254184
Indian Patent Application Number 95/CHENP/2008
PG Journal Number 40/2012
Publication Date 05-Oct-2012
Grant Date 28-Sep-2012
Date of Filing 07-Jan-2008
Name of Patentee FIDIA FARMACEUTICI S.P.A
Applicant Address VIA PONTE DELLA FABRICA 3/A, I-35031 ABANO TERME
Inventors:
# Inventor's Name Inventor's Address
1 VACCARO, SUSANNA FIDIA FARMACEUTICI S.P.A VIA PONTE DELLA FABRICA 3/A, I-35031 ABANO TERME
2 GENNARI, GIOVANNI FIDIA FARMACEUTICI S.P.A VIA PONTE DELLA FABRICA 3/A, I-35031 ABANO TERME
3 CALLEGARO, LANFRANCO FIDIA FARMACEUTICI S.P.A VIA PONTE DELLA FABRICA 3/A, I-35031 ABANO TERME
4 GIANNELLI, ANTONIO FIDIA FARMACEUTICI S.P.A VIA PONTE DELLA FABRICA 3/A, I-35031 ABANO TERME
5 CARUSO, SALVATORE FIDIA FARMACEUTICI S.P.A VIA PONTE DELLA FABRICA 3/A, I-35031 ABANO TERME
PCT International Classification Number A61K 31/728
PCT International Application Number PCT/EP06/06616
PCT International Filing date 2006-07-05
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 PD2005A000207 2005-07-07 Italy