U.S. patent application number 16/267464 was filed with the patent office on 2019-06-06 for ready-to-use, hydrophilic, self-dispersive, fragmentable and biodegradable porous sponge matrix and a method of manufacturing th.
The applicant listed for this patent is DATT LIFE SCIENCES PRIVATE LIMITED. Invention is credited to Rajan DATT, RAMADHAR KUMAR, SIDDHARTH PANDEY, PALLAVI SHRIVASTAVA.
Application Number | 20190167837 16/267464 |
Document ID | / |
Family ID | 59495944 |
Filed Date | 2019-06-06 |
United States Patent
Application |
20190167837 |
Kind Code |
A1 |
DATT; Rajan ; et
al. |
June 6, 2019 |
READY-TO-USE, HYDROPHILIC, SELF-DISPERSIVE, FRAGMENTABLE AND
BIODEGRADABLE POROUS SPONGE MATRIX AND A METHOD OF MANUFACTURING
THEREOF
Abstract
The invention relates to porous absorbent Composite Material,
which may be used e.g. in the form of a plug or tampon, for
instance for controlling bleeding, wound closure, prevent tissue
adhesion and/or support tissue regeneration. The invention provides
a hydrophilic Self-Dispersive, fragmentable and Bio-Absorbable
Porous Composite foams, suitable for packing antrum or other
cavities of the body, comprising of composite of polymers, which
polymer preferably comprises --C(O)--O--; NH2/3+; --OH;
--CH2OCH2C(O)O-- groups as functional or --CH--O-- (e.g. C2H4O;
C6H10O5; C6H8O6); --CH--N--O-- (e.g. C8H13NO5); O--C--C-- (e.g.
O-CH2-CH2); --C(O)N-- groups in the backbone of the polymers e.g.
gelatin, chitosan, collagen, alginate, polyvinyl alcohol,
polyethylene glycol, keratin, cellulose.
Inventors: |
DATT; Rajan; (NEW DELHI,
IN) ; KUMAR; RAMADHAR; (NEW DELHI, IN) ;
PANDEY; SIDDHARTH; (NEW DELHI, IN) ; SHRIVASTAVA;
PALLAVI; (NEW DELHI, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
DATT LIFE SCIENCES PRIVATE LIMITED |
NEW DELHI |
|
IN |
|
|
Family ID: |
59495944 |
Appl. No.: |
16/267464 |
Filed: |
February 5, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15081202 |
Mar 25, 2016 |
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16267464 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61F 13/2082 20130101;
A61L 24/0036 20130101; A61F 13/2005 20130101; A61L 24/0015
20130101; A61L 24/0042 20130101; A61F 13/2074 20130101; A61F
2013/2014 20130101; A61L 24/043 20130101; A61F 13/2017 20130101;
A61F 13/36 20130101; C08J 2207/10 20130101 |
International
Class: |
A61L 24/00 20060101
A61L024/00; A61F 13/36 20060101 A61F013/36; A61F 13/20 20060101
A61F013/20; A61L 24/04 20060101 A61L024/04 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 8, 2016 |
IN |
201611004371 |
Claims
1-15. (canceled)
16. A porous sponge matrix, comprising: a biocompatible and
biodegradable polymer scaffold comprising a blend of synthetic and
natural polymers as a three-dimensional scaffold polyelectrolyte
complex (PEC) having vesicular micro-voids and an inner surface
area larger than its outer surface area; and at least one of an
antioxidant, clotting agent, growth factor, primary cells and stem
cells impregnated within the vesicular micro-voids of the
three-dimensional scaffold PEC, wherein the three-dimensional
scaffold PEC comprises a lyophilized and homogenized polymer formed
from a sequential timed and patterned physico/chemical treatment of
the synthetic and natural polymers as a polymer solution comprising
polyvinyl chloride at about 5% to 15%, Gelatin at about 2% to 7%
and Sodium Alginate at about 0.5% to 2%.
17. The porous sponge matrix according to claim 16, wherein the
sequential timed and patterned physico/chemical treatment of the
synthetic and natural polymers as a polymer solution further
comprises polyethylene glycol-200 at about 1 ml to 5 ml.
18. The porous sponge matrix according to claim 17, wherein the
sequential timed and patterned physico/chemical treatment of the
synthetic and natural polymers as a polymer solution further
comprises chitosan at about 0.5% to 1.0%.
19. The porous sponge matrix according to claim 16, wherein
three-dimensional scaffold PEC includes a cross-linker.
20. The porous sponge matrix according to claim 16, wherein the at
least one of an antioxidant, clotting agent, growth factor, primary
cells and stem cells comprises at least one of thrombin, calcium
chloride, polyphenol and tranexamic acid.
21. The porous sponge matrix according to claim 16, wherein the
three-dimensional scaffold PEC comprises a patch configuration.
22. The porous sponge matrix according to claim 16, wherein the
three-dimensional scaffold PEC comprises a plug, sheet or tampon
configuration.
23. A porous sponge matrix, comprising: a biocompatible and
biodegradable polymer scaffold comprising a blend of synthetic and
natural polymers as a three-dimensional scaffold polyelectrolyte
complex (PEC) having vesicular micro-voids and an inner surface
area larger than its outer surface area; and at least one of an
antioxidant, clotting agent, growth factor, primary cells and stem
cells impregnated within the vesicular micro-voids of the
three-dimensional scaffold PEC, wherein the three-dimensional
scaffold PEC comprises a lyophilized and homogenized polymer formed
from a sequential timed and patterned physico/chemical treatment of
the synthetic and natural polymers as a polymer solution comprising
polyvinyl alcohol at about 7.5%, Gelatin at about 10%, Sodium
Alginate at 1%, and polyethylene glycol-200 at about 3 ml.
24. The porous sponge matrix according to claim 23, wherein the
sequential timed and patterned physico/chemical treatment of the
synthetic and natural polymers as a polymer solution further
comprises chitosan at about 0.75 grams.
25. The porous sponge matrix according to claim 24, wherein the
sequential timed and patterned physico/chemical treatment of the
synthetic and natural polymers as a polymer solution further
comprises mucilage at about 1%.
26. The porous sponge matrix according to claim 23, wherein
three-dimensional scaffold PEC includes a cross-linker.
27. The porous sponge matrix according to claim 23, wherein the at
least one of an antioxidant, clotting agent, growth factor, primary
cells and stem cells comprises at least one of thrombin, calcium
chloride, polyphenol and tranexamic acid.
28. The porous sponge matrix according to claim 23, wherein the
three-dimensional scaffold PEC comprises a patch configuration.
29. The porous sponge matrix according to claim 23, wherein the
three-dimensional scaffold PEC comprises a plug, sheet or tampon
configuration.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application takes priority from and claims the benefit
of Indian Patent Application No. 201611004371 filed on Feb. 8,
2016, the contents of which are herein incorporated by
reference
BACKGROUND OF THE INVENTION
Field of the Invention
[0002] The present invention relates to the field of Medical
Biosciences. The present invention provides, generally, porous
absorbent materials which are suitable for packing antrum or
cavities of the human or animal body.
[0003] Particularly, the present invention provides a ready-to-use,
self-dispersive, biodegradable and biocompatible device.
[0004] More particularly, the invention relates to medical nonwoven
porous textiles.
[0005] Even more particularly, the invention relates to a device to
be used as nasal packing in the form of a plug, sheet or tampon,
for instance for controlling bleeding, endoscopic sinus surgery, in
most common procedures of ear dressing, wound closure, prevent
tissue adhesion and/or support tissue regeneration, wound healing
process, epistaxis purposes.
[0006] The present invention provides a porous scaffold meant as a
therapeutic carrier.
[0007] The present invention is a sterile product to carry the
therapeutic and/or bioactive molecules, biological or chemicals.
The present invention provides an art with preference to upregulate
and downregulate the process of self-dispersive nature of the
porous matrix.
[0008] The present invention also relates to a method of preparing
such a device for biomedical field.
[0009] The terms sponge/matrix/scaffold/device have been used
interchangeably throughout the specification and they all refer to
the same product, as discussed and covered in the scope of this
specification.
Description of the Related Art
[0010] Nasal packs are indispensable in ENT practice where the pack
is applied to the nasal cavities. The most common purpose of nasal
packing is to control bleeding following surgery to the septum or
nasal reconstruction, to prevent adhesion or restenosis and to
treat epistaxis. Further, the packing is also used to provide
support to the septum after surgery.
[0011] The range of materials used for this purpose is wide,
including both removable and absorbable materials. In cases of
septoplasty and rhinoplasty surgery, conventional non-biodegradable
packings are frequently removed within 24-48 hours following
surgery. In the case of epistaxis, packing is left in for extended
periods of time to promote healing and to prevent the patient from
touching and accidentally interfering with the recovery of the
wound. The packing may be left in the nose for as long as 7-10
days. If the wound is high up in the nasal cavity, packings treated
with petrolatum and/or antibiotics are sometimes used. In the art,
biodurable wound dressings are used for nasal packing. These
biodurable packs have to be removed after several days as described
above.
[0012] Numerous materials have been proposed in the prior art for
use as foams for absorbing or removing body fluids. Conventional
packs consisting of gauze or cotton have several disadvantages: the
fluid absorption capacity of the material is relatively low, the
structure is relatively fragile and individual threads or fibers
may break off, erroneous failure to remove the material from the
body after internal surgery may lead to serious complications and
the material is relatively expensive. Certain hydrophilic synthetic
materials intended for biomedical applications have improved
properties when compared to conventional materials when it comes to
absorption capacities and physico-mechanical properties. Examples
of such material are the cross-linked polyurethane--based hydrogels
as disclosed in e.g. U.S. Pat. Nos. 3,903,232, 3,961,629, 4,550,126
and EP-A-0 335 669. However, these materials are biodurable and not
biodegradable.
[0013] The ideal packing would be that which, besides of
controlling the hemorrhage and acting as a barrier to adhesion
formation, is easily adaptable and reasonably well tolerated by the
patient. Numerous packing agents are available, including
vaseline-soaked ribbon gauze; fingerstall packs, polyvinyl acetate
sponge (Merocel); various balloon tamponade devices. Even if most
of them are very effective in what it concerns the hemostasis,
these agents cause considerable discomfort for patients, both in
terms of pain and bleeding on removal (von Schoenberg M. et. al,
Nasal packing after routine nasal surgery--which is not justified.
J Laryngol Otol, 1993; 107:902-5; Samad I. et. al, The efficacy of
nasal septal surgery. J Otolaryngol, 1992; 21:88-91; Pomerantz J.
et. al, Platelet gel for endoscopic sinus surgery. Ann Otol Rhinol
Laryngol, 2005; 114:699-704; Vaiman M. et. al, The use of fibrin
glue as hemostatic in endonasal operations: a prospective,
randomized study. Rhinology, 2002; 40:185-8).
[0014] Other complications associated with removable nasal packing
(Weber R. et al., Packing in endonasal surgery. Am J Otolaryngol,
2001; 22:306-20; Weber R. et. al, Packing and stents in endonasal
surgery. Rhinology, 2000; 38:49-62): septal perforation (due to
pressure necrosis); pack dislodgement; aspiration; toxic shock
syndrome; foreign body granuloma; myospherulosis; obstructive sleep
apnea secondary to nasal obstruction and death.
[0015] One of the most important disadvantages of removable nasal
packing could be considered its impact on nasal mucosa, and
especially on the ciliated mucosal surface area. Animal studies
investigating the mucosal trauma caused by removable nasal packing
have shown a 50% to 70% loss of the ciliated mucosal surface area
in the region of the pack (Shaw C. L. et al., Effect of packing on
nasal mucosa of sheep. J Laryngol Otol, 2000; 114:506-9).
Therefore, a transient impairment of the patient's innate immune
system, the mucociliary clearance, may be associated with the use
of removable nasal packing (Chandra R. K. et. al, The effect of
FloSeal on mucosal healing after endoscopic sinus surgery: a
comparison with thrombinsoaked gelatin foam. Am J Rhinol, 2003;
17:51-5). The impact on patients' quality of life and also the
possible complications of removable nasal packing have led to the
ongoing development and application of absorbable biomaterials that
do not require subsequent removal and still achieve positive
effects on hemostasis, promote wound healing, and provide middle
turbinate support.
[0016] This lack of biodegradability makes such materials less
suitable for use in body cavities during surgery, since there is
always a possibility that the foam is left accidentally in the
body. Furthermore, removing non-biodegradable foams after
application in a natural body orifice may be very uncomfortable for
a patient and may open up the wound and/or lead to additional
scarring of the tissue. In order to prevent these undesired
effects, biodegradable sponges or absorbing foams comprising
materials of a natural source such as gelatine, proteins, collagen,
chitin, chitosan, cellulose or polysaccharides have been
suggested.
[0017] A wide range of absorbable materials with use in nasal
surgery were developed in the last years, including absorbable
porcine gelatin (Surgiflo, Ethicon Inc) and thrombin combination;
carboxy-methyl-cellulose (CMC, AthroCare); chitosan gel (Department
of Chemistry, University of Otago, Dunedin, New Zealand); Fibrin
glue (Quixil, Omrix Co.); FloSeal (Baxter International Inc);
hyaluronic acid (MeroGel, Medtronic); microporous polysaccharide
hemispheres (MPH, Medafor Inc); Platelet gel (PPAI Medical);
Surgiflo hemostatic matrix combined with thrombin; topical
antifibrinolytics such as epsilon-aminocaproic acid (Amicar,
Lederle Parenterals Inc) and tranexamic acid (Cyklokapron, Pfizer).
NasoPore, Polyganics B.V., Groningen, the Netherlands.
[0018] However, all of these materials lack the required mechanical
strength and have decrete effects on hemostatic, adhesion and
healing features. For example, the haemostatic sponge of
denaturated gelatin of WO 90/13320 does not have sufficient
mechanical strength to stop a severe nose-bleeding, because the
compression strength of the material in the wet condition is too
low and the sponge liquefies too fast after being applied in the
nasal cavity. U.S. Pat. Nos. 3,902,497 and 3,875,937 disclose
surgical dressings of bio-absorbable polymers of poly glycolic acid
(PGA).
[0019] Such materials are, although useful in other applications,
not useful in applications where sufficient counter pressure from
the foam is required, such as in nose-bleeding, because the
material is quite hard and brittle and is not resilient. Moreover,
the PGA material is not sufficiently hydrophilic to absorb the
blood during severe bleeding. Some hydrophilic synthetic polymers
based on polyurethene (WO 2004062704 A1) are used for nasal plug
(e.g nasopore, polyganic) but applicability covering all features
is not clear. No published literature has investigated the
hemostatic or wound-healing properties of polyethylene glycol
(NasoPore, Polyganics B.V., Groningen, the Netherlands) after ESS.
Further, the mechanical properties are compromised to make it
highly fragmentable.
[0020] Because of lack of standardization in this matter, still the
choice is in the surgeon's hand, according to his abilities,
beliefs, or technical possibilities. Now there is generally
recognized standard for which types of materials should be used,
how longs packs should remain placed, or when placement is
indicated. This invention relates current indications,
effectiveness and overcoming the risks of nasal packs and stents.
The need for absorbable sponges or absorbent foams that can be left
in the wound is now well recognized.
[0021] Nasal packs should always have smooth surfaces to minimize
mucosal damage, improve wound healing and increase patient comfort.
Functional endoscopic endonasal sinus surgery allows the use of
modern nasal packs, since pressure is no longer required. So called
hemostatic/resorbable materials are a first step in this direction.
However, they may lead to adhesions and foreign body reactions in
mucosal membranes. Simple occlusion is an effective method for
creating a moist milieu for improved wound healing and avoiding
dryness. Stenting of the frontal sinus is recommended if surgery
fails to produce a wide, physiologically shaped drainage path that
is sufficiently covered by intact tissue.
[0022] Requirements of such foams: a high and rapid absorption
capacity, particularly for blood, strength to be readily handled in
surgical procedures, conformable so as to fit into any topography,
maintenance of tissues' mechanical properties, for a specific
period of time during or after surgery or after application of the
matrix, soft so as to avoid injury to sensitive tissues. In some
instances, the softness of the foam may be increased by wetting of
the foam. Therefore, the absorbing foam should also have enough
mechanical strength and elasticity in the wet condition and can
also be cleared off via natural process to reduce doctors'
dependency.
[0023] Reference is made to U.S. Pat. No. 9,039,657, titled
"Implantable devices and methods for delivering drugs and other
substances to treat sinusitis and other disorders" dated 26 May
2015. This invention relates to implantable devices and methods for
delivering drugs and other substances to locations within the body
of a human or animal subject, to treat or diagnose sinusitis and a
variety of other disorders. The invention includes implantable
substance delivery devices that comprise reservoirs and barriers
that control the rate at which substances pass out of the
reservoirs. The delivery devices may be advanced into the body
using guide-wires, catheters, ports, introducers and other access
apparatus. In some embodiments the delivery devices may be loaded
with one or more desired substance before their introduction into
the body. In other embodiments the delivery devices are loaded
and/or reloaded with a desired substance after the delivery device
has been introduced into the body. The present invention relates
generally to medical devices and methods and more particularly to
substance delivering implants and methods for treating a broad
range of disorders including but not limited to sinusitis and other
ear, nose and throat disorders.
[0024] Further reference is made to United States Patent
Application Publication 2004/0116958A1, (now U.S. Pat. No.
8,740,929) titled "Spacing device for releasing active substances
in the paranasal sinus "by Gopferich et al, dated 3 Jun. 2014. This
invention relates to a tubular sheath or "spacer" formed of
biodegradable or non-biodegradable polymer that, prior to insertion
in the patient's body, is loaded with a controlled amount of an
active substance, such as a corticosteroid or anti-proliferative
agent. Surgery is performed to create a fenestration in a frontal
sinus and the sheath is inserted into such fenestration.
Thereafter, the sheath which has been preloaded with the active
substance is inserted into the surgically created fenestration
where it a) deters closure of the surgically created fenestration,
b) serves as a conduit to facilitate drainage from the sinus and d)
delivers the active substance. The sheath of the invention of U.S.
Pat. No. 8,740,929 remains substantially in a single configuration
(i.e., it does not transition between a collapsed configuration and
an expanded configuration) although it may be coated with a
material that swells when in contact with mucous or body fluid. In
some embodiments, the sheath is formed of multiple layers of
polymeric material, one or more of which is/are loaded with the
active substance and one or more of which is/are free of the active
substance. In other embodiments, the sheath has a "hollow body"
which forms a reservoir system wherein the active substance is
contained and a membrane which controls the release of the active
substance from the reservoir. In some embodiments, the sheath may
be anchored by causing the end of the sheath that extends into the
sinus to swell or otherwise enlarge.
[0025] Another reference is made to U.S. Pat. No. 3,948,254 titled
"Novel drug delivery device" by Zaffaroni dated 6 Apr. 1976. This
invention relates to implantable drug delivery devices comprising a
drug reservoir surrounded by a micro-porous wall. The reservoir may
be formed of a solid drug carrier that is permeable to passage of
the drug. The rate of passage of the drug through the wall may be
slower than the rate at which the drug passes through the solid
drug carrier that forms the reservoir. This invention describes a
number of applications for the implantable drug delivery devices
including placement in a nasal passage. Specifically, this
invention claimed a nasal delivery device for dispensing a drug
within a nasal passage at a controlled rate wherein the nasal
device is comprised of (a) a wall defining the device dimensioned
for insertion and placement within a nasal passage, with the wall
formed of a nasal acceptable micro-porous material, (b) a reservoir
surrounded by the wall and comprised of a solid carrier permeable
to drug and containing drug in an amount sufficient for the device
to meter it at a continuous and controlled rate for a prolonged
period of time from the device, (c) a liquid medium permeable to
the passage of drug by diffusion charged in the micro-pores, and
(d) wherein the device releases drug when in a nasal environment by
passage of drug from the carrier and through the liquid to the
exterior of the device to produce a useful result. There are also
several examples in the patent literature where various sustained
release mechanisms have generally been proposed using systems with
pre-incorporated drugs into matrices or polymers. These include
U.S. Pat. No. 3,948,254 (Zafferoni), US 2003/0185872A2 (now U.S.
Pat. No. 7,074,426) (Kochinke), WO 92/15286 (Shikani), and U.S.
Pat. No. 5,512,055 (Domb, et al.). In general, these references
discuss various materials and structures that may be used to
construct sustained drug delivery vehicles and provide a good
overview of the state of sustained drug delivery art. These are
helpful in laying out certain materials and schemes for creating
sustained release systems for drugs.
[0026] Further reference is made to U.S. Pat. No. 8,784,893, titled
"Polymer formulations for delivery of bioactive agents" dated 22
Jul. 2014. This invention provides compositions comprising a
bioresorbable polymer matrix and a bio active agent, wherein the
bioactive agent is dispersed within polymer matrix as a solid. Also
provided herein are methods for preparing a bioactive agent
formulation, wherein the agent is present in a solid form and,
wherein the agent is occluded into a polymeric matrix by
polymerization of polymer matrix precursors or by self-assembly of
the polymer. This invention provides a hydrogel composition formed
by combining an aqueous buffer, a thiol-functionalized hyaluronic
acid and a crosslinking accelerant in the presence of a
gel-persistence-enhancing compound selected from the group
consisting of N-acetyl cysteine, glutathione,
2,3-dimercapto-1-propanesulfonic acid,
2,3-dimercapto-1-propanesulfonic acid sodium salt monohydrate,
cysteine, dihydrolipoic acid, and pharmaceutically acceptable salts
thereof, wherein the hydrogel comprises disulfide crosslinks. This
composition also comprises an excipient and is having a pH of
between 5 and 8 when in aqueous solution. The composition further
comprises a bioactive agent as solid particles. The bioactive agent
is a steroid, selected from the group consisting of triamcinolone,
triamcinolone diacetate, triamcinolone acetonide, triamcinolone
hexacetonide, methylprednisolone and dexamethasone. The solid
particles have a particle size between about 0.1 micron and 2 mm.
The bioactive agent is not covalently bound to the
thiol-functionalized hyaluronic acid. The composition forms in
about 1 second to 30 minutes after combining the
thiol-functionalized hyaluronic acid, the gel-persistence enhancing
compound, and the cross-linking accelerant in aqueous buffer. There
is also provided a kit for providing a hydrogel composition, the
kit comprising container with a thiol-functionalized hyaluronic
acid, a gel-persistence enhancing compound, and a cross-linking
accelerant and an aqueous buffer. The kit may also comprise another
container with a steroid selected from the group consisting of
triamcinolone, triamcinolone diacetate, triamcinolone hexacetonide,
triamcinolone acetonide, methylprednisolone and dexamethasone.
[0027] Another reference is made to U.S. Pat. No. 8,535,709 titled
"Agents for controlling biological fluids and methods of use
thereof" by Kennedy, et al. 17.09.2013. Therapeutic formulations
adapted for positive-pressure application for controlling
biological fluid at a desired site in a subject, absorbent articles
comprising therapeutic formulations, and anti-infective devices
coated with therapeutic formulations, said formulations comprising
about 25% to about 99% by weight liquid-crystal forming compound
and 0% to about 75% by weight solvent. In addition, methods of
using said formulations including methods for controlling
biological fluid at a desired site in a subject, methods for
controlling blood loss, and methods for facilitating effective
closure of a vascular wound or incision site at a desired site in a
subject are disclosed, the methods comprising administering
particular formulations comprising liquid-crystal forming compounds
and solvents that are described herein.
[0028] Reference is made to U.S. Pat. No. 8,475,824 titled
"Resorbable matrix having elongated particles" by McKay dated 2
Jul. 2013. The invention relates to Compression resistant matrices
and methods having elongated particles embedded therein. The
compression resistant matrices provide improved stability and
mechanical strength and resists shifting, extrusion and rotation
after implantation. In some embodiments, the matrices provided
reduce or prevent surface compression of the implantable matrix
which will cause unwanted increased amounts of growth factor (e.g.,
bone morphogenic protein) to leak from the matrix.
[0029] However, none of the inventions discussed above comprises of
featured product and a method to prepare the same as covered in the
present invention. The distinguishing features of the present
invention as compared to prior art discussed above are very
significant and prominent, hence the present invention is novel and
inventive over the prior art.
[0030] It is a particular objective of the present invention to
overcome the drawbacks and the problems associated with the sponges
and absorbent foams of the prior art and to provide a biocompatible
porous material that is controlled and tunable self-dispersive,
biodegradable, that is able to absorb fluids and that has improved
and tunable mechanical properties, such as a high elasticity, even
when wet.
[0031] A self-dispersive, fragmentable and biodegradable porous
sponge, made up of lyophilized blend of different polymers
synthetic and natural with high flexibility and absorbent capacity,
to be used for various biomedical application. The said matrix is
prepared using sequential mixing of pre-made solution of polymers
and one of them as powdered solid form. The sponge mentioned is
soft, highly flexible, porous and hydrophilic in nature. The same
is tunable self-dispersive, fragmentable and biosorable at body
temperature and pH.
SUMMARY OF THE INVENTION
[0032] The main objective of the invention is to provide a porous
sponge matrix and a method of manufacturing thereof.
[0033] Another objective of the invention is to provide a
ready-to-use, hydrophilic, self-dispersive, fragmentable and
biodegradable sponge.
[0034] A further objective of the invention is to provide a sponge
device for porous absorbent materials which are suitable for
packing antrum or cavities of the human or animal body.
[0035] Another objective of the invention is to provide a method of
preparation of such sponge/device.
[0036] A further objective of the invention is to provide a porous
scaffold meant as therapeutic carrier, more specific as a
Hemostasis and packing product.
[0037] A further objective of the invention is to provide a device
to be used as nasal packing in the form of a plug, sheet or tampon,
for instance for controlling bleeding, endoscopic sinus surgery, in
most common procedures of ear dressing, wound closure, prevent
tissue adhesion and/or support tissue regeneration, wound healing
process, epistaxis purposes.
[0038] Another objective of the invention is to provide a sterile
wound dressing product to carry the therapeutic and/or bioactive
molecules, biological or chemicals.
[0039] Another objective of the invention is to provide an art with
preference to upregulate and downregulate the process of
self-dispersiveness and bioaborbability of the porous matrix.
[0040] The present invention provides a ready-to-use, hydrophilic,
Self-Dispersive, fragmentable and Bio-Absorbable Porous Composite
biocompatible device and a method of preparation thereof. The
device of present invention comprises a novel porous scaffold
composed of polymeric composites and Polyelectrolyte complex (PEC)
comprising of composite of polymers. The preferred polymers used
comprise functional groups: --C(O)--O--; NH.sub.2/3.sup.+; --OH;
--CH.sub.2OCH.sub.2C(O)O.sup.- groups as functional or --CH--O--
(e.g. C.sub.2H.sub.4O; C.sub.6H.sub.10O.sub.5;
C.sub.6H.sub.8O.sub.6); --CH--N--O-- (e.g.
C.sub.6H.sub.13NO.sub.5); O--C--C-- (e.g. O-CH.sub.2-CH.sub.2);
--C(O)N-- groups in the backbone of the polymers.
[0041] The porous matrix is suitable for packing antrum or other
cavities of the body and as carrier of plurality of therapeutics to
be used as nasal packing in the form of a plug, sheet or tampon,
for instance for controlling bleeding, endoscopic sinus surgery, in
most common procedures of ear dressing, wound closure, prevent
tissue adhesion and/or support tissue regeneration, wound healing
process, epistaxis purposes.
BRIEF DESCRIPTION OF THE DRAWINGS
[0042] FIG. 1 represents an SEM image of scaffold: A) sectional
view; B) sectional view at higher magnification; C) surface
view.
[0043] Accordingly, the present invention provides a ready-to-use,
hydrophilic, self-dispersive, fragmentable and biodegradable porous
sponge matrix with high flexibility and absorbent capacity and a
method of manufacturing thereof, said sponge is porous having
interconnected vesicular micro-voids for holding or encapsulating
the therapeutics/drugs/cells inside, with large surface area and
micro-areas for reactions to occur, said sponge is obtained using
lyophilized blend of polymers, preferably sequential mixing of two
or more polymers followed by homogenization with specific aspect
ratio of shaft, impeller and vessel of the system for mixing, for a
definite period of time, such that the resulting matrix sponge
performs at significant level for using in various biomedical
applications.
DETAILED DESCRIPTION OF THE SEVERAL EMBODIMENTS
[0044] It should be noted that the particular description and
embodiments set forth in the specification below are merely
exemplary of the wide variety and arrangement of instructions which
can be employed with the present invention. The present invention
may be embodied in other specific forms without departing from the
spirit or essential characteristics thereof. All the features
disclosed in this specification may be replaced by similar other or
alternative features performing similar or same or equivalent
purposes. Thus, unless expressly stated otherwise, they all are
within the scope of present invention. Various modifications or
substitutions are also possible without departing from the scope or
spirit of the present invention. Therefore, it is to be understood
that this specification has been described by way of the most
preferred embodiments and for the purposes of illustration and not
limitation.
[0045] The present invention provides a generally, porous absorbent
materials which are suitable for packing antrum or cavities of the
human or animal body and method of preparation thereof. The device
of present invention is a novel porous scaffold to be used as nasal
packing in the form of a plug, sheet or tampon, for instance for
controlling bleeding, endoscopic sinus surgery, in most common
procedures of ear dressing, wound closure, prevent tissue adhesion
and/or support tissue regeneration, wound healing process,
epistaxis purposes.
[0046] The present invention basically relates to the efficient
deployment of a biodegradable, biocompatible medical aid through a
novel highly porous scaffold that can be deployed at the point of
proposed use. The scaffold under the present invention allows the
medical aid suitable for packing antru or cavities of the human or
animal body with an ability to stop bleeding and also reduce
dependency on medical staff, preserve tissue after injury and
facilitate surgical speed.
[0047] The present invention is a hydrophilic self-dispersive,
fragmentable and bio-absorbable porous composite foam/sponge,
suitable for packing antrum or other cavities of the body. The
sponge preferably comprises polymers having functional groups
--C(O)--O--; NH.sub.2/3.sup.+; --OH; --CH.sub.2OCH.sub.2C(O)O.sup.-
groups as functional or --CH--O-- (e.g. C.sub.2H.sub.4O;
C.sub.6H.sub.10O.sub.5, C.sub.6H.sub.8O.sub.6); --CH--N--O-- (e.g.
C.sub.8H.sub.13NO.sub.5); O--C--C-- (e.g. O--CH.sub.2--CH.sub.2);
--C(O)N-- groups in the backbone of the polymers.
[0048] The said spongy patch under the present invention consists
of synthetic and natural polymers to name a few polyvinylalcohol,
alginic acid salt, modified cellulose, gelatin, chitosan and other
having the groups mentioned before. The said sponge can be
impregnated with therapeutics such as growth factors, antioxidants,
clotting agents for instance, including but not limited to
thrombin, calcium chloride (CaCl.sub.2), polyphenol, and tranexamic
acid. The same can also be impregnated with biological materials
such as cells e.g. primary cells and stem cells. These constituents
are held in the vesicular voids of the matrix, on the internal
surface of the sponge which are able to act rapidly when blood
flows into the dressing. Once the scaffold under the present
invention is in contact with blood, the dressing enables sealing
and stabilization of wound surfaces.
[0049] The said sponge/foam is a porous scaffold characterized in
that the structure is reticulate and has an inner surface
considerably larger than its outer surface, that it contains hollow
spaces, pores within the reticulate structure and that it can
absorb many times its own weight in liquids in a short period of
time. On the other hand, it may be used for wound closure, e.g. to
prevent infection and/or tissue adhesion, or for tissue
regeneration purpose (cell in-growth into pores).
[0050] Such sponge/foams are the subject of the present invention
and are also referred to as absorbent foams/sponges. The said
sponge/foam are biodegradable as the ability of a polymer to be
acted upon biochemically in general by living cells or organisms or
part of these systems, including hydrolysis, and to degrade and
disintegrate into chemical or biochemical products. Further, the
invention is bioresorbable feature, i.e. it comprises an ability of
being completely metabolized by the human or animal body making
this packing suitable for internal body application.
[0051] The novel scaffold under the present invention provides a
highly soft, smooth and exudates absorbency property to the
scaffold. The presence of hydrophilic group in the matrix of the
polymer from which the foam of the invention is comprised further
provides said foam with required characteristics such as the
capacity to absorb aqueous liquids and being readily biodegradable,
bioresorbable and self-dispersive to get naturally clean off from
the cavity/antrum such as nasal sinuses.
[0052] The polymer of the present invention may be produced in
bulk, or, more preferably, it may be produced in a solvent. A very
suitable such solvent is water or acidified water. The advantage of
producing a polymer of the present invention in said solvent is
that a very advantageous starting material is thus provided for the
preparation of sponge of the invention. This starting material is
already present in the form of a solution, and no time consuming
dissolution of polymers in solvents needs to be accomplished. Most
preferred is the use of the solvent acidified water. The one of the
polymers used must be added as solid powdered form.
[0053] The present invention aims to overcome the problems in the
existing prior arts and provides the novel and unique features in
the scaffold by providing on-demand services for nasal packing
sponge with high porosity and regulated pores on the same platform
of a matrix. The technologies involved are the timed patterned
physico-chemical treatment of the two or more polymers used stated
above using a very simplified process to obtain tunable
self-dispersive interaction and orientation between the molecules
out of all at least one of the preferred polymers, which are used
in form of powder solid. The used technology provides the proper
interaction and orientation between the functional and backbone
groups of the polymers used, resulted into a typical
polyelectrolyte complex (PEC) and polymer sandwich.
[0054] The present invention provides the requirements of such
sponge with a high and rapid absorption capacity, particularly for
blood, strength to be readily handled in surgical procedures,
conformable so as to fit into any topography, maintenance of
tissues' mechanical properties, for a specific period of time
during or after surgery or after application of the matrix, soft so
as to avoid injury to sensitive tissues. In some instances, the
softness of the foam may be increased by wetting of the foam.
Therefore, the absorbing foam should also have enough mechanical
strength and elasticity in the wet condition and can also be
cleared off via natural process to reduce doctors' dependency.
[0055] Further, the present invention is to overcome the drawbacks
and the problems associated with the sponges and absorbent foams of
the prior art and to provide a biocompatible porous material that
is controlled and tunable self-dispersive, biodegradable, that is
able to absorb fluids and that has improved and tunable mechanical
properties, such as a high elasticity, even when wet.
[0056] A ready-to-use, hydrophilic, self-dispersive, fragmentable
and biodegradable porous sponge with high flexibility and absorbent
capacity, made up of lyophilized blend of different polymers, to be
used for various biomedical application. The said matrix is
prepared using sequential mixing of pre-made solution of polymers
and one of them as powdered solid form. The sponge mentioned is
soft, highly flexible, porous and hydrophilic in nature. The
resulting product is tunable self-dispersive, fragmentable and
biosorable at body temperature and pH. Further, the interconnected
vesicular micro-voids hold the drug/cells inside and as a result
the encapsulated therapeutics of the matrix perform at significant
level. Further the highly porous structure of the present invention
results into interconnected small voids, provide a large surface
area and micro-areas for reactions to occur and thus exert a
pseudo-catalytic effect on blood clotting. The PEC containing
micro-mesh and body's fibrinogen converted into fibrin forms an
efficacious plug and prevents the loss of blood and stops the loss
of clotting factor. The novel device of the present invention makes
the product light weighted, to be more physical and also altering
the blood clotting mechanism. The scaffold of the present invention
can be removed easily usually without causing additional/secondary
hemorrhage from the application site.
[0057] The novel porous scaffold of the present invention is also
capable of being used as a carrier for other therapeutics/bioactive
molecules/cell (primary or stem cell) towards tissue engineering
and other biomaterial applications. Moreover, the scaffold of the
present invention is also capable of being used as a cover for the
compromised tissues either as a cellular or cellular product.
[0058] The utilization of more than one type of polymer & their
properties for multi-therapeutics loaded preparation and
impregnation of the same with PEC scaffold, a system for more than
one types of the pharmaceuticals (like clotting factors,
co-factors, clot stabilizers, antibiotics, analgesics,
anti-allergic, antioxidants, growth factors, etc.) to get delivered
in phase-wise and controlled manner for extended period of
time.
[0059] The novel aspect of the present invention is the sequential
timed patterned physico-chemical treatment of the synthetic and
natural polymers by using a very simplified process to obtain a
highly flexible stabilized tunable self-dispersive porous scaffold,
which can be further tuned using any cross-linker, if required.
Further, the invention comprises the preparation of said PEC
containing sponge, which is achieved using a specific aspect ratio
of shaft, impeller and vessel of the system for mixing. One of the
ingredient polymers is added in powder form and rest are in
solution from using the water or acidified water as solvent.
[0060] The present invention comprises polyelectrolyte complex such
as of gelatin and alginate in porous sponge. The present invention
provides, a method for preparing a biodegradable absorbent
sponge/foam suitable for as hemostatic sponge, wound dressing
material, packing antrum or other cavities of the human or animal
body, including dental packs, or as a drug delivery vehicle,
comprises preparing a polymer according to the invention in
acidified water or water, diluting the polymer solution during
interaction of the functional and backbone group of the polymers
with the solvent and the polymer solution, freezing the reaction
mixture, and subliming the solvent, under vacuum at low
temperature.
[0061] The invention also provides a process for preparing said
sponge scaffold, which is provided below in detail:
[0062] In a preferred embodiment, said polymers are preferably
selected from but not limited to gelatin, chitosan, collagen,
alginate, polyethylene glycol, polyvinyl Pyrrolidone, polyvinyl
alcohol, polyurethane, keratin, Carboxy-methyl cellulose, gelatin
hydrolysate, chitosan hydrolysate, partially denatured collagen
and/or synthetic or naturally derived molecules such as
phytochemicals.
[0063] In another embodiment, said therapeutics and pharmaceuticals
are selected from but not limited to Tannic acid, Catechin family,
tranexamic acid, calcium chloride, thrombin and/or glucosamine,
Polylysine.
[0064] In a preferred embodiment, said sponge/scaffold is produced
by the steps: [0065] a) preparing a homogeneous solution of the
individual polymers with different ratio in water or in water and
acetic acid and subjecting for hot air treatment to obtain polymer
solution at 50-90 degree C.; [0066] b) mixing of polymer solution
obtained in step (a) at controlled parameters
(18.degree.-25.degree. C. and 55.+-.5% RH) and sequential manner to
obtain polymer composite solution (illustrated in Example 1);
[0067] c) mixing of powder form solid of one of polymers to obtain
final polymer composite solution obtained in step (b) containing
PEC followed by freezing and drying at low temperature under
vacuum, respectively at -80.degree. C. and -5.degree. C. for 4000
min; [0068] d) Cutting the above obtained porous
scaffold/sponge/foam obtained at the end of step (c) as per
requirement at 18.degree.-25.degree. C. and 55.+-.5% RH. [0069] e)
Optionally, the obtained scaffolds in steps (c) & (d) are
subjected for the stabilization either by ammonia vapor or ammonia
solution or alkali solution following aldehyde vapor or EDC as per
requirement for 10-12 hrs at 18.degree.-25.degree. C. and 55.+-.5%
RH. [0070] f) subsequently treatment of the obtained scaffold in
step (d) & (e) under vacuum at 25-40 degree C. overnight (10-12
hrs); [0071] g) Followed by gamma irradiation of the scaffold
obtained in steps (d) & (f) to obtain the final ready to use
product. [0072] h) Optionally, loading the required
pharmaceutical/therapeutic solution containing different ratio of
drugs as per the requirement into the obtained scaffold in step (f)
followed by step (g) to obtain the final ready to use product at
18.degree.-25.degree. C. and 55.+-.5% RH. [0073] i) Optionally,
loading the required cells (primary/stem cells) as per the
requirement into the obtained scaffold in step (g) under aseptic
condition to obtain the final ready to use product at
18.degree.-25.degree. C. and 55.+-.5% RH.
[0074] In another embodiment, said method involves physico-chemical
treatment of said polymers using a very simplified process in order
to obtain a stable molecular interaction and orientation between
the molecules of the said polymers, causing an interaction and
orientation between the functional groups of the polymers used,
resulting into a typical polyelectrolyte complex (PEC), so as to
obtain a highly porous matrix.
[0075] Accordingly, the present invention provides a ready-to-use,
hydrophilic, self-dispersive, fragmentable and biodegradable porous
sponge matrix and a method of manufacturing thereof, said sponge is
porous having interconnected vesicular micro-voids for holding or
encapsulating the therapeutics/drugs/cells inside, with large
surface area and micro-areas for reactions to occur, said sponge is
obtained using lyophilized blend and sequential mixing of two or
more biopolymers with high flexibility and absorbent capacity,
followed by homogenization with specific aspect ratio of shaft,
impeller and vessel of the system for mixing, for a definite period
of time, such that the resulting matrix sponge performs at
significant level for using in various biomedical applications.
[0076] In an embodiment, said sponge is prepared using sequential
mixing of pre-made solution of polymers with one of them as
powdered solid form to get differential solubility of polymer
complex and tunable self-dispersiveness, fragmentability and
bioabsorbility and thus obtained homogenized composite mixture is
casted immediately within a time limit.
[0077] In another embodiment, said sponge is soft, highly flexible,
porous, hydrophilic, self-dispersive, fragmentable in nature and is
biosorable at body temperature and pH.
[0078] In another embodiment, said polymers used for synthesizing
said sponge are preferably selected from but not limited to
gelatin, chitosan, collagen, alginate, polyvinyl alcohol,
poly(vinyl pyyrolidone), polyurethane, polyethylene glycol,
polypropylene glycol keratin, hyaluronic acid, carboxymethyl
cellulose, gelatin hydrolysate, chitosan hydrolysate, partially
denatured collagen and/or synthetic or naturally derived molecules
such as mucilaginous polysaccharides.
[0079] In yet another embodiment, said sponge is obtained by mixing
different polymer solutions preferably polyvinyl chloride (5%-15%),
Gelatin (2%-7%), Sodium Alginate (0.5%-2%) polyethylene glycol-200
(1 ml-5 ml), and chitosan (0.5%-1%).
[0080] In another embodiment, the sequential timed patterned
physico-chemical treatment of polymers is preferably dissolution of
polymers to form the solution with concentration mentioned in claim
at temperature 40-70.degree. C. preferably [0081] Stirring of the
polymer blend temp 18-25.degree. C., 55.+-.5% RH for 20-30 min
using a stirrer with aspect ratio of the diameter of container and
impeller ranging between 1.17 to 1.57 for 20 mins at the 1000-3600
rpm. [0082] Adding of acid preferably glacial acetic acid
(0.5-2.5%) at rate of 1 ml/min and at temp 18-25.degree. C.,
55.+-.5% RH for 5-10 min. [0083] adding of solid powder preferably
of chitosan, 0.5%-1.2% final concentration at the rate of 1 mg/ml
at temp 18-25.degree. C., 55.+-.5% RH for 30-40 min.
[0084] In another embodiment, said mucilaginous polysaccharides are
obtained from various plants sources like Irish moss, Marshmallow
roots, Fenugreek seed, Flax seeds, Psyllium husk seed and any other
equivalent.
[0085] In another embodiment, said mucilaginous plant extract
mentioned is obtained using a sequential method of dilution,
filtration and by drying the plant source and then dissolving in
ultrapure water to prepare a solution of concentration 0.2%-1%
followed by thermal treatment; diluting the solution thus obtained
2-3 times and homogenizing to form a homogenized solution for 23-30
min at 18-25.degree. C., 55.+-.5% RH; filtering the homogenized
solution and subjecting to 55.degree. C. under hot air for 12-15
hr; using the dried extract ranging from 0.5% to 2% to obtain the
desired sponge.
[0086] In another embodiment, said sponge is prepared in the same
manner using the mucilaginous polysaccharide extract solution of
concentration ranging from 0.4% to 1.5%.
[0087] In yet another embodiment, said sponge is stabilized and
tuned using different chemicals and radiation or a combination of
both, wherein said chemicals are preferably selected from but not
limited to glutaraldehyde, formaldehyde, EDC, ammonia, and using
solution or vapor to form a stable cross linked matrix following
treatment with ammonia vapor and preferably followed by Gamma
irradiation.
[0088] In another embodiment, said sponge can degrade thermally and
can be easily removed from the site of application in the body
cavity.
[0089] In another embodiment, said sponge comprises interconnected
small voids, providing a large surface area and micro-areas which
is hydrophilic in nature and retains water, resulting in formation
of soft flexible dressing which provides support for the healing
tissue in nasal cavity and external auditory meatus.
[0090] In another embodiment, said sponge is used for various
applications like dressing for nasal interventions, ear and other
body cavities, absorbent foam dressing for exudating wounds,
diabetic foot ulcers, venous ulcers, as a drug and cell carrier and
cell growth matrix, as carrier for various therapeutic and
antimicrobial agents, nanoparticles, etc., as a cover for the
compromised tissues, as a dressing for body cavity where it is
difficult to cover the wound using traditional dressing
methods.
[0091] In an embodiment, said sponge is preferably prepared in the
form of a plug, tampon or sheet.
Advantages of the Invention
[0092] Product has a high and rapid absorption capacity for fluids,
particularly for blood [0093] Good strength to be readily handled
in surgical procedures [0094] Conformable so as to fit into any
topography [0095] Good mechanical strength and elasticity in the
wet condition [0096] Easy to clear-off via natural process to
reduce doctors' dependency [0097] Light weight in nature [0098]
Easy to remove without causing additional/secondary hemorrhage from
the application site
EXAMPLES
[0099] The following example is for the purposes of illustration
only and therefore should not be construed to limit the scope of
the present invention:
Example 1
[0100] Take 30 ml of 7.5% PVA solution at 3300 RPM, 22 degree C.
and add 15 ml of 10% Gelatin solution to it to get mixture B. Add
15 ml of 1% Alginate solution to mixture B to get mixture C at 2800
RPM, 22 degree C. Add 3 ml of PEG-200 to mixture C to get mixture D
at 3000 RPM, 22 degree C. Following this add 30 ml of mucilage (1%)
to the solution mixture D stir using homogenizer for 20 min at 2300
RPM, 22 degree C. and then add 0.75 ml of Acetic acid and
homogenize for 1 min to get mixture E. Add 0.75 gm of chitosan to
mixture E and homogenize for 30 min at 1800 RPM, 22 degree C. Cast
the samples in Teflon tray followed by drying at low temperature
under vacuum. Cut the sample into the desirable size and shape
followed by stabilization and gamma irradiation.
* * * * *