A ready-to-use, hvdro~hilics, elf-dis~ersive,f raa. mentable-and ~
biodearadable Dorous sDonae matrix and a method of manufacturinq
thereof
Field of the invention:
The present invention relates to the field of Medical ~ibsciences.
The present invention provides, generally, porous absorbent materials which are
suitable for packing antrum or cavities uf the human or animal body.
Particularly, the present invention provides a ready-to-use, self-dispersive,
biodegradable and biocompstible device.
More particularly, the invention relates to medical nonwoven porous textiles.
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.
The present invention provides a porous scaffold meant as a therapeutic carrier.
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.
The present invention also relates to a method of preparing such a device for
biomedical field.
The terms s~onqe/matrix/scaffold/device have been used interchanueablv
throuuhout the specification and thew all refer to the same product, as
discussed and covered in the scope of this specification.
Backaround of the invention:
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.
The range of materials used for this purpose is wide, including both removable and
absorbable materials. I n cases of: septoplasty and rhinoplasty surgery, conventional
non- biodegradable packings are frequently removed within 24-48 hours following
surgery. I n the case of epistaxis, packing is left in for extended periods of time to
promote healing and to prevent the patient from touching and aecidentaily interfering
with the rgcovery ul'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. I n the art, biodurable wound
dressings are used for nasal packing. These biodurable packs have to be removed
after several days as described above.
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. US 3,903,232, US
3,961,629, US 4,550,126 and EP-A-0 335 669. However, these materials are
biodurable and not biodegradable.
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 vaselinesoaked
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
I
't '
" -
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. 3 Otolaryngol, 1992;
21:88-91;Pomerantz 3. 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, randotmized study. Rhinology,
2002; 40:.185-8).
Other complications associated with removable nasal packing (Weber R. et al.,
Packing in endonasal surgery. Am J Otolaryngol, 2001; 22:306=20; Wcber' K. et.al,
Packing and &tents ill 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.
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. 3
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.
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. I n 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.
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); SUI-giflu t~emostatic 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.
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 denat~rated~elatoinf 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. US 3,902,497 and US 3,875,937 disclose
surgical dressings of bio-absorbable polymers of poly glycolic acid (PGA).
Such materials are, although useful in other applications, not useful in applications
where sufficient counter pressure from the foam is required, such as in nosebleeding,
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 A l ) 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.
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.
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.
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. I n 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.
Reference is made to United States Patent Number 9,039,657, titled "Implantable
devices and methods for delivering drugs and other substances'to treat sinusitis and
other disorders" dated 26.05.2015. 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 guidewires,
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. I n 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.
F u ~ h e r reference is made to United States Patent Application Publication
2004/0116958Al, (now US Patent umber 8,740,929) titled "Spacing device for
releasing active substances in the paranasal sinus "by Gopferich et al, dated
03.06.2014. This invention relates to a t ~ r h ~ ~sl haera th or "spas~r"f ormed 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 US patent number
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 islare loaded with the active substance and one or more of
which is/are free of the active substance. I n 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.
Another reference is made to US Patent Number 3,948,254 titled "Novel drug
delivery device" by Zaffaroni dated 06.04.1976. 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 92115286 (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.
Further reference is made to United States Patent number 8,784,893, titled
"Polymer formulations for delivery of bioactive agents" dated 22.07.2014. 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 selfassembly
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. Thebioactive 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
I kit comprising container with a thiol-functionalized hyaluronic acid, a gel-persistence
I ~ enhancing compound, and a cross-linking accelerant and an aqueous buffer. The kit
I
may also comprise another container with a steroid selected from the group
consisting of triamcinolone, triamcinolone diacetate, triamcinolone hexacetonide,
: triamcinolone acetonide, methylprednisolone and dexamethasone.
Another reference is made to United States Patent 8,535,709 titled "Agents for
controlling biological fluids and methods of use thereof" by Kennedy, et al.
17.09.20 13. 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 liquidcrystal
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.
Reference is made to United States Patent 8,475,824 titled "Resorbable matrix
having elongated particles" by McKay dated 02.07.2013. 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.
However, none of the inventions discussed above com~rises of featured
product and a method to DreDare the same as covered in the ~resent
invention. The distinauishina features of the Dresent invention as com~ared
to ~ r i oarr t discussed above are verv sianificant and ~rominent,h ence the
present invention is novel and inventive over the ~ r i oarr t.
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 selfdispersive,
biodegradable, that is able to absorb fluids and that has improved and
tunable mechanical properties, such as a high elasticity, even when wet.
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.
Obiects of the invention:
The main objective of the invention is to provide a porous sponge matrix and a
method of manufacturing thereof.
Another objective of the invention is to provide a ready-to-use, hydrophilic, selfdispersive,
fragmentable and biodegradable sponge.
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
bod\/.
Another objective of the invention is to provide a method of preparation of such
sponge/device.
A further objective of the invention is to provide a porous scaffold meant as
therapeutic carrier, more specific as a Hemostasis and packing product.
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.
Another objective of the invention is to provide a sterile wound dressing product to
carry the therapeutic and/or bioactive molecules, biological or chemicals.
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.
Sum'marv of the invention:
The present invention provides a 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)-0-; NH2/3+; -OH; -CH20CH2C(O)O- groups as functional or
-CH-O- (e.g. CzH40; C6H1005; C6H806); -CH-N-O- (e.9. C~H~~NO0S-C);-C - (e.g. 0-
CH2-CH2); -C(O)N- groups in the backbone of the polymers.
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 drawincrs:
Figure 1 represents an SEM image of scaffold: A) sectional view; B) sectional view at
higher magnification; C) surface view.
Statement of the invention:
Accordingly, the present invention provides a ready-to-use, hydrophilic, selfdispersive,
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 invention:
I t 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
I by similar other or alternative features performing similar or same or equivalent
I purposes. Thus, unless expressly stated otherwise, they all are within the scope of -
I 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.
' 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.
The presen't 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 antrum 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.
The present invention is a hydrophilic self- dispersive, fragmentable and bioabsorbable
porous composite foam/sponge, suitable for packing antrum or other
cavities of the body. The sponge preferably comprises polymers having functional
groups -C(O)-0-; NH2/3+; -OH; -CH20CH2C(O)O- groups as functional or -CH-0- (e.g.
C2H40; C6H1005; C6H806); -CH-N-0- (e.g. C~HI~NOS); 0-C-C- (e.g. 0-CH2-CH2); -
C(0)N- groups in the backbone of the polymers.
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, anti-oxidants, clotting agents
for instance, including but not limited to thrombin, calcium chloride (CaC12),
polyphenol, and tranexamic acid. The same can also be impregnated with biological
I
I materials such as cells e.g. primary cells and stem cells. These constituents are held
I
I in the vesicular voids of the matrix, on the internal sufiace 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.
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 weiqht 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).
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.
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 w'hich 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.
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.
- - -
.2
-- -* #-
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 physicochemical
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.
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.
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.
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
-- - - - - -
HPO DELWI D8-QE-ED46 17:43
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
additionaI/.secondary hemorrhage from the application site.
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 acellular or cellular product.
The utilization of more than one type of polymer & their properties for multitherapeutics
loaded preparation and impregnation of the same with PEC scaffold, a
system for more than one types of the pharmaceuticals (like clotting factors, cofactors,
clot stabilizers, antibiotics, analgesics, anti-allergic, antioxidants, growth
factors, etc.) to get delivered in phase-wise and controlled manner for extended
period of time.
The novel aspect of the present invention is the sequential timed patterned physicochemical
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.
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.
The invention also provides a process for preparing said sponge scaffold,
which is provided below in detail:
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.
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.
In a preferred embodiment, said sponge/scaffold is produced by the steps:
a) preparing a homogeneous sol'ution 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;
b) mixing of polymer solution obtained in step (a) at controlled parameters (18O-
2S°C and 55*5% RH) and sequential manner to obtain polymer composite
solution (illustrated in Example 1);
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°C and -5OC for 4000 min;
d) Cutting the above obtained porous scaffold/sponge/foam obtained at the end of
step (c) as per requirement at 18O-25OC and 55kS0/0 RH.
I 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 18O-25OC
~ and 5555% RH.
I
i f) subsequently treatment of the obtained scaffold in step (d) & (e) under vacuum
I
at 25-40 degree C overnight (10-12 hrs);
g) Followed by gamma irradiation of the scaffold obtained in steps (d) & (f) to obtain
the final ready to use product.
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 18O-2S°C and
55&5O/o RH.
i) Optionally, loading the required cells (primarylstem cells) as per the requirement
into the obtained scaffold in step (g) under aseptic condition to obtain the final
ready to use product at 18O-2S°C and 55*5O/0 RH.
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.
Accordingly, the present invention provides a ready-to-use, hydrophilic, selfdispersive,
fragmentable and biodegradable porous sponge matrix and a method of
manufacturing thereof, said sponge is porous having interconnected vesicular microvoids
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. - -
-" -- . - --
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.
I n another embodiment, said sponge is soft, highly flexible, porous, hydrophilic, selfdispersive,
fragmentable in nature and is biosorable at body temperature and pH.
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(viny1 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.
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 (lml-5ml), and chitosan (0.5%-1%).
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 5 at temperature 40-70°C preferably
Stirring of the polymer blend temp 18-25O C, 55*5% RH for 20-30min 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.
Adding of acid preferably glacial acetic acid (0.5-2.5%) at rate of lml/min and at
temp 18-25O C, 55&5% RH for 5-l0min.
adding 'of solid powder preferably of chitosan, 0.5% - 1.2% final concentration at
the rate of lmg/ml at temp 18-250 C, 55&5% RH for 30-40min.
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.
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°/~-10/f~o llowed
by thermal treatment; diluting the solution thus obtained 2- 3 times and
homogenizing to form a homogenized solution for 23-30 min at 18-2S0 C, 55*5%
RH; filtering the homogenized solution and subjecting to 55OC under hot air for 12-
15. hr; using the dried extract ranging from 0.5% to 2% to obtain the desired sponge.
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%.
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 fo11owed by Gamma irradiation.
In another embodiment, said sponge can degrade thermally and can be easily
removed from the site of application in the body cavity.
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.
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 t'he compromised tissues, as a dressing for body
cavity where it is difficult to cover the wound using traditional dressing methods.
I n an embodiment, said sponge is preferably prepared in the form of a plug, tampon
or sheet.
Advantages of the invention:
PI-oduct I- as a I,iiyl~a ~ i drd pid dbsurpliu~c~a paclty fur fluids, particularly for
blood
Good strength to be readily handled in surgical procedures
Conformable so as to fit into any topography
Good mechanical strength and elasticity in the wet condition
Easy to clear-off via natural process to reduce doctors' dependency
Light weight in nature
Easy to remove without causing additionaI/secondary hemorrhage from the
application site
Examples:
The followins example is for the pur~oseso f illustration onlv and therefore
should not be construed to limit the scope of the present invention:
Take 30 ml of 7.5 O/O PVA solution at 3300 RPM, 22 degree C and add 15 ml of 10%
Gelatin solution to it to get mixture 0. Add 15 ml of l0/0 Alginate solution to mixture
0 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, 22degree
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.

We claim:
1. 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.
2. The ready-to-use, 'hydrophilic, self-dispersive, fragmentable and biodegradable
porous sponge as claimed in claim 1, wherein said sponge is prepared using
sequential mixing of pre-made solution of polymers, with at least one of the
polymers in powdered solid form to get differential solubility of polymer complex
and tunable self-dispersiveness, fragmentability and bioabsorbility; thus resulting
in homogenized composite mixture, which is casted immediately withiri a specific
time limit.
3. The ready-to-use, hydrophilic, self-dispersive, fragmentable and biodegradable
porous sponge as claimed in claim 1, wherein said sponge is soft, highly flexible,
porous, hydrophilic, self-dispers,ive, fragmentable in nature and is biosorable at
body temperature and pH.
4. The ready-to-use, hydrophilic, self-dispersive, fragmentable 'and biodegradable
porous sponge as claimed in claim 1, wherein said polymers used for synthesizing
said sponge are preferably selected from but not limited to gelatin, chitosan,
collagen, alginate, polyvinyl alcohol, poly(viny1 pyrrolidone), 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.
5. The ready-to-use, hydrophilic, self-dispersive, fragmentable and biodegradable
porous sponge as claimed in claim 1, wherein said sponge is obtained by mixing
different polymer solutions, preferably polyvinyl chloride (5%- 15%), Gelatin
(2°/~-70/~),S odium Alginate (0.5%-2%) polyethylene glycol-200 (lml-5ml), and
chitosan (0.5%-1%).
6. The ready-to-use, hydrophilic, self-dispersive, fragmentable and biodegradable
porous sponge as claimed in claims 1 and 5, wherein the sequential timed
patterned physico-chemical treatment of polymers is performed, preferably .
dissolution of polymers to form the solution at temperature 40-70°C preferably
with following steps:
a. stirring of the polymer blend at temperature 18-2S0 C, 55*S0/0 RH for
20-30min 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.
b. adding of an acid, preferably glacial acetic acid (0.5-2.5%) at rate of
lml/min and at temp 18-25O C, 55*5% RH for 5-l0min.
c. adding of solid powder preferably of chitosan, 0.5% - 1.2% final
concentration at the rate of lmg/min at temp 18-2S0 C, 55*5% RH for
30-40min.
7. The ready-to-use, hydrophilic, self-dispersive, fragmentable and
biodegradable porous sponge as claimed in claim 4, wherein 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.
8. The' ready-to-use, hydrophilic, self-dispersive, fragmentable and
biodegradable porous sponge as claimed in claim 1 and 7, wherein said
mucilaginous plant extract 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°/~-10/~ followed by thermal
treatment; diluting the solution thus obtained 2- 3 times and homogenizing to
form a homogenized solution for 23-30 min at 18-2S0 C, 55*S0/0 RH; filtering
I the homogenized solution and subjecting to 55OC under hot air for 12-15 hr;
I using the dried extract ranging from 0.5% to 2% to obtain the desired sponge.
9. The ready-to-use, hydrophilic, self-dispersive, fragmentable and biodegradable
porous sponge as claimed in claim 1, wherein said sponge is prepared in the same
manner using the mucilaginous polysaccharide extract solution of concentration
ranging from 0.4% to 1.5%.
10. The ready-to-use, hydrophilic, self-dispersive, fragmentable and biodegradable
porous sponge as claimed in claim 1, wherein 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.
11. The ready-to-use, hydrophilic, self-dispersive, fragmentable and biodegradable
porous sponge as claimed in claim 1, wherein said sponge has ability to degrade
thermally and is easily removed from the site of application in the body cavity.
12. The ready-to-use, hydrophilic, self-dispersive, fragmentable and biodegradable
porous sponge as claimed in claim 1, wherein 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 tissues in body cavities and
external auditory meatus.
13. The ready-to-use, hydrophilic, self-dispersive, fragmentable and biodegradable
porous.sponge as claimed in claim 1, wherein 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.
14;The ready-to-use, hydrophilic, self-dispersive, fragmentable. and biodegradable
porous sponge as claimed in claim 1, wherein said sponge is preferably prepared
in the form of a plug, tampon or sheet.
15.The ready-to-use, self-dispersive, fragmentable and biodegradable porous sponge
and method of manufacturing thereof, substantially as hereinbefore claimed in
any of the proceeding claims, specification and drawings.