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 CHO (e.g. C2H4O; C6H10O5; C6H8O6); CHNO (e.g. C8H13NO5); OCC (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.

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

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 CHO (e.g. C.sub.2H.sub.4O; C.sub.6H.sub.10O.sub.5, C.sub.6H.sub.8O.sub.6); CHNO (e.g. C.sub.8H.sub.13NO.sub.5); OCC (e.g. OCH.sub.2CH.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 (18-25 C. and 555% 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 C. and 5 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 1825 C. and 555% 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 1825 C. and 555% 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 18-25 C. and 555% 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 18-25 C. and 555% 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 C. preferably [0081] Stirring of the polymer blend temp 18-25 C., 555% 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 C., 555% 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 C., 555% 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 C., 555% RH; filtering the homogenized solution and subjecting to 55 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.