TRANEXAMIC ACID SPRAY FOR KNEE ARTHROPLASTY

Abstract

The present invention relates to novel formulations comprising a sprayable composition comprising tranexamic acid and chitosan for use in the treatment of wounds or injuries, in particular for use as a topical hemostatic composition or for surgical intervention and the process for preparation thereof.

Claims

1-10. (canceled)

11. A topical spray composition comprising about 1% w/w to about 10% w/w tranexamic acid, about 0.1% w/w to about 1% w/w chitosan, and water, wherein the tranexamic acid and the chitosan are present in ratio of at least about 2.5:1, respectively.

12. The topical spray composition of claim 11, wherein the tranexamic acid and the chitosan are present in ratio of at least about 10:1, respectively.

13. The topical spray composition of claim 11, wherein the tranexamic acid and the chitosan are present in ratio of at least about 50:1, respectively.

14. The topical spray composition of claim 11, comprising about 10% w/w tranexamic acid and from about 0.1% w/w to about 1% w/w chitosan.

15. The topical spray composition of claim 11, comprising about 10% w/w tranexamic acid and about 0.2% w/w chitosan.

16. The topical spray composition of claim 11, further comprising glacial acetic acid.

17. A topical spray composition comprising tranexamic acid, chitosan, water, and glacial acetic acid, wherein the tranexamic acid and the chitosan are present in ratio of at least about 2.5:1, respectively.

18. The topical spray composition of claim 17, wherein the tranexamic acid and the chitosan are present in ratio of at least about 10:1, respectively.

19. The topical spray composition of claim 17, wherein the tranexamic acid and the chitosan are present in ratio of at least about 50:1, respectively.

20. A method of treating a wound or reducing bleeding at a hemorrhaging site, comprising administering the topical spray composition of claim 1.

21. The method of claim 20, wherein the wound is selected from the group consisting of abrasions, cuts, scrapes, scratches, burns, sunburns, ulcers, internal venous bleeding, and external venous bleeding.

22. The method of claim 20, wherein the wound is selected from surgical interventions, wherein the surgical interventions are selected from gastrointestinal surgery; surgery on parenchymal organs; surgical interventions in the ear, nose and throat area (ENT); cardiovascular surgery; aesthetic surgery; spinal surgery; neurological surgery; lymphatic, biliary, and cerebrospinal (CSF) fistulae; air leakages during thoracic and pulmonary surgery; thoracic surgery; orthopaedic surgery; gynaecological surgical procedures; vascular surgery; emergency surgery; liver resection; and soft tissue injury or surgery.

23. The method of claim 20, wherein the composition is topically applied to a wound, the site of a traumatic injury, or during or after surgery.

24. The method of claim 20, wherein administering the composition results in at least a 3-fold increase in cell proliferation when compared to control.

25. The method of claim 24, wherein the 3-fold increase is measured 4 hours or 24 hours after administration.

26. A method of preparing the topical spray composition of claim 1, comprising a) dissolving Chitosan in 1% glacial acetic acid; b) dissolving tranexamic acid in the solution of a); c) adding water; and d) sterilizing by filtration.

27. The method of claim 26, wherein the composition is sterilized by filtration using a pre-filter of 8 m followed by 0.45 m and 0.22 m at a constant pressure of 1.5 bar.

28. The method of claim 27, further comprising a filter surface area of 13 cm.sup.2 for one liter.

29. The method of claim 26, wherein the composition is filtered for about 10 minutes to about 15 minutes per liter of the composition.

30. A topical spray composition comprising about 10% w/w tranexamic acid, about 0.2% w/w chitosan, water, and glacial acetic acid.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0027] FIG. 1 discloses the sterilization process by filtration of one-liter spray composition as disclosed in example-5 using a pre-filter of 8 m followed by 0.45 m and 0.22 m at a constant pressure of 1.5 bar with a filter surface area of 13 cm.sup.2.

[0028] FIG. 2 discloses the cell proliferation of spray composition of example-5, as compared with control for 4 hours.

[0029] FIG. 3 discloses the cell proliferation of spray composition of example-5, as compared with control for 24 hours.

DETAILED DESCRIPTION OF THE INVENTION

[0030] In describing and claiming the present invention, the following terminologies will be used in accordance with the definitions set out below.

[0031] The term Wound as used herein refers to any damage to any tissue of a patient which results in the loss of blood from the circulatory system and/or any other fluid from the patient's body. The damage may have been caused by any agent or source, including traumatic injury, infection or surgical intervention. A wound may be in a soft tissue, such as an organ, or in hard tissue, such as bone. The tissue may be an internal tissue, such as an organ or blood vessel, or an external tissue, such as the skin. The loss of blood may be internal, such as from a ruptured organ, or external, such as from a laceration.

[0032] The term bleeding as used herein refers to conditions where blood flows through a break in the skin or mucosa of a subject. Non-limiting examples of bleeding includes a wound selected from the group consisting of a) minor abrasions, cuts, scrapes, scratches, burns, sunburns. ulcers, internal venous bleeding, external venous bleeding, and b) surgical interventions selected from gastrointestinal surgery, surgery on parenchymal organs; surgical interventions in the ear, nose and throat area (ENT), cardiovascular surgery, aesthetic surgery, spinal surgery, neurological surgery; lymphatic, biliary, and cerebrospinal (CSF) fistulae, air leakages during thoracic and pulmonary surgery, thoracic surgery, orthopaedic surgery including knee arthroplasty and hip arthroplasty; gynaecological surgical procedures; vascular surgery and emergency surgery, liver resection, and soft tissue injury or surgery.

[0033] The term total knee arthroplasty as used herein refers to surgical treatment of knee Pain which comprises 1) Partial knee replacement: The surgeon replaces the damaged portions of the knee with plastic and metal parts and 2) Total knee replacement: In this procedure, the knee is replaced with an artificial joint. It requires a major surgery and hospitalization.

[0034] The terms local administration and locally administering as used herein refer to treatment of bleeding by administering at sites proximate to the bleeding. In certain embodiments, local administration or locally administering refers to external administration at the site of a wound. In other embodiments, local administration or locally administering refers to instillations, such as knee installation, nasal instillation, bladder instillation, and rectal instillation

[0035] The term spray, as used herein, means to dispense the composition as a mass or jet of droplets from a dispensing system.

[0036] As used herein in connection with numerical values, the terms about mean/10% of the indicated value, including the indicated value.

[0037] The present invention provides herein, compositions consisting essentially of a therapeutically effective amount of tranexamic acid and pharmaceutically acceptable excipients that facilitates local administration, and methods of use thereof for treating bleeding in a subject in need thereof comprising locally administering to the subject the compositions.

[0038] The present invention provides a composition that can treat wounded tissue. including wounded tissue resulting from a traumatic injury or other severe and/or uncontrolled bleeding conditions, such as surgery. The present invention also provides a method of treating wounded mammalian tissue, particularly human tissue.

[0039] In one embodiment of the invention, the pharmaceutical composition of the invention is a topical spray.

[0040] In another embodiment of the invention, the topical spray composition comprises tranexamic acid and pharmaceutically acceptable excipients.

[0041] In embodiments of the invention, topical spray composition comprises tranexamic acid from about 1% to about 10% of tranexamic acid based on the total weight of the composition, and more preferably 1% w/w, 1.5% w/w, 2% w/w, 2.5% w/w, 3% w/w, 3.5% w/w, 4% w/w, 4.5% w/w, 5% w/w, 5.5% w/w, 6% w/w, 6.5% w/w, 7% w/w, 7.5% w/w, 8% w/w, 8.5% w/w, 9.5% w/w and 10% w/w.

[0042] In a still another embodiment, the topical spray composition comprises tranexamic acid, water soluble polymer. penetration enhancers and stabilizing polymer.

[0043] Examples of the water soluble polymer is selected from the group consisting of polyethylene glycol (PEG), branched PEG, polysialic acid (PSA), carbohydrate, polysaccharides, pullulan, chitosan, hyaluronic acid, chondroitin sulfate, dermatan sulfate, starch, dextran, carboxymethyl-dextran, polyalkylene oxide (PAO), polyalkylene glycol (PAG), polypropylene glycol (PPG), polyoxazoline, poly acryloylmorpholine, polyvinyl alcohol (PVA), polycarboxylate, polyvinylpyrrolidone, polyphosphazene, polyoxazoline, polyethylene-co-maleic acid anhydride, polystyrene-co-maleic acid anhydride, poly(l-hydroxymethylethylene hydroxymethylformal) (PHF), 2-methacryloyloxy-2-ethyltrimethylammoniumphosphate (MPC), polyethylene glycol propionaldehyde, copolymers of ethylene glycol/propylene glycol, monomethoxy-polyethylene glycol, carboxymethylcellulose, polyacetals, poly-1, 3-dioxolane, poly-1,3,6-trioxane, ethylene/maleic anhydride copolymer, poly(-amino acids) (either homopolymers or random copolymers), poly(n-vinyl pyrrolidone)polyethylene glycol, propropylene glycol homopolymers (PPG) and other polyakylene oxides, polypropylene oxide/ethylene oxide copolymers, polyoxyethylated polyols (POG) (e.g., glycerol) and other polyoxyethylated polyols, polyoxyethylated sorbitol, or polyoxyethylated glucose, colonic acids or other carbohydrate polymers, Ficoll or dextran and combinations or mixtures thereof. Preferably, the water soluble polymer is selected from chitosan, and chitosan is preferably used in the pharmaceutical spray composition of about 0.1% to about 1% based on the total weight of the composition. Chitosan is dissolved in glacial acetic acid to form the solution and glacial acetic acid is preferably used in the concentration of about 0.1% to about 2% based on the total weight of the composition.

[0044] In a specific embodiment, the topical spray composition comprises tranexamic acid and chitosan.

[0045] In a further embodiment, the topical spray composition consists essentially of tranexamic acid chitosan.

[0046] In still a further embodiment, the topical spray composition consists of tranexamic acid chitosan.

[0047] Examples of the permeation enhancers are selected from glycol ethers, fatty acids, fatty acid esters, glycol esters. glycerides, azones, polysorbates, alcohols, dimethyl sulfoxide, and mixtures thereof. Preferred permeation enhancers for use herein include, but are not limited to, diethylene glycol monoethyl ether (Transcutol), Oleyl alcohol, Oleic acid, Azone (Laurocapram or 1-n-Dodecyl azacycloheptan-2-one), Propylene glycol mono-and diesters of fats and fatty acids (e.g. propylene glycol monocaprylate, propylene glycol monolaurate), Triglycerides and lipids (e.g. linoleic acid), macrogolglycerides or Polyethylene glycol glycerides and fatty esters (e.g. stearoyl macrogolglycerides, oleoyl macrogolglycerides, lauroyl macrogolglycerides, Oleyl macrogol-6-glycerides, lauroyl macrogol-6 glycerides), Glycerides and fatty acid esters of polyethylene glycol 400, Polyoxyl 40 Hydrogenated Castor Oil (Cremophor RH 40), Polysorbate 80, Dodecylazacycloheptanone, SEPA such as described in U.S. Pat. No. 4,861,764 (e.g. 2-n-nonyl-1,3-dioxolane), and mixtures thereof.

[0048] Preferred mixture of permeation enhancers are selected from polyethylene glycol 400 and polysorbate 80. Penetration enhancers preferably used in the pharmaceutical spray composition of about 1% to about 7% based on the total weight of the composition, preferably polysorbate 80 is used in the range of about 0.1% to about 10% based on the total weight of the composition and polyethylene glycol is used in the range of about 1% to about 5% based on the total weight of the composition.

[0049] Example of the stabilizing polymer include recurring structural units containing an amide group. In general, it has been found that polyvinyl pyrrolidone having a wide range of average molecular weights give excellent aerosol pharmaceutical compositions, in particular suspensions. Particularly preferred embodiments of the invention are when the stabilizing polymer is polyvinylpyrrolidone (PVP), also known as povidone. Different types of PVP may be characterized by their viscosity in solution, expressed as a K-value (see European Pharmacopoeia, 5.sup.th ed., 2004, vol. 2, page 2289). Preferably the K-value of the PVP used is between 10 and 150, more preferably between 15 and 80, more preferably between 20 and 40, most preferably about PVP K30. Stabilizing polymer preferably used in the pharmaceutical spray composition of about 0.1% to about 0.5% based on the total weight of the composition.

[0050] In another embodiment the topical spray composition comprises tranexamic acid, chitosan, polyethylene glycol, polysorbate 80, polyvinyl pyrrolidone, glacial acetic acid and water.

[0051] In a further embodiment the topical spray composition consists essentially of tranexamic acid, chitosan, polyethylene glycol, polysorbate 80, polyvinyl pyrrolidone, glacial acetic acid and water.

[0052] In still a further embodiment the topical spray composition consists of tranexamic acid, chitosan, polyethylene glycol, polysorbate 80, polyvinyl pyrrolidone, glacial acetic acid and water.

[0053] In a specific embodiment, the topical spray composition consists of [0054] (a) about 1% to about 10% tranexamic acid, [0055] (b) about 0.1% to about 1% water soluble polymer, [0056] (c) about 1% to about 7% penetration enhancers, [0057] (d) about 0.1% to about 0.5% stabilizing polymers [0058] (e) glacial acetic acid and [0059] (f) water

[0060] In another embodiment the topical spray composition comprises of about 1% w/w to about 10% w/w of tranexamic acid, about 0.1% w/w to about 1% w/w of chitosan, about 1% w/w to about 5% w/w of polyethylene glycol, about 0.1% to about 1% of polysorbate 80, about 0.1% to about 0.5% of polyvinyl pyrrolidone, glacial acetic acid and water.

[0061] In a further embodiment the topical spray composition consists essentially of about 1% w/w to about 10% w/w of tranexamic acid, about 0.1% w/w to about 1% w/w of chitosan, about 1% w/w to about 5% w/w of polyethylene glycol, about 0.1% to about 1% of polysorbate 80, about 0.1% to about 0.5% of polyvinyl pyrrolidone, glacial acetic acid and water.

[0062] In a still further embodiment the topical spray composition consists of about 1% w/w to about 10% w/w of tranexamic acid, about 0.1% w/w to about 1% w/w of chitosan, about 1% w/w to about 5% w/w of polyethylene glycol, about 0.1% to about 1% of polysorbate 80. about 0.1% to about 0.5% of polyvinyl pyrrolidone, glacial acetic acid and water.

[0063] In another embodiment the topical spray composition comprises of about 10% tranexamic acid, about 1% of chitosan, about 5% of polyethylene glycol, about 0.2% of polysorbate 80, about 0.25% polyvinyl pyrrolidone, glacial acetic acid and water.

[0064] In a further embodiment the topical spray composition consists essentially of about 10% tranexamic acid, about 1% of chitosan, about 5% of polyethylene glycol, about 0.2% of polysorbate 80, about 0.25% polyvinyl pyrrolidone, glacial acetic acid and water.

[0065] In a still further embodiment the topical spray composition consists of about 10% tranexamic acid, about 1% of chitosan, about 5% of polyethylene glycol, about 0.2% of polysorbate 80,about 0.25% polyvinyl pyrrolidone, glacial acetic acid and water.

[0066] In a specific embodiment, the present invention discloses a topical spray composition comprising tranexamic acid. chitosan, polyethylene glycol, polysorbate 80, polyvinyl pyrrolidone and water prepared by a process comprising the steps of a) dissolving Chitosan in 1% glacial acetic acid b) dissolving tranexamic acid in above solution c) adding polyethylethylene glycol, polysorbate 80, polyvinyl pyrrolidone and water to above solution and [0067] d) sterilization by filtration

[0068] In embodiments of the invention after the preparation of topical spray composition comprising tranexamic acid, chitosan, polyethylene glycol, polysorbate 80, polyvinyl pyrrolidone, acetic acid and water. the inventors have sterilized the spray composition by moist heat sterilization at 121 C. for 10 minutes and 20 minutes respectively and found that there was change in colour of solution due to depolymerisation of chitosan. The inventors of the present invention have surprisingly found that the topical spray composition is sterilized by filtration method using a pre-filter of 8 m followed by 0.45 m and 0.22 m at a constant pressure of 1.5 bar with a filter surface area of 13 cm.sup.2 for one-liter topical spray composition and no decolouration of composition was observed. The time vs filtration rate was depicted in FIG. 1 and filtration time for one-liter spray composition was found to be 12.2 minutes.

[0069] In another embodiment the topical spray composition of the present invention is used for treating a wound or reducing bleeding at haemorrhaging site.

[0070] In a specific embodiment the topical spray composition of the present invention is used for the topical treatment of a wound, and the wound is selected from the group consisting of a) minor abrasions, cuts, scrapes, scratches, burns, sunburns, ulcers, internal venous bleeding. external venous bleeding, and b) surgical interventions selected from gastrointestinal surgery, surgery on parenchymal organs; surgical interventions in the ear, nose and throat area (ENT), cardiovascular surgery, aesthetic surgery, spinal surgery, neurological surgery; lymphatic, biliary, and cerebrospinal (CSF) fistulae, air leakages during thoracic and pulmonary surgery, thoracic surgery, orthopaedic surgery; gynaecological surgical procedures; vascular surgery and emergency surgery, liver resection, and soft tissue injury or surgery.

[0071] In another embodiment the topical spray composition of the present invention is topically applied to a traumatic injury in the battle field, a wound or during or after surgery.

[0072] In yet another embodiment of the invention, the spray composition of present inventing is used for minor abrasions, cuts, scrapes. scratches, burns, sunburns, ulcers and other skin injuries and irritations. such as bleeding during and post-surgery, and uncontrolled internal and external haemorrhage from heavy trauma and/or battlefield wounds.

[0073] In a further embodiment of the invention is provided a method of treating a wound or reducing bleeding at a haemorrhaging site, or the use of a composition according to the invention for hemostasis, tissue sealing and tissue gluing, wherein application or use of the pharmaceutical composition further comprises the application of moderate manual pressure for not less than about 30 seconds, or not less than about 60 seconds, or not less than about 2 minutes. or not less than about 3 minutes, or not less than about 5 minutes, or not less than about 7 minutes, or not less than about 10 minutes, or longer.

[0074] In a most preferred embodiment of the invention is provided a pharmaceutical spray composition comprising tranexamic acid and chitosan for use in surgical interventions such as such as in the gastrointestinal system, e.g. the oesophagus, stomach, small intestine, large intestine, bowel, rectum, on parenchymal organs such as the liver. pancreas, spleen, lungs, kidney, adrenal glands, lymph and thyroid glands; surgical interventions in the ear, nose and throat area (ENT) including dental surgery, epistaxis, cardiovascular surgery, such as carotid endarterectomy, femoropopliteal bypass or coronary artery bypass grafting (CABG); aesthetic surgery, spinal surgery, neurological surgery, such as posterior lumbar interbody fusion, microdiscectomy or craniotomy; lymphatic. biliary, and cerebrospinal (CSF) fistulae, air leakages during thoracic and pulmonary surgery, thoracic surgery including surgery of the trachea, bronchi and lungs; orthopaedic surgery, such as knee or hip arthroplasty, total knee arthoplasty; gynaecological surgical procedures such as caesarian section, hysterectomy, fibroid surgery; vascular surgery, such as shunts; urological, bone (e.g. spongiosa resection), and emergency surgery. Particularly preferred surgical interventions include orthopaedic surgery, liver resection, soft tissue injury/surgery and vascular surgery.

[0075] The following examples are provided to illustrate the present invention. It is understood, however, that the invention is not limited to the specific conditions or details described in the examples below. The examples should not be construed as limiting the invention as the examples merely provide specific methodology useful in the understanding and practice of the invention and its various aspects. While certain preferred and alternative embodiments of the invention have been set forth for purposes of disclosing the invention, modification to the disclosed embodiments can occur to those who are skilled in the art.

Example-1: Spray Composition Containing Tranexamic Acid

TABLE-US-00001 Composition: Percent S. NO Ingredient (% w/w) 1. Tranexamic acid 1.0-3.0% 2. Chitosan 0.1-1.0% 3. PEG 400 1.0-5.0% 4. Polysorbate 80 0.1-1.0% 5. PVP K30 0.1-0.5% 6. Glacial acetic acid 0.1-2% 7. Distilled water Q.s

Process for Preparation

[0076] 1. A required amount of chitosan was dissolved in required quantity of glacial acetic acid [0077] 2. To the above solution known amount of Tranexamic acid was added and the solution is kept under continuous stirring. [0078] 3. To the above solution required quantities of PEG 400, polysorbate 80 and PVPK 30 is added slowly with continuous stirring and adjusted the volume. [0079] 4. The above solution is sterilized by filtration

[0080] Example-2: Spray Composition Containing Tranexamic Acid

TABLE-US-00002 Composition: Percent S. NO Ingredient (% w/w) 1. Tranexamic acid 2.5% 2. Chitosan 0.1-1.0% 3. PEG 400 1.0-5.0% 4. Polysorbate 80 0.1-1.0% 5. PVP K30 0.1-0.5% 6. Glacial acetic acid 0.1-2% 7. Distilled water Q.s

[0081] The process for preparation is similar to that of example-1.

Example-3: Spray Composition Containing Tranexamic Acid

TABLE-US-00003 Composition: Percent S. NO Ingredient (% w/w) 1. Tranexamic acid 5% 2. Chitosan 0.1-1.0% 3. PEG 400 1.0-5.0% 4. Polysorbate 80 0.1-1.0% 5. PVP K30 0.1-0.5% 6. Glacial acetic acid 0.1-2% 7. Distilled water Q.s

[0082] The process for preparation is similar to that of example-1.

Example-4: Spray Composition Containing Tranexamic Acid

TABLE-US-00004 Composition: Percent S. NO Ingredient (% w/w) 1. Tranexamic acid 10% 2. Chitosan 0.1-1.0% 3. PEG 400 1.0-5.0% 4. Polysorbate 80 0.1-1.0% 5. PVP K30 0.1-0.5% 6. Glacial acetic acid 0.1-2% 7. Distilled water Q.s

[0083] The process for preparation is similar to that of example-1.

Example 5: Spray Composition Containing Tranexamic Acid

TABLE-US-00005 Composition: Percent S. NO Ingredient (% w/w) 1. Tranexamic acid 10% 2. Chitosan 1.0% 3. PEG 400 5.0% 4. Polysorbate 80 0.2% 5. PVP K30 0.25% 6. Glacial acetic acid 1% 7. Distilled water Q.s

[0084] The process for preparation is similar to that of example-1.

Example 6: Sterilization by Filtration

[0085] The topical spray composition as disclosed in example-5 was sterilized by moist heat sterilization at 121 C. for 10 minutes and 20 minutes respectively and found that there was change in colour of solution due to depolymerisation of chitosan.

[0086] Then the composition as disclosed in example-5 was sterilized by filtration method using a pre-filter of 8 um followed by 0.45 um and 0.22 um at a constant pressure of 1.5 bar with a filter surface area of 13 cm.sup.2 for one-liter topical spray composition and no decolouration of composition was observed. The time vs filtration rate was depicted in FIG. 1 and filtration time for one-liter spray composition was found to be 12.2 minutes.

Example 7: Biocompatibility Studies

[0087] The fibroblasts (L929) cell line obtained from National Centre for Cell Science (NCCS), Pune, India. The cells were grown in growth medium (MEM) supplemented with 10% of Fetal Bovine Serum (FBS, Sigma Aldrich, India) and 100 units/ml of Penicillin/Streptomycin (Sigma Aldrich, India) at 37 C. with humidified air containing 5% of CO.sub.2.

[0088] Cytotoxic effect of tranexamic acid spray composition as disclosed in example-5 was determined against L929 cell line were tested by MTT assay. Tranexamic acid spray sample showed significant cell proliferation at 3-fold increase when compared to control at 4 hours (FIG. 2) and at 24 hours (FIG. 3). Further the cell proliferation of tranexamic acid spray as disclosed in example-5 was compared with Tranexamic acid spray 75% (75 ml of tranexamic acid spray as disclosed in example-5)+25ml of complete media containing 10% Fetal bovine serum and Tranexamic acid spray 75% (75 ml of tranexamic acid spray as disclosed in example-5)+25ml of incomplete media and was depicted in FIG. 2 for 4 hours and FIG. 3 for 24 hours.