WO2024194781A1 - Improved compositions - Google Patents

Abstract

The present disclosure provides methods for sustained release of therapeutic agents for treatment of diseases in the body, more specifically localized diseases in human or veterinary applications. It relates in particular to means and methods for treatment of localised diseases of internal body cavities by delivering therapeutic agents in a slowly eluting biocompatible matrix when applied to the affected tissue. The novel compositions provide ease of compounding and administration over the prior art methods. Methods of preparing and administering these compositions are also described.

Description

IMPROVED COMPOSITIONS CROSS-REFERENCE TO RELATED APPLICATIONS The present application is an International application which claims priority to Indian 5 Provisional application 202341020598 filed on March 23, 2023 and to International application PCT/IB2023/059902 filed on October 03, 2023; both of which are incorporated herewith by reference. FIELD OF THE INVENTION The invention relates in general to methods for sustained release of therapeutic agents for 10 treatment of diseases in the body, more specifically localized diseases in human or veterinary applications. It relates in particular to means and methods for treatment of localised diseases of internal body cavities by delivering therapeutic agents in a slowly eluting biocompatible matrix when applied to the affected tissue. The novel compositions provide ease of compounding and administration over the prior art methods. 15 BACKGROUND OF THE INVENTION Several localized diseases are known to mankind. The term localized as used herein is intended to cover all conditions which are restricted within any part of the body in human beings or in animals. Such conditions include for example solid tumors or cancerous growths within organs such as brain, liver, pancreas, lungs, urinary bladder, kidney and the like. Other 20 forms of cancer which are localized are also within the scope of this definition including where the cancer has metastasized to other parts of the body. Other areas where disease conditions are localized include for example infections in the lung, gastrointestinal tract, tooth cavities, skin such as in burn therapy, etc. Any part of the body which is accessible through orifices in the body or through image guided delivery such 25 as laparoscopic administration or through a imaging guided needle or catheter or topical application which can benefit from prolonged local exposure of an active is covered within the scope of this invention. The skin, mouth, oesophagus, larynx, vagina and anal canal among others are directly accessible through natural orifices. Others such as superficial tumors, the lungs, liver, urinary 5 bladder, kidneys among others can be accessed through the use of syringes, catheters and guidance provided by imaging technologies. Any organ, cavity or disease condition which can benefit from prolonged local exposure of a therapeutic agent is covered within the scope of this invention. It is very well known scientifically that high local concentrations of drug substances at the site of action, such as a tumor, lead to much better efficacy than transient 10 low concentrations over longer periods of time, such as obtained by the delivery of medicines orally or parenterally. In the oncology area there have been efforts to treat such conditions locally through for example intra tumoral administration of anticancer agents; peri-tumoral administration; intra- cavitary administration and the like with attempts to release the active at the tumor site for 15 prolonged periods of time. Such administration has the advantage of delivering the chemotherapeutic agent directly to the cancerous cells at high doses while sparing the normal cells all over the body from the toxic effects of the chemotherapeutic agents. Such high concentrations of the chemotherapeutic agent allow for a reduction in the tumor volume which can then be removed surgically by resection. The cavity left behind by the removal of the 20 tumor is then filled with a modified release composition comprising a chemotherapeutic agent(s) to prevent spread of the disease. This approach has met with limited success thus far due to a variety of issues. Two areas where there has been success is in the treatment of tumors of the brain (intracavitary administration) and in the treatment of the urinary bladder cancer (direct administration into 25 an organ through a catheter). US 9040074, 9950069, 10039832 for example provide an excellent description of local cavities and properties of delivery systems required for drug delivery to such cavities and are all incorporated herein by reference for these details. Some products approved by the food and drug administration in the United States of America for such therapy include for example GLIADEL WAFER for intra cavitary administration 5 after tumor resection for glioblastoma multiforme wherein thin wafers of a polyanhydride polymer impregnated with Carmustine (BCNU) are left within the surgical cavity after tumor removal to prevent the spread of disease. A second is a product, JELMYTO^TM, for local application into the urinary bladder for the treatment of bladder cancer. This composition uses the concept of reversible thermal gelling type of polymeric systems for therapy as explained 10 below. Reversible thermal gelling (RTG) compositions for pharmaceutical applications are generally based on the use of a group of polymers selected from POLOXAMERS which are block copolymers of polyoxyethylene and polyoxypropylene in various ratios and molecular weights. Certain grades of these polymers which are solid polymers demonstrate unique 15 properties of reversible thermal gelation (RTG) in aqueous or aqueous-organic solutions. RTG as the term used herein is intended to include all polymeric systems where the composition is a liquid at lower temperatures and gels at elevated temperatures. The range of temperatures over which the compositions are liquid and then turn to gels vary a lot based on the polymer selected, the comonomer ratio, the types and properties of comonomers used, the molecular 20 weight and polydispersity, use of additives, concentration of the polymer(s) used among other such variables. Such aqueous RTG compositions have found use in topical delivery for example for the treatment of wound or burn therapy due to the hydrogel nature of the RTG. The liquid RTG composition for example with or without an active agent which is a liquid at a lower 25 temperature (say 2-8 ^C) is applied on to the external wound or burn whereupon coming in contact with the application site which is at an elevated temperature (37 ^C), the composition converts to a gel. The use of the RTG compositions for internal application to body cavities for localised administration is not widely known and even less approved for commercial use in clinical 5 practice. An example of such therapy into an organ through guided administration is JELMYTO^TM® (Urogen Inc.) for intra pyelocalyceal administration for treatment of various types of cancers of the urinary bladder/tract. The delivery system comprises a RTG composition comprising Mitomycin C (MMC) as an active which is administered as a liquid formulation into the bladder through a catheter and which converts into a gel at body 10 temperature. The gel conforms to the shape of the cavity; releases the active over a period of time and is then eliminated via the urine. The product is rapidly becoming the current standard of care for such treatment of a condition which earlier required surgery as the only option. While there are many products currently under development, this is the only product of its kind approved for local therapy of tumors. 15 JELMYTO^TM is provided as a kit comprising two 40 mg vials of lyophilized MMC injection and one vial containing 20 mL of a RTG. The gel is a liquid at refrigeration temperature (2-8 ^C) and converts to a non-flowable gel at about 20 ^C. The reconstitution of the lyophilized MMC vials to convert into the final gel form loaded with MMC is a laborious procedure involving multiple complex steps comprising chilling the mould and all vials, syringes, etc. at 20 each stage; preparing a pre-wetting solution of MMC with the hydrogel in multiple syringes/vials; bringing together all of the solutions before administration. The whole procedure is thus prone to problems since the entire processing has to be done at 2-8 ºC, in a clean environment. The product mixture should not be mixed vigorously. Also, the drug solution is dark purple in colour and hence it is difficult to define whether the lyophilized 25 MMC has been solubilized completely or not. See Table 1 in descriptive Example 1 below for the reconstitution procedure. The compounding procedure for preparing the final Jelmyto^TM for administration is thus suboptimal for the pharmacist or nurse practitioner and requires a lot of rigorous training and controls. Secondly, as per the patient information leaflet provided by Urogen the final amount of MMC 5 administered to the patient is 60 mg. The remaining gel and the MMC is thus discarded resulting in product wastage. Another product based on this technology is at an advanced stage of clinical studies for the administration of the composition to patients with urinary bladder cancer, at home. This thus requires the composition to be compounded in the pharmacy and then to be transported to the patient’s home under controlled low temperature conditions for 10 administration. Such complications place a limitation on the use of this product and such other products based on this technology due to the rigor required in the compounding process. The need for moisture sensitive actives available only as lyophilized formulations for reconstitution places an undue burden for delivery with the RTG compositions. It would thus be beneficial in clinical practice to have compositions and kits for delivery wherein the 15 sensitive active agent is present in a solution form and can be readily, rapidly and uniformly mixed with the RTG composition for immediate use without the rigorous controls required for JELMYTO^TM as described above. There is thus a need for a product which can be readily mixed by the nurse practitioner or doctor just before the administration. There is a further need for a product which can be rapidly 20 reconstituted with minimal in-process handling. There is a further need for a composition whereby the active compound can be rapidly and uniformly solubilized or suspended in the RTG composition. There is also a need for a composition with the flexibility to adjust the dose and reduce wastage. There is a further need for a kit which allows the rapid compounding of the final composition as well as a method for the preparation and administration of the composition to a subject in need thereof. These and other needs are addressed by this invention. SUMMARY OF THE INVENTION The present inventors have through rigorous research found that it is possible to overcome the 5 above-mentioned issues associated with the laborious reconstitution of the lyophilized active and then incorporation into the RTG drug delivery vehicle through the use of specially designed solutions or suspensions of the active substance in carefully selected non-aqueous organic solvents, either alone or in combination of solvents. Such a delivery system comprises a kit comprised of (1) A RTG hydrogel composition and (2) A non-aqueous liquid 10 composition comprising the active. The final compounding procedure is thus a mixing of two liquids which results in the final composition for administration. Surprisingly, the mixing of the two liquids does not significantly modify the rheological properties or the rate of release of the active from the final composition while substantially improving the compounding and administration procedure for such products. 15 The delivery compositions thus devised have the following comparable characteristics in comparison with a similar delivery composition prepared by using a lyophilized active as captured in the following embodiments: 1. The delivery system has similar physicochemical characteristics as well as a similar performance 202. Similar rheological profile including parameters such as solution to gel transition temperatures; viscosity at solution state (2-8 ^C), at gel point (17-20 ^C) and at body temperature (about 37 ^C) 3. Similar bio-adhesion and muco-adhesion 4. Comparable release of the active from the composition: rate and extent 5. Comparable physical and chemical stability of the active and the composition, both on storage and in use 6. Comparable syringeability and spreadability 5 WHILE providing the following advantages over prior art RTG delivery systems: 1. Significantly simplified reconstitution and mixing of the active phase with the RTG phase with reduced number of steps 2. Reduced number of steps and overall time in the preparation of the final composition for administration 103. Reduction in the amount of training of the pharmacy or nurse practitioner 4. Reduction in the amount of wasted product through defining the exact amount of formulation to be mixed together per patient 5. Tailoring of the dose per patient while avoiding wastage 6. Possibility of mixing the two phases right at the time of administration 157. Achieving uniformity of the active rapidly 8. Providing a simplified kit capable of compounding the final composition rapidly 9. Possibility of incorporating biologic actives and highly moisture sensitive actives in the composition through the use of non-aqueous suspensions of actives These and other embodiments of the invention are further described below in detail. 20 DETAILED DESCRIPTION OF THE INVENTION The improved delivery system of the invention comprises a kit comprised of (1) A RTG hydrogel composition and (2) A non-aqueous liquid composition comprising the active. The final compounding procedure is thus a mixing of two liquids which results in the final 25 composition for administration. Surprisingly, the mixing of the two liquids does not significantly modify the rheological properties or the rate of release of the active from the final composition while substantially improving the compounding and administration procedure for such products. Reference is made to US 9040074, 9950069, 10039832 for detailed descriptions of the internal 5 cavities; types of conditions; properties of internal cavities; topical treatment of diseases; types of therapeutic agents; more specifically to urinary bladder cancer and the need of improved delivery; physicochemical characteristics of internal cavities and of therapeutic agents for delivery. Specific sections pertain to the treatment of a variety of bladder and associated cancers and the state of the art in delivery of cytotoxic therapeutic agents to the bladder. All 10 of these details in the patent references are incorporated herein by reference as if described here and are meant to cover all of those details. It is currently proven that providing and maintaining higher concentrations of actives locally for a longer period of time will significantly improve the efficacy of any active and hence the therapy. Certainly, for different types of bladder cancer the clinical use of JELMYTO^TM has 15 demonstrated this abundantly. JELMYTO^TM is thus the current standard of care for this type of cancer and has significantly reduced the need for surgery, which was the erstwhile only option. There is now a further push for the delivery of JELMYTO^TM in the patient’s home setting as against in the hospital setting. For such local therapy to be effective the drug delivery system should have certain properties. 20 The properties of the materials to be used in such admixture must be adapted to the needed medical effect; i.e. the disease condition to be treated locally. Some important properties include: ^ Rheological properties such as viscosity, thixotropy, gel transition temperature, gel strength defined by G′, G″ etc required for the introduction of the material into the internal cavity 25 ^ Mechanical properties such as syringeability, flowability, tensile strength, etc. ^ Duration of time that the delivery system remains in the cavity before it degrades ^ Suitable active or combination of actives and their concentrations: small molecule or biologic ^ Adequate bio-adhesion / muco-adhesion to retain the delivery system within the cavity ^ The ability of the matrix/mixture to release the drug in a controlled manner such that the actual 5 drug concentration vis-à-vis the organ tissue or lining upon which the mixture is adhered will be optimal for each treatment. ^ Stability of the active in the formulation Stability of the delivery system upon reconstitution Many other such requirements can thus be further defined for such a delivery system. 10 Attention is drawn to US 9040074, 9950069, 10039832 for detailed descriptions of the strength, viscosities, bio-adhesion, muco-adhesion, tensile strength and other properties of the RTG hydrogel and the final delivery system. These details are all incorporated herein by reference as if they were described here in detail. The current invention is designed to answer along felt need of a composition for the delivery 15 of active agents to internal cavities wherein the composition is easy to prepare and needs minimal steps in compounding before administration. It comprises a series of systems that combine therapeutic materials and application means for the topical treatment of diseases that are focused on internal cavities. It is therefore an object of the present invention to disclose the use of a RTG hydrogel composition in a system for delivery of an active agent to the 20 urinary tract, characterized in that said RTG hydrogel composition comprises a RTG hydrogel and a liquid solution or suspension of an active agent. In the following description, various aspects of the invention will be described. For the purposes of explanation, specific details are set forth in order to provide a thorough understanding of the invention. It will be apparent to one skilled in the art that there are other 25 embodiments of the invention that differ in details without affecting the essential nature thereof. Therefore, the invention is not limited by that which is illustrated in the figure and described in the specification, but only as indicated in the accompanying claims, with the proper scope determined only by the broadest interpretation of said claims. The reader is directed to US 9040074, 9950069, 10039832for details of RTG hydrogel compositions and 5 their use in local topical therapy; specifically for cancers and conditions of the urinary bladder and urinary tract. All details in the above mentioned are incorporated herein by reference as if they we described in detail. The delivery composition and delivery system described herein are a significant improvement over the systems defined in US 9040074, 9950069, 10039832 while providing similar delivery properties. 10 As used herein, the term “internal cavity” is used to describe locations in the body that are accessible through an orifice such as mouth, bladder, intestine, oesophagus, rectum, lungs, vagina, stomach, renal pelvis, etc, or by way of minimally invasive surgery such as through the use of a guided catheter or a cavity left behind after surgery such as the removal of a tumor during debulking in the pleura, abdomen, peritoneum, pelvis, etc. and in internal organs such 15 as the liver, lung, kidney, heart, intestine, etc. that are accessible by image guided laparoscopic techniques. In its broadest sense the term will also include the skin and any cavities in the skin such as through burns, etc. The present invention provides a bio-erodible, bio-compatible RTG hydrogel mixed with an active agent, such as a small molecule active or a biological agent such as an peptide, antibody, 20 protein, vaccine and the like. Thus, such a RTG loaded with an active agent, either alone or in combination, is then administered to the internal cavity such as the upper urinary tract in the form of a liquid where it solidifies to for a thick viscous gel to form a drug reservoir from which the drug is then released locally through a combination of mechanisms: diffusion and then erosion of the gel. The active(s) are thus released locally within the cavity restricted by 25 the gel and hence there is minimal exposure of the active to the rest of the body. Also, given the nature of the gel which is a flowable liquid at refrigeration temperature (2-8 ^C) and which then forms a non-flowable viscous gel at body temperature (37 ^C) it is possible to load high concentrations of the active(s) into the composition. Consequently, the composition and delivery system provide high local concentrations of the active(s) at the target site of action. 5 The RTG composition is then eliminated via the urine over a period of time. The present invention is thus a combination of the following embodiments: 1. The RTG hydrogel composition 2. A liquid active composition 3. A delivery composition or delivery system prepared by the mixing of the RTG hydrogel 10 composition and the liquid active composition. 4. A means of mixing the RTG hydrogel composition and the liquid active composition 5. A means or method of delivering the delivery composition to a body. These and other embodiments are described in further detail below. 151. The RTG hydrogel composition: The present invention provides a design of such RTG hydrogel compositions that is based on the characteristics of the internal cavities to be treated and the specific requirements for said treatments in order to determine the required properties of hydrogel systems that can satisfy all these requirements. 20 The RTG hydrogels comprise water-soluble, hydrogel-forming polymers, preferably with RTG capabilities. RTG as defined herein is intended to include all polymers and hydrogel systems which are flowable liquids at refrigeration temperature (2-8 ^C) and which then form a non-flowable viscous gel at body temperature (37 ^C). These polymers having a nominal viscosity of at least 0.015 Pa s, preferably at least 0.050 Pa s (measured as 2% strength aqueous 25 solution at 20 °C.). A preferred family of RTG polymers is called Poloxamers. Poloxamers are a group of block copolymers of polyethylene glycol (PEG) and polypropylene glycol (PPG) that produce reverse thermal gelation (RTG) compositions, with the characteristic that their viscosity increases with increasing temperature up to a point after which viscosity again decreases. One Poloxamer in particular, Poloxamer 407 (also called (Pluronic F 127), 5 possesses a gelling temperature which is above 10 °C. but below the human body temperature, i.e., 37 °C. This characteristic provides the ability of a composition containing the active(s) to be injected or infused in a liquid state into a local internal cavity at a low temperature and as the composition warms, it solidifies into a viscous gel entrapping the active, thus stabilizing upon the wall of the inner body cavity. This characteristic has allowed Poloxamer 407 to be 10 used as a carrier for most routes of administration including oral, topical, intranasal, vaginal, rectal, ocular and parenteral routes. Poloxamer 407 (P 407) is a non-ionic surfactant composed of PEG-PPG-PEG triblock copolymers in a concentration ranging from 20-30%. Poloxamers in general and P 407 in particular are highly soluble in water as well as many organic solvents. At low concentrations 15 in aqueous solutions, they form mono-molecular micelles, but higher concentrations result in multimolecular aggregates consisting of a hydrophobic central core with their hydrophilic polyoxyethylene (POE) chains facing the external medium. Micellization occurs in dilute solutions of block copolymers in selected solvents above the critical micellar concentration, at a given temperature. At higher concentrations, above a critical gel concentration, the 20 micelles can order into a lattice. The nature of the lattice and the characteristic properties of the lattice differ based on the solvent composition, concentration of the P 407, temperature and other additives among other parameters. Aqueous solutions of poloxamers are stable in the presence of acids, alkalis, and metal ions. Commonly used Poloxamers include the P 88 (F68 grade), P 237 (F87 grade), P 338 25 (F108 grade) and P 407 (F127 grade) which are freely soluble in water and many organic solvents. These polymers have been studied and are used in clinical practise due to their high solubilising capacity, excellent stability and safety in the human body. Use of these polymers by various routes of administration is known in clinical practise and products are commercially approved for oral, intravenous, topical, pyelocalyceal administration attesting 5 to the safety of these polymers for clinical use. P 407 is a commercially available POE-PPG triblock copolymer that possesses a general formula E106 P70 E106, with an average molar mass of 13,000. It contains approximately 70% ethylene oxide, which accounts for its hydrophilicity. It is one of the series of poloxamer ABA block copolymers. The concentration of the RTG polymer should preferably be in the range of 10-50% w/v; more preferably 10- 10 35% w/v and even more preferably 15-30% w/v based on the RTG hydrogel composition. In addition to the RTG polymer the compositions further contain other water-soluble polymers to modify the adhesion of the gel to biological tissues, modify drug release, etc. Water-soluble or water-swellable matrix forming polymers preferably employed are hydroxypropylmethyl celluloses (HPMC), hydroxyethylmethyl celluloses (HEC), 15 hydroxypropyl celluloses (HPC), hydroxyethyl celluloses, methyl celluloses (MC), hydroxyalkyl celluloses and hydroxyalkylmethyl celluloses, sodium carboxymethyl celluloses (NaCMC), alginates, galactomannans such as, for example, guar and carob flour, xanthans, polyethylene oxides, polyacrylic acids, polymethacrylic acids, polymethacrylic acid derivatives, polyvinyl alcohols (PVA), partially hydrolysed polyvinyl acetate (PVAc), 20 polyvinylpyrrolidone (PVP), agar, pectin, gum arabic, tragacanth, gelatin, starch or starch derivatives and mixtures of these substances. A preferred water- soluble polymer is HPMC due to its known use in drug delivery and approved use for treatment in internal cavities. The RTG hydrogel of the invention should preferably comprise at least 0.1-5% w/v, more preferably 0.1-2.0% w/v of a HPMC type 25 whose nominal viscosity (measured as 2% strength aqueous solution at 20 °C) is at least 0.015 Pa s, preferably at least 0.050 Pa s. HPMC types preferably used have a degree of substitution of methoxy groups of 16.5-30%, particularly preferably 19-30%, and a degree of substitution of hydroxypropoxy groups of 4-32%, particularly preferably 4-12%. In a particularly preferred embodiment of this invention, pH modifiers may be added 5 to the RTG hydrogel composition to adjust the pH to modify or enhance the stability of the active(s) or to modify the release of the active(s). Examples of suitable excipients which can be added to the RTG composition according to the invention to achieve release include adipic acid, malic acid, L-arginine, ascorbic acid, aspartic acid, benzene sulphonic acid, benzoic acid, succinic acid, cellulose phthalates, in particular cellulose acetate phthalate and 10 hydroxypropylmethyl cellulose phthalate, cellulose succinates, in particular cellulose acetate succinate and HPMCAS, citric acid, ethanesulphonic acid, 2-hydroxyethanesulphonic acid, fumaric acid, gluconic acid, glucuronic acid, glutamic acid, potassium hydrogen tartrate, maleic acid, malonic acid, methanesulphonic acid, polymethacrylates (e.g. EUDRAGIT® types), toluenesulphonic acid, trometamol, tartaric acid. Citric acid, succinic acid, tartaric 15 acid, HPMCAS, and polymethacrylates (e.g. EUDRAGIT® L) are preferably employed. As required, the composition may be a buffered composition with the aqueous phase of the RTG hydrogel being buffered with various buffering excipients well known to a person skilled in the art. If these excipients are present in the RTG composition according to the invention, they are typically added in a proportion of from 1 to 50% w/v preferably 1-30% w/v based on the 20 total mass of the RTG hydrogel. Examples of plasticizing excipients in the hydrogel formulation are propylene glycol, glycerol, triethylene glycol, butanediols, pentanols, such as pentaerythritol, hexanols, long- chain alcohols, polyethylene glycols, polypropylene glycols, polyethylene/propylene glycols, silicones, phthalic acid derivatives (e.g. dimethyl phthalate, diethyl phthalate, dibutyl 25 phthalate), benzoic acid and benzoic esters, other aromatic carboxylic esters (e.g. trimellithic esters), citric acid derivatives (e.g. triethyl citrate, tributyl citrate, acetyl triethyl citrate), aliphatic dicarboxylic esters (e.g. dialkyl adipates, sebacic esters, in particular diethyl sebacate, tartaric esters), glycerol monoacetate, glycerol diacetate or glycerol triacetate, fatty acids and derivatives (e.g. glycerol monostearates, acetylated fatty acid glycerides, castor oil 5 and other natural oils, Miglyol), fatty acid alcohols (e.g. cetyl alcohol, cetylstearyl alcohol), sugars, sugar alcohols and sugar derivatives (e.g. erythritol, isomalt, lactitol, mannitol, maltitol, maltodextrin, xylitol). The concentration of plasticizers is normally from 0 to 30%, preferably from 0 to 20% based on the total mass of the gel. Examples of further suitable water-swellable polymers which may be incorporated in 10 the hydrogel are high-molecular weight polyethylene oxides, xanthan gum, copolymers of vinylpyrrolidone and vinyl acetate, polyvinylpyrrolidones, crospovidones, crosslinked sodium carboxymethylcellulose, crosslinked sodium carboxymethyl starch, low-substituted hydroxypropylmethyl cellulose (L-HPC), poly (hydroxyalkyl methacrylate), alginates and galactomannans and mixtures thereof. 15 The vehicle for the RTG hydrogel composition is preferably water. But it is possible to form RTG hydrogels using combinations of water with other water-miscible organic solvents or partially miscible organic solvents. The use of small percentages of water- immiscible organic solvents is included within the scope of the invention. Such water-miscible solvents could include for example dimethyl acetamide (DMA), N-methyl pyrrolidone 20 (NMP), dimethyl sulfoxide (DMSO), benzyl alcohol, ethanol, and the like without limitation. Water-immiscible or partially miscible organic solvents include for example benzyl benzoate, triacetin, triethyl citrate, propylene carbonate, etc and the like. As long as the solvents are miscible with water completely or in smaller proportions; they are included within the scope of the invention without limitation. 25 2. A liquid active composition The second component of the delivery composition or the delivery system is a liquid active composition. The liquid active composition comprises a solution or suspension of an active or combination of active substances in biocompatible organic solvents. The solvents of the 5 invention can be water-miscible organic solvents or water-immiscible organic solvents. The use of small percentages of water-immiscible organic solvents is included within the scope of the invention. Such water-miscible solvents could include for example dimethyl acetamide (DMA), N-methyl pyrrolidone (NMP), dimethyl sulfoxide (DMSO), benzyl alcohol, ethanol, and the like without limitation. Water-immiscible or partially miscible organic solvents 10 include for example benzyl benzoate, triacetin, triethyl citrate, propylene carbonate, etc and the like. As long as the solvents are miscible with water completely or in smaller proportions; they are included within the scope of the invention without limitation. Thus, as per this embodiment of the invention a solution or suspension of the active substance is provided. The concentration of the active and the solvent or combination of 15 solvents to be used will be determined based on the active and the concentration of the active required to be delivered. The use of such solutions allows for concentrations greater than 200 mg/mL for some actives. Attention is directed to patent application IN 202241058449 which covers such liquid compositions of MMC in a wide variety of solvents and is incorporated herein by reference completely for detailed descriptions of the types of solvents and 20 procedures for the preparation of such solutions. Though the reference speaks specifically about MMC liquid compositions; it is intended that any active which can be converted into a liquid composition is included within the scope of this invention. Existing liquid compositions such as for example for bendamustine, melphalan, busulfan among others already available on the market commercially for therapeutic use which can benefit from a combination with the RTG hydrogel delivery system for local internal use are all within the scope of the invention without limitation. In one aspect of this embodiment the active is present as a solution. In another aspect the active is present as a suspension. The use of non-aqueous solvents for the preparation of 5 suspensions of actives has been shown to be especially beneficial in preparing composition with high drug loads. Compositions of actives such as antibodies and other large molecules containing greater than 200-300 mg/mL of active have been demonstrated. Such compositions are specially beneficial for actives which are unstable in solution in water or water-miscible organic solvents. Biological active such as monoclonal antibodies, proteins, peptides, RNA 10 actives, oligonucleotides and all actives which currently and in the future require means such as lyophilization are included within the scope of this invention. In this embodiment, the suspension of the active in the water-immiscible organic solvent is mixed with the RTG hydrogel composition to provide a dispersion of the active and the solvent. The active is then released from the delivery system through a combination of diffusion and erosion as described 15 above. The use of non-aqueous solvents with different water miscibility allows for the combination of multiple active substances with the RTG hydrogel composition. Thus, it is envisaged that the RTG hydrogel could be combined with a solution of a small molecule active in a water-miscible organic solvent and a solution or suspension on another active in a water- 20 immiscible organic solvent; for example a protein. In another embodiment, the use of a preservative such as benzyl alcohol as one of the solvents allows for a composition where a multi-dose liquid composition of the active can be provided for repeated use with the RTG hydrogel composition. Active substances that can benefit from the current invention include but are not limited25 to actives from the following classes : Antineoplastic drugs, chemotherapeutic agents, anti- infective agents (e.g. Antimicrobial drugs, Antiparasitic agents, Antivirals), genito-urinary system drugs, anti-inflammatory products, analgesics, musculoskeletal system acting drugs, drugs acting on the blood (antihemorrhagics, antithrombotic agents, antianemic), dermatologic drugs (antifungals, antiseptic), gastrointestinal system (antiobesity, acid related 5 disorders), metabolism drugs, neurological drugs, respiratory drugs including nasal drugs, cardio-vascular drugs, otological drugs, anti-infective drugs, corticosteroids drugs, analgesics drugs, anti-parasitic drugs, anasthetic drugs including local anaesthetics, and the like without limitation. In other cases, the active could be biologic compounds such as for example proteins, peptides, gene therapy agents, growth factors, radionuclide compounds, RNA or 10 DNA therapeutics, oligonucleotides, enzymes and the like. Whatever the indication wherever the active can benefit from incorporation into the delivery system of the invention through converting to the liquid composition all such indications and actives are covered within this description without limitation. Where actives are already present in liquid formulations these can then be directly incorporated into the 15 delivery system of the current invention. Where actives are currently available as lyophilised powders or other sterile powders for reconstitution it is envisaged that these will be converted into liquid compositions and these will then be incorporated into the delivery system of the invention. The current invention thus provides a unique simplified platform for the redesign of drugs 20 to make them suitable for topical local administration. 3. A delivery composition or delivery system prepared by the mixing of the RTG hydrogel composition and the liquid active composition In the third embodiment of this invention is provided a delivery composition or delivery system. The delivery composition is prepared by mixing the RTG hydrogel composition described above with the liquid active composition described in the above embodiment. Thus, in this embodiment the RTG hydrogel composition and the liquid active composition are independently cooled to 2-8 ^C by any cooling means. The cooling means could be a refrigerator or a chilling block available in the pharmacy or hospital or a bucket of ice. Any 5 cooling means is acceptable for the purposes of the invention as long as it is able to cool the two compositions uniformly to a temperature of 2-8 ^C. The two liquid compositions are now mixed together using mixing means to achieve the final delivery system ready for administration. Precautions are to be taken such that all mixing is carried out at 2-8 ^C. The present invention provides a delivery composition which releases active(s) in a 10 controlled fashion over a prolonged period. It is further an object of the present invention to provide active compositions with particular release profiles through which the prior art problems. As an example an average release rate between 80% in 6 hours and 80% in 24 hours is maintained. More prolonged release rates can also be achieved by modulation of the RTG hydrogel composition. A prolonged release locally of the active(s) allows for high local 15 concentrations of the active to be achieved at the site of action, for example a tumor, with very low concentrations of the active leaving the site of administration resulting in increased efficacy and reduced toxicity. Similarly a combination of actives allows for delivery compositions with dual or more actions to be achieved. All that is required is to provide liquid compositions of one or more active and mix them with the RTG hydrogel composition 20 sequentially to achieve the delivery system of the invention. The mass ratio of active ingredient to the total mass of the delivery composition in these novel formulations is in the range from 1:1 to 1:10,000, preferably in the range from 1:2 to 1:1,000. 4. A means of mixing the RTG hydrogel composition and the liquid active composition The RTG hydrogel composition described above could be provided in a vial or a prefilled syringe. Similarly, the liquid active composition could be provided in a vial or a prefilled syringe. The vial could be a single-dose or multiple-dose vial. The vial and syringe could be connected through appropriate connectors. For use of sterile compositions all vials, prefilled 5 syringes and connectors should be sterile. Thus, for example in one embodiment the RTG hydrogel could be provided in a sterile vial and the liquid active composition in a sterile prefilled syringe. The practitioner would thus connect the vial with the prefilled syringe through a suitable luer-lock connector. The two liquids at 2-8 ^C are then mixed back and forth to achieve the final delivery system ready for administration. 10 The size and type of vial, prefilled syringe and the mixing means are readily defined by a person skilled in the art and will vary based on the amount of RTG hydrogel, the amount of the liquid active agent and the final dosage to be administered. Thus, any packaging configuration which will allow for the rapid preparation, mixing, administration of the delivery composition are included within the scope of this invention without limitation to the 15 type of packaging or packaging material of construction. 5. A means or method of delivering the delivery composition to a body. Interestingly, the delivery system thus designed as per the current invention allows their comfortable administration through a thin tube, for example a urethral catheter, without exerting more than the common pressure required to inject a saline through such a device; and 20 at the same time, as the liquid polymer settles upon the bladder wall, it solidifies creating a gelatinous film that then gradually releases the therapeutic ingredient upon said bladder wall. This feature is of fundamental importance and is enabled by the fact that the polymeric composition was designed so as to possess reverse thermal gelling properties (see below), that is, to possess low viscosity at low temperatures (below 15-19 °C) and increase dramatically 25 its viscosity as its temperature increases due to the body heat. Interestingly, it is observed that the preparation of the delivery composition and system does not substantially modify the properties of the composition compared to a RTG delivery system prepared by the use of a lyophilized composition. These details are explained by way of different examples. The reconstitution procedure of the present delivery composition is significantly simplified when compared with that of the only approved product on the market for pyelocalyceal administration for the treatment of bladder cancer. The use of the liquid active composition not only allows for an improved ease of mixing and preparation of the composition but it also allows for providing the same rheological characteristics as well as drug release as seen with the JELMYTO^TM composition. The end effect is a significantly improved delivery system. The non-limiting examples presented below illustrate the versatility that is provided by the diverse compositions, that allows its engineering to render different release profiles, flow characteristics, instillation temperatures, coating layer thickness and additional features as required by the specific treatment to be applied upon an internal cavity. A comparison is drawn between the only approved such composition, JELMYTO^TM, for pyelocalyceal administration for the treatment of bladder cancer using MMC. These examples are illustrative of the flexibility of the delivery composition and delivery system thus achieved and can be applied for any other active which can benefit from local application of actives for a variety of disease conditions. EXAMPLES Descriptive Example 1: Comparative reconstitution procedure for JELMYTO^TM vis-à-vis inventive product JELMYTO^TM is provided as a kit comprising 2 vials each containing 40 mg of lyophilized MMC along with mannitol and a 20 mL vial containing a RTG hydrogel composition for reconstitution. WHEREAS The inventive composition of the instant invention is envisaged to be provided as a kit comprising a single drug product vial or prefilled syringe or such other suitable packaging containing 60-80 mg of MMC in a non-aqueous liquid composition and a 20 mL vial containing a RTG hydrogel composition for mixing. Table 1 below demonstrates the multiple complex steps required for the reconstitution of JELMYTO^TM (extracted from the JELMYTO^TM reconstitution procedure detailed in the label which is incorporated herein by reference) and the ease with which a ready-to-administer delivery composition can be prepared by the instant delivery composition and process. It is apparent that the instant delivery composition and process to make the composition significantly reduces the number of steps and the need for multiple syringes and connectors, etc required for JELMYTO^TM reconstitution. Also, the ease with which the composition and process achieve uniformity vis-à-vis JELMYTO^TM is quite apparent. The reduction of burden on the hospital pharmacy as well as the nursing staff is quite apparent not to mention the significant reduction in training, preparation time, consistency achieved, ease of mixing, etc. There is also the added flexibility of making dose modifications since the required amount of the MMC in the liquid formulation can be mixed with the RTG hydrogel instantaneously. There is the additional component of reduction in product losses and the ability to titrate the dose for the patient. Furthermore, it is envisaged that the delivery composition for administration can be prepared by the nurse practitioner right at the time of administration resulting in a reduced preparation, transportation time over JELMYTO^TM. This possibility thus increases the flexibility of use of the composition since the time for storage after reconstitution becomes a non-issue when compared with JELMYTO^TM. These and other advantages of the inventive composition will become apparent from the examples below. Table 1: Step JELMYTO^TM Inventive Benefit Composition Pre- Product Product Inventive requisites Requirements: 2 Requirements: 1 composition before product vials, 1 product vial, 1 has a single starting diluent vial diluent vial product vial preparation Documents: Same as containing a admixture label, JELMYTO^TM liquid composition vs prescribing information, 2 product vials instructions for in Pharmacy, Pharmacy supplies JELMYTO^TM. instructions for - 2nos of vial All other label administration adaptors, 2 nos. of and pharmacy Syringe adaptors, supplies are the Pharmacy supplies: 3 2 luer lock same for both nos. of vial adaptors, connector, 1 nos. products. The 3 nos. of Syringe of 2 mL luer lock overall number adaptors, 1 luer lock syringes, 1 no of of vials, connector, 2 nos. of 20 mL luer lock syringes and 10 mL luer lock syringe, 1 no of connectors will syringes, 1 no of 20 20-25G needle, reduce mL luer lock syringe, 70% IPA, 1 no of significantly. 1 no of 20-25G light protective needle, 2 mL sterile bag, 1 no of water, 70% IPA, 1 no Urogen pharma of light protective chilling block bag, 1 no of Urogen pharma chilling block Step 1: The day before Same as Same as Freezing of preparation, put the JELMYTO^TM JELMYTO^TM the chilling Chilling Block in the block freezer at -20 °C to - 12 °C (-4°F to 10.4°F) upside down overnight. Step 2: 1. Take out the 1. Take out the Preparation chilling block from chilling block of supplies freezer, spray the from freezer, spray 70% IPA, allow to the 70% IPA, air dry and then place allow to air dry the chilling block in and then place the isolator, wait for 20 chilling block in min to continue the isolator, wait for next steps. 20 min to continue Handling steps the next steps. and time is 2. Connect the vial greatly reduced adaptors to the 2 2. Connect the vial during supplies adaptors to the 1 product and one product and one preparation diluent vial diluent vial step 3. Not required 3. Connect the syringe adaptors to 4. Place 1 product one of the 10 mL and vial and 1 diluent 20 mL syringes vial in chilling 4. Place the 3 vials, block for 10 10 mL and 20 mL minutes syringes in chilling 5. Not required block for 10 min 5. Take 2 mL of WFI into another 10 mL syringe and set aside for later use Step 3: 1. Slowly withdraw 1. Not required Steps 3 is Preparation 14 mL of hydrogel completely of Pre- into 20 mL of chilled eliminated. wetting syringe and place the There is no solution syringe in the need to prepare chilling block a pre-wetting 2. Slowly withdraw 4 2. Not required solution. mL of the hydrogel Required into the 10 mL of the volume of the chilled syringe. liquid product Discard un-use can be drawn portion of the with a sterile hydrogel 3. Not required syringe and 3. Withdraw 2 mL of transferred the sterile water into directly to the another 10 mL of the hydrogel vial syringe, replace the needle with the luer 4. Not required lock connector 4. Remove the syringe adaptor from the 4 mL of the 10 mL syringe and connect to the other 5. Not required end of the connector of 2 mL sterile water syringe 5. Gently mix the hydrogel with the sterile water by pushing both the plunger stoppers 6. Not required back and forth for minimum 25 times to create the pre-wetting solution (PWS) 6. Transfer the PWS total 6 mL of the volume into one of the 10 mL syringe, remove the luer-lock connector and re- place with the new syringe adaptor, place the 6 mL of the PWS syringe in the chilling block back Step 4: Mix 1.Take out the 2 nos. 1. Not required Steps 4 is the of product vial from completely admixture the chilling block eliminated. 2. Gently tap the Required bottom of each vial 2. Not required volume of the on the table to ensure liquid product all the Mitomycin can be drawn with a sterile syringe and powder on the transferred bottom of the vials. 3. Not required directly to the 3. Remove the 6 mL hydrogel vial of the PWS chilled solution syringe from the chilling block 4. Not required 4. Inject 3 mL of the PWS in to each JELMYTO^TM vial Note: To ensure accurate dosing the contents of each vial must be the same. 5. Not required 5. Discard the empty PWS solution syringe 6. Gently swirl each 6. Not required JELMYTO^TM vial upright at least 15 times, to ensure all powder and admixture is contain at the bottom of the vial Note: Do not invert or shake the JELMYTO^TM vials 7. Not required 7. Immediately remove the 14 mL of the hydrogel syringe from the chilling block, add 7 mL of the hydrogel into each JELMYTO^TM vial Note: To ensure accurate dosing the contents of each vial 8. Not required must be the same. 8. Gently swirl each JELMYTO^TM vial upright at least 15 times, to ensure all powder and admixture is contain at the bottom of the vial 9. Not required Note: Do not invert or shake the JELMYTO^TM vials 9. Recap and place the 20 mL syringe in the chilling block Step 5: Mix 1. Re-cap and replace 1.Not required This step is both the both the also eliminated JELMYTO^TM JELMYTO^TM vials in since the vials: the chilling block for required 5 min volume of the 2. Remove both the 2. Not required liquid product vials and vigorously can be drawn swirl each vial with a sterile upright at least 15 syringe and times ensuring all the transferred admixture containing directly to the bottom of the vial hydrogel vial 3. Not required 3. Place both the vials in the chilling block. Repeat these steps every 5 min for a total of 30 min. Note: Do not invert or shake the vials Step 6: 1. Remove one 1.Remove Required Prepare JELMYTO^TM vial inventive volume of the admixture from the chilling composition vial liquid product vial block, vigorously from the chilling can be drawn swirl the vial upright block and swirl a with a sterile at least 15 times few times to syringe and Note: Do not invert ensure uniformity transferred of the solution. directly to the or shake the vials hydrogel vial. 2. Using the chilled This is a 20 mL syringe significantly slowly withdraw 7 2. Using chilled xx simplified mL of the admixture mL syringe, process from the vial withdraw xx mL compared to Note: If you are of MMC solution that used for having difficulty from the vial JELMYTO^TM withdrawing the through an adaptor admixture, place the and inject into the vial back in the chilled hydrogel chilling block until diluent vial. This the admixture is the final MMC – liquifies again 3. Discard the empty hydrogel JELMYTO^TM vial. admixture via. 4. Remove the other JELMYTO^TM vial from the chilling 3. Discard the block inject the empty JEL ^TM content of the 20 mL MYTO vial. syringe into the vial, now all the admixture contains in one vial. Recap the vial adaptor. Vigorously swirl the vial upright at least 15 times. Note: Do not invert or shake the vials 5. Your JELMYTO^TM admixture vial is complete. Step 7: Write the "Discard Same as Jelmyto^TM Same as Dispense of after" date and time JELMYTO^TM admixture on the admixture vials label and apply to the prepared JELMYTOTM admixture vial Note: The discard after date and time is " 8 hrs" from the completion of preparation at room temperature. 2. Place the JELMYTOTM admixture vial in a light-protective bag 3. Transport to the treatment facility along with the " JELMYTOTM instructions for administration" Experimental Examples: Example 1: Liquid compositions of MMC Various MMC liquid compositions were prepared at concentrations of 60-80 mg/mL in either plain DMA or combinations of PEG 400 and DMA in different ratios (70:30 to 80:20% w/v) by dissolving the required amounts of MMC in the different solvent or combinations. The liquid compositions thus prepared were then exposed to molecular sieves (Molecular sieves 3 5 A^o beads, 4 to 8 mesh) at a ratio of 0.5:1 (molecular sieves: concentrate) in a sealed container under nitrogen as per procedures described in IN 202241058449 which is incorporated herein by reference, to reduce the moisture content of the liquid compositions. The compositions thus obtained were subsequently filtered and filled into vials for further testing. 10 Example 2: Preparation of RTG hydrogel composition RTG hydrogels were prepared using Poloxamer 407, HPMC E15 and PEG 400 excipients and water as per the Table 2 below. Certain compositions were also prepared free of PEG 400. Table 2: S. No. Ingredients mg/mL 1 HPMC 2.0 2 Poloxamer 407 283.5 3 PEG 400 10.5 4 WFI (water for injection) q.s. to 1 mL 15 Manufacturing Process: In a 500 mL glass container, the required quantity of HPMC was dissolved in 160 mL of cooled WFI. Upon complete solubilization the required quantities of poloxamer 407 and PEG 400 were added and mixed till completely solubilized. The final volume was made up to the 20 350 mL with WFI. Example 3: Preparation of the delivery composition of the invention About 1 mL of different MMC liquid compositions described above were mixed with the RTG hydrogel composition described in Example 2 by simple addition of the defined amounts in a beaker or a Schott glass bottle to achieve the delivery composition. The two liquids were 5 mixed by using a simple magnetic stirrer at a temperature of 2-8 ^C. Similar compositions were prepared by adding the solvent vehicles: DMA or DMA : PEG 400 mixtures in different ratios to the RTG hydrogel composition to prepare placebo compositions. In every case it was observed that all the compositions mixed rapidly and formed the delivery composition of the invention. The compositions were uniform with no presence of 10 undissolved particles. Example 4: Rheological characterization of the delivery compositions The novel delivery compositions as prepared above were subjected to rheological testing to understand the impact of the use of different solvents and combinations on the flow properties of the delivery system. 15 An Anton Paar MCR 302e rheometer with parallel plate geometry was used for the testing. Parameters such as gel point, viscosity (at 2-8 and 37 °C), yield point and flow point were studied using different scans such as viscosity curve, shear curve, amplitude sweep, frequency sweep. The details of each of these scans are provided in Table 3 below. 20 Table 3: No Method Parameters/ Operating range 1 Viscosity curve Shear rate- 101/s, temperature- 5-50 °C, data point- 91 (2pt/°C) 2 Shear curve Shear strain (oscillating)- 0.5%, angular frequency- 10 rad/s, temperature- 5-50 °C, data point- 91 (2pt/°C) 3 Amplitude sweep Shear strain (oscillating)- 0.01-100%, angular frequency- 10 rad/s, data point- 25 (6pt/dec); Temperature- 37 °C The RTG hydrogel and the RTG hydrogel (20 g) mixed with 1 g of either WFI, DMA, DMA : PEG (70:30 or 80:20 %v/v) were used for this testing to study the impact of addition of different vehicles to the RTG composition. The results are summarised in Table 4 below. 5 Table 4: Tests Parameters Hydrogel Hydrogel Hydrogel Hydrogel Hydrogel + Water + DMA + PEG: + PEG: (20 + 1 DMA DMA ratio) 70:30 80:20 Viscosity Viscosity, 110.7 96.8 113.4 123.8 110.6 curve 5 °C (cP) Viscosity, 57341 47373 50576 50033 49701 37 °C (cP) Gel point 17.06 18.53 17.53 16.48 15.44 (°C) Viscosity, 963 781.6 897.7 2542.1 1151.4 gel point (cP) Viscosity, 48051 39145 40647 43119 44220 25°C (cP) Shear curve/ Gel point 17.64 19.13 18.12 16.63 16.63 Temperature temp (°C) ramp test Amplitude Yield 294.6 245.4 249.5 247.2 226.4 sweep point (Pa) (at 37 ^C) Flow point 894.7 733.3 659.2 702.9 653.2 (Pa) Overall, the RTG hydrogel when mixed with water in a ratio of 20:1 and the RTG hydrogel when mixed with the solvents DMA, DMA: PEG in ratios of either 70:30 or 80:20 demonstrate gel points, viscosities at 2-8 ^C, gel point and at 37 ^C and other parameters that 5 are quite similar. This demonstrates that the addition of these solvents to the RTG gel composition does not impact these properties which are crucial for the performance of the drug delivery system. Example 5: Drug release from different delivery compositions 10 Different delivery compositions were prepared as per Table 5 below and were subjected to a drug release study. Table 5: Composition, % w/w S. No Ingredients 1383 1384 1408A 1408B 1408C Liquid compositions of MMC 1 MMC 7.4 7.4 7.4 7.4 7.4 2 DMA 27.8 27.8 27.8 27.8 27.8 3 PEG 400 64.8 64.8 64.8 64.8 64.8 RTG hydrogel composition 1 HPMC 0.2 0.2 0.0 0.2 0.2 2 Poloxamer 407 28 28 28 22.68 34.02 3 PEG 400 1.05 0.0 1.05 1.05 1.05 4 WFI 70.4 70.4 70.4 70.4 70.4 All RTG hydrogel compositions, MMC liquid compositions and the final delivery composition obtained upon mixing the RTG hydrogel compositions with the liquid compositions were prepared as per procedures described in the examples above. The 5 compositions were then subjected to a drug release study using a USP type II apparatus with a suspension cup.500 mL of a phosphate buffer pH 6.8 at 37 ^C was used for the drug release study. Samples were drawn and analysed by an HPLC method. The drug release from the different compositions is provided in Table 6. 10 Table 6: Cumulative drug release, % 15 30 60 90 Number 120 min 150 min 180 min min min min min 1383 13 21 38 52 69 84 95 1384 19 27 48 64 82 93 102 1408A 16 24 45 60 76 90 98 1408B 11 23 44 63 81 90 94 1408C 10 18 32 46 60 74 86 It is quite apparent that drug delivery compositions can be prepared with a wide range of MMC release. Example 6: Rheological characterization of MMC containing delivery compositions 5 Different RTG hydrogel compositions as well as MMC liquid compositions were prepared as per procedures described above and delivery compositions were prepared by mixing them. Details of these compositions are provided in Table 7 below. The RTG hydrogel and the RTG hydrogel mixed with MMC in either WFI, DMA, DMA : PEG (70:30% v/v) or a lyophilized market product (Accord) were used for this testing 10 to study the impact of addition of different vehicles to the RTG composition. A RTG hydrogel (equivalent to the JELMYTO composition) was mixed with a lyophilized MMC product as per the procedure described in the JELMYTO label as a comparison. The details are summarised in Table 7 below. Mixing of the RTG hydrogel with the different MMC liquid compositions was as described above and was all performed at 2-8 ^C. 15 Table 7: Lyophilized Novel compositions, %w/w MMC composition, No Ingredients %w/w 1385 1386 1387 1498 (Market sample), 1395 MMC composition 1 MMC 33.3 7.4 7.4 7.4 7.4 2 DMA 0.0 27.8 27.8 92.6 92.6 3 Meglumine 0.0 0.0 0.01 0.0 0.0 4 PEG 400 0.0 64.8 64.8 0.0 0.0 5 Mannitol 66.7 0.0 0.0 0.0 0.0 DILUENT VIAL 1 HPMC 0.2 0.2 0.2 0.2 0.2 Poloxamer 2 28.0 28.0 28.0 28.0 28.0 407 3 PEG 400 1.05 1.05 1.05 0.0 4.55 4 WFI 70.4 70.4 70.4 70.4 70.4 All delivery compositions prepared as per the above table were then subjected to rheological characterization and drug release as per procedures described above. Table 8 describes the rheological characterization data. 5 Table 8: Tests Parameters Batch Number 1395 1385 1386 1387 1498 Viscosity Viscosity at 5 15.1 16.7 15.4 14.9 Not curve °C (cP) 11071 11170 11019 11451 performed Viscosity at 37 °C (cP) Shear curve/ Gel point 19.15 17.11 17.11 19.64 Temperature temp (°C) 0.155 0.124 0.116 0.134 ramp test 0.071 0.012 0.015 0.026 Tan delta at gel point Tan delta at 37 °C Amplitude Yield point 2923 3180 2724 2954 sweep (Pa) G’ 939 875 923 951 (at 37 °C) Flow 528 552 558 527 transition (Pa) G” Flow point (Pa) G’ It is quite apparent that the novel delivery compositions using the MMC liquid composition are quite similar in all rheological characteristics as well as in vitro drug release (Table 9 below) when compared with a delivery composition prepared using a lyophilized product. 5 Different RTG hydrogel compositions as well as MMC liquid compositions stored at 5 °C for long term stability evaluation of the products. At 6 months stability station, different RTG hydrogel compositions as well as MMC liquid compositions are diluted as per the procedure and evaluated for in vitro drug release (Table 9 below). The characterization data of diluted 10 samples at 6 Months stability time point was found comparable to the initial (T0) station.

Table 9: Cumulative drug release, % Number Time, 15 30 60 90 120 150 180 min ^ Initial samples (T0) 1385 13 21 38 52 69 84 95 1386 11 20 39 55 71 87 97 1387 10 19 35 51 68 83 94 1395 8 16 30 41 57 65 71 1498 9 15 32 49 67 86 96 6 Month stability station (2-8 °C) 1385 10 19 36 52 73 85 94 1386 9 18 37 54 73 89 98 1387 11 18 35 51 69 87 96

Claims

CLAIMS We Claim: 1. A pharmaceutical composition comprising (1) A therapeutically effective amount of Mitomycin C in solution or in suspension in an organic solvent or a mixture of solvents and 5 (2) a reversible thermal hydrogel composition. 2. The composition of claim 1 wherein the Mitomycin C is present in a concentration of 0.1 mg/mL to the saturation solubility of Mitomycin C in the solvent or mixture of solvents. 3. The composition of claim 1 wherein the organic solvent is a water-miscible or partially water- miscible solvent selected from dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide, 10 N-methyl pyrrolidone, ethanol, polyethylene glycol, propylene glycol, glycerol, benzyl alcohol, benzyl benzoate, triacetin, triethyl citrate and the like. 4. The composition of claim 3 wherein the non-aqueous solvent is N, N-dimethylacetamide. 5. The composition of claim 1 wherein the Mitomycin C is provided as a solution in N, N- dimethyl acetamide at a concentration of 1% w/w up to its saturation solubility in the solvent. 15 6. The composition of claim 5 wherein the Mitomycin C solution in N, N-dimethyl acetamide has a moisture content less than 0.5% w/w. 7. The composition of claim 1 comprising a biocompatible reversible thermal hydrogel comprising 15-40% of a reversible thermal gelling agent; from 0.01-5% of a mucoadhesive polymer, from 0% up to 5% of polyethylene glycol of 300 to 1000 g/mol and the balance 20 water. 8. A kit for the delivery of a pharmaceutical composition comprising (1) A therapeutically effective amount of Mitomycin C in solution or in suspension in an organic solvent or a mixture of solvents in a suitable packaging means; (2) a reversible thermal hydrogel composition; (3) a means for mixing. 25