| Title of Invention | TOPICAL FORMULATION FOR DIABETIC FOOT ULCERS |
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| Abstract | This invention relates to a new topical gel formulation of the drug Esmolol hydrochloride for treatment of chronic wounds such as diabetic wounds, burn wounds, venous ulcers and pressure ulcers. |
| Full Text | FORM 2 THE PATENTS ACT. 1970 (39 of 1970) And The Patents Rules, 2003 Provisional Specification (See section 10 and Rule 13) 1. Title of the invention: Topical formulation for diabetic wound healing 2. Applicant(s) (a) Name: VLife Sciences Technologies Pvt. Ltd. (b) Nationality : Indian (c) Address : VLife Sciences Technologies Pvt. Ltd., Pride Purple Coronet, S.No. 287, Baner Road, Pune-411045, India 3. Preamble to the description: The invention relates to a new formulation of Esmolol hydrochloride as a topical gel and its use in treatment of diseases such as non-healing diabetic wounds, more specifically for diabetic foot ulcers. Provisional The following specification describes the invention 4. Description (Description shall start from next page) 5. Claims (Not applicable for provisional specification. Claims should start with the preamble 'I/We claim' on separate page) 6. Date & signature ( To be given at the end of last page of specification) 7. Abstract of the invention ( To be given along with complete specification on separate page) Topical Formulation for Diabetic Foot Ulcers Name of Inventors: Sudhir A. Kulkarni, Reena R. Gollapudy, Supreet K. Deshpande (VLife Sciences Technologies Pvt. Ltd., Pride Purple Coronet, S.No. 287, Baner Road, Pune-411045, India) Assignee: VLife Sciences Technologies Pvt. Ltd., Pride Purple Coronet, S.No. 287, Baner Road, Pune-411045, India Field of Invention The invention relates to a new topical formulation of the drug Esmolol hydrochloride and its use in the treatment of diseases or conditions such as non¬healing diabetic wounds including diabetic foot ulcers. Abstract of the disclosure A method for preparing a topical gel formulation for treating diabetic wounds, more specifically, diabetic foot ulcers by administration of a beta-1 blocker, Esmolol hydrochloride is disclosed. Diabetic complications arise from diabetes and have few or no existing treatment options. Compositions for treating diabetic complications, such as diabetic wounds, are disclosed. The present invention includes employing a topical formulation of a beta-blocker, having substantially no antibacterial activity, to improve the process of diabetic wound healing. This new topical formulation of Esmolol hydrochloride (Galnobax™) has hitherto unused excipients and additives making it a novel formulation for diabetic foot ulcer treatment. Background of Invention The present invention is generally in the field of controlled drug delivery and particularly in the area of direct delivery of a new topical formulation of Esmolol hydrochloride to the surface of diabetic wounds, more specifically, in the case of diabetic foot ulcers. Esmolol hydrochloride is a short-acting beta-1 blocker used for treatment or prophylaxis of cardiac disorders in mammals. Esmolol hydrochloride contains 2 an ester functional group and possesses the typical beta-1-adrenergic blocking activity. However, it differs from conventional beta-blocking compounds in that, Esmolol hydrochloride has a short duration in vivo due to presence of the ester group. Thus, Esmolol hydrochloride is advantageous compared to the conventional beta-blockers because of its unique short-acting activity. The present invention relates to a topical pharmaceutical composition suitable for external administration for the treatment of diabetic wounds, more specifically diabetic foot ulcers, comprising (Esmolol hydrochloride) methyl-3-[4-2-hydroxy-3-isopropylamino)propoxy]phenylpropionate hydrochloride, and Excipient Lutrol F108NF, 40% water, and further relates to a method for its manufacture in a container. It is therefore an object of this invention to provide controlled delivery of Esmolol hydrochloride through direct application of tissue adherent thermo-reversible polymeric gel. Summary of Invention The present invention relates to a new topical gel formulation along with a new method of delivery of a pharmaceutical composition suitable for external administration for the treatment of diabetic wounds, more specifically, non¬healing diabetic foot ulcers, comprising the active pharmaceutical ingredient (API), methyl-3-[4-(2-hydroxy-3-isopropylamino) propoxy] phenyl propionate hydrochloride (Esmolol hydrochloride), an excipient Lutrol F108NF (Pluronic F108NF Prill Poloxamer 338 from BASF), purified water USP and an additive BTC 50 NF (Stepan) i.e. Benzalkonium Chloride. Detailed Description of Invention In accordance with this detailed description, the following abbreviations and definitions apply. It must be noted that as used herein, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "the dosage" includes reference to one or more dosages and equivalents thereof known to those skilled in the art. 3 By the term "subject" or "patient" as used herein is meant to include a mammal. The mammal can be a canine, feline, primate, bovine, ovine, porcine, camelid, caprine, rodent, or equine. Preferably the mammal is human. By the phrases "pharmaceutically acceptable carrier" and "pharmaceutically acceptable excipient" are intended to mean any compound(s) used in forming a part of the formulation that is intended to act merely as a carrier. The pharmaceutically acceptable carrier or excipient is generally safe, non-toxic, and neither biologically nor otherwise undesirable. A pharmaceutically acceptable carrier or excipient as used herein includes both one and more than one such carrier or excipient. There are at least 17 million people with diabetes in the United States, and approximately 1 million new cases are diagnosed each year. A majority of the diabetic population is diagnosed with severe diabetic complications, including diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic retinopathy, diabetic cataract, diabetic cystopathy, diabetic corneal keratopathy, diabetic dermopathy, diabetic microangiopathy, myocardial infarction, macular edema, impaired neural conduction and diabetic wounds. Presently there are limited treatment options for patients suffering from diabetic complications. It is this immediate need for effective treatments for diabetic complications that forms the subject matter of the present invention. The invention provides a method of determining whether a diabetic subject is a healing wound diabetic or a non-healing wound diabetic. A "healing wound diabetic" refers to a diabetic subject whose wound healing capability is approximately the same as that of a non-diabetic subject. A "non-healing wound diabetic" refers to a diabetic subject whose wound healing capability is reduced from that of a non-diabetic subject and who consequently is at risk for lower extremity ulcers (LEU). For example, in one clinical study, non-wound healing diabetics were considered to be those patients with a history of one or more diabetic foot ulcers with incomplete healing after 20 weeks of Regranex® treatment. A human or animal with a diabetic condition is a human or animal whose regulation of plasma glucose concentration is defective, usually as a 4 result of insufficient production of insulin or resistance to the physiological effects of insulin. For example, the subject can be a human patient who is diagnosed by a physician as having either type I or type II diabetes, A subject according to the invention can be any human or animal with a diabetic condition such as diabetes mellitus. The animal may be a mammal. The mammal may be a canine, feline, primate, bovine, ovine, porcine, camelia, caprine, rodent, or equine. Preferably, the subject is a human. Composition The composition contains a biocompatible, polymeric matrix that is tissue adherent and biodegradable and has thermo-reversible properties apart from Benzalkonium chloride as an antimicrobial additive and Esmolol hydrochloride as an active pharmaceutical ingredient (API), preferably in an amount effective to heal and/or close non-healing diabetic foot ulcers. A. Polymeric Matrix The present topical formulation consists of Lutrol F108NF which is poloxamer 338 manufactured by BASF Inc. The physical and chemical properties of the poloxamer include a form of prills, cast solid and pastilles. It has a mild odour of polyol and is white to cream in colour. The molecular formula for poloxamer 338 is The pH of Lutrol is between 6-7. It has a freezing point of approximately 57°C (1,013 hPa) and a density of approximately and a dynamic viscosity of 2.8 mPa.s (77°C). The average molecular weight is 14600,specific gravity 1.06, solubility in water at 25°C is greater than 10%. B. Additive: Benzalkonium Chloride The additive benzalkonium chloride is a biocide used in pharmaceutical antimicrobial preparations. Quaternary ammonium compounds belong to a group of ammonium salts in which organic radicals have been substituted for all four hydrogens of the original ammonium cation. They have a central nitrogen atom 5 which is joined to four organic radicals and one acid radical. The organic radicals may be alkyl, aryl, or aralkyl, and the nitrogen can be part of a ring system. They are prepared by treatment of an amine with an alkylating agent. They show a variety of physical, chemical, and biological properties and most compounds are soluble in water and strong electrolytes. Such compounds include Benzalkonium chloride and Benzalthonium chloride among others. They have properties of disrupting micro-organisms' cell processes and surfactants. C. The active pharmaceutical agent: Esmolol Hydrochloride The active pharmaceutical agent in the present invention is Esmolol hydrochloride. The present invention describes the use of Esmolol hydrochloride in the range of 0.001% to 50% as the active pharmaceutical ingredient. More preferred concentrations of Esmolol hydrochloride are 20% and 14%. D. Formulation delivery The topical formulation described above is delivered topically at the wound or ulcer site in a gel composition through a tube such as aluminium or laminated tubes. The formulation is contained in the tube in a liquefied form and forms a uniform gel upon exposure to the broken, fractured wound site. The gel is liquid at 4°C and solid at ambient temperature. It is fluid at 25°C. Methods of Administration One aspect of the invention contemplates the use of beta-1 adrenergic blockers, their prodrugs, or pharmaceutically acceptable salts thereof in the treatment of conditions, including diabetic complications arising from any form of diabetes. The beta-1 adrenergic blocker specifically used in the formulation is Esmolol hydrochloride. Prodrugs thereof include all derivatives of the beta-1 adrenergic blocker that can deliver the beta-1 adrenergic blocker upon metabolism in the body. For example, all derivatives of Esmolol that can deliver Esmolol upon metabolism are potential prodrugs of Esmolol. 6 The beta-1 adrenergic blockers, prodrugs and salts thereof intended for wound healing are preferably topically administered in a physiologically acceptable carrier to a subject. The correct dosage of a pharmaceutical composition comprising compounds with the beta-1 adrenergic receptor antagonists will vary according to the pharmaceutical formulation, the mode of application, as well as the particular situs, host and diabetic complication being treated. Other factors including age, body weight, sex, diet, time of administration, rate of excretion, condition of the host, drug combinations, reaction sensitivities and severity of the disease may be readily taken into account by a treating professional or one of skill in the art. Administration may be carried out continuously or periodically within the maximum tolerated dose. The administration may be conducted, for example, hourly, once every two hours, once every three hours, once every six hours, once every twelve hours, daily, weekly, every two weeks, every three weeks, or monthly, as needed. The topical route of administration is a preferred route for treatment of diabetic complications such as non-healing diabetic wounds. Suitable compositions for topical administration may include creams, lotions, soaps, shampoos, aerosol, balm, gel, serum, mousse, patch, pump spray, roll-on, topical solution, stick, towelette, footcare product, ointment, wipe, emulsion, cosmetic, topical swab and any combination thereof. Accordingly, the present invention provides a pharmaceutical composition for topical administration, for the treatment of diabetic wound healing, comprising Esmolol, a prodrug thereof, or a pharmaceutical^ acceptable salt thereof, and a pharmaceutically acceptable topical carrier, vehicle, or diluent. The topical composition is preferably in the form of a cream, ointment, topical swab, emulsion, spray or lotion. The composition may be provided in sustained release form. In the treatment of diabetic wound healing, Esmolol has been found to be useful. Thus, the present invention provides a pharmaceutical composition for topical administration, for the treatment of diabetic wound healing, comprising 7 Esmolol, a prodrug thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutical^ acceptable topical carrier, vehicle, or diluent. The topical composition comprising Esmolol is preferably in the form of a gel, a patch, topical solution, cream, ointment, topical swab, emulsion, spray or lotion. The composition may be provided in sustained release form. Depending upon the manner of introduction, the beta-1 adrenergic blockers, their prodrugs, or pharmaceutical^ acceptable salts may be formulated in various ways. The concentration of therapeutically active ingredient in a formulation for topical administration may vary from a concentration of about 0.001% to 50.0%. Preferably, the concentration of therapeutically active ingredient in a formulation for topical administration may vary from a concentration of about 0.01% to 40.0%. More preferably, concentration of therapeutically active ingredient in a formulation for topical administration may vary from a concentration of about 0.001% to 20.0%. There are references of existing topical formulations of beta blockers in the forms of ophthalmic solutions (drops) and ophthalmic gels for treatment of enhanced intraocular pressure (IOP). Transdermal patches of beta-blockers for treatment of cardiac conditions have also been prepared (International Patent Publication No.WO/2000/035439/United States Patent No. 5362757). However, there are no existing references to formulation of Esmolol hydrochloride for topical application to the skin or dermis. The present invention provides the formulation of beta-1 adrenergic blockers, such as Esmolol, as a topical application. In treating diabetic complications such as diabetic wound, a composition containing Esmolol hydrochloride as the active ingredient may be advantageously administered to subject in need by way of a topical preparation, having a concentration of Esmolol hydrochloride of about 0.001% to 50.0%. Preferably, the beta-1 adrenergic blockers, their prodrugs, or pharmaceutically acceptable salts are formulated for topical administration in a suitable inert carrier. For example, the concentration of beta-1 adrenergic blockers, their prodrugs, or pharmaceutically acceptable salts in the carrier 8 solution is typically between about 0.1% to about 50.0%- The dose administered will be determined by route of administration. For parenteral administration, the beta-1 adrenergic blockers, their prodrugs, or pharmaceutically acceptable salts Of the invention can be administered as injectable dosages of a solution or suspension of the substance in a physiologically acceptable diluent with a pharmaceutical carrier, which can be a sterile liquid such as water and oils with or without the addition of a surfactant. Other acceptable diluents include oils of animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, #nd mineral oil. In general, glycols such as propylene glycol or polyethylene glycol (PEG) are preferred liquid carriers, particularly for injectable solutions. The beta-1 adrenergic blockers, their prodrugs, or pharmaceutically acceptable salts of this invention can be administered in the form of a depot injection or implant preparation, which can be formulated in such a manner as to permit a controlled or sustained release of the active ingredient(s). According to one aspect of the invention, a beta-1 adrenergic blocker, itsr prodrug, or pharmaceutically acceptable salts may be administered alone, or in combination with other agents as discussed above to treat and/or ameliorate a condition such as diabetes complications occurring from any form of diabetes. These reagents can also be used in the preparation of a medicament for use in treating a patient. Administration of therapeutic agents for the treatment of diabetes related conditions can occur prior to, concurrent with, or after administration with the beta-1 adrenergic blocKers, their prodrugs, or pharmaceutically acceptable salts. Administration of the subject beta-1 adrenergic blockers, their prodrugs, or pharmaceutically acceptable salts can occur before, during or after any other diabetes treatment modality. Administration of the subject beta-1 adrenergic blockers, their prodrugs, or pharmaceutically acceptable salts can occur hourly, daily, weekly, or monthly as needed, based on the severity of the wound and other factors well known to the skilled medical provider. Preferably, the beta-1 adrenergic blockers, their prodrugs, or pharmaceutically acceptable salts are administered daily (either 9 once or twice) for one or more weeks. The preferred regimen for treatment is continuous or intermittent topical application of the preferred formulation varying as per patient's profile as well as location and severity of diabetic wound. Pharmaceutical compositions comprising beta-1 adrenergic blockers, their prodrugs, or pharmaceutically acceptable salts may also include pharmaceutically acceptable, non-toxic carriers or diluents, which are vehicles commonly used to formulate pharmaceutical compositions for animal or human administration. The formulations may also contain conventional additives, such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives. The compositions may be formulated for sustained release. The beta-1 adrenergic blockers, their prodrugs, or pharmaceutically acceptable salts of this invention can be administered in a sustained release form, for example a depot injection, implant preparation, or osmotic pump, which can be formulated in such a manner as to permit a sustained release of the active ingredient. Implants for sustained release formulations are well-known in the art. Implants are formulated as microspheres, slabs, etc. with biodegradable or non-biodegradable polymers. For example, polymers of lactic acid and/or glycolic acid form an erodible polymer that are well-tolerated by the host. The present invention further provides methods of treating diabetic complications mediated by aldose reductase, comprising administering a therapeutically effective amount of a beta-1 adrenergic blocker, a prodrug thereof, or pharmaceutically acceptable salt thereof having aldose reductase mediating activity. Preferably, the beta-1 adrenergic blocker is Esmolol hydrochloride. The aldose reductase mediated diabetic complications may include, but are not limited to, diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic retinopathy, diabetic cataract, diabetic cystopathy, diabetic corneal keratopathy, diabetic dermopathy, diabetic microangiopathy, myocardial infarction, macular edema, impaired neural conduction and diabetic wounds. 10 |
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| Patent Number | 270284 | ||||||||||||
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| Indian Patent Application Number | 1476/MUM/2009 | ||||||||||||
| PG Journal Number | 50/2015 | ||||||||||||
| Publication Date | 11-Dec-2015 | ||||||||||||
| Grant Date | 09-Dec-2015 | ||||||||||||
| Date of Filing | 22-Sep-2009 | ||||||||||||
| Name of Patentee | VLIFE SCIENCES TECHNOLOGIES PVT.LTD. | ||||||||||||
| Applicant Address | VLIFE SCIENCES TECHNOLOGIES PVT.LTD. PRIDE PURPLE CORONET, S.NO.287, BANER ROAD, PUNE. | ||||||||||||
Inventors:
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| PCT International Classification Number | A61K36/00 | ||||||||||||
| PCT International Application Number | N/A | ||||||||||||
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