Regulation 3.2 AUSTRALIA Patents Act 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT (ORIGINAL) Name of Applicant: Professor Thierry Vancaille AND Dr Alan Hewitt Actual Inventors: Professor Thierry Vancaille AND Dr Alan Hewitt Address for Service: DAVIES COLLISON CAVE, Patent Attorneys, Level 3, 303 Coronation Drive, Milton, Queensland, 4064, Australia Invention Title: "Topical anesthesia formulation for bodily cavities" The following statement is a full description of this invention, including the best method of performing it known to us: Q:\OPER\EJH\2006\March\ 2740870 com prov 83.doc - 24/3/06 P:\OPER\Ejh\Ejh\Provs\ 2740870 spei 074.doc-24/03i06 TOPICAL ANESTHESIA FORMULATION FOR BODILY CAVITIES BACKGROUND 5 FIELD OF THE INVENTION This invention relates generally to topical anesthetics and more specifically to a combination of topical anesthetic ingredients having pH, viscosity, and bio-availability 10 properties suitable for use in bodily cavities. DESCRIPTION OF THE PRIOR ART Prior to describing the present invention in detail, it is to be understood that unless 15 otherwise indicated, the subject invention is not limited to specific fragments or formulation or fraction components, manufacturing methods, dosage regimens, or the like, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. 20 In their "natural" state, topical anesthetics such as Lidocaine, also known as Lignocaine, have a low (acidic) pH of 3.5 to 4.5, good solubility in aqueous solution, and potentially indefinite stability. Objectionably though, low pH anesthetics when applied to patients can be irritating and are not as active as when the pH is within the range of the human tissues. 25 In contrast, it has been observed that an anesthetic solution buffered to a pH of around neutral pH=7 is less irritating and hence more patient acceptable. The onset of action of buffered anaesthetics may be more rapid (DiFazio et al, Anesthetic Analg. 65(7):760-764, 1986) and more effective on prior inflamed tissue (Murakami et al, Journal Dermatology Surgical Oncology, 1994). 30 P:\OPER\Ejh\Ejh\Provs\12740870 spei 074.doc-24/03/06 -2 However, raising the pH from 3.5 to neutral makes the anesthetic gradually less soluble and more likely to precipitate (Larson et al, Journal Dermatology Surgical Oncology 17:411-414, 1991 and Trisiel, Stability of Compounded Formulations, 2nd ed, 2000). When precipitated, the anesthetic molecules are not bio-available and have no anesthetic 5 effect. To compensate for the decrease in solubility caused by increasing pH, commercially available preparations of higher (neutral) pH-caine anesthetics limit their concentrations to a low (<1%) percentage. This trade-off of concentration against pH maintains the 10 anesthetic in solution. However, the active ingredients are subject to degradation in higher pH solutions. For example, lignocaine maintained at a pH of 7 even at low concentration can degrade 35% within 4 weeks. A low concentration of an anesthetic with tissue adjusted pH may be satisfactory for injection right into the site of action, but not when the anesthetic molecules must penetrate through the mucosa to reach the site of action. For 15 topical applications, anesthetics need high concentrations to promote penetration of the molecules toward the tissues. Low concentration preparations, even at a pH close to the target tissue, are not effective. Resorting to administering drugs intravenously causes major side effects. 20 There is therefore a need for a topically applied product which delivers anesthetic molecules at body-adjusted pH, and which maintains its bio-availability.
C NRPortbl\DCC\MDT,13144740_1.DOC-1/09/2010 -3 SUMMARY OF THE INVENTION The invention in a preferred embodiment includes pharmacological agents which can be used as topical anesthetic with 1) body-adjusted pH, 2) viscosity agents which provide the ability to displace blood and exudates without preventing the product from reaching all 5 areas of the cavity and to increase retention of the product within the cavity, and 3) chemical agents which prevent crystallization of the active molecules to increase their availability for migration from the product toward the target tissue, which provides for optimal usage within bodily cavities. Disclosed herein is a method of delivering a near neutral pH topical anesthetic agent in a io mixture into a natural body cavity to cause a rapid onset anesthetic effect without precipitation of the anesthetic said mixture comprising an amide anesthetic at a pH of 5 or less and having a viscosity greater than 1. In a first aspect the present invention provides a method of making an anesthetic solution, comprising the steps of: is providing a buffering agent having a pH of between 7 and 11 in a buffering solution which, when mixed with a -caine anesthetic agent having a pH of between 2.5 and 5, will yield a buffered anesthetic solution having a pH of at least 5.5; providing an aide anesthetic agent having a pH in a range between about 3.5 and 4.5 and greater than 2% concentration in an unbuffered solution; and 20 mixing the buffering solution and the unbuffered solution to produce a buffered anesthetic solution having a pH of at least 5.5, wherein a solubilising agent is added to the buffering solution before mixing the buffering solution and the unbuffered solution, and wherein a viscosity agent is added to at least one of the buffering solution and the unbuffered solution before mixing the buffering solution and the unbuffered solution. 25 In a second aspect the present invention provides a kit when used for preparing a buffered anesthetic solution having a pH of at least 6 comprising: a first component including; C:\NRPob\DCC\MDT2954044_ DOC-8/0W2010 -4 a buffering agent having a pH such that, when mixed with an amide anesthetic compound having a pH of at least 3.5, will yield a buffered anesthetic solution having a pH of at least 6; a solubilising agent; 5 a viscosity agent; and a second component including an amide anesthetic agent having a pH in a range between about 3.5 and 4.5 and at least 2% concentration in aqueous solution; and a viscosity agent, wherein said first and second components are mixed to provide the o buffered anesthetic solution.
P:\OPER\Ejh\Ejh\Provs\l2740870 spc 074.doc.24/03/06 -5 DETAILED DESCRIPTION OF THE INVENTION An un-buffered solution of amide anesthetic can remain stable for years, but once it is buffered to make it more bio-active, the solution will remain stable for only a few days 5 before it loses solubility, precipitates, and becomes useless. To mitigate the problem of insolubility following buffering high concentration anesthetics, the invention provides two components, an aqueous solution of anesthetic at low pH, and a buffering solution comprising preferably a mixed phosphate base. The invention stores the anesthetic component and the buffer component separately, which allows maximizing the buffer pH 10 independently of the anesthetic concentration. Mixing a high (>8) pH buffer solution with a high (>2%) concentration anesthetic solution produces a high (>1%) concentration aqueous solution of topical anesthetic having a pH around 7. This combination verges on instability: A small increase in pH would cause the 15 active ingredient to become insoluble and to precipitate immediately, thereby dramatically reducing the bio-availability of the active ingredient. To obtain a margin of solubility, preferably a mixed phosphate base (Potassium Dihydrogen Orthophosphate and Dipotassium Hydrogen Orthophosphate) buffering 20 solution having a pH of 8 is used for the buffering component. Sodium Hydroxide may also be a suitable buffering component. A >2% concentration of pH 3.8 Lidocaine is preferably used for the anesthetic component, although other amide anesthetics may also be suitable. The pH and viscosity levels are set to reflect the target organ.
P:\PER\Ejh\Ejh\Pro 2740870 spci 074.doc-24/03/06 -6 Ranges of pH and concentration in components and mixture: Anesthetic Buffering Component Component Mixture pH 2.5-5 7-11 5.5-7 Concentration >2% 0 >1% of Anesthetic To delay coalescence and postpone precipitation of the ingredient molecules within the 5 mixture of the two solutions, the two solutions are rapidly mixed together in a special technique called "speed mixing". Enhancer 10 Anesthetic compound molecules in a solution naturally tend to combine, crystallize, and precipitate as larger solids which can no longer penetrate through tissue to a target. A solubilizing agent (or "enhancer") in a solution inhibits crystallization, and thereby increases the solubility, of chemicals (e.g., anesthetic agents) in the solution. This enables the solution to hold a higher concentration of the anesthetic agent and thereby increases the 15 bio-availability, potency, and effect of the anesthetic agent. Since anesthetic concentration is not lost, it does not need to begin at a higher than optimum level. The invention in an embodiment having Lignocaine as the active ingredient and having a phosphate based buffer preferably incorporates into the buffer N-Methyl-2-Pyrrolidone as 20 an enhancer. Afterwards, upon mixing the buffer and the anesthetic, any small quantities of drug that begin to crystallize are immediately solubilized and forestalled from acting as seed sites for precipitation. Viscosity 25 Topical anesthetics need to be applied directly to their site of action. Doing this may be P:\OPER\Ejh\Ejh\Provs\2740870 spci 074.doc.24/03/06 -7 relatively simple when the target tissue is visible to the physician and accessible without the need to pass body openings. However when the target tissue is within a body cavity, a major barrier is presented by the cumulative mass of secretions, tissue debris, blood, exudates, etc. In order to displace this mass, the viscosity of the anesthetic vehicle must be 5 higher than that of blood and exudates, and high enough to help the solution adhere to uterine walls. A benefit of having a viscosity slightly higher than that of blood is that capillary force attracts the vehicle containing the anesthetic molecules to remain within the bodily cavity for the time needed for the anesthetic molecules to transfer from the liquid vehicle into the target tissue. 10 On the other hand the viscosity must not be much higher than that of blood, to preserve the solution's ability to flow easily and enter intended-to-be-anesthetized nooks and crannies of the bodily cavity that are inaccessible to more viscous gels. Viscous aqueous X-Ray solutions are known to spread to nooks and crannies of uterine cavities and into tubes, and 15 to remain there for hours. To obtain a suitable viscosity, the invention preferably adds Hydroxypropyl Methylcellulose in 50:50 proportions to both components. Various concentrations were tested to find a level that provided a good balance of properties stable at the natural and 20 buffered pH. A concentration of 0.1% was found to provide a suitable viscosity. This agent effectively maintains the viscosity of the aqueous solution, and is generally unaffected by pH in the range of 3 to 11. Sonography has shown the invention, with a similar level of viscosity in an embodiment identified as HystagelTM, penetrating and being retained in uterine cavities for several hours after instillation. 25 Mixing is postponed until just prior to the procedure, and then done up to a number of hours prior to use. Mixing these anesthetic and buffering components in a 1:1 ratio produces a >1% concentration aqueous solution having a pH of around 7. This delivers the product with good bio-availability and effectiveness. Once mixed, the anesthetic is stable 30 for several hours, and in terms of efficacy, ease of use, application and persistence it is very effective as a local anesthetic.
C \NRPorbl\DCC\MD12954044_1.DOC.8/062010 -8 While the present invention is described in terms of a preferred embodiment, it will be appreciated by those skilled in the art that this embodiment may be modified without departing from the essence of the invention. It is therefore intended that the following claims be interpreted as covering any modifications falling within the true spirit and scope s of the invention. Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. o Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or 15 more of said steps or features. The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of 20 endeavour to which this specification relates. Examples Example 1: Compositions The following compositions were prepared in accordance with the invention: Composition 1 25 Unbuffered composition: Lignocaine HCl monohydrate 23.7 g Benzyl alcohol 200 ptL 2% MethocelTM syrup 10 g Sterile water 200 mL CANRPortbI\DCC\MD1T2954044I DOC-8/0O2010 - 8a Buffering composition (pH 7.8): Benzyl alcohol 200 ptL Dipotassium phosphate 6.0 g s Potassium dihydrogen phosphate 2.0 g Pharmasolve 20 mL 2% MethocelTM syrup 10 g Sterile water 200 mL 10 Composition 2 Unbuffered composition: Lignocaine HCl monohydrate 11.85 g Benzyl alcohol 100 pL 2% MethocelTM syrup 50 g is Sterile water 100 mL Buffering composition (pH 7.8): Benzyl alcohol 100 tL Dipotassium phosphate 3.0 g 20 Potassium dihydrogen phosphate 1.0 g Pharmasolve 10 mL 2% Methocel TM syrup 50 g Sterile water 100 mL Composition 3 25 Unbuffered composition: Lignocaine HCI monohydrate 23.7 g Methyl parabens 200 mg 2% MethocelTM A4M aqueous syrup 20 g Sterile water 200 mL C-\NRPortbl\DCCMDT2954044 LDOC-8106'2010 - 8b Buffering composition (pH 7.8): Methyl parabens 200 mg Dipotassium phosphate 6.0 g Potassium dihydrogen phosphate 2.0 g 5 N-methyl-2-pyrrolidone 20 mL Sterile water 200 mL -9 BIBLIOGRAPHY DiFazio et al, Anesthetic Analg. 65(7):760-764, 1986 Larson et al, Journal Dermatology Surgical Oncology 17:411-414, 1991 Murakami et al, Journal Dermatology Surgical Oncology, 1994 Trisiel, Stability of Compounded Formulations, 2nd ed, 2000 P:\OPER\Ejh\Ejh\Provs\1 2740870 speci 074.doc - 24/3/06