KR20210143254A - Anesthetic compositions and methods of anesthesia of the eye - Google Patents

Abstract

A topical ophthalmic anesthetic composition comprises an amount of articaine to provide anesthetic properties when applied topically to the eye, a pH, viscosity, osmolarity, dissociation constant, and antioxidants, buffers to achieve efficacy and safety. , formulations with additives such as methylcellulose. The composition may contain articaine in an amount from about 4.0 % w/v to about 12.0 % w/v and has a pH from about pH 3.5 to pH 7.0. The buffer may be a borate/mannitol complex obtained from boric acid or a salt thereof and D-mannitol. The articaine formulation can achieve adequate anesthesia of the inner side of the ocular wall by topical application without the use of injectable anesthetics. Representative embodiments of the present disclosure comprising formulations comprise articaine in an amount of at least 7.0 % w/v, wherein the formulation is in an aqueous solution, gel, ointment or encapsulated form.

Description

Anesthetic compositions and methods of anesthesia of the eye

In general, representative embodiments of the present disclosure relate to anesthetic compositions, and in particular methods of administering said anesthetic compositions to a patient for anesthetizing at least a portion of an eye. The present disclosure relates to a local anesthetic composition or formulation that can be applied topically to the surface of the eye. Representative embodiments of certain embodiments of the present disclosure provide for topical administration of a local anesthetic agent, e.g., a droplet, to achieve a high enough level of pars plana anesthesia to permit intravitreal injection without undue discomfort to the patient. It provides a method to apply it effectively. Representative embodiments of certain embodiments of the present disclosure provide a method for applying a topical solution comprising articaine to achieve anesthesia of the ocular surface as well as the internal aspect of the ocular wall.

Injection of pharmaceutical agents into the vitreous cavity for the purpose of treating various disorders of the retina as well as inflammatory diseases of the eye has become mainstream. In 2016, CMS alone covered approximately 2.7 million injections. In almost all cases, the injections were typically made through the squamous section. Injection into the eye through the flat portion with a properly oriented needle is posterior to the human lens or intraocular lens implant but anterior to the retina, preventing damage to the lens and retina. The flattened portion is the area of the annulus surrounding the periphery of the eye that extends 3.0 to 5.5 mm from the edge of the cornea. Prior topical agents such as proparacaine can achieve anesthesia on the outer surface of the eye, but do not numb or anesthetize the inner side of the extremely sensitive squamous area.

There are no known approved local anesthetics that cause anesthesia of the inner side of the squamous part. Currently, doctors first inject lidocaine under the conjunctiva (which covers the tissue of the eye), and then do a second injection through the squamous part. In some applications, lidocaine gel is used prior to performing an intravitreal injection. With each of these approaches, patients often report moderate to severe discomfort.

Certain complications of intravitreal injections may occur, including endophthalmitis, in which an infection develops inside the eye. Although treatment of endophthalmitis is often successful, permanent loss of vision, at least to some extent, is common. Treatment includes additional intravitreal injections of antibiotics and/or steroids, and vitrectomy surgery. Blindness or eye loss is not uncommon. Although ophthalmologists want to prevent complications caused by infection, many of the anesthetics used are not always sterile.

Traditionally, articaine has only been used via the injectable route. Currently available local ophthalmic anesthetics act on the outer ocular surface, but do not penetrate sufficiently to cause sufficient anesthesia on the inner side of the ocular wall. These areas are perfectly sensitive to penetration, pressure, and laser or refrigeration applications. One commonly performed ophthalmic procedure is the injection of various pharmaceutical agents into the eye. To achieve uniform and adequate anesthesia for such injections, the physician first performs a periocular injection of an anesthetic agent, waits for the anesthetic to become effective, and then performs an intraocular injection.

Articaine preparations containing up to 4% articaine and a vasoconstrictor, usually epinephrine, are known for use as injectable anesthetics formulated for injection into tissues in patients. Such formulations are generally used in dentistry to perform dental procedures. The prior compositions are generally not suitable or effective for topical administration or application in the eye.

Currently, there are no standard procedures for the preparation of ocular anesthesia and intravitreal injections. Also, there are no drugs approved specifically to treat the eye prior to intravitreal injection. The flat part is a unique area of the eyeball. Standard topical ophthalmic agents achieve anesthesia of the outer surface of the eye. However, because the injection needle penetrates into the vitreous cavity through the inner side of the squamous portion, the patient without anesthesia experiences severe pain to the extent that completion of the injection is not possible.

Although prior compositions and formulations have generally been suitable for their intended purpose, there is a continuing need for improved anesthetic compositions.

[Summary of the invention]

Representative embodiments of the present disclosure provide an anesthetic composition containing articaine. The anesthetic composition is suitable for topical ophthalmic use by topical application to the ocular surface to achieve a level of anesthesia sufficient for intravitreal injection and other medical procedures. The anesthetic composition may be administered in an amount sufficient to allow intravitreal injection in the eye without undue discomfort to the patient.

The topical ophthalmic composition includes articaine in a concentration high enough to induce ocular anesthesia by topical administration prior to performing various medical procedures, including surgical procedures. The composition is particularly suitable for providing anesthesia to the eye to enable injection into or through the flat part of the eye with minimal or no pain to the patient.

Representative embodiments of the present disclosure include formulations comprising articaine and which may be medium potency short acting amide local anesthetics, and/or variations and/or uses thereof. Due to the presence of ester groups in the molecular structure, the metabolism of articaine can be rapid. Articaine has previously been administered as an injection for peripheral nerve, spinal, epidural, periocular, or regional nerve block.

In one embodiment, the topical ophthalmic anesthetic composition comprises articaine in an amount effective to provide an anesthetic effect to the eye of a patient without the need for repeated application or injection of the anesthetic into the eye. Articaine may be included in the local anesthetic composition in an amount and concentration that provides the desired anesthetic properties by controlled dosing. The composition may comprise articaine in an amount of about 13% w/v or less, based on the total volume of the composition. In some embodiments, the composition may comprise articaine in an amount from about 4 % w/v to about 12 % w/v based on the total volume of the composition. Articaine in higher concentrations of ophthalmic compositions can provide the desired anesthetic effect to the eye while being administered in lower doses.

In one embodiment, the topical ophthalmic anesthetic composition comprises from about 7.0 % w/v to about 8.5 % w/v of articaine, and a buffer that is not reactive with and/or does not promote degradation of articaine. It is an aqueous composition containing. The buffer of one embodiment can provide a pH of about pH 3.5 to about pH 7.0 and an osmolality of about 280 to about 320 mOsm/kg. In one embodiment, the ophthalmic anesthetic composition has a pH of from about pH 4.5 to about pH 5.0. In one embodiment, the buffer is a complex obtained from an acid and a sugar alcohol. The acid may be selected from the group consisting of boric acid, citric acid, and mixtures thereof. In one specific embodiment, the acid is boric acid. The sugar alcohol may be D-mannitol, sorbitol, and mixtures thereof. Particularly suitable buffers are borate/mannitol complexes obtained from boric acid or a borate salt and D-mannitol. The buffer may be a complex obtained from about 13% to about 17% by weight of boric acid and about 83% to about 88% by weight of D-mannitol, based on the total weight of boric acid and D-mannitol. The anesthetic composition of the above embodiment may comprise sodium acetate trihydrate, acetic acid and disodium edetate dihydrate. The anesthetic composition may have a pH range from about pH 4.5 to about pH 7.0.

The topical ophthalmic anesthetic composition of one embodiment comprises at least about 7.5% w/v of articaine, a buffer comprising a complex formed from boric acid and D-mannitol, sodium acetate, acetic acid, disodium edetate, and the balance water ( balance water), the composition having a pH of from pH 4.5 to about pH 5.0. It has been found that a pH of less than about pH 5.0 improves the long-term stability of the articaine composition.

In another embodiment, the topical ophthalmic anesthetic composition is not reactive with articaine in an aqueous composition in an amount of at least about 8 % w/v of a pH of from about pH 4.5 to about pH 5.5, and the degradation of articaine It is a stable aqueous composition containing buffers and excipients that do not promote The composition may include articaine as the sole anesthetic agent or compound, usually in the absence of a vasoconstrictor such as epinephrine. In one embodiment, the composition is in the absence of sodium metabisulfite and/or sodium bisulfite. The buffer of this embodiment is a borate/mannitol complex.

Characteristic of the aqueous topical ophthalmic anesthetic composition comprises: from about 4.0 % w/v to about 12.0 % w/v of articaine, and a buffer in an amount to provide a pH of from about pH 3.5 to about pH 7.0, wherein the buffering agent is non-reactive with articaine and stabilizes articaine. The buffer may be a complex obtained from boric acid and D-mannitol.

In one embodiment, the aqueous ophthalmic anesthetic composition comprises a buffer comprising about 4% w/v articaine, NaOH and HCl, a pH of about pH 5.5, a pKa of about 7.8, a viscosity of about 20-25 cp, about an osmolality of 275 to 1171 mOsm/kg, and a tonicity of about 0.5 to 5.0%.

In another embodiment, the aqueous local anesthetic composition comprises 80 mg/g articaine HCl, 1.373 mg/g sodium phosphate monobasic monohydrate, 1.413 mg/g sodium phosphate dibasic anhydride, 8.1 mg/g hydro oxypropylmethyl cellulose, 4 mg/g of PEG400, wherein the composition has a pH of between pH 6.0 and pH 7.0, a viscosity of 743-803 cps, and an osmolality of 517 mOsm/kg.

Another feature of the present disclosure provides a method of inhibiting pain and/or discomfort in a patient's eye during various surgical procedures in the eye and/or injection in the eye by a needle. The method introduces a local anesthetic composition into the eye in an amount to induce anesthesia of the eye, wherein the anesthetic composition contains articaine in an amount effective to treat the surface of the eye and subsurface tissue, including squamous portions. The method comprises a topical composition wherein the surface of the eye contains at least 4.0% w/v of articaine, and a non-reactive buffer that provides a pH of about pH 4.5 to about pH 7.0 and generally about pH 4.5 to about pH 5.5 It is particularly suitable for procedures for injecting substances or agents into the eye, which is treated with In another embodiment, the topical composition has a pH of from 4.5 to about pH 5.0.

These and other features will become apparent in the detailed description that follows.

The problems illustrated in this detailed description are provided to provide a comprehensive understanding of the representative embodiments of the present disclosure. Accordingly, those skilled in the art will recognize that various changes and modifications can be made to the embodiments described herein without departing from the scope and spirit of the disclosure. Also, for the sake of clarity and conciseness, descriptions of well-known functions and configurations are omitted. In the present disclosure, regions of the various components and features of the composition may be combined with regions or features of other embodiments. The described embodiments are not intended to be limiting, so that features of one embodiment may be combined with other embodiments.

The phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. As used herein, the use of "comprising", "comprising" or "having" and variations thereof is intended to encompass the items listed thereafter and equivalents thereof, as well as additional items. The embodiments are not intended to be mutually exclusive, so that features of one embodiment may be combined with other embodiments unless they contradict each other. Terms such as “substantially,” “about,” and “approximately” refer to a reasonable range in the vicinity of and to a given value and a range outside the given value, e.g., in general associated with the manufacture, assembly, and use of the embodiments. It is understood by those skilled in the art to include tolerances. The term “substantially” when referring to a structure or feature includes features that are most or all present in the feature or structure.

Representative embodiments of the present disclosure provide a methodology for using a local anesthetic composition or formulation containing articaine with an enhanced ocular anesthetic effect and a reduced risk of ocular infection. As used herein, the terms composition and formulation are used interchangeably to refer to a mixture or combination of compounds, including the active compound and excipients. In the embodiment described, the composition is an aqueous mixture containing articaine, a buffer and other excipients to obtain a stable composition having a suitable pH, osmolarity and articaine concentration for topical application to the eye.

The topical ophthalmic anesthetic composition is an anesthetic composition containing an anesthetic agent in an effective amount for anesthetizing the surface and inner side of a patient's eye by topical administration to perform various medical procedures such as intravitreal injection. In one embodiment, a topical ophthalmic anesthetic composition is prepared as a topical composition and applied directly to the ocular surface to anesthetize the surface of the eye and the inner side of the eye. The topical ophthalmic anesthetic composition provides an anesthetic effect to the eye, thereby reducing or inhibiting pain and/or discomfort in a patient during a medical procedure in the eye, such as an intravitreal injection or other surgical procedure. contain phosphorus.

The topical ophthalmic anesthetic composition containing articaine may have various pH ranges and various amounts of articaine depending on the buffers and stabilizers included in the anesthetic composition. In embodiments of anesthetic compositions, buffers and stabilizers provide effective local anesthetic compositions, wherein the buffers and stabilizers enable multiple pH ranges to stabilize the composition and maintain a suitable osmolarity of the composition.

The topical ophthalmic anesthetic compositions in various embodiments contain from about 4.0 % w/v to about 13 % w/v of articaine at a pH that stabilizes articaine and a pH that minimizes patient discomfort. Suitable anesthetic compositions may be prepared to contain at least 6% w/v of articaine. The composition in the described embodiment is an aqueous ophthalmic anesthetic composition. In one embodiment, the topical ophthalmic anesthetic composition contains articaine in an amount of at least about 7.0 % w/v and generally at least about 8.0 % w/v of articaine, based on the total volume of the composition. In another embodiment, the topical ophthalmic anesthetic composition contains articaine in an amount of at least about 8.5% w/v articaine. As used herein, w/v refers to grams per 100 ml of composition. The ophthalmic composition generally comprises at least about 4% w/v articaine and up to about 8.5% w/v articaine. In one embodiment, the topical composition comprises at least about 7.0% and generally at least about 8.0% w/v of articaine. Articaine when used in topical compositions is usually prepared from hydrochloride salts.

The topical ophthalmic composition of an embodiment comprises articaine in an amount of at least about 4% w/v and a buffer to adjust the pH in the desired range. In one embodiment, the topical composition has a pH ranging from pH 4.5 to pH 7.0. Other embodiments may have a pH of from about pH 6.0 to about pH 7.0. In another embodiment, the topical composition may have a pH of less than pH 5.0. The buffer is non-reactive with articaine between pH 4.0 and pH 7.0, thereby inhibiting degradation of articaine and providing a storage stable composition. The topical ophthalmic composition may include articaine in an amount greater than about 4.0% w/v and a buffer that is not reactive with articaine and provides a stable mixture at a pH of about pH 6.0 or less.

The pH of topical ophthalmic compositions is generally adjusted to maintain the desired long-term stability of articaine and to minimize patient discomfort when topically applied to the surface of the eye. The pH generally ranges from about pH 4.5 to about pH 7.0. For compositions containing articaine in an amount greater than about 4.0%, typically greater than about 6.0% w/v, a particularly suitable pH of the articaine composition is from about pH 4.5 to about pH 5.5. One suitable composition containing at least 7.0% w/v or more has a pH range of about pH 4.5 to about pH 5.5, and has been found to exhibit long-term storage of articaine in the composition for several months at room temperature. Compositions having a pH of 5.0 or less provide long-term articaine storage that inhibits the degradation of articaine during storage. Compositions having from about pH 4.5 to about pH 5.0 provide excellent long-term storage without patient discomfort when applied topically.

A topical ophthalmic anesthetic composition containing articaine adjusts, modifies, pH and osmolarity within desired ranges to stabilize articaine without causing decomposition or interaction with articaine in the composition during storage. and/or retaining buffers. Buffers and other excipients in the local ophthalmic anesthetic composition are 7.5% without degradation of articaine while maintaining articaine in solution or suspension, with minimal patient discomfort when the composition is administered topically to the ocular surface. Allows higher articaine concentrations from w/v to 8.5% w/v or higher. Buffers according to embodiments of the compositions provide compositions that are stable at higher articaine concentrations not present in prior compositions.

Are the Mathematica is Rouge ah certain bacteria, for example Pseudomonas labor (Pseudomonas aeruginosa), Proteus Mira Billy's (Proteus mirabilis ), Staphylococcus Lei's brother (Staphylococcus aureus), and the Escherichia It can inhibit the growth of Escherichia coli. The mechanism of antibacterial action is understood to be mediated by inhibition of cell wall synthesis or distortion of the cytoplasmic membrane.

A topical ophthalmic anesthetic composition as described is a stable composition that can be applied topically to the surface of the eye without adverse effects. The topical ophthalmic anesthetic composition may be applied directly to the ocular surface in the form of droplets. A topical ophthalmic anesthetic composition contains articaine in an amount capable of providing an anesthetic effect to the eye by a single dose to the surface of the eye. The dosage is selected to provide the desired anesthetic effect based on the final concentration of articaine and other buffers, pH adjusters and other excipients in the composition. In one embodiment, the topical composition is applied in a single dosage of from about 2 μl to about 30 μl single droplet at a concentration of about 8.0 mg/g of articaine in the anesthetic composition. One example of a droplet size is about 15 μl. In one embodiment, for an ophthalmic composition containing about 8% w/v of articaine, a suitable dosage is about 0.5 μl. In other embodiments, the articaine composition may be administered to the surface of the eye by about 3-5 drops to provide a dosage of about 20 μl or up to about 100 μl units. In another embodiment, the topical ophthalmic anesthetic composition is applied to the surface of the eye by 3-8 drops, typically, to provide a dosage of about 40 μl to about 80 μl of a composition containing about 8% w/v articaine. It is applied in a dosage of about 3-5 drops.

In a first embodiment of the local anesthetic composition, the composition is an aqueous mixture containing a buffer and has a pH in the range of about pH 3.5 to about pH 7.0. The composition may have a dissolved oxygen content of less than 2 ppm to stabilize the composition and inhibit oxidation of articaine and/or other compounds in the composition. A particularly suitable pH range is from about pH 4.5 to about pH 5.0, with an osmolality of from about 580 to about 630 mOsm/kg. The amount of articaine in a suitable composition is from about 7.0% to about 8.5% w/v of articaine. The buffer of this embodiment may be a complex obtained from a mixture of boric acid and D-mannitol. The borate/mannitol complex formed from boric acid and D-mannitol stabilizes articaine and when applied topically to the ocular surface, exceeds about 4% w/v and 7% at a pH ranging from pH 4.5 to pH 5.0 without ocular irritation. It has been found that articaine concentrations greater than w/v provide long storage stability of articaine in the composition. Without wishing to be bound by any particular theory, it is believed that the borate component of the borate/mannitol complex provides a suitable stabilizing effect for articaine, thereby enabling a stable articaine concentration of at least 7% w/v at a pH less than about pH 5.5. is understood to be The buffer provides articaine with a stable pH range of about pH 4.5 to about pH 5.0, thereby allowing articaine concentrations in excess of 4% w/v without irritation to the eye.

In other embodiments, the buffer may be obtained from another source of borate anion, such as a borate salt. Examples of borate salts include sodium borate, calcium borate, magnesium borate, manganese borate, and the like. Buffer complexes can be obtained from reaction mixtures of boric acid, citric acid or mixtures thereof with sugar alcohols such as D-mannitol, sorbitol and mixtures thereof. It has been found that the borate/mannitol complex is particularly suitable for stabilizing high articaine concentrations, such as articaine 8% w/v or higher. The borate salt and/or citrate salt may be used as a source of borate and/or citrate to the reaction mixture to form borate/mannitol complexes, citrate/mannitol complexes and/or borate/citrate/mannitol complexes. .

The anesthetic composition of one embodiment comprises a buffer complex obtained from boric acid and a sugar alcohol such as D-mannitol, wherein the buffer complex is a borate/mannitol complex. The ratio or relative amount of boric acid and alcoholic sugar is selected based on the desired pH, osmolarity, compatibility with articaine, and articaine concentration in the anesthetic composition. The buffer may be obtained from a mixture of boric acid in an amount from about 13% to about 15% by weight and D-mannitol in an amount from about 85% to about 87% by weight, based on the total weight of the mixture of boric acid and D-mannitol. The buffer of one embodiment may be obtained from a mixture of about 14 wt % boric acid and about 86 wt % D-mannitol, based on the combined weight of boric acid and D-mannitol. Based on the total volume of the local ophthalmic anesthetic composition, in the local ophthalmic anesthetic composition forming the borate/mannitol complex, boric acid may be in an amount of about 0.08 % w/v to about 0.10 % w/v, and D-mannitol may be 0.50 % w/v to about 0.60 % w/v.

The amount of borate/mannitol complex included in the topical ophthalmic anesthetic composition is based on the amount of articaine in the final composition that stabilizes articaine and provides long-term storage of the ophthalmic composition. The amount of borate/mannitol complex may be from about 0.4 % w/v to about 0.75 % w/v based on the total volume of the ophthalmic composition. In one embodiment, the amount of borate/mannitol complex may be from about 0.5 % w/v to about 0.75 % w/v based on the total volume of the ophthalmic composition. In another embodiment, the borate/mannitol complex included in the final ophthalmic composition is in an amount from about 6.5 parts by weight to about 7.5 parts by weight based on 100 parts by weight of articaine in the ophthalmic composition.

In another embodiment, the buffer complex is prepared from an acid, such as boric acid, citric acid, and mixtures thereof, and a sugar alcohol, such as mannitol, sorbitol, and mixtures thereof, wherein the ratio of acid to sugar alcohol is about 1:10 to 10: It may be in the range of 1. In the described embodiment, the amount of sugar alcohol is greater than the amount of acid, ie the acid to sugar alcohol ranges from 1:3 to 1:10. The boric acid to mannitol ratio can be from about 1:3 to about 1:7 by weight. In one embodiment, the ratio of boric acid to mannitol may be from about 1:4 to about 1:6 by weight. Another example of a suitable boric acid to mannitol ratio may be from about 1:4.5 to about 1:5.5 by weight. Another example of a suitable buffer complex is a borate/citrate/mannitol complex obtained from a mixture of boric acid, citric acid and mannitol.

In addition to boric acid and D-mannitol, other buffer and antioxidant components of the embodiments may be included. Examples of additional buffer and/or antioxidant compounds include acetate anions, such as sodium acetate trihydrate. Additional buffers and/or antioxidant compounds may be included in an amount of from about 0.3% to about 0.5% w/v based on the total volume of the topical ophthalmic anesthetic composition. In such an embodiment, sodium acetate trihydrate is included in an amount of 0.33% w/v based on the total volume of the topical ophthalmic anesthetic composition. Sodium acetate in combination with a complex derived from boric acid and D-mannitol in an amount from about 33% to about 35% and typically about 34% by weight, based on the combined weight of a buffer comprising boric acid, D-mannitol and sodium acetate may be included.

In other topical ophthalmic anesthetic compositions, excipients include pH adjusting agents or preservatives. Acetic acids, such as glacial acetic acid, are examples of suitable acids with antiseptic properties, adjusting the pH to be compatible with topical ophthalmic anesthetic compositions containing articaine. Acetic acid, which is typically added as glacial acetic acid, is included in an amount of about 0.05 % w/v to about 0.07 % w/v based on the total volume of the anesthetic composition. Other excipients may include chelating agents such as disodium edetate dihydrate.

The topical ophthalmic anesthetic composition of one embodiment comprises a complex formed from articaine in an amount of about 4.5% to about 8.5% w/v, boric acid as a buffer and D-mannitol, sodium acetate, acetic acid, disodium edetate and the balance water. includes In a suitable embodiment, the topical ophthalmic anesthetic composition comprises from about 7.5 % to about 8.5 % w/v of articaine, from about 0.08 % w/v to about 0.10 % w/v of boric acid and about, based on the total volume of the composition. complex obtained from 0.5 % w/v to about 0.6 % w/v of D-mannitol, about 0.30 to 0.36 % w/v of sodium acetate, about 0.05 % w/v to about 0.07 % w/v of glacial acetic acid, about 0.05% w/v to about 0.07% w/v disodium edetate dihydrate. The topical composition may have an osmolality of about 580 to 630 mOsm/kg. In another embodiment, the composition consists essentially of articaine, boric acid and a buffer obtained from D-mannitol, sodium diacetate, acetic acid, disodium edetate and water.

Another suitable example of a suitable topical ophthalmic composition comprises from about 7.5% to about 8.5% w/v of articaine, a borate/mannitol complex buffer, and an articaine stabilizer compound, based on the total volume of the composition, wherein the composition has a pH of about pH 4.5 to pH 7.0, an osmolality of about 500 to 700 mOsm/kg, and a viscosity of about 700 to 850 cps.

In another embodiment, the topical ophthalmic anesthetic composition is at least 4% w/v of articaine and is non-reactive with articaine to provide a stable composition without degradation of articaine and with minimal irritation to the eye It is an aqueous composition containing a buffering agent. In another embodiment, the topical ophthalmic anesthetic composition contains articaine in an amount of about 5.0% to 8.5% w/v, based on the total volume of the composition. In another embodiment, the topical ophthalmic anesthetic composition contains articaine in an amount of at least about 8.0 % w/v, based on the total volume of the composition.

The buffer is compatible with articaine to avoid reaction with articaine, inhibits degradation of articaine during storage, provides a pH that stabilizes articaine, and provides a pH in the desired composition with minimal irritation to the eye. selected to provide articaine concentrations. Buffers stabilize articaine by stabilizing reactive groups such as amino groups. Stabilizers include compounds which inhibit oxidation of reactive groups on articaine by oxygen and/or oxo radicals. In certain embodiments, sodium sulfite is an example of a stabilizer that inhibits oxidation. Other antioxidants include sodium EDTA, sodium metasulfite and ascorbic acid. The topical ophthalmic anesthetic composition of one embodiment has a pH of about pH 4.5 to about pH 7.0 and an osmolality of 280 to 320 mOsm/kg. In another embodiment, the buffer contains a compound that maintains the pH in the topical ophthalmic anesthetic composition between about pH 5.0 and pH 7.0. The buffer may yield a composition having a pH of from about pH 4.7 to about pH 5.5, depending on the composition and buffer. In another embodiment, the topical ophthalmic anesthetic composition may have a pH of at least pH 5.4. The pH may vary depending on the buffer, and the concentration of articaine in the topical ophthalmic anesthetic composition.

A topical ophthalmic anesthetic composition may be prepared by any method or procedure for obtaining a composition suitable for topical application to the eye. In embodiments containing a buffer complex, the complex is generally prepared prior to mixing or combining with articaine to provide a stabilizing effect to articaine. In one embodiment, the method of making the composition prepares the complex in an aqueous medium by first adding an acid component to water to form an acid solution. The acid compound may be boric acid, citric acid, or a mixture thereof. A sugar alcohol, such as mannitol, sorbitol, or a mixture thereof, is then added to the acid solution and reacted for a time sufficient to form a complex such as a borate/mannitol complex. Next, excipients are added to the solution of the borate/mannitol complex to obtain the desired pH and final composition. Examples of excipients include the addition of sodium acetate trihydrate to the borate/mannitol complex solution until dissolved. To acidify the solution, acetic acid such as glacial acetic acid is added. Next, EDTA dihydrate is added to obtain the desired pH. Articaine HCl salt is added and dissolved to obtain an articaine composition for obtaining an ophthalmic composition having a desired articaine concentration.

Various methods may be used for administering the topical ophthalmic anesthetic articaine composition to the eye of a patient and anesthetizing it. In one embodiment, the aqueous local anesthetic composition is administered directly to the ocular surface in an amount effective to provide sufficient anesthesia to the eye. The topical ophthalmic anesthetic composition containing 7% w/v or more may be administered dropwise to the ocular surface to provide sufficient anesthesia for the ocular. For compositions containing at least about 7% w/v of articaine, a suitable dosage is typically about 30 μl. Compositions containing less than 7% w/v of articaine may require higher doses or repeated dosing to achieve the desired anesthetic effect by administering an effective amount of articaine to the ocular surface.

In other embodiments, the buffer may be borate/mannitol (pH 6.0), citrate (pH 5.5), acetate (pH 5.5) or phosphate (pH 6.5, 7.0, 7.5). Buffers may be included in amounts of up to 25 mM and may provide a pH of less than 7.0 and generally less than pH 5.5. In another embodiment, the buffer may comprise a mixture of sodium hydroxide and hydrochloric acid. Other suitable buffers include monobasic sodium phosphate and dibasic sodium phosphate.

The local anesthetic composition may also include optional lubricants and viscosity modifiers. Examples of other additives and excipients may include polyethylene glycol, glycerol, sodium sulfite, sodium metasulfite, cetyl alcohol, hydroxypropyl B-cyclodextrin, polaxmer, tyloxapol and ascorbate.

Representative embodiments of the present disclosure include a topical formulation comprising a native formulation having a desired articaine concentration, pH, viscosity, dissociation constant, and additives such as antioxidants, buffers, viscosifiers such as methylcellulose to achieve efficacy and safety. Provides an ophthalmic anesthetic. Representative embodiments of the present disclosure include formulations comprising liquid, gel, ointment or encapsulated form.

Other exemplary embodiments of the present disclosure may take into account the practicality of preparing formulations according to exemplary embodiments. For example, for exemplary embodiments comprising ophthalmic solutions, varying amounts of methylcellulose may be added to increase the potency of articaine by increasing its viscosity and thus increasing contact time with the external ocular surface. . Suitable viscosity modifiers do not negatively interact with or destabilize articaine. Other viscosity modifiers include polyvinyl alcohol and hydroxypropyl methyl cellulose.

Another exemplary embodiment of a topical ophthalmic anesthetic composition comprises articaine in an amount from about 4% to about 8.0% w/v supplemented with epinephrine 1:100,000 as a sterile composition for topical application by ophthalmic droplets. The composition may be applied topically to treat the eye as a formulation for intravitreal injection. The topical composition may be applied as a single drop or by multiple applications to provide the desired anesthetic effect to the eye. The topical ophthalmic composition may be applied dropwise by 3 to 6 applications with 3-5 minute time between applications. In another embodiment, the topical composition may be applied or administered as a single drop and reapplied 3-5 times after 2-5 minutes.

Another exemplary embodiment comprises articaine as a local ophthalmic anesthetic comprising 4% to 8.0% w/v of articaine having a pH of about pH 4.5 to about pH 5.5 and a pKa of about 7.0 to about 8.5 It provides a topical ophthalmic anesthetic composition. An example of an aqueous anesthetic composition is about 4% w/v having a pH of 5.5, a pKa of 7.8, a viscosity of 20-25 cps (centipoise), an osmolality of 275-1171 mOsms/kg, and a tonicity of 0.5% - 5.0%. to about 5 w/v articaine, NaOH buffer and HCl buffer.

Another example of a suitable aqueous topical ophthalmic composition is from about 4 % w/w to about 13 % w/v of articaine and generally at least about 7 % w/v of artica at a pH of from about pH 6.0 to about pH 7.0. phosphorus, sodium phosphate monobasic monohydrate, dibasic sodium phosphate, viscosity enhancing agents such as hydroxypropylmethyl cellulose and polyethylene glycol. An example of an anesthetic composition is 80 mg/g of articaine HCl, 1.373 mg/g of sodium phosphate monobasic monohydrate, 1.413 mg/g of sodium phosphate dibasic anhydride, 8.1 mg/g of hydroxypropylmethyl cellulose, 4 mg/g PEG400, wherein the composition has a pH of from pH 6.0 to pH 7.0, a viscosity of 743-803 cp, and an osmolality of 517 mOsm/kg.

Topical compositions containing 4% w/v of articaine applied in one or two doses did not provide a complete anesthetic effect. However, it has been observed that three or more administrations of 1 drop per application, which are 3-5 minutes apart, result in effective anesthesia. In addition, the patient did not complain of burning, itching, redness, or other findings of ocular surface irritation commonly experienced with currently used local ophthalmic anesthetics.

A feature of the present disclosure is a method of providing anesthesia to the eye by topical application or delivery to the eye of said local anesthetic ophthalmic composition. Anesthetics are administered topically prior to surgery, such as prior to intraocular injection, squamous vitrectomy, and the like.

Typically, the physician administers an injectable anesthetic to anesthetize the eye and then must wait for a suitable period of time for the anesthetic to take effect before starting the procedure. An advantage of a topical approach according to an exemplary embodiment of the present disclosure is the ease of administration of the anesthetic by topically applying the composition without the need to inject the anesthetic into the eye.

Articaine's efficacy and safety are well known for its use as an anesthetic by injection, such as in the dental industry. Articaine HCl has the molecular formula of 4-methyl-3 (2-[propylamino] proprioamido)-2-thiophenecarboxylic acid, methyl ester hydrochloride, has a molecular weight of 320.84 g/mol, and is highly It is protein-bound and has a pKa of 7.8. Articaine is an amide-containing anesthetic containing a thiophene ring and an additional ester group. The thiophene ring provides increased lipid solubility of articaine relative to other amide-containing anesthetics. Articaine is highly diffusive, effectively penetrating tissue and bone when administered by injection. The presence of amide groups and ester linkages minimizes toxic reactions when biotransformation occurs in both plasma (hydrolysis by plasma esterases) and liver (microsomal enzymes). Metabolism is initiated by hydrolysis of the ester group to produce a free carboxyl group. Articainic acid is the primary metabolite. Additional inactive metabolites are being detected in small amounts. 5 to 10% are excreted by the kidneys unchanged, and 89% are excreted as metabolites. The injectable form of articaine is commonly used in industry as an anesthetic.

Articaine works by inhibiting nerve conduction through blockade of sodium channels in tissues. Articaine acts by reversibly binding to the alpha subunit of voltage-gated sodium channels in neurons. This reduces the sodium influx and thus does not reach the threshold potential of the nerve, thereby stopping the conduction of the stimulus. Articaine is a short-acting, rapidly-onset, tissue-penetrating local anesthetic. Articaine has been used in combination with epinephrine in injectable compositions to cause local vasoconstriction, increase absorption and increase duration of action. In injectable applications, articaine is typically used at a concentration of 4% w/v. A commercially available injectable formulation contains articaine hydrochloride (4%) with epinephrine in an amount of 1:1000,000 (0.01 mg/ml).

No serious side effects have been reported with the commercially available injectable form of Articaine. Although allergic reactions are rare, sodium bisulfite as a preservative in some commercially available formulations can cause allergic reactions such as edema, urticaria, erythema and anaphylactic shock in some patients. Articaine is not associated with an increase in methemoglobin. Articaine is contraindicated in patients allergic to amide-containing anesthetics and metabisulfite. Articaine is not contraindicated in patients with sulfa allergy in that there is no cross-allergenicity between the thiol group of the articaine thiophene ring and the sulfonamide.

[ Example ]

The following examples are provided to illustrate suitable compositions and methods, but are not intended to limit the scope of this detailed description.

Example 1

In Dutch Belted rabbits, two subparts of one study: an ocular tolerability study followed by an ocular biodistribution study were performed.

In an ocular tolerability study, a total of 12 male Dutch striped rabbits randomly divided into 4 groups were administered placebo in phosphate buffered saline (PBS) or articaine at 4%, 8% or 12% respectively. The dose was administered via bilateral topical administration (35 μL/eye 2 drops). The rabbits in the dose tolerance study were observed for any signs/symptoms of adverse drug effects for 24 hours after treatment. Dose tolerance at 5, 10 and 20 minutes, 1, 2, 4 and 24 hours after administration of the second eye drop and pre-dose in each eye using the modified Hackett-McDonald Scoring System Ophthalmic examinations were performed in animals (Groups 1 to 4). Modified Hackett-McDonald scoring followed by localization of each eye by a Cochet-Bonnet tactometer prior to dosing in each eye, and approximately 5, 10, and 20 minutes, 1 hour after administration of the second eye droplet. The anesthetic effect was monitored. Articaine ocular drops were well tolerated in all animals at concentrations up to 12% w/v, and no treatment-related adverse effects were observed. Topical ocular administration of articaine provided anesthetic effects up to 20 minutes after administration without noticeable tolerability problems.

In the ocular biodistribution study, at least 72 hours following completion of the ocular tolerability study, 12 rabbits were re-assigned to group 5 for the ocular biodistribution study. Group 6 was added, consisting of 3 naive rabbits. Group 6 was included to evaluate the potential carryover effect of articaine over a 72 hour period after treatment. Animals in groups 5 and 6 were dosed with 8% and 12% w/v of articaine, respectively. The dose was administered through bilateral topical administration (35 μL/2 eye drops). At 10 minutes, 1, 4 and 8 hours post treatment, animals in group 5 were sacrificed (N=3 at each time point). Group 6 rabbits were sacrificed 24, 48 and 72 hours after treatment (N=1 at each time point). Immediately prior to sacrifice, blood samples were collected from each animal. The animals were then euthanized and aqueous humor, conjunctiva (blepha and ocular), lens, cornea, vitreous humor, iris-ciliary body [ICB], optic nerve, lacrimal gland, retina and choroid were collected. Plasma, aqueous body fluids, conjunctiva (blepha and ocular), lens, cornea, ICB, choroid, and lacrimal gland tissues were analyzed for concentrations of articaine (active parent) and articanic acid (inactive metabolite), and the remaining tissues were It was stored frozen for future analysis. Articaine concentrations showed a typical profile after topical ocular administration of the 8% formulation; The highest was at the first time point investigated (0.167 h) and then decreased at later time points (1, 4 and 8 h). Articaic acid concentrations followed a similar profile in all matrices, with the exception of aqueous body fluids, where the concentration increased from 0.167 h to 1 h and then decreased at later time points (4 and 8 h). Low residual concentrations of articaine and articanic acid were detected after topical ocular administration of 12% articaine in all ocular matrices irradiated at 24, 48 and 72 hours post-dose (with the exception of articainic acid in the choroid). In all ocular matrices except the cornea, articaine concentrations were higher compared to articainic acid. As expected, Tmax after topical ocular administration of articaine was recorded at the first time point (0.167 h) investigated in all ocular matrices and plasma. The Cmax of articaine was highest in the iris-ciliary body (294,000 ng/g), followed by blepharoptosis (131,000 ng/g), choroid (103,000 ng/g), ocular conjunctiva (94,000 ng/g) and cornea (53,500). ng/g) followed. Plasma Cmax was 457 ng/mL, the lowest of all matrices investigated. The AUC values representing the exposure of the matrix to articaine generally followed the same order from the highest (ie iris-ciliary) to the lowest (ie plasma) as seen for the Cmax values. The T1/2 (half-life) of articaine in the ocular matrix ranged from 1.95 to 3.83 hours, with the exception of the blepharoconjunctiva, which had a T1/2 of 6.31 hours, which was associated with topical dosing pooling in the lower eyelid after administration. seemed The T1/2 of articaine in plasma was approximately 0.5 hours. The Cmax of articainic acid was highest in the blepharic conjunctiva (71,100 ng/g), followed by the cornea (53,500 ng/g), the ocular conjunctiva (29,100 ng/g) and the iris-ciliary body (12,600 ng/g). Plasma Cmax was 217 ng/mL, the lowest of all matrices investigated. The AUC values representing the exposure of the matrix to articain generally followed the same altitude to low order as articaine, but were substantially less than that of articaine, with the exception of the cornea and plasma. When expressed as the ratio of AUC0-last articain to AUC0-last articain, the ratio is approximately 2 in both the cornea and plasma, the more to articain to articain in these two matrices. A large exposure was indicated. For all other matrices, the ratio was <0.7. The T1/2 (half-life) of articainic acid in most ocular matrices ranged from 1.70 to 3.29 hours. The T1/2 of articainic acid in plasma was approximately 1.5 hours.

In summary, topical ophthalmic administration of articaine provided anesthetic effects up to 20 minutes post-administration without appreciable tolerability problems. Articaine and articanic acid were detected in all ocular matrices irradiated, with the highest exposure found in the iris-ciliary body, followed by the ocular and blepharic conjunctiva and cornea. Given the presence of esterase activity in the ocular tissue, rapid metabolism of articaine to articainic acid is expected. Systemic exposure as expressed as plasma AUC was minimal.

The purpose of this study was to confirm the tolerability of placebo, and Articaine HCl ophthalmic solution at concentrations of 4, 8 and 12% (w/v), and 8% Articaine HCl ophthalmic solution after topical ocular droplet administration. The purpose of this study was to confirm the ocular pharmacokinetics and biodistribution of articaine and articainic acid after topical ocular droplet administration of the solution. Rabbit was a standard non-rodent species used for preclinical pharmacokinetic studies, including ocular pharmacokinetics of novel chemicals and several test article formulations. The number of animals is believed to be an appropriate number to adequately perform this tolerability and ocular biodistribution study, to account for inter-animal variability, as well as to enable the generation of descriptive statistical analyses. The topical route was chosen because it is the intended route of administration in humans. The ocular formulation dosage level selected by the Sponsor was designed to achieve the therapeutic ocular tissue concentration of the test article. For the determination of pharmacokinetics, a single dose of test article was common.

A study using an approved aqueous articaine formulation was conducted in humans, confirming the results of the rabbit study as very positive initial results.

Example 2

As shown in Table 1 below, a topical ophthalmic anesthetic composition containing articaine HCl at a concentration of 8.0% w/v was prepared.

The composition was prepared by adding boric acid until dissolved in a mixing vessel containing a volume of water. Mannitol was then added, mixed until dissolved, and stirred to form a borate/mannitol buffer complex. Then sodium acetate trihydrate was added and stirred until dissolved, then glacial acetic acid was added. EDTA dihydrate was added to obtain a pH of about pH 4.5 to pH 5.2. Articaine HCl was added and stirred until dissolved. The resulting composition had a pH of pH 4.7 to pH 4.9 and an osmolality of 580 to 630 mOsm/kg.

Example 3

Topical ophthalmic compositions having the compositions shown in Table 2 below were prepared. Cystan and Cystan + 8% Articaine HCl were included here as they were used for viscosity comparison only and are not otherwise part of the formulation study.

Formulations C and F were evaluated for formulation stability over a period of 8 weeks in containers stored at 5° C., 25° C. and 45° C.

Storage results at 5° C., 25° C. and 45° C. showed acceptable impurity levels, stable pH, viscosity and osmolarity. Formulation F has been shown to be useful in terms of degradation levels. PEG400 appeared to be highly reactive with articaine. Buffers with as low a pH as possible are still shown to be acceptable for patients. The boric acid/mannitol buffer achieved the required stability.

In one embodiment, the composition consisted of 35 mM acetate, pH 4.8, 15 mM borate-mannitol complex and 0.055% EDTA (disodium, dehydrated salt). The acetate may be obtained from acetic acid, sodium acetate or mixtures thereof. This formulation exhibited stable pH and also a low hydrolysis rate of ˜0.04% articainic acid formed per week over a 4-week period at 40° C. (1.53% total over 8 weeks) and 0.061 at 25° C. Hydrolysis at a %/host rate (0.49% total over 8 weeks) was shown. This is more than four times lower than the formulations known to date.

Several aspects of the process were confirmed in the 100-g scale experiment, and then the scale was increased to 500-g.

When the two excipients are combined in the absence of other excipients or buffers, a much more acidic borate-mannitol complex is readily formed compared to boric acid (pKa 9.14) alone, resulting in a pH of about 4.2. In terms of the order of addition, these two excipients are added first and then the formulations are mixed to ensure that the complex is fully formed.

To avoid the need for any pH adjustment after dissolution of Articaine HCl, a suitable molar ratio of sodium acetate to acetic acid is 70:30 (24.5 mM to 10.5 mM). When this ratio was used, the final pH after addition of 90.2 mg/mL of Articaine HCl (equivalent to 80 mg/mL of Articaine as free base) was reproducibly about pH 4.80±0.05.

The process was easily scaled up to 500 mL using a final pH of 4.80 and a final osmolality of 622 mOsm/kg. Later, it was scaled up to 1 L, the final formulation after filtration had a pH of 4.85 and an osmolality of 597 mOsm/kg.

Next, the drug product prepared in the process development experiment was used in the filtration study to confirm whether PVDF was an appropriate filter material for such a formulation and to confirm the appropriate filter size.

There were no signs of API binding to the PVDF filter material as drug concentrations both before and after filtration were consistent and there was no loss of initial aliquot concentration. Thus, no waste volume is required.

The Vmax study showed a very small decrease in flow rate over time, indicating that filter adhesion is not an issue in such formulations, and that a relatively small filtration area can be used to filter 1-L batches of drug product. indicated that there is Thus, the filter size can be selected mostly based on the required flow rate, which in turn can be adjusted by the use of higher pressures.

Although this disclosure has been shown and described with reference to specific exemplary embodiments thereof, various changes in form and detail may be made therein to those skilled in the art without departing from the spirit and scope of the disclosure. you will understand that

Publications cited throughout this document are incorporated herein by reference in their entirety. Each feature described herein and each combination of two or more such features is included within the scope of the present disclosure provided that the features included in such combination are not mutually exclusive.

Claims (29)

An aqueous ophthalmic anesthetic composition comprising:
articaine in an amount from about 4.0 % w/v to about 12.0 % w/v by volume of the composition; and a buffer in an amount to provide a pH of about pH 3.5 to about pH 7.0, wherein the buffer is non-reactive with and stabilizes articaine.
An aqueous ophthalmic anesthetic composition. The method of claim 1 , wherein said composition has a pH of from about pH 4.5 to about pH 5.5, wherein said buffering agent is a sugar alcohol selected from the group consisting of citrate, acetate or mixtures thereof, and mannitol, sorbitol and mixtures thereof. A composition comprising a complex obtained from The composition of claim 1 , comprising from about 7.5% w/v to 8.5% w/v of articaine and having a pH from about pH 4.5 to about pH 5.0. The composition of claim 1 , comprising at least about 7.0% w/v of articaine and having a pH of from about pH 4.5 to about pH 5.0. The composition of claim 1 , wherein the buffer comprises a borate/mannitol complex obtained from borate and D-mannitol. 6. The composition of claim 5, wherein the borate/mannitol complex is included in an amount of from about 0.5 % w/v to about 0.75 % w/v by volume of the composition. The composition of claim 5, wherein the borate/mannitol complex is included in an amount of about 6.5 parts by weight to about 7.5 parts by weight based on 100 parts by weight of articaine in the composition. 6. The composition of claim 5, wherein said borate/mannitol complex is obtained from a borate/mannitol ratio of from about 1:3 to about 1:7 by weight. 6. The composition of claim 5, further comprising sodium acetate, acetic acid and disodium edetate. The composition of claim 1 , wherein the composition comprises at least about 7.0 % w/v of articaine and the buffer comprises a complex of boric acid and D-mannitol in an amount to provide a pH of between about pH 4.5 and about pH 5.0. and wherein the composition further comprises sodium acetate, acetic acid and disodium edetate. 5. The method of claim 4, wherein said articaine is present in an amount of at least about 7.0 % w/v, based on the total volume of the composition, and wherein said boric acid and D-mannitol complex is from about 0.08 % w/v to about 0.10 % w /v boric acid and from about 0.50 % w/v to about 0.6 % w/v D-mannitol. The method of claim 1 , wherein at least about 8.0 % w/v of articaine, about 0.08 % w/v to about 0.10 % w/v of boric acid and about 0.5 % w/v to about 0.60 % w/v of D- a buffer complex obtained from mannitol, about 0.3 to 0.36 % w/v of sodium acetate, about 0.05 % w/v to about 0.07 % w/v of disodium edetate and the balance of water, about 280 to 320 mOsm A composition having an osmolality of /kg, wherein the amounts are based on the total volume of the composition. The composition of claim 1 , wherein said composition comprises about 4% w/v articaine, said buffer comprises NaOH and HCl, and wherein said composition has a pH of about pH 5.5, a pKa of about 7.8, about 20-25 A composition having a viscosity of cp, an osmolality of about 275 to 1171 mOsm/kg, and a tonicity of about 0.5 to 5.0%. The method of claim 1, wherein 80 mg/g of articaine HCl, 1.373 mg/g of sodium phosphate monobasic monohydrate, 1.413 mg/g of sodium phosphate dibasic anhydride, 8.1 mg/g of hydroxypropylmethyl cellulose, A composition comprising 4 mg/g of PEG400 and having a pH of pH 6.0 to pH 7.0, a viscosity of 743-803 cp and an osmolality of 517 mOsm/kg. An aqueous ophthalmic anesthetic composition comprising:
articaine in an amount of at least about 7.0 % w/v by volume of the composition; and a buffer in an amount that provides a pH of about pH 4.0 to about pH 5.5 and stabilizes articaine, wherein the buffer is boric acid or a complex obtained from a borate salt and a sugar alcohol.
An aqueous ophthalmic anesthetic composition. 16. The aqueous ophthalmic anesthetic composition of claim 15, wherein said buffer is a borate/mannitol complex in an amount of from about 6.5 parts by weight to about 7.5 parts by weight based on 100 parts by weight of articaine in the composition. 17. The aqueous ophthalmic anesthetic composition of claim 16, wherein said borate/mannitol complex is obtained from a borate/mannitol ratio of from about 1:3 to about 1:7 by weight. 18. The aqueous ophthalmic anesthetic composition of claim 17, further comprising sodium diacetate, acetic acid and disodium edetate. A method of providing anesthesia to the eye comprising the step of topically applying the composition of claim 1 to the ocular surface of a patient in an amount effective to anesthetize the eye of the patient. 20. The method of claim 19, wherein the composition comprises articaine in an amount of at least about 5.0% by total volume of the composition, and wherein the buffer complex comprises from about 0.08% w/v to about 0.10% w/v boric acid and from about 0.50 % w/v to about 0.6 % w/v of D-mannitol. 20. The composition of claim 19, wherein said composition comprises at least about 7.5% w/v articain; a buffer comprising a complex obtained from boric acid and D-mannitol in an amount non-reactive with articaine; sodium acetate; acetic acid; disodium edetate; and the balance of water, wherein the composition has a pH of about pH 4.5 to about pH 5.5. 20. The method of claim 19, wherein said composition comprises at least about 7% w/v of articaine. 23. The method of claim 22, wherein said composition has a pH of from about pH 4.5 to about pH 5.0. 20. The formulation of claim 19, wherein said formulation comprises 4% w/v of articaine, pH 5.5, pKa of 7.8, viscosity of 20-25 cp, osmolality of 275-1171 mOsms/kg, 0.5%- A method having a tonicity of 5.0% and comprising a NaOH buffer and an HCl buffer. 20. The method of claim 19, wherein said composition comprises 80 mg/g of articaine HCl, 1.373 mg/g of sodium phosphate monobasic monohydrate, 1.413 mg/g of sodium phosphate dibasic anhydride, 8.1 mg/g of hydroxypropyl A method comprising methyl cellulose, 4 mg/g of PEG400, wherein said composition has a pH of pH 6.0 to pH 7.0, a viscosity of 743-803 cp and an osmolality of 517 mOsm/kg. A method for preparing the composition according to claim 1,
mixing an acid or a salt thereof with a sugar alcohol in a solution to form a complex;
adjusting the pH to about 3.5 to about pH 7.0; and
adding articaine to the resulting solution in an amount to obtain said composition having from about 4.0 % w/v to about 12.0 % w/v by volume of the composition
A method for preparing a composition according to claim 1, comprising a. 27. The method of claim 26, wherein said acid is selected from the group consisting of acetic acid, citric acid and mixtures thereof, and said sugar alcohol is selected from the group consisting of D-mannitol, sorbitol and mixtures thereof. 27. The method of claim 26, wherein said acid or salt thereof is a borate salt, said sugar alcohol is D-mannitol, said complex is a borate/mannitol complex, said composition comprises at least 7.0% articaine and has a pH of about 6.0. to pH 7.0. 29. The method of claim 28, wherein said borate/mannitol complex is obtained from a borate/mannitol ratio of from about 1:3 to about 1:7 by weight.