JP2022527621A - Anesthetic composition and how to anesthetize the eye - Google Patents

Abstract

The topical anesthetic composition is an amount of articaine that provides anesthetic properties when applied topically to the eye, as well as pH, viscosity, osmotic pressure, dissociation constants to achieve efficacy and safety. , As well as formulations containing additives such as antioxidants, buffers, methylcellulose and the like. The composition can contain an amount of articaine from about 4.0% w / v to about 12.0% w / v and can have a pH of about pH 3.5 to pH 7.0. The buffer can be a borate / mannitol complex obtained from boric acid or a salt thereof and D-mannitol. The articaine preparation can achieve proper anesthesia of the inner surface of the eye wall by topical application without the use of injectable anesthetics. An exemplary embodiment of the present disclosure comprises a pharmaceutical product comprising an amount of at least 7.0% w / v of articaine, wherein said pharmaceutical product is in aqueous solution, gel, ointment, or encapsulated form. ..

Description

1. 1. Disclosure Fields Typically, exemplary embodiments of the present disclosure relate to a method of administering an anesthetic composition and an anesthetic composition to a patient, in particular a method of anesthetizing at least a portion of the eye. The present disclosure relates to a local anesthetic composition or formulation that can be applied topically to the surface of the eye. An exemplary embodiment of a particular embodiment of the present disclosure is to achieve a high level of pars plana anesthesia sufficient to allow intravitreal injection without causing undue discomfort to the patient. , Provide a method for topically applying a local anesthetic formulation, eg, one drop. An exemplary embodiment of a particular embodiment of the present disclosure provides a method for applying a topical solution containing articaine to achieve anesthesia on the surface of the eye and the inner surface of the eye wall.

2. 2. Background of Disclosure Injection of drugs into the vitreous cavity for the purpose of treating various disorders of the retina and intraocular inflammatory diseases has become the mainstream. In 2016, about 2.75 million injections were refunded for CMS alone. In almost all cases, these injections are usually given through the pars plana. Injection into the eye through the pars plana with the needle properly pointed is posterior to the human lens or intraocular lens implant, but anterior to the retina, thereby into the lens and retina. Avoid damage. The pars plana is an annular region surrounding the eye that extends from the edge of the cornea to a range of 3.0 to 5.5 mm. Conventional external preparations such as proparakine can be anesthetized on the outer surface of the eye, but do not paralyze or anesthetize the inner surface of the highly sensitive pars plana.

There are no known approved local anesthetics that produce anesthesia on the inner surface of the pars plana. Currently, doctors first inject lidocaine under the conjunctiva (covering the tissue of the eye) and then a second injection from the pars plana. In some applications, lidocaine gel is used prior to intravitreal injection. Patients often report moderate to severe discomfort with each of these approaches.

Several complications of intravitreal injection can occur, including endophthalmitis, where the infection occurs inside the eye. Treatment of endophthalmitis is often successful, but at least some permanent loss of vision is common. Treatment includes intravitreal injection of antibiotics and / or steroids, as well as vitrectomy surgery. Blindness or loss of eyes is not uncommon. Ophthalmologists seek to prevent complications caused by infections, although many of the anesthetics used are not always sterile.

Traditionally, articaine has only been used by injectable routes. Currently available topical ophthalmic anesthetics function on the outer surface of the eye, but do not penetrate sufficiently to produce sufficient anesthesia on the inner surface of the ocular wall. This region is very sensitive to penetration, pressure, laser or freezing applications. One of the common eye surgeries is to inject various drugs into the eye. To achieve uniform and appropriate anesthesia for this injection, the physician will first give a periocular injection of the anesthetic, wait for the anesthetic to be effective, and then give an intraocular injection.

Articaine preparations containing up to 4% articaine and a vasoconstrictor, commonly epinephrine, are known for use as injectable anesthetics formulated for injection into a patient's tissue. Such formulations are commonly used in dentistry to perform dental treatment. Previous compositions are generally unsuitable or ineffective for topical or ocular application.

Currently, there are no standard procedures for preparing for ocular anesthesia and intravitreal injection. In addition, there are no specially approved drugs to treat the eye prior to intravitreal injection. The pars plana is a unique area of the eye. Standard topical ophthalmic agents achieve anesthesia on the outer surface of the eye. However, because the needle penetrates the inner surface of the pars plana into the vitreous cavity, patients without anesthesia experience severe pain that makes it impossible to complete the injection.

Conventional compositions and formulations have generally been suitable for the intended purpose, but there is a continuing need for improved anesthetic compositions.

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

The topical ophthalmic composition comprises articaine at a concentration high enough to induce anesthesia in the eye by topical administration prior to performing various medical procedures, including surgical procedures. The composition is particularly suitable for providing anesthesia to the eye to allow injection within or through the ciliary flats of the eye with minimal or no pain to the patient. There is.

Exemplary embodiments of the present disclosure include formulations and / or modifications and / or uses thereof, comprising articaine, which can be an intermediate potency, short-acting amide local anesthetic. The metabolism of articaine can occur rapidly due to the presence of ester groups in the molecular structure. Traditionally, articaine has been administered by injection of peripheral nerve, spinal cord, epidural, periocular, or local nerve block.

In one embodiment, the topical ophthalmic anesthetic composition comprises an effective amount of articaine to provide an anesthetic effect on the patient's eye without the need for repeated application or injection of the anesthetic into the eye. Articaine may be included in a local anesthetic composition in an amount and concentration to provide the desired anesthetic properties at a controlled dose. The composition may contain up to about 13% w / v of articaine based on the total volume of the composition. In some embodiments, the composition may contain an amount of about 4% w / v to about 12% w / v of articaine, based on the total volume of the composition. Higher concentrations of articaine in ophthalmic compositions can be administered in lower doses while providing the desired anesthetic effect on the eye.

In one embodiment, the topical ophthalmic anesthetic composition does not react with or / or decomposes articaine at about 7.0% w / v to about 8.5% w / v. An aqueous composition containing a buffer solution that does not promote. The buffer solution in one embodiment may provide a pH of about pH 3.5 to about pH 7.0 and an osmotic pressure of about 280 to about 320 mOsm / kg. In one embodiment, the ophthalmic anesthetic composition has a pH of about pH 4.5 to about pH 5.0. The buffer solution of one embodiment is a complex obtained from an acid and a sugar alcohol. The acid can be selected from the group consisting of boric acid, citric acid, and mixtures thereof. In one particular embodiment, the acid is boric acid. The sugar alcohol can be D-mannitol, sorbitol, or a mixture thereof. A particularly suitable buffer is a borate / mannitol complex obtained from boric acid or borate and D-mannitol. The buffer is a complex obtained from about 13% to about 17% by weight boric acid and about 83% to about 88% by weight D-mannitol based on the total weight of boric acid and D-mannitol. could be. The anesthetic composition in one embodiment may include sodium acetate trihydrate, acetic acid, and disodium edetate dihydrate. The anesthetic composition may have a pH range of about pH 4.5 to about pH 7.0.

The topical ophthalmic anesthetic composition in one embodiment is an aqueous mixture of at least about 7.5% w / v of articine, boric acid and D-mannitol, sodium acetate, acetic acid, disodium edetate, and the balance of water. Yes, it has a pH of about pH 4.5 to about pH 5.0. A pH below about pH 5.0 has been found to improve the long-term stability of the articaine composition.

In another embodiment, the topical ophthalmic anesthetic composition does not react with articaine in an amount of at least about 8% w / v at a pH of about pH 4.5 to about pH 5.5, as well as the articaine. A stable aqueous composition comprising a buffer solution and an excipient that does not promote the decomposition of the articaine in the aqueous composition. The composition can contain articaine as the only anesthetic or compound and is usually free of vasoconstrictors such as epinephrine. In one embodiment, the composition is in the absence of sodium metabisulfite and / or sodium hydrogen sulfite. The buffer in this embodiment is a borate / mannitol complex.

The aqueous topical ophthalmic anesthetic composition is characterized by an amount of articaine from about 4.0% w / v to about 12.0% w / v and an amount providing a pH of about pH 3.5 to about pH 7.0. The buffer is non-reactive with the articaine and stabilizes the articaine. The buffer can be a complex obtained from boric acid and D-mannitol.

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

In another embodiment, the aqueous topical anesthetic composition comprises 80 mg / g articain hydrochloride, 1.373 mg / g sodium dihydrogen phosphate monobasic monohydrate, 1.413 mg / g phosphorus. It comprises disodium hydrogen phosphate anhydride, 8.1 mg / g hydroxypropylmethylcellulose, 4 mg / g PEG400, the composition having a pH of 6.0-pH 7.0, a viscosity of 743-803 cp, and 517 mOsm / kg. Has an osmotic pressure of.

Other features of the present disclosure provide methods for controlling pain and / or discomfort to the patient's eye during various surgical procedures in the eye and / or injection into the eye with a needle. The method introduces a local anesthetic composition in an amount that induces anesthesia in the eye, and the anesthetic composition is effective for treating subsurface tissues including the surface of the eye and pars plana. Contains an amount of articaine. The method is particularly suitable for procedures for injecting a substance or drug into the eye, wherein the surface of the eye is at least 4.0% w / v articaine, and from about pH 4.5 to about pH 7.0. It is generally treated with a topical composition containing a non-reactive buffer that provides a pH of about pH 4.5 to about pH 5.5. In another embodiment, the topical composition has a pH of 4.5 to about pH 5.0.

These and other features will become apparent from the detailed description below.

Detailed Description of Exemplary Embodiments The matters exemplified in this description are provided to aid in a comprehensive understanding of the exemplary embodiments of the present disclosure. Accordingly, one of ordinary skill in the art will recognize that various changes and amendments to the embodiments described herein can be made without departing from the scope and ideas of the present disclosure. Also, for the sake of clarity and brevity, well-known features and structures are omitted. In the present disclosure, the range of various components and features of the composition may be combined with the range or features of other embodiments. The embodiments described are not intended to limit the features of one embodiment so that they can be combined with other embodiments.

The terms and terms used herein are for illustration purposes only and should not be considered limiting. The use of "listed", "included", or "having" and variations thereof herein is to include the items described thereafter and their equivalents, as well as additional items. Since the embodiments are not intended to be mutually exclusive, the features of one embodiment may be combined with other embodiments as long as they do not contradict each other. Terms of degree such as "substantially", "about" and "nearly" are used by those skilled in the art to a reasonable range, including around a given value and outside a given value, eg, manufacture, assemble. , And general tolerances associated with the use of embodiments. The term "substantially" when referring to a structure or property includes properties that are largely or completely present in the property or structure.

Exemplary embodiments of the present disclosure provide a methodology for using a local anesthetic composition or formulation containing articaine, which has an improved anesthetic effect on the eye and a reduced risk of eye infection. As used herein, the terms composition and formulation are used interchangeably to refer to a mixture or combination of compounds, including active compounds and excipients. In the described embodiments, the composition comprises articaine, a buffer and other excipients to obtain a stable composition having a pH, osmotic pressure and articaine concentration suitable for topical application to the eye. Aqueous mixture containing.

The topical ophthalmic anesthetic composition is an anesthetic composition containing an amount of anesthetic that is effective for anesthetizing the surface and inner surface of a patient's eye by topical administration for performing various medical procedures such as intravitreal injection. be. In one embodiment, the local ophthalmic anesthesia composition is prepared as a local composition and applied directly to the surface of the eye to anesthetize the surface of the eye and the inner surface of the eye. The topical ophthalmic anesthetic composition provides an anesthetic effect on the eye to reduce or inhibit pain and / or discomfort in a patient during an eye medical procedure such as intravitreal injection or other surgical procedure. Contains an effective amount of articaine.

Local ophthalmic anesthetic compositions containing articaine may have different pH ranges and different amounts of articaine, depending on the buffers and stabilizers contained in the anesthetic composition. In embodiments of the anesthetic composition, the buffer and stabilizer allow the buffer and stabilizer to have different pH ranges to stabilize the composition and maintain an appropriate osmotic pressure for the composition. To provide an effective local anesthetic composition.

The local ophthalmic anesthesia compositions in various embodiments have a pH for stabilizing the articaine and a pH for minimizing patient discomfort, from about 4.0% w / v to about 13%. Includes w / v articaine. Suitable anesthetic compositions containing at least 6% w / v articaine may also be prepared. The composition in the described embodiment is an aqueous ophthalmic anesthetic composition. In one embodiment, the topical ophthalmic anesthetic composition comprises 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. include. In another embodiment, the topical ophthalmic anesthetic composition comprises 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%, generally at least about 8.0% w / v of articaine. The articaine used in the topical composition is usually prepared from hydrochloride.

The topical ophthalmic composition in one embodiment comprises at least about 4% w / v of articaine and a buffer to control the pH to a desired range. In one embodiment, the topical composition has a pH in the range of pH 4.5 to pH 7.0. Other embodiments may have a pH of about pH 6.0 to about pH 7.0. In yet another embodiment, the topical composition may have a pH of less than pH 5.0. The buffer solution is non-reactive with articaine having a pH of 4.0 to 7.0, inhibits the decomposition of articaine, and provides a composition having storage stability. The topical ophthalmic composition comprises an amount of articaine greater than about 4.0% w / v and a buffer to provide a stable mixture at a pH below about pH 6.0 where the buffer does not react with articaine. May include.

The pH of the topical ophthalmic composition is generally adjusted to maintain the desired long-term stability of articaine and to minimize patient discomfort when applied topically to the surface of the eye. To. The pH is generally in the range of about pH 4.5 to about pH 7.0. A particularly suitable pH for an articaine composition is from about pH 4.5 to about pH 5 for compositions containing an amount of articaine above about 4.0% and typically above about 6.0% w / v. It is .5. One suitable composition comprising at least 7.0% w / v or more has a pH range of about pH 4.5 to about pH 5.5 and long-term storage of articaine in the composition for several months at room temperature. Has been found to indicate. Compositions having a pH of 5.0 or less provide long-term storage of articaine in order to inhibit the degradation of articaine during storage. Compositions having from about pH 4.5 to about pH 5.0 provide excellent long-term storage without causing patient discomfort when applied topically.

Topical anesthetic compositions containing articaine are pH and osmotic to stabilize articaine without interacting with articaine or causing degradation of articaine in the composition during storage. Includes a buffer to adjust, modify, and / or maintain the pressure within the desired range. Buffers and other excipients in the topical anesthetic composition provide articaine while minimizing discomfort to the patient when the composition is administered topically to the surface of the eye. It allows articaine to be in high concentrations of 7.5% w / v and up to 8.5% w / v and above without degrading articaine while maintaining it in solution or suspension. The buffer according to the embodiment of the composition provides a stable composition with a higher concentration of articaine, which is not present in the previous composition.

Articaine can inhibit the growth of certain bacteria such as Pseudomonas aeruginosa, Proteus mirabilis, Staphylococcus aureus, and Escherichia coli. The mechanism of antibacterial action is understood to be mediated by inhibition of cell wall synthesis or strain of the cell membrane.

The topical ophthalmic anesthetic compositions described are stable compositions that can be applied topically to the surface of the eye without adverse effects. The topical ophthalmic anesthetic composition can be applied directly to the surface of the eye in the form of a drop. The topical ophthalmic anesthetic composition comprises an amount of articaine that may provide an anesthetic effect on the eye upon a single dose to the surface of the eye. The dose is selected based on the final concentration of articaine and other buffers, pH regulators and other excipients in the composition to provide the desired anesthetic effect. In one embodiment, the topical composition is applied as a single drop of about 2 μl to about 30 μl at an articaine concentration of about 8.0 mg / g of the anesthetic composition. An example of a drop size is about 15 μl. In one embodiment, the appropriate dose is about 0.5 μl for an ophthalmic composition containing about 8% w / v articaine. In other embodiments, the articaine composition may be administered to the surface of the eye in about 3-5 drops to provide a dose of about 20 μl or units up to about 100 μl. In another embodiment, the topical ophthalmic anesthesia composition is applied at a dose of 3-8 drops, typically about 3-5 drops on the surface of the eye, containing about 8% w / v articaine. A dose of about 40 μl to about 80 μl of the composition is provided.

In the first embodiment of the local anesthetic composition, the composition is an aqueous mixture containing a buffer and has a pH range of about pH 3.5 to about pH 7.0. The composition may have a dissolved oxygen content of less than 2 ppm in order to stabilize the composition and inhibit the 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 and the osmotic pressure is from about 580 to about 630 mOsm / kg. Suitable amounts of articaine in the composition are about 7.0% to about 8.5% w / v articaine. The buffer in this embodiment can be a complex obtained from a mixture of boric acid and D-mannitol. The borate / mannitol complex formed from boric acid and D-mannitol has been shown to stabilize articaine at articaine concentrations above approximately 4% w / v and 7% w / v. , A pH in the range of pH 4.5 to pH 5.0, provides long-term storage stability of articaine in the composition without irritating the eye when applied topically on the surface of the eye. Unintentionally bound by a particular theory, the borate component of the borate / mannitol complex provides a suitable stabilizing effect on articaine, at least 7 at a pH below about pH 5.5. It is understood to enable a stable articaine concentration of% w / v. The buffer provides a stable pH range of about pH 4.5 to about pH 5.0 for articaine, allowing concentrations of articaine above 4% w / v without irritation to the eye.

In other embodiments, the buffer can be obtained from other sources of borate anions, such as borate. Examples of borate include sodium borate, calcium borate, magnesium borate, manganese borate and the like. The buffer complex can be obtained from a reaction mixture of boric acid, citric acid, or a mixture thereof with a sugar alcohol such as D-mannitol, sorbitol, and mixtures thereof. The borate / mannitol complex has been found to be particularly suitable for stabilizing high concentrations of articaine, such as 8% w / v or higher articaine. Borates and / or citrates are used as a source of borates and / or citrates in the reaction mixture to borates / mannitol complexes, citrates / mannitol complexes, and /. Alternatively, a borate / citrate / mannitol complex can be formed.

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

The amount of borate / mannitol complex contained in the topical ophthalmic anesthetic composition is based on the amount of articaine in the final composition to stabilize the articaine and provide long-term storage of the ophthalmic composition. .. The amount of borate / mannitol complex can 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 can 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 contained in the final ophthalmic composition is from about 6.5 parts by weight to about 6.5 parts by weight based on 100 parts by weight of articain in the ophthalmic composition. It is an amount of 7.5 parts by weight.

In another embodiment, the buffer complex is formed from an acid such as boric acid, citric acid, and a mixture thereof and a sugar alcohol such as mannitol, sorbitol and a mixture thereof, and the ratio of the acid to the sugar alcohol. Can be in the range of about 1:10 to 10: 1. In the described embodiment, the amount of the sugar alcohol is higher than the amount of the acid, that is, the ratio of the acid to the sugar alcohol is in the range of 1: 3 to 1:10. The ratio of boric acid to mannitol can be from about 1: 3 to about 1: 7 by weight. In one embodiment, the ratio of boric acid to mannitol can be from about 1: 4 to about 1: 6 by weight. A further example of a suitable boric acid to mannitol ratio can 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 buffers and antioxidants of the embodiment may be included. Examples of additional buffers and / or antioxidant compounds include acetate anions such as sodium acetate trihydrate. The additional buffer and / or antioxidant compound may be included in an amount of about 0.3% w / v to about 0.5% w / v based on the total amount of the topical ophthalmic anesthetic composition. .. In this embodiment, the 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 of boric acid and D-mannitol, is about 33% by weight to about 35% by weight, usually based on the total weight of the buffer containing boric acid, D-mannitol, and sodium acetate. Can be contained in an amount of about 34% by weight.

Other excipients in the topical ophthalmic anesthetic composition include pH regulators or disinfectants. Acetic acid, such as glacial acetic acid, is an example of a suitable acid for adjusting pH and has antiseptic properties compatible with topical ophthalmic anesthetic compositions containing articaine. Acetic acid, typically added as glacial acetic acid, is contained in an amount of about 0.05% w / v to about 0.07% w / v, based on the total amount of the anesthetic composition. Other excipients may include chelating agents such as disodium edetate dihydrate.

The topical anesthetic composition in one embodiment is 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. Contains sodium acetate, acetic acid, disodium edetate, and the balance of water. In a suitable embodiment, the topical ophthalmic anesthetic composition is about 7.5% to about 8.5% w / v articain, about 0.08% w / v, based on the total volume of the composition. V to about 0.10% w / v boric acid and about 0.5% w / v to about 0.6% w / v D-mannitol, about 0.30 to 0.36% w / v acetic acid From sodium, about 0.05% w / v to about 0.07% w / v glacial acetic acid, about 0.05% w / v to about 0.07% w / v disodium edetate dihydrate Contains the resulting complex. The topical composition may have an osmotic pressure of about 580-630 mOsm / kg. In a further embodiment, the composition comprises substantially the buffer solution obtained from articine, boric acid and D-mannitol, sodium diacetate, acetic acid, disodium edetate, and water.

Another suitable example of a suitable topical ophthalmic composition is an articaine, borate / mannitol complex buffer of about 7.5% to about 8.5% w / v, based on the total volume of the composition. , And an articaine stabilizer compound, the composition having a pH of about pH 4.5 to pH 7.0, an osmotic pressure of about 500 to 700 mOsm / kg, and a viscosity of about 700 to 850 cp.

In other embodiments, the topical anesthetic composition is at least 4% w / v articaine and non-reactive with articaine, without degradation of articaine and with minimal irritation to the eye. It is an aqueous composition containing a buffer solution that provides a stable composition with limited limits. In another embodiment, the topical ophthalmic anesthetic composition comprises an amount of about 5.0% to 8.5% w / v of articaine based on the total volume of the composition. In yet another embodiment, the topical ophthalmic anesthetic composition comprises an amount of at least about 8.0% w / v of articaine based on the total volume of the composition.

The buffer is compatible with articaine such as avoiding reaction with articaine and inhibiting the decomposition of articaine during storage, providing a pH for stabilizing articaine and to the eye. It is selected to provide the desired concentration of articaine in the composition with minimal irritation. The buffer stabilizes articaine by stabilizing reactive groups such as amino groups. Stabilizers include compounds that inhibit the oxidation of reactive groups of articaine by oxygen and / or oxo radicals. Sodium sulfite is an example of a stabilizer for inhibiting oxidation in certain embodiments. Other antioxidants include EDTA sodium, sodium meta sulfite, and ascorbic acid. The topical ophthalmic anesthetic composition in one embodiment has a pH of about pH 4.5 to about pH 7.0 and an osmotic pressure of 280 to 320 mOsm / kg. In another embodiment, the buffer contains a compound for maintaining the pH in a topical ophthalmic anesthetic composition at about pH 5.0 to pH 7.0. The buffer can also produce a composition having about pH 4.7 to about pH 5.5, depending on the composition and the buffer. In other embodiments, the topical ophthalmic anesthetic composition may have a pH of at least pH 5.4. The pH may depend on the concentration of buffer and articaine in the topical ophthalmic anesthetic composition.

The topical ophthalmic anesthesia composition can be prepared by a method or procedure for obtaining a composition suitable for topical application to the eye. In embodiments comprising the buffered complex, the complex is generally prepared prior to mixing or binding to articaine in order to provide a stabilizing effect on articaine. The method for producing a composition in one embodiment prepares a complex in an aqueous medium by first adding an acid component to water to form an acidic solution. The acid compound can be boric acid, citric acid, or a mixture thereof. Next, sugar alcohols such as mannitol, sorbitol, or a mixture thereof are added to the acid solution and reacted for a sufficient time to form a complex such as a borate / mannitol complex. The excipient is then added to the solution of the borate / mannitol complex to obtain the desired pH and final composition. Examples of excipients include adding sodium acetate trihydrate to a solution of the borate / mannitol complex until it dissolves. Add acetic acid such as glacial acetic acid to acidify the solution. Next, EDTA dihydrate is added to obtain the desired pH. The articaine hydrochloride is added and dissolved to obtain an articaine composition, and an ophthalmic composition having a desired articaine concentration is obtained.

Various methods can be used to administer and anesthetize the patient's eye using the local ophthalmic anesthetic articaine composition. In one embodiment, the aqueous local anesthetic composition is administered directly to the surface of the eye in an amount effective to provide sufficient anesthesia to the eye. A local ophthalmic anesthesia composition containing 7% w / v or more may be administered by dropping on the surface of the eye to provide sufficient anesthesia to the eye. A suitable dose is usually about 30 μl for a composition containing at least about 7% w / v articaine. Compositions containing less than 7% w / v articaine may require higher doses or repeated doses to administer an effective amount of articaine to the surface of the eye to achieve the desired anesthetic effect.

In a further embodiment, the buffer is borate / mannitol (pH 6.0), citrate (pH 5.5), acetate (pH 5.5), or phosphate (pH 6.5, 7.0). , 7.5). The buffer may be contained in an amount of 25 mM or less and may provide a pH of less than 7.0, generally less than 5.5. In another embodiment, the buffer may contain 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 contain a lubricant and a viscosity modifier. Examples of other additives and excipients may include polyethylene glycol, glycerol, sodium sulfite, sodium metasulfite, cetyl alcohol, hydroxypropyl B-cyclodextrin, pollakmer, tyroxapol, and ascorbate.

Exemplary embodiments of the present disclosure include desirable articaine concentrations, pH, viscosities, dissociation constants, and thickeners such as antioxidants, buffers, and methylcellulose to achieve efficacy and safety. Provided is a topical ophthalmic anesthetic containing a unique formulation with an additive. Exemplary embodiments of the present disclosure include formulations comprising liquids, gels, ointments, or encapsulated forms.

Further exemplary embodiments of the present disclosure may take into account the practicality of manufacturing a pharmaceutical product according to an exemplary embodiment. For example, in the case of an exemplary embodiment comprising an ophthalmic solution, various amounts of methylcellulose may be added to increase the viscosity, thereby increasing the contact time with the external ocular surface and increasing the efficacy of articaine. .. Suitable viscosity modifiers do not interact negatively with articaine or destabilize articaine. Other viscosity modifiers include polyvinyl alcohol and hydroxypropylmethyl cellulose.

Another exemplary embodiment of the topical ophthalmic anesthesia composition is about 4% to about 8.0% w / supplied with epinephrine 1: 100,000 as a sterile composition for topical application by ophthalmic instillation. Contains v amount of articaine. The composition may be applied topically to treat the eye in preparation for intravitreal injection. The topical composition may be applied as a drop or by several applications to provide the desired anesthetic effect on the eye. The topical ophthalmic composition can be applied as a drop in 3 to 6 coats over a time of 3 to 5 minutes between coats. In other embodiments, the topical composition can be applied or administered as a drop and reapplied 3-5 times after 2-5 minutes.

Other exemplary embodiments include 4% to 8.0% w / v articaines with a pH of about pH 4.5 to about pH 5.5 and a pKa of about 7.0 to about 8.5. Provided is a local ophthalmic anesthetic composition containing articaine as a local ophthalmic anesthetic. Examples of aqueous anesthetic compositions have a pH of 5.5, pKa7.8, a viscosity of 20-25 cp (centipores), an osmotic pressure of 275 to 1717 mOsms / kg, and a tonicity of 0.5% to 5.0%. Includes about 4% w / v to about 5 w / v articaine, NaOH buffer, and HCl buffer.

Further examples of suitable aqueous topical ophthalmic compositions are articines from about 4% w / w to about 13% w / v at a pH of about pH 6.0 to about pH 7.0, and generally at least about 7% w /. v Contains thickeners such as articain, sodium monobasic monohydrate, sodium dibasic phosphate, hydroxypropylmethylcellulose and polyethylene glycol. Examples of the anesthetic composition include 80 mg / g articaine hydrochloride, 1.373 mg / g sodium dihydrogen phosphate monobasic monohydrate, 1.413 mg / g disodium hydrogen phosphate anhydrous. Contains 8.1 mg / g of hydroxypropylmethylcellulose, 4 mg / g of PEG400, wherein the composition has a pH of 6.0-pH 7.0, a viscosity of 743-803 cp, and a penetration of 517 mOsm / kg. Have pressure.

Local compositions containing 4% w / v articaine applied in one or two doses did not provide a complete anesthetic effect. However, it has been observed that administration of one drop at least three times per application at 3-5 minute intervals results in effective anesthesia. In addition, the patient did not complain of the burning sensation, itching, redness, or other symptoms of ocular surface irritation commonly experienced with topical ophthalmic anesthetics currently in use.

A feature of the present disclosure is a method of providing anesthesia to the eye by topical application or transport to the eye with a topical anesthetic ophthalmic composition. The anesthetic is administered topically before surgery, such as before intraocular injection, pars plana vitreous resection, and the like.

Typically, the physician should administer an injectable anesthetic to anesthetize the eye and then wait an appropriate period for the anesthetic to take effect before initiating the procedure. An advantage of the topical approach according to the exemplary embodiments of the present disclosure is the ease with which the anesthetic is administered by topical application of the composition without the need to inject the anesthetic into the eye.

The efficacy and safety of articaine have been well established for use as injectable anesthetics, such as in the dental industry. The articaine hydrochloride is a hydrochloride of a molecular formula 4-methyl-3 (2- [propylamino] proprioamide) -2-thiophenecarboxylic acid and a methyl ester having a molecular weight of 3200.84 g / mol and having high protein binding properties. Yes, it 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 an increased lipophilicity of articaine as compared to other amide-containing anesthetics. Articaine is highly diffusive and, when administered by injection, effectively penetrates tissues and bone. The presence of amide groups and ester bonds minimizes toxic reactions because in vivo changes occur in both plasma (hydrolysis by plasma esterase) and liver (microsomal enzymes). The metabolism is initiated by hydrolysis of the ester group to produce a free carboxyl group. Articaine is a primary metabolite. A small amount of additional inactive metabolites have been detected. 5-10% is excreted unchanged from the kidney and 89% is excreted as metabolites. The injectable form of articaine is commonly used as an anesthetic in dentistry.

Articaine acts by inhibiting nerve conduction through the blockade of sodium channels in tissues. Articaine acts by reversibly binding to the alpha subunit of voltage-gated sodium channels in nerves. This reduces the influx of sodium, does not reach the threshold potential of the nerve, and stops impulse conduction. Articaine is short-acting and begins to act rapidly, allowing tissue to penetrate the local anesthetic. Articaine is used in combination with epinephrine in injectable compositions to cause local vasoconstriction, increase absorption and increase duration of action. For injectable applications, articaine is typically used at a concentration of 4% w / v. Commercially available injectable formulations contain articaine hydrochloride (4%) containing an amount of 1: 1,000,000 (0.01 mg / ml) of epinephrine.

No serious side effects have been reported for commercially available injectable forms of articaine. Although allergic reactions are rare, sodium bisulfite as a preservative in some over-the-counter formulations can cause allergic reactions such as edema, urticaria, erythema, and anaphylactic shock in some patients. Articaine has nothing to do with an increase in methemoglobin. Articaine is contraindicated in patients allergic to amide-containing anesthetics and sodium metabisulfate. Articaine is not contraindicated in patients with sulfa drug allergies in that there is no cross-allergenicity between the thiol group of the articaine thiophene ring and the sulfonamide.

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

Example 1
Two subparts of one study were performed on Dutch-belted rabbits, i.e., an eye tolerance study followed by an eye biodistribution study.

In an eye tolerance study, a total of 12 male Dutch-belted rabbits were randomly divided into 4 groups with 4%, 8%, or 12 phosphate buffered saline (PBS) placebo or articaine, respectively. % Administered. The dose was administered via bilateral topical administration (35 μL / 2 drops in the eye). Rabbits in the dose tolerance test were observed 24 hours after treatment for signs / symptoms of drug side effects. Ophthalmic examinations include an improved Hackett McDonald scoring system before administration of dose-tolerant animals (Groups 1-4), 5, 10, 20 minutes, and 1, 2, 4, 24 hours after the second eye drop administration. Performed using. Following improved Hackett-McDonald's scoring, the local anesthetic effect was approximately 5, 10, 20 minutes, and 1 hour after the second eye drop was administered to each eye by premedication with Coche-Bonet anesthesia measurement. Monitored with each eye. Articaine eye drops were well tolerated in all animals at concentrations up to 12% w / v with no treatment-related side effects. Topical ocular administration of articaine produced an anesthetic effect up to 20 minutes after administration, with no significant tolerability problems.

In an eye biodistribution study, at least 72 hours after the completion of the eye tolerance study, 12 rabbits were reassigned to Group 5 for eye biodistribution studies. Group 6 was added, which consisted of three naive rabbits. Group 6 was included to assess the potential carryover effect of articaine over 72 hours after treatment. Animals in groups 5 and 6 received 8% and 12% w / v articaine, respectively. The dose was administered via bilateral topical administration (35 μL / 2 drops in the eye). Animals in Group 5 were sacrificed 10 minutes, 1, 4 and 8 hours after treatment (N = 3 at each time point). Rabbits in Group 6 were sacrificed 24, 48, 72 hours after treatment (N = 1 at each time point). Blood samples were collected from each animal just prior to sacrifice. The animals were then euthanized and the aqueous humor, conjunctiva (eyelids and bulbs), lens, cornea, vitreous fluid, iris-ciliary body [ICB], optic nerve, lacrimal gland, retina, and choroid were collected. Plasma, aqueous humor, conjunctiva (eyelids and eyeballs), lens, cornea, ICB, choroid, and lacrimal gland tissue were analyzed to analyze the concentrations of articain (active parent) and articinic acid (inactive metabolite). The remaining tissue was cryopreserved for scheduled future analysis. Articaine concentration showed a typical profile after topical ocular administration of 8% formulation; highest at the earliest time point investigated (0.167 hours) and decreased at subsequent time points (1, 4, and 8 hours). .. Articaine concentrations followed a similar profile for all matrices, except for aqueous humor, where the concentration increased from 0.167 hours to 1 hour and then decreased at subsequent time points (4 hours and 8 hours). Low residual concentrations of articaine and articaine after topical administration of 12% articaine were detected in all eye matrices examined 24, 48, and 72 hours after administration (choroidal articaine). except). Articaine levels were higher than articaine in all eye matrixes except the cornea. As expected, Tmax after topical ocular administration of articaine was observed at the first time point (0.167 hours) examined in all ocular matrices and plasma. The Cmax of articain is highest in the iris-ciliary body (294,000 ng / g), followed by the palpebral conjunctiva (131,000 ng / g), choroid (103,000 ng / g), and eyeball conjunctiva (94,000 ng / g). g), followed by the cornea (53,500 ng / g). Plasma Cmax was 457 ng / mL, the lowest of all the matrices examined. AUC values indicating matrix exposure to articaine generally followed the same order from highest (ie, iris-ciliary) to lowest (ie, plasma), as seen in Cmax values. The T1 / 2 (half-life) of articaine in the eyelid matrix ranged from 1.95 to 3.83 hours, with the exception of the palpebral conjunctiva with a T1 / 2 of 6.31 hours. May be related to the local dose pool. The T1 / 2 of articaine in plasma was about 0.5 hours. Cmax of articaine is in the palpebral conjunctiva (71,100 ng / g), cornea (53,500 ng / g), bulbar conjunctiva (29,100 ng / g), and iris-ciliary body (12,600 ng / g). It was the highest. Plasma Cmax was 217 ng / mL, the lowest of all the matrices examined. The AUC values, indicating exposure of the matrix to articaine, generally ranged from high to low in the same order as articaine, but were significantly lower than those of articaine, except for the cornea and plasma. As indicated by the ratio of AUC0-last articaine to AUC0-last articaine, the ratio is about 2 in both cornea and plasma, with more exposure to articaine than articaine in these two matrices. It shows that there are many. For all other matrices, the ratio was <0.7. The T1 / 2 (half-life) of articaine in most eye matrixes ranged from 1.70 to 3.29 hours. The T1 / 2 of articaine acid in plasma was about 1.5 hours.

In summary, topical ocular administration of articaine provided an anesthetic effect up to 20 minutes post-dose without significant tolerability problems. Articaine and articaine were detected in the iris-ciliary body, bulbar palsy and palpebral conjunctiva, and in all eye matrix examined at the highest exposure found in the cornea. Considering the presence of esterase activity in ocular tissue, rapid metabolism of articaine to articaine is expected. Systemic exposure was minimal, as indicated by plasma AUC.

The purpose of this study was to determine the tolerability of placebo and articaine HCl ophthalmic solutions at concentrations of 4, 8, and 12% (w / v) after topical eye drop administration, and 8% articaine hydrochloride. It was to determine the ocular pharmacokinetics and biodistribution of articaine and articaine after topical instillation of ophthalmic solution. The rabbit is a standard non-rodentate species used in preclinical pharmacokinetic studies of novel chemicals and various test formulations, including ocular pharmacokinetics. The number of animals is considered to be the appropriate number needed to properly perform this study of tolerability and biodistribution of the eye, explaining variability between animals and enabling the generation of descriptive statistical analysis. .. The local route was chosen because this is the intended route of administration in humans. The dose level of the eye formulation selected by the sponsor was designed to achieve the therapeutic ocular tissue concentration of the study product. A single dose of the test product is common in determining pharmacokinetics.

Studies with approved aqueous articaine formulations have been performed in humans, with highly favorable initial results supporting the results of the rabbit study.

Example 2
As shown in Table 1, a topical ophthalmic anesthetic composition containing articaine hydrochloride at a concentration of 8.0% w / v was prepared.

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

Example 3
A topical ophthalmic composition having the compositions shown in Table 2 below was prepared. Systemane and Systemane + 8% articaine hydrochloride are included here only because they were used as a viscosity comparison, but are not otherwise part of the formulation study.

The pharmaceuticals C and F were evaluated for the stability of the pharmaceuticals over 8 weeks in containers stored at 5 ° C, 25 ° C, and 45 ° C.

Results of storage at 5 ° C, 25 ° C, and 45 ° C showed acceptable impurity levels, stable pH, viscosity, and osmolality. The pharmaceutical product F has been demonstrated to be useful based on the degradation level. PEG400 appears to be very reactive with articaine. Buffers that have the lowest possible pH and are patient tolerable have been shown. Boric acid / mannitol buffer achieved the required stability.

In one embodiment, the composition was composed of 35 mM acetate, pH 4.8, 15 mM borate-mannitol complex, and 0.055% EDTA (disodium, dehydrated salt). Acetate can be obtained from acetic acid, sodium acetate or a mixture thereof. This product exhibits a stable pH, has a low hydrolysis rate (1.53% total in 8 weeks) at 40 ° C., forming about 0.04% articinic acid per week over 4 weeks, and 25 ° C. Hydrolysis at a rate of 0.061% / week (total 0.49% in 8 weeks) was also shown. This is more than four times slower than previously known formulations.

Some embodiments of the method were determined by experimentation on a 100 g scale and then scaled up to 500 g for confirmation.

The borate-mannitol complex, which is much more acidic than boric acid (pKa 9.14) alone, is easy when these two excipients are combined in the absence of other excipients or buffers. Formed in, resulting in a pH of about 4.2. Regarding the order of addition, these two excipients are added first and the pharmaceuticals are mixed to completely form the complex.

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

The method was easily scaled up to 500 mL at a final pH of 4.80 and a final osmolality of 622 mOsm / kg. After that, it was also scaled up to 1 L, and the pH of the final pharmaceutical product after filtration was 4.85, and the osmotic pressure was 597 mOsm / kg.

The drug prepared in the process development experiment was then used in the filtration study to determine if PVDF was the appropriate filter material for this formulation and to determine the appropriate filter size.

Concentrations of the drug were consistent both before and after filtration, and there were no signs of API binding to the PVDF filter material, with no loss of concentration in the initial aliquots. Therefore, no waste amount is required.

Vmax studies show that there is little decrease in flow rate over time and that filter degradation is not a problem with this formulation and that 1 L batch of medicine can be filtered using a relatively small filtration area. .. Therefore, the size of the filter can be selected primarily based on the required flow rate. The required flow rate can also be adjusted using higher pressures.

Although this disclosure has been shown and described with reference to its particular exemplary embodiments, those skilled in the art will make various changes in form and detail without departing from the ideas and scope of the present disclosure. Let's understand what you get.

Publications cited throughout this document are hereby incorporated 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 contained in such combinations are not mutually exclusive.

Claims (29)

Aqueous ophthalmic anesthetic composition comprising:
Articaine in an amount of about 4.0% w / v to about 12.0% w / v based on the volume of the composition; and non-reactive with articaine, stabilizing articaine, about pH 3. An amount of buffer that provides a pH of 5 to about pH 7.0. The buffer has a pH of about pH 4.5 to about pH 5.5 and is obtained from a citrate, acetate or a mixture thereof and a sugar alcohol selected from the group consisting of mannitol, sorbitol and mixtures thereof. The composition according to claim 1, which comprises the complex to be added. The composition according to claim 1, wherein the composition comprises about 7.5% w / v to 8.5% w / v of articaine and has a pH of about pH 4.5 to about pH 5.0. The composition of claim 1, comprising at least about 7.0% w / v articaine and having a pH of 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. The composition according to claim 5, wherein the borate / mannitol complex is contained in an amount of about 0.5% w / v to about 0.75% w / v based on the volume of the composition. The composition according to claim 5, wherein the borate / mannitol complex is contained 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. thing. The composition of claim 5, wherein the borate / mannitol complex is obtained from a borate / mannitol ratio of about 1: 3 to about 1: 7 by weight. The composition according to claim 5, further comprising sodium acetate, acetic acid, and disodium edetate. It contains at least about 7.0% w / v of articain, and the buffer contains an amount of the complex of boric acid and D-mannitol that provides a pH of about pH 4.5 to about pH 5.0, and The composition according to claim 1, wherein the composition further comprises sodium acetate, acetic acid, and disodium edetate. The articain is present in an amount of at least about 7.0% w / v and the boric acid and D-mannitol complex is from about 0.08% w / v to about 0.08% w / v based on the total volume of the composition. The composition according to claim 4, which is obtained from 0.10% w / v boric acid and about 0.50% w / v to about 0.6% w / v D-mannitol. At least about 8.0% w / v articain, about 0.08% w / v to about 0.10% w / v boric acid and about 0.5% w / v to about 0.60% w / Buffer complex obtained from v D-mannitol, about 0.3% w / v to 0.36% w / v sodium acetate, about 0.05% w / v to about 0.07% w / v edetonic acid. The composition according to claim 1, which comprises disodium and the balance of water, has an osmotic pressure of about 280 to 320 mOsm / kg, and the amount is based on the total volume of the composition. Contains about 4% w / v articaine
The buffer contains NaOH and HCl and contains
Claim 1 has a pH of about pH 5.5, a pKa of about 7.8, a viscosity of about 20-25 cp, an osmotic pressure of about 275 to 1171 mOsm / kg, and a tonicity of about 0.5 to 5.0%. The composition according to. 80 mg / g articain hydrochloride, 1.373 mg / g sodium dihydrogen phosphate monobasic monohydrate, 1.413 mg / g disodium hydrogen phosphate dibasic anhydride, 8.1 mg / g The composition of claim 1, comprising hydroxypropylmethyl cellulose, 4 mg / g of PEG400, having a pH of 6.0 to 7.0, a viscosity of 743 to 803 cp, and an osmotic pressure of 517 mOsm / kg. Aqueous ophthalmic anesthetic composition comprising:
An amount of at least about 7.0% w / v of articain based on the volume of the composition; an amount of boric acid or borate that provides a pH of about pH 4.0 to about pH 5.5 and stabilizes the articain. A buffer solution, which is a complex obtained from a salt salt and a sugar alcohol. 15. 15. The buffer is a borate / mannitol complex 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. Aqueous ophthalmic anesthetic composition. The aqueous ophthalmic anesthetic composition of claim 16, wherein the borate / mannitol complex is obtained from a borate / mannitol ratio of about 1: 3 to about 1: 7 by weight. The aqueous ophthalmic anesthetic composition according to claim 17, further comprising sodium diacetate, acetic acid, and disodium edetate. A method of providing anesthesia to an eye, comprising the step of topically applying the composition of claim 1 to the surface of the patient's eye in an amount effective to anesthetize the patient's eye. .. The composition comprises at least about 5.0% amount of articaine based on the total volume of the composition, and the buffer complex is from about 0.08% w / v to about 0.10% w. 19. The method of claim 19, obtained from boric acid / v and D-mannitol from about 0.50% w / v to about 0.6% w / v. The composition comprises at least about 7.5% w / v articain; a buffer containing a complex obtained from boric acid and D-mannitol in an amount non-reactive with articain; sodium acetate; acetic acid; edet. 19. The method of claim 19, wherein the composition comprises disodium acid acid and the balance of water and has a pH of about pH 4.5 to about pH 5.5. 19. The method of claim 19, wherein the composition comprises at least about 7% w / v articaine. 22. The method of claim 22, wherein the composition has a pH of about pH 4.5 to about pH 5.0. The pharmaceutical product contains 4% w / v articine, pH 5.5, pKa7.8, viscosity 20-25 cp, osmotic pressure 275-1171 mOsms / kg, tonicity 0.5% -5.0%, NaOH buffer, 19. The method of claim 19, comprising a hydrochloric acid buffer. The composition is 80 mg / g articaine hydrochloride, 1.373 mg / g sodium dihydrogen phosphate monobasic monohydrate, 1.413 mg / g disodium hydrogen phosphate anhydride, 8.1 mg. 19. The composition comprising / g hydroxypropylmethylcellulose, 4 mg / g PEG400, said composition having a pH of pH 6.0 to pH 7.0, a viscosity of 743 to 803 cp, and an osmotic pressure of 517 mOsm / kg. The method described. The method for producing the composition according to claim 1, which comprises the following steps:
Mixing an acid or a salt thereof with a sugar alcohol in a solution to form a complex;
Adjust the pH to about 3.5 to about pH 7.0; and
To the resulting solution is added articaine in an amount to obtain the composition having from about 4.0% w / v to about 12.0% w / v based on the volume of the composition. 26. The method of claim 26, wherein the acid is selected from the group consisting of acetic acid, citric acid, and mixtures thereof, and the sugar alcohol is selected from the group consisting of D-mannitol, sorbitol, and mixtures thereof. .. The acid or salt thereof is a borate, the sugar alcohol is D-mannitol, the complex is a borate / mannitol complex, and the composition comprises at least 7.0% articain. 26. The method of claim 26, comprising and having a pH of about pH 6.0 to pH 7.0. 28. The method of claim 28, wherein the borate / mannitol complex is obtained from a borate / mannitol ratio of about 1: 3 to about 1: 7 by weight.