Ophthalmic chloroprocaine gel with improved functionality

Abstract

A sterile ophthalmic gel of chloroprocaine having improved functionality, pharmacokinetics, and stability, particularly with respect to clarity, and methods of making and using the same.

Description

[Technical Field]

[0001] The present invention relates to chloroprocaine ophthalmic gels with improved functionality, pharmacokinetics, and stability, particularly with respect to clarity, and methods of making and using same. [Background technology]

[0002] Topical anesthetics are sold without a prescription for the relief of a variety of conditions, including sunburn, minor burns, insect bites, poison ivy, poison oak, poison sumac, and minor cuts and abrasions. Topical anesthetics are also used during minor surgery. Dentists use topical anesthetics to numb oral tissues before injecting a local anesthetic; ophthalmologists use topical anesthetics to numb the surface of the eye when performing minor surgeries and medical procedures; and otolaryngologists use topical anesthetics when performing procedures in the ear canal. Molecules approved as topical anesthetics in the United States and Europe include tetracaine, lidocaine, benzocaine, prilocaine, and oxybuprocaine, among others.

[0003] What is needed are topical anesthetics, particularly ophthalmic gels, that have improved functionality, pharmacokinetics, and stability compared to prior art formulations. There is also a need for methods of producing ophthalmic gels that exhibit viscous, sterile formulations with consistent physical properties, appearance, and anesthetic properties. Summary of the Invention

[0004] After extensive research and experimentation, the inventors have developed chloroprocaine ophthalmic gels and methods for making and using the gels that rely on the mixing of a sterile drug solution phase and a separate sterile gel matrix. Thus, in a first primary embodiment, the present invention provides an ophthalmic gel comprising an acidic aqueous solution of chloroprocaine hydrochloride, having a pH of 2.4 to 3.2, mixed with an aqueous matrix of hydroxyethylcellulose, having a viscosity of greater than 25,000 cP at 25° C. and a pH of, in some cases, greater than 6, wherein: (a) the gel comprises 3% chloroprocaine hydrochloride; (b) the gel has a pH of 2.8 to 3.8; and (c) the matrix viscosity is measured at 20 rpm with a Brookfield DV III+Pro Spindle 3 as described in Section 2.2.10 of the European Pharmacopoeia 2016 Edition.

[0005] The gels of the present invention flow in the form of droplets that are easy to administer, maintain a continuous anesthetic effect on the surface of the eye, and remain clear to facilitate surgical procedures. This flow is non-Newtonian and pseudoplastic and is the result of the unique additives used in the formulation and the unique manufacturing process. Thus, in a second principal embodiment, the present invention provides an ophthalmic gel exhibiting non-Newtonian pseudoplastic behavior, comprising: (a) 3% chloroprocaine hydrochloride; (b) 1.0% to 1.25% hydroxyethylcellulose; (c) hydrochloric acid sufficient to achieve a pH of 2.8 to 3.8; and (d) water.

[0006] The third principal embodiment relates to the use of any of the compositions of the present invention to induce analgesia in the eye. These methods have been found to be particularly useful when performed in conjunction with small corneal incisions, phacoemulsification, and cataract surgery with lens replacement. Thus, in the third principal embodiment, the present invention provides a method for inducing anesthesia or analgesia on the corneal surface, comprising applying to the corneal surface a drop containing 0.03 to 0.1 g of the gel of the present invention.

[0007] A fourth principal embodiment relates to a method of making the formulation of the invention. Accordingly, in the fourth principal embodiment, the invention relates to a method of making the formulation of the invention, comprising: (a) mixing hydroxyethyl cellulose and water to form a hydroxyethyl cellulose solution in a BrookField DV III+Pro Spindle ... (b) heat-sterilizing the water-soluble matrix at a temperature above 35 or 40°C (preferably at or below 60°C) to reduce the viscosity of the water-soluble matrix by 40% or less; (c) mixing water, hydrochloric acid, and chloroprocaine hydrochloride to prepare an acidic aqueous solution having a pH of 2.4 to 3.2 at a temperature of 35 or 40°C or higher (preferably at or below 60°C); (d) filter-sterilizing the acidic aqueous solution at a temperature of 35 or 40°C or higher (preferably at or below 60°C); (e) mixing the water-soluble matrix and the acidic aqueous solution to form a gel; and (f) filling the gel into a container.

[0008] Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

[0009] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and, together with the description, serve to explain the principles of the invention. [Brief explanation of the drawings]

[0010] [Figure 1] FIG. 1 shows a schematic diagram of a preferred method of manufacturing a gel of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0011] Definitions and Terminology Use Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon.

[0012] As used in this specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, the term "pharmaceutical excipient" refers to one or more pharmaceutical excipients for use in the presently disclosed formulations and methods.

[0013] As used herein, the term "about" accounts for variability inherent in the pharmaceutical industry and in pharmaceutical products, such as differences in product strength due to variations and time-induced product degradation. In one embodiment, the term allows for any variation, which would allow a pharmaceutical practitioner to assess that the product would be considered pharmaceutically equivalent or bioequivalent to the listed strength. In another embodiment, the term allows for any variation within 5% of the listed strength or concentration of the formulation.

[0014] The terms "treating" and "treatment," as used herein, refer to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, injury, or disorder (collectively, "disorders"). The term includes active treatment, i.e., treatment given specifically to ameliorate a disorder, and also includes causal treatment, i.e., treatment given to eliminate the cause of the associated disorder. In addition, the term includes symptomatic treatment, i.e., treatment designed to alleviate symptoms but not cure the disorder; preventative treatment, i.e., treatment given to minimize or partially or completely prevent the occurrence of a disorder; and supportive treatment, i.e., treatment used to supplement another specific therapy given to ameliorate a disorder.

[0015] As used herein, the term "therapeutically effective amount" refers to an amount sufficient to induce a desired biological response. The therapeutically effective amount or dose depends on the age, sex, and weight of the patient and the patient's current medical condition. Those skilled in the art can determine the appropriate dosage depending on these and other factors, in addition to the present disclosure.

[0016] "Pharmaceutically acceptable" generally means something that is useful in preparing pharmaceutical compositions that are safe, non-toxic, and not biologically undesirable, and includes something that is acceptable for veterinary use as well as human pharmaceutical use. "Pharmaceutically acceptable salt" means a salt that is pharmaceutically acceptable, as defined above, and that possesses the desired pharmacological activity.

[0017] When a compound is expressed without indicating whether it exists as a free base or a salt, it is understood to include both the free base and salt forms.Similarly, when a weight, dosage, or ratio range for a compound is given, it refers to the range being calculated based on the weight of the free base or salt, unless a specific salt is mentioned, in which case it is understood that the weight refers to the weight of the salt mentioned.Thus, when 100 mg chloroprocaine, or 100 mg chloroprocaine or a pharmaceutically acceptable salt thereof is mentioned, it is understood that the disclosure includes, among other salts, 100 mg chloroprocaine hydrochloride per weight of the free base or 100 mg chloroprocaine hydrochloride per weight of the salt.When 100 mg chloroprocaine hydrochloride is mentioned, it is understood that the disclosure only includes 100 mg chloroprocaine hydrochloride per weight of the salt.

[0018] When a range is expressed herein by specifying alternative upper and lower limits of the range, it is understood that the endpoints can be combined in any manner mathematically possible. Thus, for example, a range of 50 or 80 to 100 or 70 can alternatively be expressed as the series of ranges 50 to 100, 50 to 70, and 80 to 100. When a series of upper and lower bounds are related using the phase and / or, it is understood that the upper bound may not be limited by or may be combined with the lower bound, and vice versa. Thus, for example, a range of more than 40% and / or less than 80% includes ranges of more than 40%, less than 80%, and more than 40% but less than 80%.

[0019] Where percentages, concentrations or other units of measure are given herein, it is understood that the unit of measure is weight percent unless otherwise specified.

[0020] Weight average molecular weight (M n ) is the following expression:

[0021]

number

[0022] When stability of a formulation over time is indicated herein, it is understood to be assessed by standard methods known to those skilled in the art, generally as set forth in ICH Q1A(R2) Stability Testing of New Drug Substances and Products (November 2003), which is assessed and reported using HPLC.

[0023] "Total impurities" generally refers to by-products formed during the synthesis of chloroprocaine hydrochloride, residual impurities remaining from the synthesis of chloroprocaine hydrochloride after purification, and impurities caused by degradation of chloroprocaine during manufacturing or storage, as further defined and evaluated under ICH Q3A(R2) Impurities in New Drug Substances (October 2006) as assessed and reported using HPLC.

[0024] Discussion of the Main Embodiments The present invention can be defined in terms of several main embodiments, which can be combined in any way that is physically and mathematically possible to create additional main embodiments.

[0025] A first principal embodiment provides an ophthalmic gel comprising an acidic aqueous solution of chloroprocaine hydrochloride, at a pH of 2.4 to 3.2, mixed with a water-soluble matrix of hydroxyethylcellulose, having a viscosity greater than 25,000 cP at 25° C. and a pH optionally greater than 6, wherein: (a) the gel comprises 3% chloroprocaine hydrochloride; (b) the gel has a pH of 2.8 to 3.8; and (c) the matrix viscosity is measured at 20 rpm with a Brookfield DV III+Pro Spindle 3 as described in Section 2.2.10 of the European Pharmacopoeia 2016 Edition.

[0026] A second principal embodiment provides an ophthalmic gel exhibiting non-Newtonian pseudoplastic behavior that includes: (a) 3% chloroprocaine hydrochloride; (b) 1.0% to 1.25% hydroxyethylcellulose; (c) hydrochloric acid in an amount sufficient to achieve a pH of 2.8 to 3.8; and (d) water.

[0027] The third main embodiment provides a method for inducing anesthesia or analgesia to the corneal surface, comprising applying a droplet containing 0.03 to 0.1 g of a gel of the invention to the corneal surface.

[0028] A fourth principal embodiment is a method of (a) mixing hydroxyethyl cellulose and water to form a hydroxyethyl cellulose solution in a BrookField DV III+Pro Spindle as described in Section 2.2.10 of the European Pharmacopoeia 2016 Edition. (b) heat-sterilizing the water-soluble matrix at a temperature above 35 or 40°C (preferably at or below 60°C) to reduce the viscosity of the water-soluble matrix by 40% or less; (c) mixing chloroprocaine hydrochloride with water and hydrochloric acid to prepare an acidic aqueous solution having a pH of 2.4 to 3.2 at a temperature of 35 or 40°C or higher (preferably at or below 60°C); (d) filter-sterilizing the acidic aqueous solution at a temperature of 35 or 40°C or higher (preferably at or below 60°C); (e) mixing the water-soluble matrix and the acidic aqueous solution to form a gel; and (f) filling the gel into a container.

[0029] The present invention can be further understood in terms of various subembodiments that can modify any of the main embodiments, and that can be combined in any manner that is mathematically and physically possible to create additional subembodiments that can modify any of the main embodiments.

[0030] Considerations for Subembodiments of the Formulation In some embodiments, the gel is characterized by the concentration of hydroxyethylcellulose in the final formulation. Thus, in some embodiments, the gel contains 1.0% to 1.25% hydroxyethylcellulose. In other embodiments, the gel contains 1.04% to 1.14% hydroxyethylcellulose. In further embodiments, the gel contains a hydroxyethylcellulose concentration of about 1.09%, most preferably at a pH of 3.0 to 3.4.

[0031] The gel may also be characterized by its pH and in any of the embodiments of the invention, the gel has a pH of 2.5 to 4.5, 2.6 to 4.0, 2.8 to 3.8, or 3.0 to 3.4.

[0032] In other embodiments, the gel is characterized by the hydroxyethyl cellulose used in the gel. In some embodiments, the hydroxyethyl cellulose has a weight average molecular weight of 800,000 to 2,000,000 daltons, 1,000,000 to 1,500,000 daltons, 1,250,000 to 1,350,000 daltons, or about 1,300,000 daltons. In any of the embodiments of the present invention, the hydroxyethyl cellulose preferably exhibits non-Newtonian pseudoplastic behavior.

[0033] Gels may also be characterized by their viscosity as measured on a Brookfield DV II+Pro Spindle 3 at 100 rpm as described in section 2.2.10 of the European Pharmacopoeia 2016. Thus, in some embodiments, the gel has a viscosity of 1000-2000 cP at 25° C. In further embodiments, the gel has a viscosity of 1000-1500 cP at 25° C. In another embodiment, the gel has a viscosity of 1500-2000 cP at 25° C.

[0034] The gels can also be characterized by significantly low levels of ACBA (4-amino-2-chlorobenzoic acid) in the finished formulation, with the gels containing less than 3.0% ACBA, less than 1.0%, less than 0.4%, less than 0.2%, less than 0.1%, and even less than 0.05% ACBA. These figures apply both at the completion of product manufacturing and throughout the shelf life of the product, including two years after storage at 25° C. and 40% relative humidity, protected from light.

[0035] The gel can also be characterized by its exceptionally low levels of total impurities (as defined herein) at the completion of product manufacturing and throughout the product's shelf life. Thus, for example, in any of the embodiments described herein, the gel preferably comprises less than 0.6% or 0.4% total impurities after a six-month storage period at 20° C. and 40% relative humidity, protected from light. At any time after manufacturing, the gel preferably contains less than 0.4% total impurities.

[0036] Treatment methods The present compositions have been found to be effective in inducing local anesthesia or analgesia on the corneal surface and can be used during ocular surgery or in response to corneal abrasion or trauma. Particularly suitable surgeries for carrying out the present invention include, for example, cataract surgery, treatment for maculopathy, conventional glaucoma surgery, vitrectomy, surgery for diabetic nephropathy, and various laser surgeries, including laser-assisted in situ keratomileusis and laser photorefractive keratectomy. These compositions induce local analgesia or anesthesia in the eye, and do so without causing significant irritation.

[0037] The preferred surgical procedure is phacoemulsification for the removal of senile or presenile cataracts, which includes an incision through the cornea, a capsulotomy, phacoemulsification, and intraocular lens implantation.

[0038] A preferred dosing regimen is as follows: - First drop instillation, then wait about 5 minutes - Disinfect the eyes, then wait approximately 2 minutes - Instill the second drop, then wait about 1 minute - Apply the third drop, then wait about 1 minute - Start of surgery.

[0039] Two other preferred dosing regimens are as follows: 3 drops (one drop every minute ±15 seconds) 3 + 3 drops (the first 3 drops are infused once at ±15 seconds per minute, then after waiting about 5 minutes, the final 3 drops are infused again at ±15 seconds per minute)

[0040] Alternatively, drops can be instilled before or during surgery at the physician's discretion. Product safety supports administration of 1-10 drops at any time before or during surgery.

[0041] Preferred drop sizes range from 0.03 to 0.1 g, 0.03 to 0.08 g, or 0.045 to 0.065 g, and preferably induce a pharmaceutically effective concentration of chloroprocaine in the aqueous humor, cornea, and conjuctivae within at least 10 minutes after the first drop is instilled, and persist for at least 30, 45, or 60 minutes after the last drop is instilled.

[0042] Manufacturing method As described in the main embodiment, in one embodiment, the gel of the present invention is made by the steps of: (a) mixing hydroxyethyl cellulose and water to form a water-soluble matrix having an initial viscosity of greater than 40,000 cP at 25°C, as measured at 20 rpm with a Brookfield DV III+Pro Spindle 3, as described in Section 2.2.10 of the European Pharmacopoeia 2016; (b) heat-sterilizing the water-soluble matrix at a temperature above 35 or 40°C to reduce the viscosity of the water-soluble matrix by 40% or less; (c) mixing chloroprocaine hydrochloride with water and hydrochloric acid to prepare an acidic aqueous solution having a pH of 2.4 to 3.2 at a temperature of 35 or 40°C or higher (preferably, 60°C or lower); (d) filter-sterilizing the acidic aqueous solution at a temperature of 35 or 40°C or higher (preferably, 60°C or lower); (e) mixing the water-soluble matrix and the acidic aqueous solution to form a gel; and (f) filling the gel into a container. In another embodiment, the gel is made by mixing a water-soluble matrix of hydroxyethyl cellulose, having a viscosity greater than 25,000 cP at 25° C. and a pH in some cases greater than 6, with an acidic aqueous solution of chloroprocaine hydrochloride, pH 2.4-3.2. In further embodiments of the invention, the aforementioned manufacturing parameters can be varied as follows: The initial viscosity of the matrix can be greater than 20,000, 30,000, 40,000, or 50,000 cP at 25°C, but preferably does not exceed 100,000 or 60,000 cP at 25°C, as measured with a BrookField DV III+Pro Spindle 3 at 20 rpm, as described in Section 2.2.10 of the European Pharmacopoeia 2016. The water-soluble matrix can be heat sterilized at temperatures above 35, 40, 45 or 50°C, preferably in the range of 35-45°C (preferably up to 60°C), most preferably at about 40°C. Heat sterilization of the water-soluble matrix preferably reduces its viscosity by no more than 40%, 35%, or 30%, preferably in the range of 5% to 40% or 10% to 30%. The viscosity of the water-soluble matrix after heat sterilization is preferably greater than 15,000, 20,000, 25,000, or 30,000 cP at 25°C, but preferably not greater than 60,000 or 40,000 cP at 25°C, as measured with a BrookField DV III+Pro Spindle 3 at 20 rpm, as described in Section 2.2.10 of the European Pharmacopoeia 2016. The pH of the water-soluble matrix is ​​preferably alkaline (i.e., 7-8), but may also be in the range of 5-9, 6-8, or 6.5-7.5. The acidic aqueous solution may be prepared at a temperature above 35, 40, 45 or 50°C (preferably below 60°C), preferably in the range of 35-45°C, most preferably at about 40°C; Acidic aqueous solutions can be prepared with pH values ​​of 2.2-4.0, 2.4-3.5, 2.4-3.2, 2.5-3.0, or 2.6-2.8 by adding HCl. The acidic aqueous solution can be sterilized at a temperature above 35, 40, 45, or 50°C (preferably below 60°C), preferably in the range of 35-45°C, most preferably at about 40°C, and preferably by filtration through a 0.22 micron filter; The weight ratio of the acidic aqueous solution to the gel matrix is ​​preferably in the range of 30:70 to 70:30.

[0043] Further embodiments of the present invention relate to the order of steps in the methods of manufacture of the present invention, as well as certain negative conditions. Thus, in other embodiments, the methods of manufacture of the present invention satisfy one, two, or all three of the following additional conditions: (i) steps (a) and (b) are performed before steps (c) and (d), (ii) the pH of the formulation is not adjusted after step (e), and / or (iii) the viscosity of the formulation is not adjusted after step (e).

[0044] Further embodiments relate to containers used to package the gel. Thus, in some embodiments, the container is a monodose container containing 0.5 to 2 grams of the gel formulation. In other embodiments, the container is a multidose container containing 1 to 25 grams of the gel formulation. [Example]

[0045] In the following examples, efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperatures, etc.), but some errors and deviations should be accounted for. The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the methods claimed herein can be used, made, and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention. [Example]

[0046] Preparation of the compound A 3% chloroprocaine gel (CHLO-1708-L02) having the semi-quantitative formulation in Table 1 is prepared according to the schematic shown in Figure 1, with the following added details: The API phase is maintained at approximately 40°C and the sterile filtration of the API phase is carried out at a temperature of approximately 40°C; The API phase contains approximately 0.06-0.07g per 1g of chloroprocaine HCl; The API phase is filter sterilized by passing the solution through a 0.22 micron filter; 1N HCl was added to the API phase to obtain a pH of 3.04; The gel (matrix) phase is heat sterilized at approximately 40°C; The gel (matrix) phase has an initial viscosity of 48,000, which decreases to 33,920 (-29.3%) during heat sterilization; The gel (matrix) phase has an initial pH of 7.31, which decreases to 7.06 during sterilization; The API phase is prepared after the gel phase; · No pH modification by adding alkaline or acidic agents to the formulation after the API and gel phase have been combined; The resulting products exhibited non-Newtonian behavior and a high degree of pseudoplasticity.

[0047] Viscosity measurements of the formulations were taken during manufacturing and after the formulations were completed. All viscosity measurements in the gel / matrix phase were taken using a Brookfield DV III Viscosimeter or equivalent at a water bath temperature of 25±0.5°C for 15 minutes, a speed of 20 rpm, and a run time of 2 minutes. All viscosity measurements on the completed gels were taken using a Brookfield DV II Viscosimeter at a water bath temperature of 25±1°C for 15 minutes, a speed of 100 rpm, and a run time of 5 minutes.

[0048] [Table 1]

[0049] The finished product had a viscosity of approximately 1247-1260 cP, an osmolality between 152-158 mOsmol / kg, and an ACBA impurity content of 0.04-0.05%. [Example]

[0050] Stability testing Further testing was performed to determine the stability of the API phase at various temperatures and pH adjustments, as reported in Tables 2a, 2b, and 2c, based on the production of ACBA impurities in solution.

[0051] [Table 2a]

[0052] [Table 2b]

[0053] [Table 2c]

[0054] As can be seen, a clearer solution was obtained when the temperature of the API phase was maintained at 40° C. and the pH of the API phase was adjusted to approximately 3.0 before combining with the gel / matrix phase. [Example]

[0055] Stability testing of finished formulations The formulation described in Example 1 was tested for stability after 6 months of storage at 25°C and 40% relative humidity, protected from light. The method for conducting the stability analysis is described in Table 3a. The results of the stability testing are listed in Table 3b.

[0056] [Table 3a]

[0057] [Table 3b] [Example]

[0058] Example 1 Pharmacokinetic Study of Formulation; Single Dose Administration The study was conducted by instilling a 50 μl volume of the gel described in Example 1 into the right eye of 42 white albino rabbits (2-2.5 kg), visually inspecting for irritation or toxicity with an ophthalmoscope, euthanizing the animals, extracting samples from the aqueous humor, cornea, and conjunctiva, and analyzing the samples for chloroprocaine content. When necessary, tissue concentrations were calculated by extrapolating the study results outside the validated concentration range, as reported in Table 4.

[0059] [Table 4]

[0060] The drug was well tolerated by the Draize test, which assesses eye irritation under an ophthalmoscope. Slight conjunctival redness (score 1 / 3) was observed immediately before euthanasia in the following rabbits: treated eyes 5 and 6 (10 minutes after administration), untreated eye 9 (20 minutes after administration), treated eye 15 (30 minutes after administration), treated eye 24 (45 minutes after administration), treated and untreated eye 30 (60 minutes after administration), and treated eye 37 (90 minutes after administration). [Example]

[0061] Example 1 Pharmacokinetic Study of Formulation; Two Dose Administration The purpose of this study was to obtain data on the PK profile of chloroprocaine in the aqueous humor, cornea, and conjunctiva (globus and eyelid) ocular tissues after two instillations, 10 minutes apart, of the chloroprocaine ophthalmic gel formulation of Example 1 in the right eyes of albino rabbits, followed by RRLC-MS / MS analysis. The results are shown in Table 5.

[0062] [Table 5]

[0063] No abnormal behavior or signs of ill health were found for any of the animals during the in-vivo phase.

[0064] Other embodiments Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

Claims

1. A droplet containing 0.03 to 0.1 g of ophthalmic gel, The ophthalmic gel comprises an acidic aqueous solution of chloroprocaine hydrochloride at a pH of 2.4 to 3.2 mixed with a water-soluble matrix of hydroxyethylcellulose having a viscosity of greater than 25,000 cP at 25° C. and a pH optionally greater than 6; a) the gel comprises 3% chloroprocaine hydrochloride; b) the gel has a pH of 2.8 to 3.8; c) matrix viscosity is measured on a Brookfield DV III+Pro Spindle 3 at 20 rpm as described in section 2.2.10 of the European Pharmacopoeia 2016; and d) Hydroxyethylcellulose droplets having a weight average molecular weight of 1,000,000 Daltons to 1,500,000 Daltons.

2. A droplet containing 0.03 to 0.1 g of ophthalmic gel, The ophthalmic gel comprises: a) 3% chloroprocaine hydrochloride; b) 1.0% to 1.25% hydroxyethylcellulose having a weight average molecular weight of 1,000,000 to 1,500,000 daltons; c) an appropriate amount of hydrochloric acid to a pH of 2.8 to 3.8; and d) water; 1. An ophthalmic gel exhibiting non-Newtonian pseudoplastic behavior comprising:

3. 3. The droplets of claim 1 or 2, wherein the acidic aqueous solution of chloroprocaine hydrochloride has been sterilized by filtration at a temperature above 35°C and the water-soluble matrix of hydroxyethyl cellulose has been sterilized by heat at a temperature above 35°C.

4. A droplet described in any one of claims 1 to 3, wherein the gel contains 1.04% to 1.14% hydroxyethyl cellulose.

5. 5. The droplet of any one of claims 1, 3 and 4, wherein the hydroxyethyl cellulose exhibits non-Newtonian pseudoplastic behavior.

6. A droplet according to any one of claims 1 to 5, comprising 0.045 to 0.065 g of gel.

7. a) mixing hydroxyethyl cellulose and water to produce a water-soluble matrix having an initial viscosity of greater than 40,000 cP at 25° C. as measured with a Brookfield DV III+Pro Spindle 3 at 20 rpm, as described in section 2.2.10 of the European Pharmacopoeia 2016, wherein the hydroxyethyl cellulose has a weight average molecular weight of 1,000,000 Daltons to 1,500,000 Daltons; b) heat sterilizing the water-soluble matrix at a temperature above 35°C to reduce the viscosity of the water-soluble matrix by no more than 40%; c) mixing chloroprocaine hydrochloride with water and hydrochloric acid to prepare an acidic aqueous solution having a pH of 2.4-3.2 at a temperature of 35°C or higher; d) filter sterilizing the acidic aqueous solution at a temperature of 35°C or higher; e) mixing the water-soluble matrix and the acidic aqueous solution to form a gel; f) filling the container with gel; 1. A method for making a 3% chloroprocaine hydrochloride ophthalmic gel, comprising:

8. 8. The method of claim 7, wherein (i) steps (a) and (b) are performed before steps (c) and (d), (ii) the pH of the formulation is not adjusted after step (e), and (iii) the viscosity of the formulation is not adjusted after step (e).

9. 9. The method of claim 7 or 8, wherein the water-soluble matrix has a viscosity after heat sterilization of greater than 25,000 cP at 25° C. as measured with a Brookfield DV III+Pro Spindle 3 at 20 rpm, as described in section 2.2.10 of the European Pharmacopoeia 2016.

10. A method according to any one of claims 7 to 9, wherein the gel contains 1.04% to 1.14% hydroxyethyl cellulose.

11. A method according to any one of claims 7 to 10, wherein the hydroxyethyl cellulose exhibits non-Newtonian pseudoplastic behavior.

12. An ophthalmic gel comprising: the ophthalmic gel is for use in a method for inducing anesthesia or analgesia at the corneal surface, the method comprising step 1 of applying to the corneal surface a drop comprising 0.03 to 0.1 g or 0.045 to 0.065 g of the gel; and The ophthalmic gel is 1. An acidic aqueous solution of chloroprocaine hydrochloride at a pH of 2.4 to 3.2 mixed with a water-soluble matrix of hydroxyethylcellulose having a viscosity of greater than 25,000 cP at 25° C. and a pH in some cases greater than 6, wherein: a) the gel comprises 3% chloroprocaine hydrochloride; b) the gel has a pH of 2.8 to 3.8; c) matrix viscosity is measured on a Brookfield DV III+Pro Spindle 3 at 20 rpm as described in section 2.2.10 of the European Pharmacopoeia 2016; and d) an ophthalmic gel, wherein the hydroxyethyl cellulose has a weight average molecular weight of 1,000,000 Daltons to 1,500,000 Daltons, and optionally the hydroxyethyl cellulose exhibits non-Newtonian pseudoplastic behavior; or a) 3% chloroprocaine hydrochloride; b) 1.0% to 1.25% hydroxyethylcellulose having a weight average molecular weight of 1,000,000 to 1,500,000 daltons; c) an appropriate amount of hydrochloric acid to a pH of 2.8 to 3.8; and d) water; wherein the ophthalmic gel exhibits non-Newtonian pseudoplastic behavior.

13. The ophthalmic gel of claim 12, wherein the method further comprises step 2, approximately 1 to 5 minutes after the first step, of applying second and third droplets containing 0.03 to 0.1 g or 0.045 to 0.065 g of gel to the corneal surface approximately 1 minute apart.

14. An ophthalmic gel for use in a method of inducing local anesthesia or analgesia of the corneal surface in a surgical procedure which is phacoemulsification for removal of senile or presenile cataracts including transcorneal incision, capsulotomy, phacoemulsification, and intraocular lens insertion, comprising: The ophthalmic gel is 1. An acidic aqueous solution of chloroprocaine hydrochloride at a pH of 2.4 to 3.2 mixed with a water-soluble matrix of hydroxyethylcellulose having a viscosity of greater than 25,000 cP at 25° C. and a pH in some cases greater than 6, wherein: a) the gel comprises 3% chloroprocaine hydrochloride; b) the gel has a pH of 2.8 to 3.8; c) matrix viscosity is measured on a Brookfield DV III+Pro Spindle 3 at 20 rpm as described in section 2.2.10 of the European Pharmacopoeia 2016; and d) an ophthalmic gel, wherein the hydroxyethyl cellulose has a weight average molecular weight of 1,000,000 Daltons to 1,500,000 Daltons; or a) 3% chloroprocaine hydrochloride; b) 1.0% to 1.25% hydroxyethylcellulose having a weight average molecular weight of 1,000,000 to 1,500,000 daltons; c) an appropriate amount of hydrochloric acid to a pH of 2.8 to 3.8; and d) water; wherein the ophthalmic gel exhibits non-Newtonian pseudoplastic behavior.

15. The acidic aqueous solution of chloroprocaine hydrochloride has been sterilized by filtration at a temperature above 35°C, and the water-soluble matrix of hydroxyethyl cellulose has been sterilized by heat at a temperature above 35°C, and / or containing 1.04% to 1.14% hydroxyethyl cellulose; The ophthalmic gel according to any one of claims 12 to 14.

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