NZ758853B2

NZ758853B2 - Process for the synthesis of an indoleamine 2,3-dioxygenase inhibitor

Info

Publication number: NZ758853B2
Application number: NZ758795A
Authority: NZ
Inventors: William Frietze; David J Meloni; Yongchun Pan; Ming Tao; Lingkai Weng; Jiacheng Zhou
Original assignee: Incyte Holdings Corporation
Priority date: 2013-11-08
Filing date: 2014-11-07
Publication date: 2022-02-01

Abstract

Provided is an adhesive that has exceptional adhesive performance and effectively utilizes bark. This adhesive includes: (A) at least one adhesive resin selected from the group consisting of phenol resins, urea resins, and melamine resins; and (B) tannin containing ground bark pulverized to the extent that cellulose nanofibers are extracted. nt that cellulose nanofibers are extracted.

Description

ATROPINE PHARMACEUTICAL COMPOSITIONS This application claims priority to a copending US provisional application with serial number 62/505,027, which was ﬁled May 11, 2017.

Field of the Invention The ﬁeld of the invention is pharmaceutical compositions comprising atropine e, ally as it relates to various storage stable, ready-to-use, preservative free compositions, and method of cturing such compositions.

Background The background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication ically or implicitly referenced is prior art.

All publications and patent applications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term ed herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.

Atropine is the tropine ester of tropic acid and is generally available as the e salt. ymatic spontaneous hydrolysis of aqueous atropine yields tropine and tropic acid that are ic but do not have biological ty in ophthalmic use. Stability has been tested, for example, for certain inj ectable formulations and ation was observed over time for in-date and out-of-date formulations (Acad EmergMed April 2004, Vol. 11, No. 4329-334).

Notably, atropine loss was significant in most cases, but less than 25% of the starting concentration. However, these ations included atropine at high concentrations between 0.4 mg/ml and 2 mg/ml and had a very low pH (typically equal or less than pH4 ), which is in most cases unsuitable for ophthalmic use.

In ophthalmic use, atropine is marketed as Atropine Care (Akom) formulated as a 1% drug on for treatment of amblyopia and further contains 0.01% w/w of the preservative benzalkonium chloride. In another indication, atropine has also been used in several pediatric studies to slow down the progression of myopia. More speciﬁcally, children who received topically administered atropine drops had a slower disease progression than a control group in the same study. Advantageously, children receiving eye drops containing low atropine concentrations (e.g., in the range of .05%% w/v (0.01% w/w)) had signiﬁcantly less hobia and other side effects (see eg, Ophthalmology, 2015: 1-9). Indeed, the use of low-dose (l'.e., 0.01%) atropine has become a preferred treatment of choice in slowing the progression of myopia. Unfortunately, the toxic effects of benzalkonium chloride have been demonstrated in the lab and in the clinic, and include tear film instability, loss of goblet cells, conj unctival us metaplasia and apoptosis, disruption of the l epithelium barrier, and damage to deeper ocular tissues (see e.g., Prog Retm Eye Res. 2010 Jul 29(4):312-34).

In still further known itions and methods, atropine formulations are described in that e various buffer ients and water soluble polymers in which most formulations had a pH of about 4.3, 4.5, or 5.0 at an atropine concentration of 0.01% w/w. While such ations were shown to reduce progression of myopia without exacerbating mydriatic action of atropine, stability of atropine as measured by an increase in tropic acid was less than ble within as little as four weeks.

As normal tears have a pH of about 7.4, an ophthalmic solution should have the same pH as the lacrimal ﬂuid. However, this is a challenge for an ophthalmic ons containing atropine sulfate, as atropine sulfate is subjected to a greater degree of hydrolysis in solutions that are closer to neutral and basic pH ions. Thus, atropine is more stable in ophthalmic solutions with a more acidic pH. For example, Atropine Care with a 1% w/w concentration of atropine is maintained at pH 5.5, but the shelf life is still limited to 15 months. Moreover, the degradation of atropine to tropic acid in aqueous solution is notably accelerated with reduced concentrations of atropine (e.g., US 9421199), which still further compounds stability issues, particularly in low-dose atropine formulations.

To reduce hydrolytic degradation, water in low-dose atropine formulations can be at least in part replaced with deuterated (heavy) water as is described in the US 9421199 patent.

While tually attractive to use kinetic e effects in stability, various disadvantages nevertheless remain. Among other things, at least some of the formulations of the ‘ 199 patent still contained a preservative. Moreover, deuterated water is still known to be subject to H/D ge, and as such delivers deuterium to a subject receiving such formulations.

Alternatively, atropine may also be delivered at reduced trations from a cross- linked gradable r matrix as is described in US 2016/0338947. unately, to maintain the polymer away from the cornea, a shaped implant must be worn on the sclera that is typically not well tolerated or may produce discomfort.

Therefore, there is a need for improved storage stable ready-to-use compositions that contain ne at low concentrations, have a physiologically desirable pH, and preferably do not contain a preservative.

Summary of the Invention The inventive subject matter is directed to ready-to-use atropine compositions having improved stability and a physiologically acceptable pH. Most preferably, such compositions are also substantially preservative free.

In one aspect of the inventive subject matter, the inventors contemplate a liquid storage-stable low-dose ophthalmic atropine composition that comprises an aqueous solution comprising a buffer, a tonicity agent, a viscosity modifier, and ne or a pharmaceutically acceptable salt thereof, wherein the atropine or the pharmaceutically acceptable salt thereof is present in the ophthalmic atropine composition in an amount of equal or less than 0.05 wt%, wherein the buffer has a concentration of equal or less than 75mM, and wherein the ophthalmic ne composition has a pH of between 5.0 and 6.0, and wherein the ophthalmic atropine composition is formulated such that after storage over at least two months at 25 0C and 60% relative humidity equal or less than 0.35% tropic acid is formed from degradation of the atropine.

Preferably, atropine or the pharmaceutically acceptable salt thereof is atropine e, and is t in the lmic atropine composition in an amount of equal or less than 0.02 wt%, or in an amount of equal or less than 0.01 wt%, or in an amount of between 0.01% and 0.05 wt%, or in an amount of between 0.001 wt% and 0.01 wt%. Most typically, the buffer has a concentration of equal or less than 60mM, or equal or less than 50mM. It is r contemplated that the buffer comprises monobasic and dibasic sodium phosphate. In r embodiments, the composition will further se a chelator, typically a bicarboxylic acid, a tricarboxylic acid, or an aminopolycarboxylic acid, and the chelator is present in the ophthalmic atropine composition in an amount of equal or less than 0.01w %.

Additionally, it is plated that the ophthalmic atropine ition has a pH of .0 (+/- 0.2), or has a pH of5.5 (+/- 0.2), or has a pH of 6.0 (+/- 0.2). The tonicity agent is preferably a pharmaceutically acceptable salt that is present in the ophthalmic atropine composition in an amount of between 0.2 wt% and 0.8 wt%. In still further embodiments, the viscosity modiﬁer is a modiﬁed ose, and preferably a hydroxyethyl ose, a hydroxypropyl cellulose, or a hydroxypropyl methylcellulose. Moreover, it is lly preferred that the ophthalmic atropine ition is substantially free of a preservative.

Therefore, the inventors also contemplate a liquid storage-stable se ophthalmic atropine composition that consists essentially of an aqueous solution comprising a buffer, a tonicity agent, a chelator, a viscosity modifier, and atropine or a pharmaceutically acceptable salt thereof In such compositions it is preferred that the atropine or the pharmaceutically acceptable salt thereof is present in the ophthalmic atropine composition in an amount of equal or less than 0.05 wt%, that the buffer has a concentration of equal or less than 75mM, and that the lmic atropine composition has a pH of between 5.0 and 6.0. Moreover, such lmic atropine compositions are formulated such that after storage over at least two months at 25 0C and 60% relative ty equal or less than 0.35% tropic acid is formed from degradation of the atropine.

Most typically, the atropine or the pharmaceutically acceptable salt thereof is atropine sulfate, and the atropine or a pharmaceutically acceptable salt thereof is present in the ophthalmic atropine composition in an amount of equal or less than 0.02 wt%, or in an amount of equal or less than 0.01 wt%, or in an amount of between 0.001 wt% and 0.01 wt%.

In some embodiments, the buffer has a concentration of equal or less than 60mM, or has a concentration of equal or less than 50mM. it is further contemplated that the buffer comprises monobasic and c sodium phosphate. The chelator is typically a bicarboxylic acid, a tricarboxylic acid, or an aminopolycarboxylic acid. For example, suitable chelators include ethylenediaminetetraacetic acid (EDTA), lly present in the ophthalmic atropine composition in an amount of equal or less than 0.01 wt%.

In other embodiments, the ophthalmic atropine composition has a pH of n 5.0 (+/- 0.2) and 5.5 (+/- 0.2), or has a pH ofbetween 5.5 (+/- 0.2) and 6.0 (+/- 0.2), and/or the tonicity agent is a pharmaceutically acceptable salt that is present in the ophthalmic atropine composition in an amount of between 0.2 wt% and 0.8 wt%. Suitable viscosity modifiers include a hydroxyethyl cellulose, a ypropyl cellulose, and a hydroxypropyl cellulose. Most lly, the lmic atropine composition is substantially free of a preservative.

For example, contemplated compositions include those in which the atropine or a pharmaceutically acceptable salt thereof is present in the ophthalmic atropine composition in an amount of between 0.001 wt% and 0.01 wt%, wherein the buffer ses sic and dibasic sodium phosphate and has a concentration of equal or less than 50le1, wherein the viscosity modiﬁer is a hydroxyethyl ose, a hydroxypropyl cellulose, or a hydroxypropyl methylcellulose, and wherein the ophthalmic atropine composition is substantially free of a preservative. In other examples, contemplated compositions e those in which the atropine or a pharmaceutically acceptable salt thereof is present in the ophthalmic atropine composition in an amount of between 0.01 wt% and 0.05 wt%, wherein the buffer comprises monobasic and dibasic sodium phosphate and has a concentration of equal or less than 50mM, wherein the ity modiﬁer is a hydroxyethyl cellulose, a hydroxypropyl cellulose, or a hydroxypropyl methylcellulose, and wherein the ophthalmic atropine composition is substantially free of a preservative.

Viewed from a different perspective, the inventors also contemplate a storage-stable preservative-free ophthalmic atropine ition that comprises an aqueous solution sing low-dose atropine or a pharmaceutically acceptable salt thereof, a low-strength buffer, a pharmaceutically acceptable salt, and a cellulosic viscosity modifier, wherein the low-strength buffer has a concentration of equal or less than 50mM, and wherein the low- dose atropine is present at a concentration of equal or less than 0.05 wt%, and wherein the ophthalmic atropine composition is substantially free of a preservative.

For example, the low-dose atropine in such compositions is present at a concentration of equal or less than 0.01 wt%, or is present in the lmic atropine composition in an amount of between 0.01% and 0.02 wt%, or is present in the ophthalmic atropine composition in an amount of between 0.001 wt% and 0.01 wt%. Most typically, the ne or a pharmaceutically acceptable salt f is ne sulfate, and/or the low-strength buffer comprises a first and a second buffer component (6. g. monobasic and dibasic sodium phosphate). Most typically, the ophthalmic atropine composition has a pH of between 5.0 and 6.0, or a pH of n 5.5 (+/- 0.2) and 6.0 (+/- 0.2). Contemplated compositions will typically also include a chelator (e.g., a bicarboxylic acid, a tricarboxylic acid, an aminopolycarboxylic acid) that is preferably present in an amount of 0.01wt% (+/- 20% abs.).

It is further contemplated that the pharmaceutically acceptable salt is present in the ophthalmic atropine ition in an amount of between 0.2 wt% and 0.8 wt%, or in an amount of 0.5 wt% (+/- 0.2 wt%).

Preferred cellulosic viscosity modiﬁers include a hydroxyethyl cellulose, a hydroxypropyl cellulose, or a hydroxypropyl methylcellulose, typically present in an amount of 0.5 wt% (+/- 0.1 wt%) of the ophthalmic ne composition. In preferred embodiments, the ophthalmic atropine composition is formulated such that after e over at least two months at 25 0C and 60% relative humidity equal or less than 0.35% tropic acid is formed from degradation of the atropine.

For example, in contemplated compositions the atropine or a pharmaceutically acceptable salt thereof is present in the ophthalmic atropine ition in an amount of between 0.001 wt% and 0.01 wt%, n the low-strength buffer ses monobasic and dibasic sodium phosphate, and wherein the lmic atropine composition has a pH of between 5.5 (+/- 0.2) and 6.0 (+/- 0.2). In r example, the atropine or a ceutically acceptable salt thereof is t in the ophthalmic atropine composition in contemplated compositions is present in an amount of between 0.001 wt% and 0.01 wt%, wherein the ophthalmic atropine composition r comprises a chelator in an amount of 0.01wt% (+/- % abs.) of the ophthalmic atropine composition, and n the ophthalmic atropine composition has a pH of between 5.5 (+/- 0.2) and 6.0 (+/- 0.2). Alternatively, the low- strength buffer in contemplated compositions comprises monobasic and dibasic sodium phosphate, wherein the ition further comprises a chelator in an amount of 0.01wt% (+/- 20% abs.) of the ophthalmic ne composition, wherein the ophthalmic atropine composition has a pH of n 5.5 (+/- 0.2) and 6.0 (+/- 0.2), wherein the salt is present in the ophthalmic atropine composition in an amount of 0.5 wt% ( +/- 0.2 wt%), and wherein the cellulosic viscosity modifier is present in an amount of 0.5 wt% (+/- 0.1 wt%) of the ophthalmic atropine composition.

In still another aspect of the inventive subject matter, the inventors also contemplate a method of increasing storage stability of atropine in a liquid low-dose ophthalmic formulation. Typical low-doses are between 0.01 wt% and 0.02 wt%, or between 0.001 wt% and 0.01 wt%, or equal or less than 0.01 wt% of the ophthalmic formulation. Preferred methods will include a step of formulating an aqueous solution with a low-strength buffer system that includes a first and second buffer component, wherein the low-strength buffer system has a concentration of equal or less than 75mM buffer, and a further step of including into the aqueous solution a pharmaceutically acceptable salt, a ity modiﬁer, and a or. In still another step, atropine or a pharmaceutically acceptable salt thereof is included into the formulation at a low dose (e.g., equal or less than 0.05 wt% of the ophthalmic formulation), and the pH of the ophthalmic formulation is adjusted to a pH between 5 and 6. Preferably, the ophthalmic formulation is formulated such that after e over at least two months at 25 0C and 60% relative humidity equal or less than 0.35% tropic acid is formed from degradation of the atropine.

For example, the first and second buffer components are monobasic and dibasic sodium phosphate, respectively, and the low-strength buffer system has a concentration of equal or less than 50mM buffer. Additionally, it is contemplated that the pharmaceutically acceptable salt is sodium chloride, typically present in the ophthalmic atropine composition in an amount of 0.5 wt% (+/- 0.2 wt%) of the ophthalmic formulation. Moreover, it is preferred that the chelator is a bicarboxylic acid, a tricarboxylic acid, or an aminopolycarboxylic acid (eg, EDTA), preferably in an amount of 0.01wt% (+/- 20% abs.) of the ophthalmic formulation.

In other embodiments, the viscosity modifier is a osic viscosity modifier, such as a hydroxyethyl cellulose, a hydroxypropyl cellulose, or a hydroxypropyl methylcellulose.

Most typically the cellulosic viscosity modifier is present in an amount of 0.5 wt% (+/- 0.1 wt%) of the ophthalmic formulation. In still further embodiments, the cellulosic viscosity modifier is ed as a separate solution, and combined with the aqueous solution containing the buffer system, the pharmaceutically acceptable salt, the viscosity modifier, the chelator, and the atropine or the pharmaceutically acceptable salt thereof. Where desired, the s solution is formulated using deoxygenated water. Most typically, the pH of the formulation is between 5.5 (+/- 0.2) and 6.0 (+/- 0.2), and the atropine or a pharmaceutically able salt thereof is atropine e. Preferably, contemplated methods also include a step of sterilizing the ophthalmic formulation, and especially sterile filtration. As desired, the ophthalmic ation is then filled into a -use or multi-dose container.

Additionally, the inventors also contemplate a method of preparing a storage stable liquid low-dose atropine ophthalmic formulation that includes the steps of formulating in a first ner a low-strength buffer low-dose atropine solution, and ting the low- th buffer low-dose atropine solution to sterile filtration to obtain a e low-strength buffer low-dose atropine solution, wherein the low-strength buffer has a first and a second buffer component that form a low-strength buffer system having a concentration of equal or less than 75mM in the ophthalmic formulation, wherein the atropine is present in an amount of equal or less than 0.05 wt% of the ophthalmic formulation, and n the low-strength buffer low-dose atropine solution further comprises a tonicity agent and a or. In another step, a polymer solution is formulated in a second container, and the polymer solution is sterilized in a process other than sterile filtration (eg, autoclaving) to so obtain a sterile polymer solution. Most typically, the r on comprises a polymer to modify ity of the low-strength buffer low-dose atropine solution upon ation. In yet another step, the e low-strength buffer low-dose atropine on and the sterile polymer on are combined to obtain a sterile liquid low-dose ophthalmic formulation.

Typically, the first and second buffer components are monobasic and dibasic sodium ate, respectively, and/or the low-strength buffer system has a concentration of equal or less than 50mM buffer in the ophthalmic formulation. The atropine is typically present in an amount of between 0.01 wt% and 0.02 wt%, or between 0.001 wt% and 0.01 wt%, or equal or less than 0.01 wt% of the ophthalmic formulation. Most preferably, the ty agent is a pharmaceutically acceptable salt, typically sodium chloride in an amount of 0.5 wt% (+/- 0.2 wt%) of the ophthalmic ation. Moreover, the chelator is typically a bicarboxylic acid, a tricarboxylic acid, or an aminopolycarboxylic acid (6. g. , EDTA), preferably in an amount of 0.01wt% (+/- 20% abs.) of the ophthalmic formulation.

It is still further contemplated that the polymer is a cellulosic polymer, and especially a hydroxyethyl cellulose, a hydroxypropyl cellulose, or a hydroxypropyl methylcellulose.

Preferably, the cellulosic polymer is present in an amount of 0.5 wt% (+/- 0.1 wt%) of the ophthalmic formulation, and/or the pH of the rength buffer low-dose atropine on is adjusted to a pH between 5 and 6, or between 5.5 (+/- 0.2) and 6.0 (+/- 0.2).

In further embodiments, the step of combining comprises mixing the sterile low- th buffer low-dose atropine solution and the sterile polymer solution for at least 30 minutes, and optionally further comprises a step of filling the ophthalmic formulation into a multi-dose container. Preferably, the ophthalmic formulation is formulated such that after storage over at least two months at 25 0C and 60% relative humidity equal or less than 0.35% tropic acid is formed from degradation of the atropine. 2018/032017 Consequently, the inventors also contemplate a treatment kit for treatment of myopia that includes a ﬁrst container that contains a liquid storage-stable low-dose atropine lmic formulation, wherein the ﬁrst container is conﬁgured as a disposable single-use container or a dose container, and a second container enclosing the ﬁrst container, wherein the liquid storage-stable low-dose atropine ophthalmic formulation comprises an aqueous solution comprising a buffer, a tonicity agent, a viscosity modiﬁer, and atropine or a pharmaceutically acceptable salt thereof, wherein the atropine or the pharmaceutically able salt thereof is present in the ophthalmic atropine ition in an amount of equal or less than 0.05 wt%, wherein the buffer has a concentration of equal or less than 75mM, and wherein the ophthalmic atropine composition has a pH of between 5.0 and 6.0, and wherein the ophthalmic atropine composition is formulated such that after storage over at least two months at 25 0C and 60% relative humidity equal or less than 0.35% tropic acid is formed from degradation of the atropine.

For example, in some embodiments, the ﬁrst container is a ll-seal (BSF) container and/or the second container is a laminated metallized pouch. In other embodiments, the atropine or pharmaceutically acceptable salt thereof is present in the ophthalmic atropine composition in an amount of equal or less than 0.01 wt%, or in an amount of between 0.01 wt% and 0.05 wt%, or in an amount of n 0.001 wt% and 0.01 wt%. Most preferably, the buffer has a concentration of equal or less than 75mM, or equal or less than 50mM. For example, preferred buffers comprise monobasic and dibasic sodium phosphate, and may further comprise a chelator (eg, a bicarboxylic acid, a tricarboxylic acid, or an aminopolycarboxylic acid such as EDTA) that is present in the ophthalmic atropine composition in an amount of equal or less than 0.01 wt%.

Most typically, the ophthalmic ne ition has a pH of 5.0 (+/- 0.2), or a pH of 5.5 (+/- 0.2), or a pH of 6.0 (+/- 0.2), and it is further contemplated that the tonicity agent is a pharmaceutically able salt that is present in the ophthalmic atropine ition in an amount of between 0.2 wt% and 0.8 wt%. Preferred viscosity modiﬁers are modiﬁed celluloses such as a hydroxyethyl ose, a hydroxypropyl cellulose, or a ypropyl methylcellulose. Still r, it is preferred that the ophthalmic atropine composition is substantially free of a preservative.

Various objects, features, aspects and advantages of the inventive subject matter will become more apparent from the following detailed ption of preferred embodiments.

Brief Description of the Drawing Figure 1 depicts an exemplary production s for the storage stable and low-dose atropine ophthalmic formulation. ed Description of the ion The inventive subject matter is directed to stable aqueous ophthalmic compositions of atropine (and pharmaceutically acceptable salts thereof) in a ready-to-use form that are sterile and preferably substantially free of preservatives. The stability of contemplated compositions is characterized by low ation of atropine to tropic acid at low atropine concentrations, as well as by a physiologically desirable pH. For example, liquid and storage-stable low-dose ophthalmic atropine compositions will typically have stability upon e over at least two months at 25 0C and 60% relative humidity such that equal or less than 0.35% tropic acid is formed by the degradation of atropine in the formulation. Most ably, the compositions are also free of preservatives, and particularly benzalkonium chloride that is commonly used as a preservative. Such stability is particularly unexpected where the atropine concentration in the lmic composition is relatively low (e.g., 0.02 wt%) and where the composition has a relatively high pH (e.g., between 5.0 and 6.0) as it was generally known that ne stability decreases at decreasing concentrations and increasing pH.

While not wishing to be bound by any particular theory or hypothesis, the inventors contemplate that low buffer strength using a two-component buffer system at a pH near to a neutral pH (such as pH 5.0-6.0) reduces hydrolysis of atropine to tropic acid where atropine concentrations are relatively low (e.g., equal or less than 0.05 wt%, or equal or less than 0.02 wt%, or equal or less than 0.01 wt%). Unless indicated otherwise, all percentages are weight percentages (wt%) or expressed as weight by volume (w/V). Moreover, it is noted that weight percentages of atropine sulfate provided herein are based on atropine sulfate monohydrate.

More specifically, and as is described in more detail below, the inventors discovered that low-dose ophthalmic atropine compositions can be ed with atropine in a ready-to- use tration (e.g., for treatment of myopia) that have a near-physiological pH, and that preferably lack any preservative in the ation. Surprisingly, the storage stability at two months at 25 0C and 60% RH of the ophthalmic compositions presented herein is remarkably high, with tropic acid formation from atropine hydrolysis in most cases at or below 0.35%, at or below 0.30%, or at or below 0.28%. rly, contemplated formulations at accelerated storage ions over two months at 40 0C and 75% RH also exhibited an equally favorable proﬁle with tropic acid formation in most cases at or below 1.7%, at or below 1.5%, at or below 1.3%, or at or below 1.2%.

Therefore, contemplated atropine formulations of the inventive subject matter can be advantageously provided in a ready-to-use format that avoids the inconvenience associated with diluting concentrated atropine formulations into diluents prior to stration. Thus, the ready-to-use formulations also eliminate microbial contamination risks and/or calculation errors associated with dilution. Most typically, plated formulations will be available in a range of concentrations commonly required by medical practitioners for treatment of myopia, and particularly pediatric myopia. Consequently, atropine will typically be present in formulations in an amount of equal or less than 0.05 wt%, or in an amount of equal or less than 0.02 wt%, or in an amount of equal or less than 0.01 wt%. For example, the atropine or a pharmaceutically acceptable salt thereof may be present in the ophthalmic composition in an amount of between 0.01% and 0.05 wt%, between 0.001 wt% and 0.02 wt%, or between 0.001 wt% and 0.01 wt%. As will be readily iated, atropine for the preparation of contemplated formulations may be atropine or any le pharmaceutically acceptable salt thereof, including mineral salts (e.g., HCl salt) and organic salts (e.g., sulfate). Similarly, where desired, the atropine may also be used in any suitable prodrug form.

For e, in one exemplary embodiment, the concentration of atropine in plated atropine ations is from about 0.001% to about 0.05% (w/w), or from about 0.005% to about 0.045% (w/w), or from about 0.006% to about 0.035% (w/w), or from about 0.007% to about 0.030% (w/w), or from about 0.008% to about 0.025% (w/w), or from about 0.009% to about 0.022% (w/w), or from about 0.01% to about 0.021% (w/w) or from about 0.01% to about 0.02% (w/w).

In another exemplary embodiment, the tration of atropine in contemplated atropine formulations is from about 0.001% to about 0.05% (w/w), or from about 0.005% to about 0.045% (w/w), or from about 0.006% to about 0.035% (w/w), or from about 0.007% to about 0.030% (w/w), or from about 0.008% to about 0.025% (w/w), or from about 0.009% to about 0.022% (w/w), or from about 0.01% to about 0.021% (w/w) or from about 0.01% to about 0.02% (w/w). id="p-18" id="p-18" id="p-18" id="p-18" id="p-18" id="p-18" id="p-18" id="p-18" id="p-18" id="p-18" id="p-18" id="p-18" id="p-18"

[0018] In still an exemplary embodiment, the concentration of atropine in contemplated ne formulations is about 0.001%, or about 0.002%, or about , or about 0.004%, or about 0.005%, or about 0.006%, or about 0.007%, or about 0.008%, or about 0.009%, or about 0.01%, or about 0.011%, or about 0.012%, or about 0.013%, or about 0.014%, or about 0.015%, or about 0.016%, or about 0.017%, or about 0.018%, or about 0.019%, or about 0.02%, or about 0.021%, or about 0.022%, or about 0.023%, or about 0.024%, or about 0.025%, or about 0.026%, or about 0.027%, or about 0.028%, or about 0.029%, or about 0.030%, or about 0.031%, or about 0.032%, or about 0.033%, or about 0.034%, or about 0.035%, or about 0.036%, or about 0.037%, or about , or about 0.039%, or about 0.040%, or about 0.041%, or about 0.042%, or about 0.043%, or about 0.044%, or about 0.045%, or about 0.046%, or about , or about 0.048%, or about 0.049% or about 0.0499% (w/w).

In yet an exemplary embodiment, the concentration of atropine in contemplated atropine formulations is about 0.001%, or 0.002%, or 0.003%, or , or 0.005%, or 0.006%, or 0.007%, or 0.008%, or 0.009%, or 0.01 %, or 0.011%, or 0.012%, or 0.013%, or 0.014%, or 0.015%, or 0.016%, or 0.017%, or 0.018%, or 0.019%, or 0.02%, or 0.021%, or 0.022%, or , or , or , or 0.026%, or 0.027%, or 0.028%, or 0.029%, or 0.030%, or 0.031%, or 0.032%, or 0.033%, or 0.034%, or 0.035%, or , or 0.037%, or 0.038%, or 0.039%, or 0.040%, or 0.041%, or 0.042%, or 0.043%, or 0.044%, or 0.045%, or 0.046%, or 0.047%, or 0.048%, or 0.049% or 0.0499% (w/w).

In further exemplary embodiments, the concentration of atropine in contemplated atropine formulations is from about 0.005% to about 0.015% (w/w), or from about 0.015% to about 0.025% (w/w), or about 0.01% (w/w), or about 0.02% (w/w), or from 0.005% to 0.015% (w/w), or from 0.015% to 0.025% (w/w), or 0.01% (w/w), or 0.02% (w/w), or from about 0.001% (w/w) to about 0.01% (w/w), or from about 0.005% (w/w) to about 0.02% (w/w), or from about 0.008% (w/w) to about 0.012% (w/w).

Suitable buffers are generally buffers that stabilize the pH of the plated liquid formulations in a eutral pH range, for example n pH 4.0 and 7.5, or between pH 4.5 and 6.5, and more preferably between pH 5.0 and 6.0. Therefore, and most typically the pH of contemplated formulations will be equal or less than 6.5 and more typically equal or less than 6.0, and most typically less than 5.8, but higher than 4.5, more typically higher than .0, and most typically higher than 5.2. For example, suitable atropine itions may have a pH of5.0 (+/- 0.2), or a pH of5.5 (+/- 0.2), or a pH of 6.0 (+/- 0.2).

In r aspects of the inventive t matter, the inventors discovered that the buffer system and/or buffer may have an unexpected inﬂuence on atropine stability as is discussed in more detail below. Most notably, once the buffer concentration was adjusted to 75 mM or less at a pH of between 5.0-6.0, the stability of the atropine dramatically increased at normal and accelerated storage conditions as determined by HPLC quantiﬁcation of tropic acid that is a byproduct of atropine ysis. While not limiting to the ive subject matter, the buffer strength is typically relatively low, for example, equal or less than 100 mM, equal or less than 75 mM, equal or less than 60 mM, equal or less than 50 mM, or between 5 mM and 50 mM (e.g., 10 mM, 20mM, 30mM, 40 HM).

Therefore, in exemplary embodiments, the buffering system is in the pharmaceutical composition in a concentration of from about 10 mM to about 75 mM, or from about 10 mM to about 60 mM, or from about 0.1 mM to about 60 mM, or from about 0.1 mM to about 55 mM, or from about 0.1 mM to about 50 mM, or from about 5 mM to about 60 mM, or from about 0.1 mM to about 10 mM, or from about 1 mM to about 10 mM, or from about 9 mM to about 20 mM, or from about 15 mM to about 25 mM, or from about 19 mM to about 29 mM, or from about 24 mM to about 34 mM, or from about 29 mM to about 39 mM, or from about 34 mM to about 44 mM, or from about 39 mM to about 49 mM, or from about 44 mM to about 54 mM, or from about 19 mM to about 54 mM, or from about 25 mM to about 54 mM.

Of course, it should be appreciated that there are many types of buffer systems and buffers known in the art, and all of those are deemed suitable for use herein, including buffer systems comprising an acid and a salt of the acid, a ﬁrst and a second salt (eg, monobasic and dibasic salt), and amphoteric buffer molecules. For e, le buffer s with an acid and a salt of the acid include citric acid/sodium citrate buffers, ethanoic acid/sodium ethanoate buffers, boric acid/sodium borate, while suitable buffers having a ﬁrst and a second salt include monobasic sodium phosphate/dibasic sodium phosphate, or monobasic sodium phosphate/sodium citrate, etc. Similarly, suitable amphoteric bugffer les include HEPES, MOPS, PIPES, MES, etc.

Moreover, in further contemplated aspects, the formulation will also include one or more chelating agents, and particularly metal ion chelators. For example, suitable chelators include various bicarboxylic acids, tricarboxylic acids, and aminopolycarboxylic acids such as ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis(B-aminoethyl ether)- N,N,N',N'—tetraacetic acid (EGTA), and penta(carboxymethyl)diethylenetriamine (DTPA), and salts and hydrates thereof. While not limiting to the inventive t matter, it is contemplated that the metal ion chelators will slow down both the baseline and metal ion- stimulated hydrolysis of atropine. Remarkably, the inventors unexpectedly observed that the desirable effect of the chelators was observable at relatively low concentrations of the chelators. For example, reduction of the baseline and metal ion-stimulated hydrolysis of atropine was observed at chelator concentrations of between 10 ug/ml and 50 ug/ml, between 50 ug/ml and 250 ug/ml, and between 100 ug/ml and 500 ug/ml. Viewed form a different perspective, chelator concentrations of equal or less than 0.03 wt%, or equal or less than 0.02 wt%, or equal or less than 0.01 wt% are especially advantageous. Interestingly, the ors, and especially the aminopolycarboxylic acids retained stabilizing effect at low trations despite the relatively low pH favoring protonated forms of the chelators.

Consequently, suitable chelating agents include monomeric polyacids such as EDTA, exanediamine tetraacetic acid (CDTA), hydroxyethylethylenediamine triacetic acid (HEDTA), diethylenetriamine pentaacetic acid (DTPA), dimercaptopropane sulfonic acid (DMPS), dimercaptosuccmic acid (DMSA), aminotrimethylene phosphonic acid , citric acid, ophthalmologically acceptable salts f, and combinations of any of the foregoing. Further suitable chelating agents include pyrophosphates, tripolyphosphates, and, hexametaphosphates, chelating otics such as chloroquine and tetracycline, nitrogen- containing ing agent containing two or more ing nitrogen atoms within an imino group or in an ic ring (e.g., diimines, 2,2'-bipyridines, etc.), and various ines such as cyclam (1,4,7,11-tetraazacyclotetradecane), N—(Cl-C30 —substituted cyclams (e.g., hexadecyclam, tetramethylhexadecylcyclam), diethylenetriamine (DETA), ne, diethylnorspermine (DENSPM), diethylhomo-spermine (DEHOP), and deferoxamine (N'-[5- [[4-[[5-(acetylhydroxyamino)pentyl]amino]-l,4-dioxobutyl]hydroxy-amino]pentyl]-N'-(5- aminopentyl)-N-hydroxybutanediamide, also known as rioxamine B and DFO).

With respect to suitable salts it is plated that the salt is a pharmaceutically acceptable salt that can be used to increase tonicity. Therefore, pharmaceutically acceptable salts are contemplated, and especially NaCl, at a concentration of at least 0.2 wt%, or at least 0.4 wt%, or at least 0.5 wt%, or at least 0.7 wt%. For example, suitable salt concentrations are between 0.2 wt% and 1.1 wt%, 0.4 wt% and 0.9 wt%, or 0.3 wt% and 0.7 wt%. ing on the particular salt concentration, additional tonicity agents may be added and le ty agents include glycerol, ycerol, mannitol, lactose, and dextrose. The amount of tonicity adjusting agent used can be adjusted to obtain osmolality of the formulations in the range of 260 to 340 mOsm/kg. An osmometer can be used to check and adjust the amount of tonicity adjusting agent to be added to obtain the desired osmolality.

As contemplated formulations are used as an ophthalmic formulation, it is lly preferred that the formulation also includes a viscosity modifier to adjust the viscosity of the formulation to a dynamic viscosity of between 5 and 50 cP (centipoise), and more preferably between 10 and 40 CF, and most preferably n 10 to 30 CF. While there are numerous viscosity modifiers known in the art such as various polymers, glycerol, and polysaccharidic polymers (all of which are contemplated herein), especially preferred viscosity modifiers include cellulosic ity modifiers. For example, particularly preferred cellulosic viscosity modifiers include modified and unmodified hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose.

As will be readily appreciated, the exact quantity of the viscosity modifier may vary depending on the type of modifier used and d final viscosity. For example, where the ity modifier is a cellulosic modifier and the final viscosity should be between 1 and 30 CF, suitable ties of the modifier will typically be in the range of 0.5 wt% (+/- 0.1 wt%) of the ophthalmic ne composition. The person of ordinary skill will be readily able to adjust the ity to a desired measure using viscometers (e.g., rotational, vibration, etc.) well known in the art.

In exemplary embodiments, suitable concentrations of the viscosity modifier in contemplated ophthalmic formulations may be any value less than 5% (w/w). For example, suitable concentrations of the viscosity modifier include 0.01% to 4.99% (w/w), or 0.05% to 4.50% (w/w), 0.10% to 3.50% (w/w), 0.15% to 3.00% (w/w), 0.20% to 2.50% (w/w), 0.21% to 2.20% (w/w), 0.22% to 2.10% (w/w), 0.23% to 2.00% (w/w), 0.24% to 1.90% (w/w), 0.25% to 1.80% (w/w), 0.26% to 1.70% (w/w), 0.27% to 1.60% (w/w), 0.28% to 1.50% (w/w), 0.29% to 1.40% (w/w), 0.30% to 1.30% (w/w), 0.31% to 1.2% (w/w), 0.32% to 1.10% (w/w), 0.33% to 1.00% (w/w), 0.34% to 0.90% (w/w), 0.35% to 0.80% (w/w), 0.36% to 0.75% (w/w), 0.37% to 0.70% (w/w), 0.38% to 0.69% (w/w), 0.39% to 0.68% (w/w), 0.40% to 0.67% (w/w), 0.41% to 0.66% (w/w), 0.42% to 0.65% (w/w), 0.43% to 0.64% (w/w), 0.44% to 0.63% (w/w), 0.45% to 0.62% (w/w), 0.45% to 0.61% (w/w), 0.45% to 0.60% (w/w), 0.45% to 0.59% (w/w), 0.45% to 0.58% (w/w), 0.45% to 0.57% (w/w), 0.45% to 0.56% (w/w), 0.45% to 0.55% (w/w), 0.46% to 0.54% (w/w), 0.47% to 0.53% (w/w), 0.48% to 0.52% (w/w) or 0.49% to 0.51% (w/w).

Therefore, appropriate concentrations of the viscosity modiﬁer in plated ophthalmic formulations include 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%,0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.40%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, 0.50%, 0.51 %, 0.52%, 0.53%, 0.54%, 0.55%, 0.56%, 0.57%, 0.58%, 0.59%, 0.60 %, 0.61%, 0.62%, 0.63%, 0.64%, 0.65%, 0.66%, 0.67%, 0.68%, 0.69%, 0.70%, 0.71%, 0.72%, 0.73%, 0.74%, 0.75%, 0.76%, 0.77%, 0.78%, 0.79%, 0.80%, 0.81%, 0.82%, 0.83%, 0.84%, 0.85%, 0.86%, 0.87%, 0.88%, 0.89%, 0.90%, 0.91%, 0.92%, 0.93%, 0.94%, 0.95%, 0.96%, 0.97%, 0.98%, 0.99%, 1.00%, 1.10%, 1.20%, 1.30%, 1.40%, 1.50%, 1.60%, 1.70%, 1.80%, 1.90%, 2.00%, 2.10%, 2.20%, 2.30%, 2.40%, 2.50%, 2.60%, 2.70%, 2.80%, 2.90%, 3.00%, 3.10%, 3.20%, 3.30%, 3.40%, 3.50%, 3.60%, 3.70%, 3.80%, 3.90%, 4.00%, 4.10%, 4.20%, 4.30%, 4.40%, 4.50%, 4.60%, 4.70%, 4.80%, 4.90% and 4.99% (w/w).

It should further be appreciated that contemplated compositions are substantially free of preservatives (i.€., preservatives not more than 0.01 wt%, and more typically not more than 0.005 wt%). For example, preservatives that are typically not included are benzalkonium chloride, cetrimide or cetrimonium chloride or bromide, benzododecinium bromide, ne, cetylpyridinium chloride, polidronium chloride or polyquatemium—l, polyquatemium—42 (also known as polixetonium), sepazonium chloride, mercurial derivatives such as the phenylmercury salts te, borate or nitrate), mercuriothiolate sodium (otherwise called thiomersal or osal) and mercurobutol, amidines such as chlorhexidine digluconate or polyhexamethylene ide (PHMB), alcohols such as chlorobutanol or phenylethanol or benzyl alcohol or phenol or m-cresol or phenoxyethanol, parabens or esters such as parahydroxybenzoic acid, methylparaben, and propylparaben).

Indeed, the inventors ctedly discovered that the formulations without preservatives had the same stability as with preservatives. 2018/032017 With respect to the sterilization of contemplated formulations it should be appreciated that contemplated formulations may be sterilized using all known manners of sterilization, including ﬁltration through 0.22 micron filters, heat sterilization, autoclaving, radiation (6. g., gamma, electron beam, microwave). Advantageously, and as is shown in more detail below, the inventors have also ered that contemplated formulations can be compounded from two batches in which the viscosity agent is separately sterilized using high-pressure saturated steam at 121 0C (for at least 5, or at least 10, or at least 15 minutes) from the atropine, buffer, and salt solution that was independently filter sterilized.

For example, in one preferred aspect of the inventive subject matter as depicted in the Figure, the production of the ophthalmic solution is performed using two distinct tion tracks in which the viscosity modifier solution is tely prepared and sterilized from the drug solution. Most notably, such s d for rapid and complete dissolution of the atropine, tonicity, buffer components, and chelator, while also enabling a sterilization process that reduces or even entirely eliminates thermal hydrolysis of atropine. Upon preparation of the sterile atropine solution, that solution can then be combined with the viscosity modifier solution that was also sterilized. While conceptually sterilizable using filter sterilization as was the case with the atropine solution, heat sterilization using an autoclave was found to help fully dissolve the viscosity modifier and render the viscous solution y mixable with the drug solution. Viewed from a different perspective, it should ore be appreciated that the separate preparation and sterilization process avoided various difficulties that would be otherwise associated with single batch ation, including increased mixing time of the component to dissolve buffer, tonicity agent, and or at increased ion, increased e filtration time due to higher viscosity, etc.

Based on the so achieved stability, the combined solutions contemplated herein can be further filtered through a particle filter (e.g., 40 micron opylene filter), and filled in to a polyethylene, polypropylene or low-density polyethylene containers using preformed ners in single-use format or dose format, or using a blow-fill-seal (BFS) s.

BFS is a form of advanced c manufacturing wherein the container is formed, filled, and sealed in one continuous, automated system not requiring human intervention. The process begins with the extrusion of plastic granules in the form of a hot hollow pipe of molten plastic called a parison. The next step is the blow molding of the container with an open top through which the container is filled, all while the plastic remains hot and in a molten state.

Once filled, the container is hermetically sealed and cooled. The blow-fill seal process can take several seconds, and contemplated ready-to-inj ect compositions advantageously are formulated to withstand the ature and pressure requirements without substantial degradation of atropine (e.g., less than 5 wt%, less than 3 wt%, less than 2 wt%, less than 1 wt% degradation).

Once the atropine formulations are ﬁlled in large volume polymeric, semi-permeable infusion containers (e.g., BFS container, typically 1.0mL BFS ampoules), the containers can optionally be layered or covered with a secondary packaging system including an aluminum pouch.

The following examples are ed for illustrative purposes only and should not be interpreted as limiting the present invention.

Examples The following examples illustrate some of the experiments leading to the ations according to the inventive subject matter, however, should not be construed to limit the scope of the claims in any way.

Quantitative Analyses: A combined test method based on Ultra Performance Liquid Chromatography (UPLC) was developed to m identification, assay and determination of related compounds in a single run. This was accomplished by using a reversed-phase gradient UPLC with the UV detection including on-line acquisition of UV absorption spectra. Octadecylsilyl- onalized silica with sub-2 um particles was used as a stationary phase for chromatographic analysis. The mobile phase is ed by mixing an aqueous buffer solution with an acidic pH and an acetonitrile-water mixture. Quantification of the active ingredient and related compounds is performed by comparing ponding peak responses from a Sample on to the atropine peak response from a Standard solution. Relative response factors are used to correct for al structure s on the responses. Two identification methods are incorporated into this test . Atropine is identified based on the retention time of the major peak in the Sample Solution chromatogram and on the UV absorption spectrum acquired within this peak.

Exemplaﬂ Formulations And Stabiliﬂ Tests: Ophthalmic ready-to-use low-dose ne formulations were prepared using a two- step process substantially as shown in Figure 1.

Step 1- Preparation of the Polymer Solution Phase: To about 60% of WFI the required quantity ofHPMC was added slowly and mixed until a clear solution was observed. The solution was then subjected to aving at 121°C for a period of about 30 min.

Step 2 — Preparation of the Drug Solution Phase: To about 30% ofWFI the required quantities of disodium edetate, monobasic sodium phosphate, dibasic sodium phosphate and sodium chloride were added sequentially upon complete dissolution of each ingredient. The pH of the solution was measured and adjusted to about 5.5::01 using hydrochloric acid/ sodium hydroxide. To the above solution atropine sulfate was added and mixed until there was complete ution.

The Drug Solution from Step 2 was then mixed with the Polymer Solution in Step 1.

The batch volume was made up using WFI to yield the pharmaceutical composition. Tables 1-3 provide exemplary formulations with and without tonicity agent, with EDTA and low EDTA, and at g buffer ths. 100mM Buffer Composition 100mM Buffer Composition Ingredient (Low EDTA) Atropine Sulfate _"mmPhosphateAnhydrous Phosphate Anhydrous -————— I() ----Hypromellose 2910 0.50 0.50 0.50 0.50 m Sodium Hydroxide (1.5. for pH adjustment (1.5. for pH adjustment a Water for Injection (1.5. to 100% (1.5. to 100% Table 1 75mM Buffer No Buffer Ingredient Composition with Composition NaCl With NaCl 2 Sodium Dihydrogen 0.044 0.04 Phosphate Anhydrous I_----Phosphate -————— -————m Hypromellose 2910 0.5 0.5 0.5 0.5 (BenecelTM E4M Pharml) Hydrochloric Acid (1.5. for pH adjustment (1.5. for pH adjustment m Sodium Hydroxide (1.5. for pH adjustment (1.5. for pH ment a Water for Injection (1.5. to 100% (1.5. to 100% Table 2 50mM Buffer 50mM Buffer 50mM Buffer Ingredient Composition Composition Composition without NaCl with NaCl with NaCl, low EDTA 2 Sodium Dihydrogen 0.0295 0.03 0.0295 0.03 0.0295 0.03 Phosphate Disodium Hydrogen 0.575 0.58 0.575 0.58 Phosphate Anhydrous 0-1 0-1 0-01 — 0-25 0-25 Hypromellose 2910 0.5 0.5 0.5 0.5 0.5 (Benecelm' E4M 7 Hydrochloric Acid (1.5. for pH adjustment (1.5. for pH adjustment (1.5. for pH adjustment m Sodium Hydroxide (1.5 for pH adjustment (1.5. for pH adjustment (1.5. for pH adjustment Water for Injection (1.5. to 100% (1.5. to 100% (1.5. to 100% Table 3 Unless otherwise indicated, pharmaceutical itions of Table 3 (50mM Buffer Composition with NaCl) were subjected to long term stability s. Lab scale batches of atropine sulfate ophthalmic solution were manufactured, (approx. 0.4 mL) ﬁlled into 1 mL Blow-Fill-Seal (BFS) ampoules, and were further packaged in aluminum pouches. A number of pouched ampoules were subjected to long term stability studies at 25°C :: 2°C / 60% :: 5% RH as per the International Committee on Harmonization stability conditions (see URL: ich.org). Pouched ampoules ted to these long term stability studies were ted after 1 week, 2 weeks, 3 weeks, 1 month, 2 months, and 3 months of stability storage, opened, and tested for levels of atropine sulfate, tropic acid, pH (where applicable) and Viscosity (where applicable). Atropine and tropic acid levels were ed using the UPLC method, and the results are shown in Tables 4-8. ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, i i y 100mM buffered compositions \ Sample Test Parameter \ Long term Stability (2\5°C / 60% RH) \ Information; Initial 1 § 2 3 1 2 3 S s s S s S s S L i week {weeks weeks gmonth §months§months§ i ~ \ x x \ '8 I 5.52 5.55 5.55 5.51 5.53 5.66 5.58 ‘ \ \ HroplcaCId(RRTO.88) ~ \ x \ \ . . ND 0.1 0.13 0.19 0.22 0.42 0.71 xx""""""""""""§xx"xxxxxxxxx"xxxxxxxxx"xxxxxxx"""\""""""""\\""""""""""\ """"\ """\"""""\\"""""""""\ """"""""§""""""""\ ""\""""" sAssay ofAtropine Sulfate ‘ : 104.2 103.4 103.3 103.2 101.3 102.4 plcaCId(RRTO.88) ND 0.07 0.08 0.12 0.15 0.30 - i \ x \ :lAssayo AtropineSu ate : 98.7 E 98 98.1 98 - PH555540\541542543,,,,,/,,,,,,/,,,,,,,,,"ﬂu/A,,,,,,,,,,,,,,A,,,,,/,,, E :\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\‘¢\\\\\\\\\\\\\\\\\\\\‘P\\\\\\\\\\\\\\\\\\\\‘P"\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\‘?\\\\\\\\\\\\\\\\V‘AAAAAAAAAAunnnnmvnnnnnnnnnnnnnnndﬁ E E E E \ E E E E E \ \ \ \ . . : E t § E {TropIc aCICl (RRT 0.88) ND ND E 0.07 0.09 0.12 - - E\‘mmmmmmm§‘\""‘\"‘"""‘\""‘\""7"‘"m"mmmm‘E\"‘"""‘\""‘\"E"""\""‘\"""‘§\"""""mm\i""‘\"‘""""‘\:\m""""m"§"\"‘"‘"m"gxmmmmE 98.2 97. 3 97.7 97.7 97.1 - - E Assay of Atropine Sulfate i E i E\""""""""""""""""""""""""""""§""""""""""\ """"\ """"""‘""‘§""""""""" """"""""E""""""""\ """"""""E \ ~ \ N \ \ EpH L 5.55 5.40 E 5.40 E 5.41 5.42 E - - Low EDTA E """"\\\""""\\\""""\\"""""""\""""\ \\\""""\\\""\\~\""""""""\"\"""""""""\ "\"\\\"""""~""""""""\ """\~\\\\\\\\\\\\\\\\\ i _ \ \ x \ \ , , E E E E‘I’ropIc aCICl (RRT 0.88) E ND ND E 0.31 0.1 0.12 - Table 4 l,,,,,,,,,,,,,,,,,,,,,,,,,,lll,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,.\\\\\\\\\\\\\\\\\\\\\\\\\\\‘\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\‘r\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\‘75mM buffered with NaCl CompositionsSample Test Parameter ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, ,,,,,,,,,,¢,,,,,,,, Long term Stability (25°C / 60% RH) Information Initial \\\\\\\\\\\\\\\\\\\\\\\\\\\\\‘\\\\\\\‘AAAAAAAgAAAAAAAAAAAAAA5"\\\\\\\\\\\\\‘\\\\\\\\\\\\\\\‘¢\\\\\\\\\\\\\\\\ 2 3 1 2 3 1 week EweeksE onthimonthsE E \\\\\\\\\\\\\\\\\\\\\\\\\\\:\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\ x"xxxxxxxxx"xxxxxx\\x"xxxxxxxxx"xxxxxxxxx"xxxxExxxx"xx"""\\"\"""""\E"""""""\:\"""\""""\\"""""\""i/" ‘Assay of Atropine Sulfate 102.4 101.9 101.7 101.5 101.3 101.0 - i i i \\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\s\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\ ‘\"\"\"m"\\mmmm\ mmmm" \m‘mmm‘" "m""mm/;;;;;;" ipH i i 28 ,,,/,,,,,,,,,, E i E _ . .

ETropIcaCId(RRT0.88) ND 0.05 0.08 0.1 0.15 0.33 i i i E E ,, i E i \\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\:‘\\\\\\\\\\\\\\\\\\\\\ \\\\\\\\\\\\\\\\\\\\\\\\\\\\\\ \\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\.

Table 5 ,11,1,,1,1,,1,1,11,11,11111111114""""""""""""""""""""""""""""""""""""""‘""""""""""""‘r""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""‘\50mM buffered Without NaClCompositionsSample Test Parameter ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,\\\\\\\\\\\\\\\\\\\\\\‘§\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\Long term Stability (25°C/ 60% RH) InformatIon Initial ‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘‘""""""""""""¢‘‘‘‘‘‘‘"""""""""""" 1 2 3 1 2 3 week EweeksE weeks: monthimonthsEmonths E ‘\""\""\""\""\"‘\\t"‘\""\""\""\""\""\""\""\""\""\‘"‘\""\""\""\""\ ""\""\""\""\" \""\""\""\"\§\""\""\"\g\""\""\"\§\""\""\"‘\‘\""\""\"‘{\""\""\"" E ‘ E §Assay of Atropine Sulfate 96. 8 96.9 E97.2E918‘ 97.9 96.9 97.6 E = E Em‘\m"""m\m"""m\m"""m\m"""m\m"""m\m\\""\"\m"""m\m"""""""""\"""""\"\""m‘m"I(1,1,41,11,1111111,,,,,, "xmm"""m‘mm‘m‘m" i i E .32 E E \E i E E E H i 5.38 E E 5.23 E - E - i - : 5.38 E :\\x"x"x"x"x"x"x"x"x"x"x"x"x"x"x"x"x"x"x"x"x"x"x"\"§""""""""""" \ x"x"x""""""‘~\"""""\"~\x"x"x"x""~\x"x"x"x""§x"x"x""""1\""""""" E i i E E E E i = E ~ i E E E E x E c aCId(RRTO.88). . ND 0.1 0.1 0.1 0.12 0.23 0.36 i E \ E \ E E \ K AIIIIIIIIIIIIl1IIIIIIIIIIIII(m1IIIII(II/(IIIIIIIIIIIIIIIIIII iAssa ofAtro IneSulfate i i i E i \ m} iH i 5.44 5.40 i5.32i E - ELow EDTA E E E\ i E E i i E E E E i E - E ETropic acid (RRTO.88) ND ND ND 0.07 0.09 - Exxxx"xx""xxxxx"xx""xx5‘"xx""xxxxx"xx""xxxxx"xx""xxxxx"xx""xx"mm"‘m‘m‘m‘E"xxx"xx""xxxxx""\"m‘m‘m‘mm "mm"‘m "xxxx""\"E‘m‘m‘mmExx"xx"""""\\"""m"m\ Table 6 \\\\\\\\\\\\\\\\\\\\\\\\\\\\}\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\V V"""’""’""’""’""’""’""’""’""’""’""’""’""’"""""""""""" 50mM buffered with NaCl Compositions Sample \\\\\\\\\\\\\\\\\p"\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\ . Test Parameter InformatIon ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, (1,1,11,71,11111 Long term Stability (25°C/ 60% RH) Initial ‘"‘\""\""\‘Et‘\""\""\""\""\""\"‘x\""\""\""\¢"‘\""\""\" 1 2 3 1 2 3 EweekE weeks§ weeksE monthimonthsE monthsE,,,,,,,,,,,,,,,,,1,,,,,,,,,,,,, """"‘"""‘"""‘""E""""‘"""‘"""‘"""‘"""‘"""‘"""‘"""‘"""‘"""‘"‘\x""""‘"""‘"""E"""‘""‘Ex"""‘"""\E"""""""E""‘"‘"""‘i""""""m\"""m‘m‘w iAssay ofAtropineSulfate i E x 98.6 98.3 98.4 E E 98.13 98 i 97.6 - i" E \\\\\\ 4 E ,/"""", Ex" a 1 1 a K \ V \ i \ E E E E E i ~ E i ETropic acid (RRTO 88) ND E0.05 E 0.07 0.08 0.12 0.25 E - E E i E E E E E i E i EAssay of Atropine Sulfate 98.8 98 98 98 97.9 - - i\\\\"\\\\\\\\\\\\\\\\\\\\\\\\\"\\\\\\\\\\\\\\\\\\\\\\\\\"\\\\\\\\\\\\\\\Ex\\\\\\\\"\\\\\\\\\\\\E\\\\\\\\\\\4‘\\\\\\\\\\\\\E\\\\\\\\\\"\\E\\\\\\\"m":immmm":"mum":i i H i 5.41 E5315 5.32 E 5.35 E 5.33 i - E - i Low EDTA9\\\\\\\ i E E E E E i E - i x E E E x E K i E E E i EWWWWE . . E E E ETropIc aCId(RRTO.88) ND ND E 0.05 0.06 0.09 - E Table 7 v"""‘""‘""‘""‘"""‘"‘""‘""‘""‘""‘""‘""‘""‘""‘""‘""‘""‘""‘""‘"""\"‘""‘""‘""‘""‘""‘""‘""‘""‘""‘""‘""‘""‘""‘""‘""‘""‘""‘""‘"""""""""""" No Buffer Composition 1",""""u Sample Test Parameter Information ,,,,,,,,,,,,,,,,,,,,1,,,,,,,,,,, Long term StabIIIty (25°C/ 60% RH) Initial 1,1,11,14,11,","""""‘\"""""""""""""""\"""""""‘\""""‘""‘"\""""""""1 2 3 1§2 3 """1"""" :weeki weeks weeksi monthimonthsi monthsi "I""I""unlnulnuuuu/"‘"""""""""""‘<‘"""""""""""‘"""""""""""‘"""""""""""‘"""\"""""""""""‘i""""""§"""‘"""‘¢"""""""\\"""""""§."""""""‘$t"""""""‘\,\ V iAssay of Atropine Sulfate 103.7 i 103.0 103.0 ‘ 102.4 1019 ‘ i i i i \\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\x\\\\\\\"""""""""""\\""""""" \\\\\\\""""‘\"""\"""" . : i i : "'1"‘"‘""‘""‘""‘""‘""‘""‘""‘""‘""‘""‘""‘""‘""‘""""‘"""""""\""‘"""\\"""‘""""""""""" "mum" ""‘""‘"m‘xm‘m‘m‘m,1""""/"""1"""" x \ \ V irropic aCId(RRTO.88) ‘ \ . . \ V \ ND i0-04i~ 0.07 0.09 0.12 0.28 i i i s i i i K\\\\\\\\\\\\\\\\\\\\\\\\\\\k\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\‘\\\\\\\\\\\\\\\&\\\\\\\\\\\\\\\\{\\\\\\ \\\\\\\\ Table 8 As can be readily seen from the above results, atropine solutions with a reduced amount of buffering system concentration (75mM, and ularly 50mM and less) had much lower levels of tropic acid (atropine degradation product) after already 1 month.

Regression analysis was used to extrapolate the ation levels at the end of 24 months.

Based on extrapolation methods commonly used in the art, the 50mM and no buffered concentrations have a shelf life of 18-24 months, which is 3-9 months beyond the 15 month extrapolated shelf life for the 100mM composition.

The above compositions were also subjected to accelerated stability studies. Lab scale batches of atropine sulfate ophthalmic solution were manufactured, (approx 0.4 mL) filled into 1 mL Blow-Fill-Seal (BFS) es, and were further packaged in aluminum pouches.

A number of pouched ampoules were subjected to accelerated ity studies at 40°C :: 2°C / 75% :: 5% RH as per the International Committee on Harmonization stability conditions. d ampoules subjected to these accelerated stability studies were collected after 1 week, 2 weeks, 3 weeks, 1 month, 2 months, and 3 months of stability storage, opened, and tested for levels of atropine sulfate, tropic acid viscosity (where applicable). Atropine and tropic acid levels were measured using the UPLC method, and the results are shown in Tables 9-13. i """""""‘""""§ i § E; I §\\\\\\\\\\\\\\\\\\\\ i amp e x i ilnformatIon. Test Parameter \ \ .. i |nItIal. . i 1 i 2 i 3 1 i 2 3 i i i i i i i i i i i i § i i i i i iweeksi:imonthmonthsi months((111111/111111/\ i i weeek \ i i ~ i \ i \ .52 5.55 i 5.55 5.48 5.60 5.55 i \ \\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\ \\\\\\\\\\\\\\\~§\\\\\\\\\\\\\\\ \\\\\\\\\\\\\~§\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\ipH i {5.51 \\\\\\\\\\\\\\\\\ i i i i i i i i i i i i i i i i il'ropic acid (RRTO.88) i ND i 0.3 i i 1 98 3 02 i i i i i i i i §\ :\ ‘\ """\:\"\"\ m"? "mix" "mix" ""im‘ mm i i i i i i § \ i s ~ i \ i \ il'ropic aCICl 88). . ND O. 19 O.35 O. 57 O.67 1. 52 - \ \ \ \ i ~ i \ i x 1IIIIIIIIIIIAIIIIII,IIIIIII("u/"unzuau/uuu WO 051 PCT/U 2017 ‘xx\\‘‘‘‘\\‘\WW\\WWW\xWWWWWWW WWW WW WWW W‘WW WWWWWWWWWW\WW x WWWWW‘ W WWW WWW Wx WWW WW WWWWxx WWWWWWWWWWWWWWx WWWWWWWWWWWx xxx xxxx SW S W.. xxx Wxxx _ _ x xx AxWx a 900 7. 7 0. ./ 7 r0. . xx xx WWyWWWfoWWAWWtW rW0W0WW.|WnWa:WSWWmWfa ..LWWWWeW\W‘WWWx... WWWWW WW W9Wxxxx ‘WW.W.0. WW W..x\ WWW.4.ATWW W xxxWxx W9W xx W$W W1W Wxxx W2W Wxxxx WWWW WWWxxW\\ W9WWW WWWW WxxWxxWxx WWWWWWWWWWWxxxWx WWWWWWxxxx xx Wxxx _ xx px\xxxx H xxxW 5 . xxxxW 5 . 4 5 5 A. . xx WxxxxWmWWWWWWWWWWWWW.WWx..Wx W \x.WWWxWW. WWW xWWWW WWxxxxx leWmW W5W5W‘3. ‘xxx. ‘xxx. _. xxxxWx WWWxxxxWW.. xxWxx. xx xx xxmW. x WWWW .WW. \x.xx.WWW.WWWxW xxxxxW.WWW W..W. xxx xx xxx xx xx xxxx xx xxx xxxx xx xx xxxx r xx xx Op.I xx Z a .cd. (x R RT 0 . 8 )8 xx N U xxx. O. 14 xxxxx 0 1.. 2 xx o 46 O 5 00 xx _ _ xxx xxx xxxx xxxxx xx xxx W\\WWW\WW\WWWxxxWxxxW"WaWW WWfWW WtAWW WW.pWW WWWsWWW W‘WW ‘WWWWWWWx\\WW W xxxx x.

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Table 12 a.4:..4 24s No Buffer Composition s S r Sample N Test Parameter .......x,....................,.......... \ \ Information Accelerated Stability (40°C/ 75% RH) § Initial \ "m"; r r r t r r ‘ \ \ \ \i" Sweeki weeksi month:months$ months§~ 4444444444444444444I"44444444444444444444444444444444"4,",444444444444 z 4444444 ,1 4444444444444’/44444444444444 44444444 Assay of Atropine e 103.7 102. 93» 102.4 102.2 101. 7 99. 9 l a,\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\x\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\""""\"\""""""\ "\""""""" pH\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\""""s"""""""\ \\\\\\\\\\\\\\\\"\""\\"""""\""\ "\"""""""1,1,11,11,11," , 1 ""11ropic acid (RRT 0.88) ND 0.15 0.26 0.4 0.51 1.17 "nun/n" \\\\\\\\\\\\\\\\\\\\\\\\\\\\ \\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\1,11,11,11 Table 13 Once more, it can be readily taken from the data that atropine solutions with a reduced amount of buffering system concentration (75mM, and particularly SOmM and less) had much lower levels of tropic acid (atropine degradation product) after already 1 month.

Regression analysis was utilized to extrapolate the degradation levels at the end of 24 months. Based on extrapolation methods commonly used in the art, the SOmM and no buffered concentrations will have a shelf life of 18-24 months, which is 3-9 months beyond the 15 month extrapolated shelf life for the 100mM composition.

Additional Stability Studies using further ions in composition again established that lower buffer strength, especially with a two component buffer system provide increased stability of the lmic low-dose atropine ations having compositions as shown in Tables 14-15 at both normal and accelerated storage conditions below (results shown in Tables 16-19.

Lot: RD—019-020 Lot: RD—019-023 Lot: RD185 Ingredient .Monohydrate.Atropine Sulfate :- Monobasic Sodium 0442 Phosphate AnhYdrous __ Dibasic Sodium Phosphate Anhydrous Hypromellose 2910 .0 5.0 5.0 (Benecel E4M Pharm) hloric Acid q.s. for pH adjustment q.s. for pH adjustment q.s. for pH adjustment nSodium Hydroxide q.s. for pH ment q.s. for pH adjustment q.s. for pH adjustment IWater for Injection q.s. to 100% q.s. to 100% q.s. to 100% Table 14 Lot: RD026 Lot: RD—019-029 Lot: RD179 ient .Atropine.Monohydrate Sulfate :- Monobasic Sodium O295 O295 0_ Phosphate AnhYdrous Dibasic Sodium Phosphate Anhydrous Hypromellose 2910 (Benecel E4M Pharm) Hydrochloric Acid q. s. for pH adjustment q.s. for pH adjustment q. s. for pH ment m Hydroxide q. s. for pH adjustment q.s. for pH ment q.s. for pH adjustment IWater for Injection q. s. to 100% q.s. to 100% q.s. to 100% Table 15 Lot Number Test Parameter Various formulations Initial Accelerated Stability (40°C / 75% RH) 1 Z 3 week month months months RD020 Assay Of Atropine SUIfate ------- Unknown 0.19 0.24 0.24 0.25 0.26 0.2 (RRT=1.21) "Human Total 0.3 1.8 2.6 impurities RD023 Assay Of Atropine SUIfate --E---- Compounds (%) Unknown 0.18 0.22 0.23 0.24 0.24 0.23 (RRT=1.21) "Hanna Total 0.3 0.7 1.8 2.5 Impurities RD185 Assay of Atropine Sulfate 102.4 101. 5 101.0 100.4 --- Compounds Unknown 0.23 0.25 0.25 0.25 0.25 0.25 (RRT=1.21) Lot Number Test Parameter Various formulations Initial Accelerated Stability (40°C / 75% RH) 1 1 Z 3 week month months months Total 0.5 0.7 1.1 2.0 2.9 Impurities Table 16 Lot Number Test Parameter Various formulations Initial Long term Stability (25°C / 60% RH) 1 week 1 Z 3 month months months RD020 Assay of Atropine Sulfate Unknown 0.1 0.11 0.14 0.21 0.2 .21) nn----- Lot: U I RD—019-023 Assay of Atropine Sulfate 98.2 Tropic acid O ._x . n O.. I—‘ .. pN (RRT= 1. 21) Apoatropine Total Impurities 2.0—IN 2.0—IN 0 . N 0 U! o \I Lot: U I 5.28 z—I Z_) 5.49 2_) RD185 Assay of Atropine Sulfate 102.4 101.9 101.7 101. 5 101.3 101.0 100.6 —n--— "HI...-(RRT=1.21) —nnnnnnm —------n Table 17 Lot Number Test Parameter Various formulations Initial Accelerated Stability (40°C / 75% RH) 1 1 Z 3 week month months months RD026 Assay of Atropine 6. 5. .495. 4. .8 Sulfate (%) Lot Number Test Parameter Various formulations Initial Accelerated ity (40°C / 75% RH) 1 1 Z 3 week month months months "------ Unknown (RRT= 1. 21) Apoatropine Total 0 . UJ Impurities Lot: U I 5.41 W RD029 Assay of Atropine 98.8 3w . m LD >1 W 97.1 LD N U'I Sulfate (% I _TropIc aCId Unknown .0G RRT= 1.21) Apoatropine Total O N.

Impurities Lot: U I 5" U1 N z—I RD179 Assay of Atropine 103. 7 102. 9 1024 1022 1017 En Sulfate (% Tropic acid O ._x Unknown 0 N..

RRT= 1.21) Total 0.4 0.5 0.7 1.5 2.2 Impurities Table 18 Lot Number Test Parameter Various formulations l Long term Stability (25°C/ 60% RH) 1 1 Z 3 week month months months RD026 Assay of Atropine 6. .9 .6 . .9 6. 6.

Sulfate (%) manna Unknown 0.11 0.18 0.20 (RRT=1.21) Total 0.1 0.2 0.4 0.5 Impurities RD029 Assay of Atropine 98.8 97.9 98.0 98.5 Sulfate (%) manna Lot Number Test Parameter Various formulations Initial Long term Stability (25°C/ 60% RH) 1 1 Z 3 week month months months Total 0.1 0.1 0.2 0.4 0.5 ties RD179 Assay of Atropine 103.7 103.0 103.0 103.0 102.4 101.9 102.2 Sulfate (%) Unknown ( 0.14 0.16 0.2 0.26 0.28 RRT=1.21) —mmnnnnn Total 0.1 0.2 0.3 0.3 0.5 0.7 Impurities Table 19 The effect of pH and stability of compositions of Table 20 was tested and exemplary test results for pH 3.5 and pH 6.0 are provided in the Tables 21-22 (pH 3.5) and Tables 23-24 (pH 6.0) below.

Table 20 1 2 months 3 months 6 months month Clear, Clear, Clear, Clear, Clear, Clear, Appearance colorless colorless ess colorless colorless colorless solution solution solution solution solution solution mun" Compounds (%) Unknown 0.07 0.07 0.11 (RRT=1.21) "nun" 1 2 months 3 months 6 months month Unknown (RRT 0.508) "nun-n n (RRT 0.683) "nun"- Table 21 1 2 months 3 months 6 months month Clear, Clear, Clear, Clear, Clear, Clear, Appearance colorless colorless colorless colorless colorless ess solution solution solution solution solution solution "nun" Unknown N) (RRT=1.21) (%) "nun" Compounds n (RRT 0.508) "nun- Unknown (RRT Related 0.683) "nun- Total Impurities "mm"- Table 22 1 2 months 3 months 6 months month Appearance Clear, Clear, Clear, Clear, Clear, Clear, colorless colorless colorless colorless colorless colorless solution solution solution solution solution solution ——————m Assay of ne Sulfate (%) 108.5 106.7 104.1 Compounds Unknown 0.32 0.32 0.29 0.29 0.27 (RRT=1.21) Total 1.3 2.3 4.6 12.0 Impurities Table 23 1 Z 3 months 6 months month months Appearance Clear, Clear, Clear, Clear, Clear, Clear, 1 Z 3 months 6 months month months colorless colorless colorless colorless colorless colorless solution solution solution solution solution solution Assay of Atropine e (%) 108. 5 108. 5 107.1 106.0 105. 5 103.1 Compounds (%) Unknown 0.21 0.25 0.29 0.29 0.29 .21) nun—M Total 0.4 1.2 1.6 2.8 Impurities Table 24 Atropine sulfate ophthalmic solution is intended to be ed as a single or multi- dose product for topical administration to the eye, which can advantageously be provided as a Blow/Fill/Seal (BFS) ampule as the primary container closure system. For example, suitable ampule materials include Lyondellbasell Purell PE 3020 D resin, which was tested as follows: Compositions as shown in Table 3 (50le[ Buffer ition with NaCl, low EDTA), ﬁlled in BFS es were tested at concentrations of 0.01% (w/v) and 0.02% (w/v) under accelerated (40°C/75% RH) and long-term (25°C/60% RH) storage conditions.

The ﬁlled BFS es were then packaged into a ary ing (here: laminated pouch) for storage as indicated. The results of this study are presented in Tables 25-28.

Atropine Concentration 0.01 wt% Test Parameter Accelerated Storage (40°C/ 75% RH) m-mmm Appearance Clear, Clear, Clear, Clear, Clear, Clear, colorless colorless colorless colorless colorless colorless solution solution solution solution solution solution 999999999 99.99 99.49 99.49 Assay of Atropine Sulfate (%) 104.2 104.6 102.0 102.5 poa ropine ds(%) . . .

TOtal impurities Table 25 ne Concentration 0.01 wt% Test Parameter Long-Term Storage (25°C/ 60% RH) m-mmm Appearance Clear, Clear, Clear, Clear, Clear, Clear, colorless colorless colorless colorless colorless colorless solution solution solution solution on solution 9299 29.99 29.99 29.42 Assay of Atropine Sulfate (%) 104.2 105.8 103.7 105.9 103.3 105.2 poa ropine ds (%) .

TOtal Impurities Table 26 Atropine Concentration 0.02 wt% Test Parameter Accelerated Storage (40°C/ 75% RH) m-mmm Appearance Clear, Clear, Clear, Clear, Clear, Clear, colorless colorless colorless colorless colorless colorless on solution solution solution solution solution v.99999299 29.29 22.29 29.92 Assay of Atropine Sulfate (%) 105.5 106.0 104.0 103.1 102.6 poa ropine ds (%) . . .

TOtal Impurities Table 27 Atropine Concentration 0.02 wt% Test Parameter Long-Term Storage (25°C / 60% RH) m-mmm Appearance Clear, Clear, Clear, Clear, Clear, Clear, ess colorless colorless colorless colorless ess solution solution solution solution solution solution Atropine Concentration 0.02 wt% Test Parameter Long-Term Storage (25°C / 60% RH) m-mmm C°mp°unds TOtal Impuritiesn." Table 28 As used in the ption herein and throughout the claims that , the meaning of "a," "an," and "the" includes plural reference unless the t clearly dictates otherwise.

Also, as used in the description herein, the meaning of "in" includes "in" and "on" unless the context clearly dictates otherwise.

In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be tood as being modiﬁed in some instances by the term ." Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary ing upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the cal parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some ments of the invention may contain certain errors arily resulting from the standard deviation found in their respective testing measurements.

It should be apparent, however, to those skilled in the art that many more modifications s those already described are possible without departing from the ive concepts herein. The inventive subject matter, therefore, is not to be restricted except in the spirit of the disclosure. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the t invention. Indeed, the present ion is in no way limited to the methods and materials described.

Moreover, in interpreting the disclosure all terms should be interpreted in the broadest le manner tent with the context. In particular the terms "comprises" and "comprising" should be interpreted as referring to the elements, components, or steps in a non-exclusive manner, indicating that the referenced elements, components, or steps can be present, or utilized, or combined with other elements, components, or steps that are not expressly referenced.

Claims

1. A liquid e-stable low-dose ophthalmic atropine composition, sing: an aqueous solution comprising a buffer, a tonicity agent, a viscosity modifier, and atropine or a pharmaceutically able salt thereof; wherein the atropine or the pharmaceutically acceptable salt thereof is present in the ophthalmic atropine composition in an amount of equal or less than 0.05 wt%; wherein the buffer has a concentration of equal or less than 75mM, and wherein the ophthalmic atropine composition has a pH of between 5.0 and 6.0; n the ophthalmic atropine composition is ated such that after storage over at least two months at 25 ºC and 60% relative humidity equal or less than 0.35% tropic acid is formed from degradation of the atropine; and wherein the ophthalmic atropine composition is substantially free of a preservative.

2. The composition of claim 1, wherein the atropine or the pharmaceutically acceptable salt thereof is atropine sulfate.

3. The composition of claim 1, wherein the atropine or a pharmaceutically acceptable salt thereof is present in the ophthalmic atropine composition in an amount of equal or less than 0.02 wt%.

4. The composition of claim 1, wherein the atropine or a pharmaceutically able salt thereof is t in the ophthalmic atropine composition in an amount of equal or less than 0.01 wt%.

5. The composition of claim 1, wherein the atropine or a pharmaceutically acceptable salt thereof is present in the ophthalmic atropine composition in an amount of between 0.01% and 0.05 wt%.

6. The composition of claim 1, wherein the atropine or a pharmaceutically acceptable salt thereof is present in the ophthalmic atropine composition in an amount of between 0.001 wt% and 0.01 wt%.

7. The composition of claim 1, wherein the buffer has a concentration of equal or less than 60mM.

8. The composition of claim 1, wherein the buffer has a concentration of equal or less than 50mM.

9. The composition of claim 7, n the buffer comprises monobasic and dibasic sodium phosphate.

10. The composition of claim 1, wherein the buffer comprises sic and dibasic sodium phosphate.

11. The composition of claim 1, further sing a chelator.

12. The composition of claim 11 wherein the or is selected from the group consisting of a bicarboxylic acid, a tricarboxylic acid, and an aminopolycarboxylic acid.

13. The ition of claim 11 wherein the chelator is present in the ophthalmic atropine composition in an amount of equal or less than 0.01w %.

14. The composition of claim 1, wherein the ophthalmic atropine composition has a pH of 5.0 (+/- 0.2).

15. The composition of claim 1, wherein the ophthalmic atropine composition has a pH of 5.5 (+/- 0.2).

16. The composition of claim 1, wherein the lmic atropine composition has a pH of 6.0 (+/- 0.2).

17. The composition of claim 1, n the tonicity agent is a pharmaceutically acceptable salt and wherein the salt is present in the ophthalmic atropine composition in an amount of between 0.2 wt% and 0.8 wt%.

18. The composition of claim 1, wherein the viscosity modifier is a modified cellulose.

19. The ition of claim 1, wherein the modified cellulose is a hydroxyethyl cellulose, a hydroxypropyl cellulose, or a hydroxypropyl methylcellulose.

20. A liquid storage-stable se ophthalmic atropine composition, consisting essentially an aqueous solution comprising a buffer, a tonicity agent, a chelator, a viscosity modifier, and atropine or a pharmaceutically acceptable salt thereof; wherein the atropine or the pharmaceutically acceptable salt f is present in the ophthalmic atropine composition in an amount of equal or less than 0.05 wt%; wherein the buffer has a concentration of equal or less than 75mM, and wherein the ophthalmic atropine ition has a pH of between 5.0 and 6.0; and wherein the ophthalmic ne composition is formulated such that after e over at least two months at 25 ºC and 60% ve humidity equal or less than 0.35% tropic acid is formed from degradation of the atropine.

21. The composition of claim 20, wherein the atropine or the pharmaceutically acceptable salt thereof is atropine sulfate.

22. The composition of claim 20, wherein the ne or a pharmaceutically acceptable salt thereof is present in the ophthalmic atropine composition in an amount of equal or less than 0.02 wt%.

23. The composition of claim 20, wherein the atropine or a pharmaceutically acceptable salt f is present in the ophthalmic atropine composition in an amount of equal or less than 0.01 wt%.

24. The composition of claim 20, wherein the atropine or a ceutically acceptable salt thereof is t in the ophthalmic atropine composition in an amount of between 0.001 wt% and 0.01 wt%.

25. The composition of claim 21, wherein the buffer has a concentration of equal or less than 60mM.

26. The composition of claim 24, wherein the buffer has a concentration of equal or less than 50mM.

27. The composition of claim 25, wherein the buffer comprises monobasic and dibasic sodium phosphate.

28. The composition of claim 26, wherein the buffer comprises monobasic and dibasic sodium phosphate.

29. The composition of claim 20, wherein the chelator is selected from the group consisting of a bicarboxylic acid, a tricarboxylic acid, and an aminopolycarboxylic acid.

30. The composition of claim 27, wherein the chelator is ethylenediaminetetraacetic acid (EDTA).

31. The ition of claim 28, wherein the chelator is ethylenediaminetetraacetic acid (EDTA).

32. The ition of claim 29 n the chelator is present in the ophthalmic atropine composition in an amount of equal or less than 0.01 wt%.

33. The composition of claim 20, wherein the ophthalmic ne composition has a pH of between 5.0 (+/- 0.2) and 5.5 (+/- 0.2).

34. The composition of claim 20, wherein the ophthalmic atropine composition has a pH of between 5.5 (+/- 0.2) and 6.0 (+/- 0.2).

35. The composition of claim 20, wherein the tonicity agent is a pharmaceutically acceptable salt and wherein the salt is present in the ophthalmic atropine composition in an amount of between 0.2 wt% and 0.8 wt%.

36. The composition of claim 20, wherein the viscosity modifier is a hydroxyethyl cellulose, a hydroxypropyl ose, or a hydroxypropyl methylcellulose.

37. The composition of claim 20, wherein the ophthalmic atropine composition is substantially free of a vative.

38. The composition of claim 20, wherein the atropine or a ceutically acceptable salt thereof is present in the ophthalmic atropine composition in an amount of between 0.001 wt% and 0.01 wt%, wherein the buffer comprises monobasic and dibasic sodium phosphate and has a concentration of equal or less than 50mM, wherein the viscosity modifier is a hydroxyethyl cellulose, a hydroxypropyl cellulose, or a hydroxypropyl methylcellulose, and wherein the ophthalmic atropine composition is substantially free of a preservative.

39. The ition of claim 20, wherein the atropine or a ceutically acceptable salt thereof is present in the ophthalmic ne composition in an amount of n 0.01 wt% and 0.05 wt%, wherein the buffer comprises monobasic and dibasic sodium phosphate and has a concentration of equal or less than 50mM, wherein the viscosity modifier is a hydroxyethyl cellulose, a hydroxypropyl cellulose, or a ypropyl methylcellulose, and wherein the ophthalmic atropine composition is substantially free of a preservative.

40. A storage-stable preservative-free ophthalmic ne composition, comprising: an aqueous solution comprising se atropine or a pharmaceutically acceptable salt f, a low-strength buffer, a pharmaceutically acceptable salt, and a cellulosic viscosity modifier; wherein the rength buffer has a concentration of equal or less than 50mM and a near to neutral pH, and wherein the low-dose atropine is t at a concentration of equal or less than 0.05 wt%; and wherein the ophthalmic atropine composition is substantially free of a preservative; and wherein the ophthalmic atropine composition is formulated such that after storage over at least two months at 25 ºC and 60% relative humidity equal or less than 0.35% tropic acid is formed from degradation of the atropine.

41. The composition of claim 40, wherein the low-dose atropine is present at a concentration of equal or less than 0.01 wt%.

42. The composition of claim 40, wherein the atropine or a pharmaceutically acceptable salt thereof is present in the ophthalmic atropine composition in an amount of between 0.01% and 0.02 wt%.

43. The composition of claim 40, wherein the atropine or a pharmaceutically acceptable salt thereof is present in the lmic atropine composition in an amount of between 0.001 wt% and 0.01 wt%.

44. The composition of claim 40, wherein the atropine or a pharmaceutically able salt thereof is atropine sulfate.

45. The composition of claim 40, wherein the low-strength buffer comprises a first and a second buffer component.

46. The composition of claim 45, wherein the low-strength buffer comprises sic and dibasic sodium phosphate.

47. The ition of claim 40, wherein the ophthalmic ne composition has a pH of between 5.0 and 6.0.

48. The composition of claim 40, wherein the ophthalmic atropine composition has a pH of between 5.5 (+/- 0.2) and 6.0 (+/- 0.2).

49. The composition of claim 40, further comprising a chelator.

50. The composition of claim 49, wherein the chelator is present in an amount of % (+/- 20% abs.)

51. The composition of claim 49, wherein the chelator is selected from the group consisting of a bicarboxylic acid, a tricarboxylic acid, and an olycarboxylic acid.

52. The composition of claim 40, wherein the pharmaceutically acceptable salt is present in the ophthalmic atropine composition in an amount of between 0.2 wt% and 0.8 wt%.

53. The composition of claim 40, wherein the pharmaceutically acceptable salt is sodium chloride and wherein the salt is t in the ophthalmic atropine composition in an amount of 0.5 wt% ( +/- 0.2 wt%).

54. The composition of claim 40, n the cellulosic viscosity modifier is a hydroxyethyl cellulose, a hydroxypropyl cellulose, or a hydroxypropyl methylcellulose.

55. The composition of claim 40, wherein the cellulosic viscosity modifier is present in an amount of 0.5 wt% (+/- 0.1 wt%) of the ophthalmic atropine composition.

56. The composition of claim 40, wherein the atropine or a pharmaceutically acceptable salt thereof is present in the ophthalmic ne composition in an amount of between 0.001 wt% and 0.01 wt%, wherein the rength buffer comprises monobasic and dibasic sodium phosphate, and wherein the ophthalmic atropine composition has a pH of between 5.5 (+/- 0.2) and 6.0 (+/- 0.2).

57. The composition of claim 40, wherein the ne or a pharmaceutically acceptable salt thereof is present in the ophthalmic ne composition in an amount of n 0.001 wt% and 0.01 wt%, n the ophthalmic atropine composition further comprises a chelator in an amount of 0.01wt% (+/- 20% abs.) of the ophthalmic atropine composition, and wherein the ophthalmic ne ition has a pH of between 5.5 (+/- 0.2) and 6.0 (+/- 0.2)

58. The ition of claim 40, wherein the low-strength buffer comprises monobasic and dibasic sodium phosphate, wherein the composition further comprises a chelator in an amount of 0.01wt% (+/- 20% abs.) of the ophthalmic atropine composition, wherein the ophthalmic atropine composition has a pH of n 5.5 (+/- 0.2) and 6.0 (+/- 0.2), wherein the salt is present in the ophthalmic atropine composition in an amount of 0.5 wt% ( +/- 0.2 wt%), and wherein the cellulosic ity modifier is present in an amount of 0.5 wt% (+/- 0.1 wt%) of the ophthalmic atropine composition.

59. A method of increasing e stability of atropine in a liquid low-dose ophthalmic formulation, comprising: formulating an aqueous solution with a low-strength buffer system that includes a first and second buffer component, n the low-strength buffer system has a concentration of equal or less than 75mM buffer; wherein the first and second buffer components are monobasic and dibasic sodium ate, respectively; including into the aqueous solution a pharmaceutically acceptable salt, a viscosity modifier, and a chelator; including into the aqueous solution ne or a pharmaceutically acceptable salt thereof at a low dose, wherein the low dose is equal or less than 0.05 wt% of the ophthalmic formulation; adjusting pH of the ophthalmic formulation to a pH between 5 and 6; and wherein the ophthalmic formulation is formulated such that after storage over at least two months at 25 ºC and 60% relative humidity equal or less than 0.35% tropic acid is formed from degradation of the atropine.

60. The method of claim 59, wherein the low-strength buffer system has a concentration of equal or less than 50mM buffer.

61. The method of claim 59, wherein the ceutically acceptable salt is sodium chloride and wherein the salt is present in the ophthalmic atropine composition in an amount of 0.5 wt% ( +/- 0.2 wt%) of the ophthalmic formulation.

62. The method of claim 59, n the chelator is selected from the group consisting of a bicarboxylic acid, a tricarboxylic acid, and an aminopolycarboxylic acid.

63. The method of claim 62, wherein the chelator is nediaminetetraacetic acid .

64. The method of claim 59, wherein the chelator is present in an amount of 0.01wt% (+/- 20% abs.) of the ophthalmic formulation.

65. The method of claim 59, wherein the viscosity modifier is a cellulosic viscosity modifier.

66. The method of claim 65, wherein the cellulosic ity modifier is a hydroxyethyl cellulose, a hydroxypropyl cellulose, or a hydroxypropyl methylcellulose.

67. The method of claim 65, n the osic viscosity modifier is present in an amount of 0.5 wt% (+/- 0.1 wt%) of the ophthalmic formulation.

68. The method of claim 65, wherein the cellulosic viscosity modifier is prepared as a separate solution, and combined with the aqueous solution containing the buffer , the pharmaceutically acceptable salt, the viscosity modifier, the chelator, and the atropine or the pharmaceutically acceptable salt thereof.

69. The method of claim 59, wherein the low dose is between 0.01 wt% and 0.02 wt% of the ophthalmic formulation.

70. The method of claim 59, wherein the low dose is between 0.001 wt% and 0.01 wt% of the ophthalmic formulation.

71. The method of claim 59, wherein the low dose is equal or less than 0.01 wt% of the lmic formulation.

72. The method of claim 59, wherein aqueous solution is formulated using deoxygenated water.

73. The method of claim 59, wherein the pH is between 5.5 (+/- 0.2) and 6.0 (+/- 0.2).

74. The method of claim 59, wherein the atropine or a pharmaceutically able salt thereof is atropine sulfate.

75. The method of claim 59, further comprising a step of sterilizing the lmic formulation.

76. The method of claim 75, wherein the step of sterilizing comprises sterile filtration.

77. The method of claim 59, r comprising a step of filling the ophthalmic formulation into a multi-dose container.

78. A method of preparing a storage stable liquid low-dose atropine lmic formulation, comprising: formulating in a first ner a low-strength buffer low-dose atropine solution, and subjecting the low-strength buffer low-dose atropine solution to sterile filtration to obtain a sterile low-strength buffer low-dose atropine solution; wherein the low-strength buffer has a first and a second buffer component that form a low-strength buffer system having a concentration of equal or less than 75mM in the ophthalmic formulation, n the atropine is present in an amount of equal or less than 0.05 wt% of the ophthalmic formulation; wherein the low-strength buffer low-dose atropine solution has a near to a neutral pH and further ses a tonicity agent and a chelator; formulating in a second container a polymer solution, and sterilizing the polymer solution in a process other than sterile filtration to obtain a sterile polymer solution; wherein the polymer solution comprises a polymer to modify viscosity of the lowstrength buffer low-dose ne solution upon combination; and combining the sterile low-strength buffer low-dose atropine solution and the sterile r solution to obtain a sterile liquid low-dose lmic formulation; and wherein the ophthalmic formulation is formulated such that after storage over at least two months at 25 ºC and 60% relative humidity equal or less than 0.35% tropic acid is formed from degradation of the atropine.

79. The method of claim 78, wherein the first and second buffer components are monobasic and dibasic sodium phosphate, respectively.

80. The method of claim 78, wherein the low-strength buffer system has a concentration of equal or less than 50mM buffer in the ophthalmic formulation.

81. The method of claim 78, wherein the atropine is t in an amount of between 0.01 wt% and 0.02 wt% of the ophthalmic ation.

82. The method of claim 78, wherein the ne is present in an amount of between 0.001 wt% and 0.01 wt% of the lmic formulation.

83. The method of claim 78, wherein the atropine is present in an amount of equal or less than 0.01 wt% of the ophthalmic formulation.

84. The method of claim 78, wherein the tonicity agent is a pharmaceutically acceptable salt.

85. The method of claim 84, wherein the pharmaceutically acceptable salt is sodium de and wherein the salt is present in the ophthalmic atropine composition in an amount of 0.5 wt% (+/- 0.2 wt%) of the ophthalmic formulation.

86. The method of claim 78, wherein the chelator is selected from the group consisting of a bicarboxylic acid, a tricarboxylic acid, and an aminopolycarboxylic acid.

87. The method of claim 86, wherein the chelator is ethylenediaminetetraacetic acid (EDTA).

88. The method of claim 78, n the chelator is present in an amount of 0.01wt% (+/- 20% abs.) of the ophthalmic formulation.

89. The method of claim 88, wherein the polymer is a cellulosic polymer.

90. The method of claim 89, wherein the cellulosic polymer is a hydroxyethyl cellulose, a hydroxypropyl cellulose, or a ypropyl methylcellulose.

91. The method of claim 89, wherein the cellulosic polymer is present in an amount of 0.5 wt% (+/- 0.1 wt%) of the ophthalmic formulation.

92. The method of claim 78, further comprising a step of adjusting the pH of the low-strength buffer low-dose atropine solution to a pH between 5 and 6.

93. The method of claim 92, wherein the pH is between 5.5 (+/- 0.2) and 6.0 (+/- 0.2).

94. The method of claim 78, wherein the s other than sterile filtration is aving.

95. The method of claim 78, wherein the step of combining comprises mixing the sterile lowstrength buffer se atropine solution and the sterile polymer solution for at least 30

96. The method of claim 95, further comprising a step of filling the ophthalmic formulation into a multi-dose container.

97. A treatment kit for treatment of , comprising: a first container that contains a liquid storage-stable low-dose ne ophthalmic formulation, wherein the first container is configured as a disposable single-use container or a multi-dose container; and a second container enclosing the first container; wherein the liquid storage-stable low-dose atropine ophthalmic formulation comprises an aqueous solution comprising a buffer, a tonicity agent, a viscosity modifier, and ne or a pharmaceutically acceptable salt thereof; wherein the atropine or the pharmaceutically acceptable salt f is present in the ophthalmic atropine composition in an amount of equal or less than 0.05 wt%; wherein the buffer has a concentration of equal or less than 75mM, and wherein the ophthalmic atropine composition has a pH of between 5.0 and 6.0; n the ophthalmic atropine composition is formulated such that after storage over at least two months at 25 ºC and 60% relative humidity equal or less than 0.35% tropic acid is formed from degradation of the atropine; and wherein the ophthalmic atropine composition is substantially free of a preservative.

98. The kit of claim 97, wherein the first ner is a blow-fill-seal (BSF) container.

99. The kit of claim 97, wherein the second container is a laminated metallized pouch.

100. The kit of claim 97, wherein the atropine or a pharmaceutically acceptable salt thereof is present in the ophthalmic atropine composition in an amount of equal or less than 0.01 wt%.

101. The kit of claim 97, wherein the atropine or a pharmaceutically acceptable salt thereof is present in the ophthalmic atropine composition in an amount of n 0.01 wt% and 0.05 wt%.

102. The kit of claim 97, n the ne or a pharmaceutically able salt f is present in the ophthalmic atropine composition in an amount of between 0.001 wt% and 0.01 wt%.

103. The kit of claim 97, wherein the buffer has a concentration of equal or less than 75mM.

104. The kit of claim 97, wherein the buffer has a concentration of equal or less than 50mM.

105. The kit of claim 103, wherein the buffer comprises monobasic and dibasic sodium phosphate.

106. The kit of claim 97, wherein the buffer comprises monobasic and dibasic sodium ate.

107. The kit of claim 97, r comprising a chelator.

108. The kit of claim 107 wherein the chelator is selected from the group consisting of a bicarboxylic acid, a tricarboxylic acid, and an aminopolycarboxylic acid.

109. The kit of claim 107 wherein the chelator is present in the ophthalmic atropine composition in an amount of equal or less than 0.01 wt%.

110. The kit of claim 97, wherein the ophthalmic atropine composition has a pH of 5.0 (+/- 0.2).

111. The kit of claim 97, wherein the ophthalmic atropine composition has a pH of 5.5 (+/- 0.2).

112. The kit of claim 97, wherein the ophthalmic atropine ition has a pH of 6.0 (+/- 0.2).

113. The kit of claim 97, wherein the ty agent is a pharmaceutically acceptable salt and wherein the salt is present in the ophthalmic atropine ition in an amount of between 0.2 wt% and 0.8 wt%.

114. The kit of claim 97, wherein the viscosity modifier is a modified cellulose.

115. The kit of claim 97, wherein the modified ose is a hydroxyethyl cellulose, a hydroxypropyl cellulose, or a hydroxypropyl methylcellulose.