Many chemical and pharmaceutical solution compositions are widely used. However, for certain chemical and pharmaceutical compositions, it is desirable to store the compositions at a first pH and to use the compositions at a second pH. For example, a pharmaceutical composition may be stable at one pH, but its efficacy is optimal at a different pH. Dipivefrin is an example of such compositions. Dipivefrin is a prod rug of epinephrine, which is widely used to treat severe allergic reactions and to reduce intraocular pressure, and dipivefrin as a liquid composition is particularly useful for treating glaucoma.

However, a stable high-efficacy dipivefrin solution composition is difficult to produce since dipivefrin is unstable in neutral and alkaline solutions and an acidic solution cannot be applied directly to the eye without causing irritation and discomfort.

There have been attempts to regulate the pH of a solution using an ion exchange resin. For example, an acidic solution of an active ingredient is passed through a bed of a cation exchange resin to increase the pH of the solution. However, the ion exchange resin not only binds cation to elevate the pH, but also binds the active ingredient, thereby lowering the active ingredient concentration in the solution. There remains a need for a solution dispensing apparatus that is capable of storing a solution at a first pH and dispensing the solution at a second pH without significantly changing the active ingredient concentration.

SUMMARY OF THE INVENTION There is provided in accordance with the invention a method for altering the pH of a solution. The method has the step of passing a solution through a pH changing device that has a modified ion exchange material selected from the group consisting of modified anion exchange materials and modified cation exchange materials, wherein the modified anion exchange materials contain a weak acid-forming counterion and the modified cation exchange materials contain a weak base-forming counterion.

The invention also provides an apparatus for dispensing a solution composition. The apparatus has a container body having a solution retaining chamber and an outlet, and a pH changing device having a modified ion exchange material selected from the group consisting of modified anion exchange materials and modified cation exchange materials, wherein the modified anion exchange materials contain a weak acid-forming counterion and the modified cation exchange materials contain a weak base-forming counterion.

The method and apparatus of the present invention change the pH of a solution composition as the composition is dispensed, and they are useful for solution compositions, particularly liquid pharmaceutical compositions, that are stored at a first pH and applied or consumed at a second pH.

DESCRIPTION OF THE DRAWING Fig. 1 illustrates an exemplary dispenser suitable for the present invention.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides an apparatus for dispensing a liquid composition. The apparatus changes the pH of the composition as the composition is dispensed. The apparatus has a section that contains a modified ion exchange material, and the modified ion exchange material does not directly contact the composition stored in the storage compartment of the apparatus but thoroughly contacts the portion of the composition that is being dispensed. The apparatus is useful for solution compositions, particularly liquid pharmaceutical compositions, that are stored at a first pH and applied or consumed at a second pH.

An exemplary apparatus of the invention is illustrated in Fig. 1. A dispenser 10 has a container 12 and a dispensing head 14. The container 12 has a storage chamber 16 which stores a solution containing active ingredients. The dispensing head 14 is placed atop of the container 12, and the dispensing head 14 has a small upper opening 18 and a lower opening 20. Between the two openings 18 and 20, a modified ion exchange material 22 is placed such that the solution exiting the container 12 makes intimate contact with the exchange material 22. The modified ion exchange material 22 may be held in place by an upper porous screen 24 and a lower porous screen 26 if the modified ion exchange material is not self-cohesive, e.g., powder or particulate. Suitable porous screen can be produce from a wide variety of materials, e.g., thermoplastics and metals, provided that the material does not adversely interact with the solution. The container 12 may also have threads, for example, just below the dispensing head 14, such that a cap 28 can be securely placed over the dispensing head 14 for storage.

The dispenser 10 is designed to dispense a controlled amount of the solution contained therein. For example, the container 12 is produced from a reversibly deformable material, for example, a thermoplastic, e.g., polypropylene or polyethylene, such that when the container is squeezed, a desired amount of the solution is dispensed, and then the container returns to its original shape once the squeezing pressure is removed. Preferably, the dispensing head 14 additionally contains means for providing one-directional flow of solution out of the container 12, e.g., a check valve, thereby preventing the solution that was contacted with the modified ion exchange material 22 from returning back to the storage chamber 16. As another example, the dispenser 10 may contain a mechanical or electrical pump that delivers a measured amount of solution from the storage chamber 16 through the modified ion exchange material 22.

The modified ion exchange materials suitable for the present invention include modified cation exchange materials and modified anion exchange materials. The term "cation exchange material" as used herein indicates a polymeric material which contains a fixed negative charge on its polymer matrix and bound thereto exchangeable counter- cations, such as Ca2+, Na+, H+ and the like. Similarly, the term "anion exchange material" indicates a polymeric material which contains a fixed positive charge on its polymer matrix and bound thereto exchangeable counter-anion, such as HC03-, so42, OH-, Cl and the like.

Suitable ion exchange materials that can be modified in accordance with the present invention are commercially available. Typically, commercial ion exchange materials are available in chloride, hydroxide and hydrogen counterion forms.

Suitable anion exchange materials include AG-1, AG-2, AG-3, AG-4, AG-1 0 and Bio- Rex5 from BIO-RAD Laboratories, Calif.; lonac(D ASB-1, ASB-2, A-490 and A-365 from Sybron Chemicals, Inc.; Amberlite IRA-93, IRA-35, IRA-400, IRA-401, IRA-402 and IRA-458 from Rohm and Haas; and the like. Suitable cation exchange materials include AG-50, AG-MP50, BIO-BS-SM2 and Bio-Rex70 from BIO-RAD Laboratories, Calif.; lonac(D C-249, C-250 and CC from Sybron Chemicals, Inc.; Amberlite IR-116, IR-120 and IR-124 from Rohm and Haas; Acropor 5A-6404, available from Gelman Sciences, Mich.; and the like.

Of these suitable ion exchange materials, preferred are non-hydrophobic or hydrophilic ion exchange materials. More particularly preferred are non-styrenic ion exchange materials, e.g., acrylic and amide-based materials. Although it is not wished to be bound by any theory, it is believed that the hydrophobic styrene portions of styrenic ion exchange materials tend to bind active ingredients more readily than non-styrene based ion exchange materials. Suitable non-styrenic anion exchange materials include AG-3, AG-4 and lonacS A-365 and A-490, and suitable non-styrenic cation exchange materials include Bio-Rex 70 and lonac CC.

Modified ion exchange materials suitable for the invention are in an ionic form of a weak acid-forming cation or weak base-forming anion. Suitable modified anion exchange materials are in an ionic form of a weak acid-forming anion, i.e., the counter-anion of the anion exchange material is exchanged with a weak acid-forming anion. Suitable weak acid- forming anions include acetate, citrate, phosphate, borate, propionate, tartarate, carbonate, glycinate and the like. Preferable weak acid-forming anions are selected from the anionic portions of acids which have an acid dissociation constant (pKa) greater than about 1, more preferably between about 3 and about 11. The selection of particularly suitable acid- forming anions depends on various factors, such as the stability of the active ingredient and the desired pH of the composition to be treated. For example, when a solution containing dipivefrin or pilocarpine is treated, the particularly suitable acid-forming anions are selected from the anionic portions of acids which have an acid dissociation constant between about 4 and about 8.

Suitable modified cation exchange materials are in ionic form of a weak base-forming cation, i.e., the counter-cation of the cation exchange material is exchanged with a weak base-forming cation. Suitable weak base-forming cations include ammonia, organic ammonium compounds, ammonium ion, glycinium, methylammoinum, dimethylammonium, ethylammonium, tromethamin and the like. Preferable weak base-forming cations are selected from the cationic portions of bases which have a base dissociation constant (pKb) greater than about 1, more preferably between about 3 and about 11.

A number of modified ion exchange materials suitable for the invention are commercially available. For example, Acetate and citric ionic forms of anion exchange materials are available from BIO-RAD Laboratories and Sybron Chemicals. Alternatively, suitably modified ion exchange materials can be produced from commercially available ion exchange materials by washing or exchanging the ion exchange material with an appropriate weak acid or weak base.

Unlike the prior art approach in increasing the pH of a solution, in which a cation exchange material is used to increase the pH, the present invention utilizes an anion exchange material in conjunction with a weak acid-forming counterion. One problem encountered with the prior art approach is that the cation exchange material, which itself is anionically charged, non-selectively attracts molecules having a cationic charge. Hence, if active ingredients are cationically charged in solution, the exchange material not only changes the pH of the solution, but also attracts and binds the active ingredients, thereby lowering the concentration of the active ingredients. In contrast, the present invention reiies on the weak acid-forming counter-anions carried by the modified exchange material to increase the pH of the solution, and the modified exchange material, which itself is cationically charged, does not attract the active ingredients. Similarly, a concentration reduction problem is also encountered with the prior art approach when an anion exchange material is used to decrease the pH of a solution and the active ingredients are anionic in solution. Again, unlike the prior art approaches, the present approach does not directly rely on the ion exchange material to change the pH of the solution, and the body of the ion exchange material of the present invention has the same ionic charge as the active ingredients in solution such that the pH of the solution is altered without affecting the concentration of the active ingredients.

As discussed above, the apparatus of the invention is adapted for changing the pH of liquid compositions as the compositions are dispensed from a container such that the composition can be stored at one pH and dispensed and used at another pH. The pH changing apparatus is particularly useful for liquid pharmaceutical compositions, including ophthalmic compositions. Suitable pharmaceutical compositions may contain a wide variety of active ingredients that are ionically charged in solution. Exemplary pharmaceutical compositions suitable for the present invention include intraocular pressure reducing agents, e.g., dipivefrin, epinephrine, pilocarpine, betaxolol and carteolol; beta-adrenoceptor blocking agent, e.g., levobunolol; allergy drops, e.g., naphazoline; anesthetic, e.g., proparacaine; antibiotics, e.g., bacitracin, polymyxin and vancomycin; and antihypertensive, e.g., hydralazine. Of the suitable pharmaceutical compositions, particularly suitable for the present invention are dipivefrin, epinephrine, pilocaprine, bacitracin, polymyxin, vancomycin, hydralazine and pharmaceutically acceptable salts thereof, and more particularly suitable are dipivefrin, epinephrine, pilocaprine and pharmaceutically acceptable salts thereof.

The present invention is further iliustrated with the following examples. However, the examples are not to be construed as limiting the invention thereto.

Examples For the following examples, the dispensing head of the dispenser is packed with between 0.2 and 0.5 g of an ion exchange material.

Example 1 An aqueous pilocarpine solution containing 2 % pilocarpine hydrochloride, 0.45 % hydroxypropyl methylcellulose (HPMC) and 0.75 % boric acid is prepared. The pH of the solution is adjusted to 4.05 using hydrochloric acid. The dispensing head of a dispenser, as disclosed in Figure 1, is packed with Bio-Rex5 in acetate ionic form, which is a styrene based anion exchange resin and available from BIO-RAD Laboratories, and the pilocarpine solution is placed in the container. The dispenser is inverted and the pilocarpine solution is dispensed drop-wise. The pilocarpine solution drops are collected, and the pH and the pilocarpine content of the collected drops are measured periodically. The concentration of pilocarpine is measured using an HPLC. The pH of the pilocarpine solution is changed to 6.2 and the concentration of pilocarpine is approximately same as the initial solution.

Example 2 An aqueous pilocarpine solution containing 2 % pilocarpine hydrochloride, 0.45 % HPMC, 0.4 % boric acid and 100 ppm benzalkonium chloride is prepared. The pH of the solution is adjusted to 4.05 using hydrochloric acid. A dispenser of the type described in Example 1 is packed with air dried Amberlite IRA-900 in acetate ionic form, which is a styrene based anion exchange resin and available from Rohm & Hass, and the pilocarpine solution is filled in the container. The drops are collected and analyzed as in Example 1.

The pilocarpine recovery % is the concentration of pilocarpine in the collected drops compared to the concentration in the original solution.

The results are shown in Table 1.

Table 1 Volume Collected Pilocarpine Recovery % (ml) (%) 0.089 103 5.71 0.177 103 5.85 0.354 110 6.00 2.020 102 5.87 3.550 98 5.86 6.626 101 5.61 Example 3 Example 2 is repeated except the dispenser is packed with vacuum dried ASB-1 in acetate ionic form, which is a styrene based anion exchange resin and available from Sybron Chemicals. The results are shown in Table 2.

Table 2 Volume Collected Pilocarpine Recovery % (ml) (%) 0.089 108 5.74 0.177 127 5.79 0.354 98 5.68 1.752 95 5.75 3.190 98 5.77 4.550 98 5.72 5.910 93 5.72 Comparative Example 1 An aqueous pilocarpine solution containing 2 % pilocarpine hydrochloride, 0.45 % HPMC, 0.6 % boric acid and 1.5 % KCI is prepared. The pH of the solution is adjusted to 4.06 using hydrochloric acid. The dispensing procedure outlined in Example 2 is repeated except Amberlite IRP-64 in sodium ionic form, a cation exchange resin, is packed in the dispenser head. The results are shown in Table 3.

Table 3 Volume Collected Pilocarpine Recovery E (ml) (%) 0.118 62 7.60 0.177 55 8.07 0.354 80 7.95 0.413 89 7.91 0.472 89 7.82 Comparative Example 2 Comparative Example 2 is repeated except the pilocarpine solution contained 2 % pilocarpine hydrochloride, 0.45 % HPMC, 0.3 % boric acid and 2 % KCI, and the pH of the solution is adjusted to 4.20. The results are shown in Table 4.

Table 4 Volume Collected Pilocarpine Recovery % (ml) (%) 0.118 62 7.67 0.177 60 8.04 0.354 84 7.92 0.413 88 7.92 0.472 89 7.83 As can be seen from Examples 1-3 and Comparative Examples 1-2, both modified anion exchange material of the present invention and cation exchange material of the comparative examples increased the pH of the pilocarpine solution. However, the complete or substantially complete recovery of the active ingredient shown by the anion exchange materials having a weak acid-forming counterion of Examples 1-3 compared to the relatively low recovery shown by the cation exchange materials of Comparative Examples 1-2 clearly demonstrates that the non-binding advantage of the present invention.

Example 4 Example 3 is repeated except AG 1-X8 in citrate ionic form, which is a styrene based anion exchange resin and available from BIO-RAD Laboratories, is used. The results are shown in Table 5.

Table 5 Volume Collected Pilocarnine Recoverv % (ml) (%) 0.089 102 5.75 0.177 115 6.58 0.354 100 6.68 0.443 97 6.49 2.208 98 6.02 The results demonstrate that an anion exchange resin having a weak acid-forming counterion other than acetate also desirably elevates the pH without significantly lowering the active ingredient concentration.

Example 5 An aqueous dipivefrin solution containing 0.1 % dipivefrin hydrochloride, 0.8 % NaCI and 0.01% EDTA is prepared. The pH of the solution is adjusted to 3.33 using hydrochloric acid. A dispenser of the type described in Example 1 is packed with a poiyethylene cartridge containing 15 wt% of A-490 in acetate ionic form, which is an acrylic based anion exchange resin and available from Sybron Chemicals, and the dipivefrin solution is filled in the container. The drops are collected and analyzed as in Example 1. The results are shown in Table 6.

Table 6 pH of pH of Volume Dipivefrin Solution Solution Collected Recoverv% Collected in the Dispenser (ml) (%) 0.09 97 6.84 - 0.36 107 6.76 3.88 0.45 106 6.75 - 0.54 98 6.78 - 2.36 105 5.94 3.82 2.45 110 5.96 - 2.54 98 6.03 3.89 Example 6 An aqueous dipivefrin solution containing 0.1 % dipivefrin hydrochloride, 0.5 % boric acid, 0.6 % NaCI, 0.01% EDTA and 0.01 % benzalkonium chloride is prepared. The pH of the solution is adjusted to 3.41 using hydrochloric acid. A dispenser of the type described in Example 1 is packed with air dried A-490 in acetate ionic form, and the dipivefrin solution is filled in the container. The drops are collected and analyzed as in Example 5. The results are shown in Table 7.

Table 7 Drops Collected Dipivefrin Recovery % (%) lst4drops 101 6.18 2nd 4 drops 109 6.69 3rd 4 drops 145 7.00 4th 4 drops 118 6.97 5th 4 drops 114 6.93 Tables 6 and 7 demonstrate that a modified acrylic based ion exchange material provides a desired pH change without absorbing the active ingredient. It is to be noted that the recovery percentage higher than 100 % is an initial phenomenon observed with non- styrenic ion exchange materials, and the recovery level promptly returns to approximateiy 100%. It is believed that the initial high recovery is due to the fact that the ion exchange material has the same ionic charge as the active ingredient, and therefore, initially when a steady state of flow is not reached, the active ingredient is repelled from the ion exchange material and rapidly passed on to the discharge opening of the dispenser, while the carrier and other components of the solution go through the interstices of the exchange material.

Example 7 Example 6 is repeated except ion exchange material SBMP1, in acetate ionic form, is used. SBMP1 is a styrene based anion exchange resin which is available from Resintech, NJ, USA. The results are shown in Table 8.

Table 8 Drops Collected Dipivefrin Recovery % (%) lst4drops 99 6.41 2nd 4 drops 91 6.80 3rd 4 drops 82 6.87 4th 4 drops 84 6.79 The styrenic ion exchange material also provides a desired pH change without absorbing significant amounts of the active ingredient. The low recovery level attained by the styrenic ion exchange material, compared to the acrylic ion exchange material, is believed to be caused by the hydrophobic styrene that forms the matrix of the ion exchange material. It is believed that the hydrophobic moiety of the ion exchange material attracts hydrophobic components of the solution including the active ingredient. It is to be noted that Examples-7 are run with a solution having a low concentration of the active ingredient in order to emphasize the efficacy of the present modified ion exchange material and to demonstrate the nonbinding nature of non-styrenic ion exchange materials.

Comparative Example 3 Comparative Example 3 and 4 are is designed to demonstrate that a strong acid- forming counterion containing ion exchange material does not provide a desirable pH change. An aqueous dipivefrin solution containing 0.1 % dipivefrin hydrochloride, 0.8 % NaCI and 0.01% EDTA is prepared. The pH of the solution is adjusted to 3.33 using hydrochloric acid. A dispenser of the type described in Example 1 is packed with an anion exchange resin in chloride form, A-490 from Sybron Chemicals, which is dried with a paper napkin. The drops are collected and analyzed as in Example 1. The results are shown in Table 9.

Table 9 pH of Volume Dipivefrin Solution Collected Recovery% Collected (ml) (%) 0.09 98 4.54 0.18 94 6.11 0.36 101 4.99 0.45 102 5.98 0.53 101 6.05 0.80 98 4.94 Comparative Example 4 Comparative Example 3 is repeated except air dried AG 1x8 in chloride form, which is available from Bio-Rad. The results are shown in Table 10.

Table 10 pH of Volume Dipivefrin Solution Collected Recovery % Collected (ml) (%) 0.09 139 4.27 0.18 81 4.53 0.27 67 4.42 0.36 60 4.34 The anion exchange resins of Comparative Examples 3 and 4, which have a strong acid-forming counter anion, only moderately elevate the pH of the solution, unlike the modified ion exchange materials of the present invention. This result clearly demonstrates that the modified ion exchange material of the present invention, which contains a weak- acid or weak-base forming counterion, provide desirable changes of the pH of a solution containing ionically charged active ingredients.

Unlike the prior art method for effecting a pH change of an active ingredient- containing solution, the present method which uses a modified ion exchange material changes the pH of the solution without significantly diminishing the concentration of the active ingredient in the solution.