PL205565B1

Olopatadine formulations for topical administration

Abstract

Topical formulations of olopatadine for treatment of allergic or inflammatory disorders of the eye and nose are disclosed. The aqueous formulations contain approximately 0.17 - 0.62% (w/v) of olopatadine and an amount of polyvinylpyrrolidone or polystyrene sulfonic acid sufficient to enhance the physical stability of the formulations.

PL205565B1, drawing sheet 1 — Sheet 1 of 1

Term

Term ended

Expired 19 June 2022, 4.3 years ago.

14 claims: 3 independent, 11 dependent

1
Topical solution composition for the treatment of allergic and / or inflammatory diseases of the eyes and nose, characterized in that it comprises 0.17 - 0.62% (w / v) olopatadine and a polymeric physical stability enhancing ingredient containing 0, 1 - 3% (w / v) polyvinylpyrrolidone or 0.1 - 1% (w / v) poly (styrene sulfonic acid), the composition does not contain polyvinyl alcohol, polyvinylacrylic acid, hydroxypropyl methylcellulose , sodium carboxymethyl cellulose and xanthan gum. 1. Kompozycja w postaci roztworu do podawania miejscowego do leczenia chorób alergicznych i/lub zapalnych oczu i nosa, znamienna tym, że zawiera 0,17 - 0,62% (wag./obj.) olopatadyny oraz polimerowy składnik zwiększający stabilność fizyczną, zawierający 0,1 - 3% (wag./obj.) poliwinylopirolidonu lub 0,1 - 1% (wag./obj.) poli(kwasu styrenosulfonowego), przy czym kompozycja nie zawiera poli(alkoholu winylowego), poli(kwasu winyloakrylowego), hydroksypropylometylocelulozy, soli sodowej karboksymetylocelulozy i gumy ksantanowej.
12
Use of olopatadine in combination with a polymeric physical stability enhancing ingredient containing polyvinylpyrrolidone or poly (styrene sulfonic acid) for the manufacture of a medicament for the treatment of allergic and / or inflammatory diseases of the eye, the medicament being in the form of a topical ophthalmic solution containing 0.17- 0.25% (w / v) olopatadine and 0.1 - 3% (w / v) polyvinylpyrrolidone or 0.1 - 1% (w / v) poly (styrene sulfonic acid) and does not contain poly (vinyl alcohol), poly (vinylacrylic acid), hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose and xanthan gum. 12. Zastosowanie olopatadyny w kombinacji z polimerowym składnikiem zwiększającym stabilność fizyczną, zawierającym poliwinylopirolidon lub poli(kwas styrenosulfonowy) do wytwarzania leku do leczenia chorób alergicznych i/lub zapalnych oczu, przy czym lek ma postać roztworu do podawania miejscowego do oczu, który zawiera 0,17 - 0,25% (wag./obj.) olopatadyny i 0,1 - 3% (wag./obj.) poliwinylopirolidonu lub 0,1 - 1% (wag./obj.) poli(kwasu styrenosulfonowego) i nie zawiera poli(alkoholu winylowego), poli(kwasu winyloakrylowego), hydroksypropylometylocelulozy, soli sodowej karboksymetylocelulozy i gumy ksantanowej.
13
Use of olopatadine in combination with a polymeric physical stability enhancing ingredient containing polyvinylpyrrolidone and / or poly (styrene sulfonic acid) in the manufacture of a medicament for the treatment of allergic and / or inflammatory diseases of the nose, the medicament being in the form of a topical nasal solution having a pH in the range of 3 5 - 8, which contains 0.17-0.62% (w / v) olopatadine and 0.1-3% (w / v) polyvinylpyrrolidone or 0.1-1% (w / v) poly (styrene sulfonic acid) and does not contain polyvinyl alcohol, polyvinylacrylic acid, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose and xanthan gum. 13. Zastosowanie olopatadyny w kombinacji z polimerowym składnikiem zwiększającym stabilność fizyczną, zawierającym poliwinylopirolidon i/lub poli(kwas styrenosulfonowy) do wytwarzania leku do leczenia chorób alergicznych i/lub zapalnych nosa, przy czym lek ma postać roztworu do podawania miejscowego do nosa o pH w zakresie 3,5 - 8, który zawiera 0,17 - 0,0,62% (wag./obj.) olopatadyny i 0,1 - 3% (wag./obj.) poliwinylopirolidonu lub 0,1 - 1% (wag./obj.) poli(kwasu styrenosulfonowego) i nie zawiera poli(alkoholu winylowego), poli(kwasu winyloakrylowego), hydroksypropylometylocelulozy, soli sodowej karboksymetylocelulozy i gumy ksantanowej.

Independent claims3

347 paragraphs in 7 sections, as filed

Description of the invention

The present invention relates to topical compositions for the treatment of allergic and inflammatory diseases. More specifically, the present invention relates to a solution composition containing olopatadine for topical administration to the eyes and nose for the treatment of allergic and / or inflammatory diseases, a method for the preparation of such a composition and the use of olopatadine in combination with a polymeric physical stability ingredient for the preparation of a medicament for the treatment and / or prevention of allergic and / or inflammatory diseases of the eyes and nose.

As reported in U.S. Patent Nos. 4,871,865 and 4,923,892, both owned by Borroughs Wellcome Co. ("Burroughs Welcom patents"), certain carboxylic (acid) derivatives of doxepin, including olopatadine (chemical name: Z-11- (3-dimethylaminopropylidene acid) -6,11-dihydrodibenz [b, e] oxepine- 2-acetic acid), have antihistaminic and anti-asthmatic effects. These two patents classify carboxyl (acid) derivatives of doxepin as mast cell stabilizers with antihistamine activity because they are believed to inhibit the release of autacoids (i.e., histamine, serotonin, and the like) from mast cells, and that they directly inhibit the effects of histamine on target cells . The Burroughs Wellcome patents disclose various pharmaceutical formulations containing carboxylic (acid) derivatives of doxepin, including nasal spray and ophthalmic formulations. See, for example, Col. 7 lines 7-26 and Examples 8 (H) and 8 (I) of the '865 Patent.

In US Patent No. 5,116,863 to Kyowa Hakko Kogyo Co., Ltd., ("Kyowa Patent"), it is disclosed that doxepin derivatives with an acetic acid group, and in particular olopatadine, have antiallergic and anti-inflammatory effects. Olopatadine is the cis form of the compound with the formula:

The drug forms disclosed in the Kyowa patent containing doxepin derivatives with an acetic acid group include a wide range of acceptable carriers; however, only oral and injectable administration forms are mentioned.

U.S. Patent No. 5,641,805 to Alcon Laboratories, Inc. and Kyowa Hakko Kogyo Co.,

Ltd., discloses topical eye formulations containing olopatadine for the treatment of allergic eye diseases. According to the '805 patent, the topical formulations may be solutions, suspensions, or gels. These formulations contain olopatadine, an isotonic agent and "if desired, a preservative, buffering agent, stabilizer, viscous carrier and the like." See col. 6, lines 30-43. As the sticky carrier, "polyvinyl alcohol, polyvinylpyrrolidone, poly (acrylic acid) or the like" is mentioned. See col. 6, lines 55 - 57.

PATANOL® (Olopatadine HCl Ophthalmic Solution) 0.1% is currently the only commercially available ophthalmic product containing olopatadine. As stated on the label, it contains olopatadine hydrochloride equivalent to 0.1% olopatadine, 0.01% benzalkonium chloride and unspecified amounts of sodium chloride, sodium hydrogen phosphate, hydrochloric acid and / or sodium hydroxide (for pH adjustment) and purified water. It does not contain polyvinyl alcohol, polyvinylpyrrolidone, polyacrylic acid or any other polymeric component.

Formulations containing olopatadine that have a prolonged therapeutic effect and are effective as products for the treatment of allergic and / or inflammatory diseases of the eye and nose are desirable. Desirable are topical olopatadine formulations which are effective as once daily products for the treatment of eye allergic diseases.

The present invention provides topical olopatadine formulations which are effective as once daily products for the treatment of allergic and / or inflammatory diseases of the eye and are effective in the treatment of allergic and / or inflammatory diseases of the nose. The formulations of the present invention are aqueous solutions that contain about 0.2-0.6% olopatadine. In addition to the relatively high concentration of olopatadine, they also contain sufficient polyvinylpyrrolidone or poly (styrene sulfonic acid) to increase the physical stability of the solutions.

PL 205 565 B1

Among other factors, the present invention is based on the finding that polyvinylpyrrolidone and poly (styrene sulfonic acid), as opposed to polyvinyl alcohol and polyacrylic acid, Carbomer 974P, increase the physical stability of solutions containing about 0.2-0, 6% olopatadine.

Thus, the topical solution composition for the treatment of allergic and / or inflammatory diseases of the eyes and nose according to the invention is characterized in that it comprises 0.17 - 0.62% (w / v) olopatadine and a polymeric stability enhancing ingredient. physical, containing 0.1 - 3% (w / v) polyvinylpyrrolidone or 0.1 - 1% (w / v) poly (styrene sulfonic acid), the composition does not contain poly (vinyl alcohol), poly ( vinylacrylic acid), hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and xanthan gum.

Preferably, the composition of the invention comprises 0.18-0.22% (w / v), and more preferably 0.38-0.62% (w / v) of olopatadine.

In one embodiment, the composition of the invention preferably comprises polyvinylpyrrolidone with an average molecular weight of 5,000-1600,000, and more preferably 50,000-60,000.

The amount of polyvinylpyrrolidone in the composition according to the invention is preferably 1.5-2% (w / v).

Preferably, the polyvinylpyrrolidone is a copolymer of vinylpyrrolidone and vinyl acetate.

In another embodiment, the composition according to the invention preferably comprises poly (styrene sulfonic acid) with an average molecular weight of 10,000-1500,000.

Preferably, the poly (styrene sulfonic acid) is a copolymer of styrene sulfonic acid and maleic anhydride.

According to the invention, the process for preparing the solution composition as defined above when it comprises polyvinylpyrrolidone comprises the step of treating the aqueous polyvinylpyrrolidone solution at a temperature above room temperature for a time sufficient to reduce or eliminate the peroxides in the aqueous polyvinylpyrrolidone solution before combining it with olopatadine .

Preferably, this method comprises the step of treating the aqueous polyvinylpyrrolidone solution having a pH of 11-13, a temperature in the range of 60-121 ° C for 30-120 minutes before combining it with olopatadine.

It is further within the scope of the invention to use olopatadine in combination with a polymeric physical stability-enhancing ingredient containing polyvinylpyrrolidone or poly (styrene sulfonic acid) for the manufacture of a medicament for the treatment of allergic and / or inflammatory diseases of the eye, the medicament being in the form of a topical ophthalmic solution. which contains 0.17-0.25% (w / v) olopatadine and 0.1-3% (w / v) polyvinylpyrrolidone or 0.1-1% (w / v) poly (acid) styrene sulfonic acid) and does not contain polyvinyl alcohol, polyvinylacrylic acid, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose and xanthan gum.

Also within the scope of the invention is the use of olopatadine in combination with a polymeric physical stability enhancing ingredient containing polyvinylpyrrolidone or poly (styrene sulfonic acid) for the manufacture of a medicament for the treatment of allergic and / or inflammatory diseases of the nose, the medicament being in the form of a topical nasal solution, pH in the range of 3.5 - 8, which contains 0.17-0.62% (w / v) olopatadine and 0.1-3% (w / v) polyvinylpyrrolidone or 0.1-1% (w / v) poly (styrene sulfonic acid) and does not contain polyvinyl alcohol, polyvinylacrylic acid, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose and xanthan gum.

Preferably, the solution contains 0.38-0.62% (w / v) olopatadine and has a pH in the range 3.8-4.4.

Unless otherwise indicated, amounts of all ingredients are% (w / v) and all references to olopatadine are to olopatadine free base.

Olopatadine is a known compound that can be obtained by the methods disclosed in US Patent No. 5,116,863, the entire contents of which are hereby incorporated by reference. The solution formulations of the present invention contain 0.17-0.62% olopatadine. Preferably, ophthalmic solution formulations contain 0.17-0.25%, and more preferably 0.18-0.22% olopatadine. Solution formulations for nasal application preferably contain 0.38-0.62% olopatadine.

Generally, olopatadine is added in the form of a pharmaceutically acceptable salt. Examples of the pharmaceutically acceptable salts of olopatadine include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, and phosphate; organic acid salts such as acetate, maleate, fumarate, tartrate, and citrate; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; metal salts such as aluminum salt

PL 205 565 B1 and zinc salt; and organic amine addition salts such as triethylamine addition salt (also known as tromethamine), morpholine addition salt and piperidine addition salt. The most preferred form of olopatadine for use in the solutions of the present invention is (Z) -11- (3-dimethylamino-propylidene) -6,11-dihydrodibenz- [b, e] -oxepine-2-acetic acid hydrochloride. When olopatadine is added to the compositions of the present invention in the form of this salt, 0.222% olopatadine hydrochloride is equivalent to 0.2% olopatadine free base, 0.443% olopatadine hydrochloride is equivalent to 0.4% olopatadine free base, and 0.665% olopatadine hydrochloride. olopatadine is equivalent to 0.6% olopatadine free base.

In addition to olopatadine, the aqueous solution compositions of the present invention contain polyvinylpyrrolidone or poly (styrene sulfonic acid) in an amount sufficient to increase the physical stability of the composition. Polyvinylpyrrolidone and poly (styrene sulfonic acid) are known polymers, and both are commercially available from a variety of sources in a variety of grades and molecular weights. For example, polyvinylpyrrolidone is available in a number of grades from International Specialty Products (Wayne, NJ): Plasdone® C-15 (average molecular weight MW = 8K), K-26/28 (average molecular weight MW = 30K), K -29/32 (average molecular weight MW = 58K), K-30 (average molecular weight MW = 50K) and K-90 (average molecular weight MW = 1300K). Polyvinylpyrrolidone is also available from BASF Corporation under the name Kollidon. The term "polyvinylpyrrolidone" as used in this specification includes vinylpyrrolidone homopolymers and vinylpyrrolidone and vinyl acetate copolymers. Vinylpyrrolidone-vinyl acetate copolymers are known as "copovidone" and are available from BASF Corporation as Kollidon VA 64. As mentioned above, the polyvinylpyrrolidone contained in the solution compositions of the invention has an average molecular weight of preferably 5,000-16,000,000, and most preferred is polyvinylpyrrolidone with an average molecular weight of 50,000-60,000. The amount of polyvinylpyrrolidone contained in the compositions of the present invention is 0.1-3%. preferably 0.2-2% and most preferably 1.5-2%.

Poly (styrene sulfonic acid) is commercially available in many grades including, for example, the following available from Alco Chemical, a Division of National Starch & Chemical Company: Versa TL-70 (average molecular weight MW = 75,000), Versa TL-125 (average weight molecular weight MW = 200,000) and Versa TL-502 (average molecular weight MW = 1,000,000). The term "poly (styrene sulfonic acid)" in this specification includes styrene sulfonic acid homopolymers and salts as well as copolymers of styrene sulfonic acid and maleic anhydride. The poly (styrene sulfonic acid) contained in the solutions of the present invention has an average molecular weight of 10,000 1,500,000, preferably 75,000 to 1,000,000, and most preferably 75,000. The amount of poly (styrene sulfonic acid) contained in the compositions of the present invention is 0.1-1%, preferably 0.15-0.4%, most preferably 0.25%.

The compositions of the present invention contain 0.17-0.62% olopatadine and a polymeric physical stability component consisting essentially of polyvinylpyrrolidone or poly (styrene sulfonic acid) in an amount sufficient to increase the physical stability of the solution. The compositions of the present invention do not contain polyvinyl alcohol, polyvinylacrylic acid, hydroxypropylmethyl cellulose, sodium carbyxymethyl cellulose, xanthan gum and other polymeric ingredients to enhance physical stability.

The compositions of the present invention have a viscosity of 5 · 10-4 - 1·10-2 Pa. S (0.5-10 cP), preferably 5 · 10-4 - 5·10-3 Pa. S (0.5-5 cP), most preferably 10-3 - 5·10-3 Pa ^ s (1-2 cP). This relatively low viscosity makes the product comfortable, non-blurry, and easy to process, transfer, and fill.

In addition to olopatadine and polyvinylpyrrolidone, the compositions of the present invention optionally contain one or more excipients. Excipients commonly used in pharmaceutical compositions intended for topical administration to the eyes or nose, such as solutions or sprays, include, but are not limited to, tonicity adjusting agents, preservatives, chelating agents, buffering agents, surfactants, and antioxidants. Suitable tonicity-adjusting agents include mannitol, sodium chloride, glycerin, sorbitol, and the like. Suitable preservatives include p-hydroxybenzoic acid ester, benzalkonium chloride, benzododecinium bromide, polyquaternium-1 and the like. Suitable chelating agents include disodium EDTA and the like. Suitable buffering agents for phosphates, borates, citrates, acetates and the like. Suitable surfactants include ionic and nonionic surfactants, although nonionic surfactants such as polysorbates, polyethoxylated castor oil derivatives and ethoxylated polymer of tertiary octylphenol and formaldehyde (tyloxapol) are preferred. Suitable antioxidants include sulfites, ascorbates, BHA and BHT. The compositions of the present invention optionally contain an additional active ingredient. With the exception of a preservative (e.g. polyquaternium-1), the compounds of the present invention preferably do not contain any polymeric component other than polyvinylpyrrolidone or poly (styrene sulfonic acid).

In particular, compositions to be administered in the form of eye drops preferably contain a tonicity adjusting agent in an amount sufficient that the final composition has an ophthalmically acceptable osmolality (generally 150-450 mOsm, preferably 250-350 mOsm). The ophthalmic compositions of the present invention preferably have a pH of 4-8, preferably 6.5-7.5 and most preferably 6.8-7.2. The nasal compositions of the present invention preferably have a pH of 3.5-8. More preferably, the nasal compositions have a pH of 3.5-4.5, most preferably a pH of 3.8-4.4.

When the compositions of the present invention contain polyvinylpyrrolidone, this component is preferably selected or prepared with the aim of minimizing the peroxide content. Freshly prepared lots of polyvinylpyrrolidone are preferred over old lots. In addition, especially in cases where the compositions contain more than 0.5% polyvinylpyrrolidone, the component should be heat treated (i.e. heated to above room temperature) prior to mixing olopatadine in order to reduce the amount of peroxides in it and to minimize the effect of peroxides on chemical stability. olopatadine. Although heat treatment of the aqueous polyvinylpyrrolidone solution over an extended period will significantly reduce the amount of peroxides, it can discolor the polyvinylpyrrolidone solution (yellow or yellowish brown). In order to significantly reduce or eliminate peroxides without discoloration of the polyvinylpyrrolidone solution, the pH of this aqueous solution should be adjusted to a value of 11-13 before heating. A much shorter heating time is required to achieve a significant reduction in the level of peroxides if the pH level of the polyvinylpyrrolidone solution is raised.

One suitable method of heat treating polyvinylpyrrolidone is as follows. First, polyvinylpyrrolidone is dissolved in purified water to form a 4 - 6% solution, then - the pH of the solution is increased to 11 - 13, preferably 11 - 11.5, and then - heated to a temperature in the range of 60 - 121 ° C, preferably 65-80 ° C, most preferably 70-75 ° C. The elevated temperature should be maintained for about 30-120 minutes (preferably 30 minutes). After cooling the warmed solution to room temperature, HCl is added to adjust the pH to 3.5-8 depending on the expected pH level of the olopatadine-containing composition.

The compositions of the present invention are preferably packaged in opaque plastic containers. A preferred container for an ophthalmic product is a low density polyethylene container that has been sterilized with ethylene oxide instead of gamma irradiation. A preferred nasal product container is a high-density polyethylene container equipped with a nasal spray pump.

Certain embodiments of the invention are illustrated in the following examples.

Example 1: Topical Ophthalmic Solution

Ingredient Concentration (% w / v

(Z) -11- (3-dimethylaminopropylidene) -6,11-dihydrodibenz [b, e] oxepine-2-acetic acid hydrochloride - ("olopatadine-HCl")

Polyvinylpyrrolidone

Sodium chloride

Benzalkonium chloride

EDTA disodium salt

Sodium hydrogen phosphate (anhydrous)

NaOH / HCl

Purified water

0,222* *

1,6 - 2,0

0,55

- 0,02

0,01

0,5

qs pH 7.0 ± 0.2 qs 100 * equivalent to 0.2% of the free base

A typical method of making a solution composition for the composition of this example is shown below.

PL 205 565 B1

Preparation of polyvinylpyrrolidone stock solution

A 4% polyvinylpyrrolidone stock solution is prepared by dissolving polyvinylpyrrolidone in purified water, adding NaOH to raise the pH to 11.5 and heating for 30 minutes at 70-75 ° C. After cooling to room temperature, HCl is added to the stock solution to adjust the pH to 7.

Procedure for the preparation of the composition

Purified water, sodium hydrogen phosphate, sodium chloride, disodium EDTA, benzalkonium chloride (as a 1% stock solution), and polyvinylpyrrolidone (as a 4% stock solution) are added to the container with mixing after adding each ingredient. NaOH is added to adjust the pH to about 7.0, then drug is added, then the final pH is adjusted to 7.0 and the rest of the purified water is added with mixing after each addition. The resulting solution is filtered through a sterilizing filter and poured under sterile conditions into LDPE containers sterilized with ethylene oxide or polypropylene containers.

Example 2: Topical Ophthalmic Solution

Ingredient Concentration (% w / v)

Olopatadine ^ HCl 0.222 *

N-lauroyl sarcosine 0.04

Poly (styrene sulfonic acid) 0.5

Mannitol 4.4

Benzalkonium chloride 0 - 0.02

Boric acid 0.4 5

EDTA disodium salt 0.05

Tromethamine qs pH 6.5 ± 0.2

Purified water_g. s. 100_ * 'equivalent to 0.2% of the free base

A typical method of making a solution composition for the composition of this example is shown below.

Procedure for the preparation of the composition

Purified water, mannitol, boric acid, EDTA disodium salt, benzalkonium chloride (as a 1% stock solution), and poly (styrene sulfonic acid) (as a powder) are added to the container with mixing as each ingredient is added. Tromethamine is added to adjust the pH to about 6.5, then N-lauroyl sarcosine and drug are added, then the final pH is adjusted to 6.5 and the rest of the purified water is added while mixing after each component has been added. The resulting solution is filtered through a sterilizing filter and poured under sterile conditions into LDPE containers sterilized with ethylene oxide or polypropylene containers.

Example 3: Nasal solution for topical administration

Ingredient Concentration (% w / v)

Olopatadine ^ HCl 0.222 *

Polyvinylpyrrolidone 1.6 - 2.0

Sodium chloride 0.3 - 0.6

Benzalkonium chloride 0 - 0.02

EDTA disodium salt 0.01

Sodium hydrogen phosphate anhydrous 0.5

NaOH / HCl qs pH 3.8 - 7

Purified water_g. s. 100_ * 'equivalent to 0.2% of the free base

A typical method of making a solution composition for the composition of this example is shown below.

Preparation of polyvinylpyrrolidone stock solution

PL 205 565 B1

Procedure for the preparation of the composition

Purified water, sodium hydrogen phosphate, sodium chloride, disodium EDTA, benzalkonium chloride (as a 1% stock solution) and polyvinylpyrrolidone (as a 4% stock solution) and the drug are added to the container with mixing as each component is added. NaOH / HCl is added to adjust the pH to about 4, then the rest of the purified water is added. The resulting solution is filtered through a sterilizing filter and poured under sterile conditions into high-density polyethylene containers with a spray pump.

Example 4: Nasal solution for topical administration

Ingredient Concentration (% w / v)

Olopatadine HCl 0.443 *

Polyvinylpyrrolidone 1.6 - 2.0

Sodium chloride 0.3 - 0.6

Benzalkonium chloride 0.01 + 3% wt.

EDTA disodium salt 0.01

Sodium hydrogen phosphate (anhydrous) 0.5

NaOH / HCl qs pH 3.8 - 4.4

Purified Water_q. s. 100_ * equivalent to 0.4% of the free base

The solution composition of this Example may be prepared using the method set out above for the solution composition of Example 3.

Example 5: The prepared compositions, shown in Table 1 below, were subjected to stability studies. In no event was the polymeric component autoclaved and none of the compositions was filtered through a 0.2 µm filter. One set of samples (two vials) of each composition was subjected to three refrigeration cycles: cooling - room temperature, and the other set of samples (two vials) was subjected to continuous low temperature exposure. The results are shown in Table 2 below.

PL 205 565 B1

Table 1

<td></td><td colspan="7">FORMULATION</td>

<td>INGREDIENT</td><td colspan="2">AB</td><td>C.</td><td>D</td><td>E.</td><td>F.</td><td>G.</td>

<td></td><td colspan="7">Concentration (% w / w)</td>

<td>Olopatadine ^ HCl</td><td> 0,222</td><td> 0,222</td><td> 0,222</td><td> 0,222</td><td> 0,222</td><td> 0,222</td><td> 0,222</td>

<td>Poly (vinyl alcohol) (Airvol 2055)</td><td> 0,1</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Hydroxy pylmethylcellulose (2910)</td><td></td><td> 0,05</td><td></td><td></td><td></td><td></td><td></td>

<td>Xanthan Gum (AR)</td><td> —</td><td> ---</td><td> 0,02</td><td> ---</td><td> ---</td><td> ---</td><td> ---</td>

<td>Carbopol 974P</td><td> —</td><td> ---</td><td> ---</td><td> 0,01</td><td> ---</td><td> ---</td><td> ---</td>

<td>Polyvinylpyrrolidone (average molecular weight MW = 58K)</td><td> ---</td><td> ---</td><td> ---</td><td> ---</td><td> 1,0</td><td> 1,8</td><td> ---</td>

<td>Sodium carboxymethylcellulose (762p)</td><td> —</td><td> ---</td><td> ---</td><td> ---</td><td> ---</td><td> ---</td><td> 0,1</td>

<td>Benzalkonium chloride</td><td>0.01 + 1% overload</td><td>0.01 + 1% over m.</td><td>0.01 + 1% overload</td><td>0.01 + 1% overload</td><td>0.01 + 1% overload</td><td>0.01 + 1% overload</td><td>0.01 + 1% overload</td>

<td>Sodium chloride</td><td> 0,6</td><td> 0,6</td><td> 0,6</td><td> 0,6</td><td> 0,6</td><td> 0,6</td><td> 0,6</td>

<td>Sodium hydrogen phosphate (anhydrous)</td><td> 0,5</td><td> 0,5</td><td> 0,5</td><td> 0,5</td><td> 0,5</td><td> 0,5</td><td> 0,5</td>

<td>Purified water</td><td>qs 100</td><td>qs 100</td><td>qs 100</td><td>qs 100</td><td>qs 100</td><td>qs 100</td><td>qs 100</td>

<td>Viscosity (cP)</td><td> 1,02</td><td> 1,40</td><td> 1,42</td><td> 0,97</td><td> 1,20</td><td> 1,45</td><td> 1,16</td>

* Brookfield viscometer (60 RPM, CP-42)

PL 205 565 B1

Table 2

<td rowspan="2">Formulation</td><td colspan="2">Cycles: chill-room temperature</td><td colspan="3">Constant low temperature operation</td>

<td>One cycle</td><td>Three cycles</td><td>Day 7</td><td>Day 14</td><td>Day 28</td>

<td>AND</td><td>Clear, no particles</td><td>Clear, few particles (one vial)</td><td>Clear, few particles</td><td>Clear, fibrous particles</td><td>Clear, particles</td>

<td>B</td><td>Clear, no particles</td><td>Clear crystal (2 mm) in one vial</td><td>Transparent, particles and crystals</td><td>Clear, crystals and fibrous particles</td><td>Clear, crystals</td>

<td>C.</td><td>Clear, no particles</td><td>Clear, crystals</td><td>Clear, crystals</td><td>Clear, crystals</td><td>Clear, crystals</td>

<td>D</td><td>Clear, lots of crystals</td><td>Clear, lots of crystals</td><td>Clear, lots of crystals</td><td>Clear, lots of crystals</td><td>Clear, crystals</td>

<td>E.</td><td>Clear, no particles</td><td>Clear, no particles</td><td>Clear, no particles</td><td>Clear, no particles</td><td>Clear, no particles</td>

<td>F.</td><td>Clear, no particles</td><td>Clear, no particles</td><td>Clear, no particles</td><td>Clear, no particles</td><td>Clear, no particles</td>

<td>G.</td><td>Clear, no particles</td><td>Transparent, crystals</td><td>Transparent, crystals</td><td>Clear, crystals</td><td>Transition , crystals</td>

Example 6: The compositions shown in Table 3 below were tested for freeze-melt stability under two different conditions (seeded and seedless; seed = 0-1 / 2 Canyon pumice (ex Charles B. Chrystal Co., Inc., New York, New York) in the amount of mg per 5 ml of formulation) at two temperatures (0 ° C or -20 ° C). In no event was the polymeric component autoclaved and none of the compositions was filtered through a 0.2 µm filter. One set of samples (two vials) of each composition was subjected to six freeze-melt cycles where one cycle was three days at low temperature (i.e., 0 ° C or -20 ° C) followed by one day at uncontrolled room temperature. The compositions were visually inspected and the results recorded. The results are shown in Table 4 below.

Table 3

<td></td><td colspan="3">FORMULATION</td>

<td>Ingredient</td><td>H.</td><td>AND</td><td>J.</td>

<td></td><td colspan="3">Concentration (% w / w)</td>

<td>Olopatadine BCl</td><td> 0,222</td><td> 0,222</td><td> 0,222</td>

<td>Benzalkonium chloride</td><td>0.01 + 3% overload</td><td>0.01 + 3% excess.</td><td>0.01 + 3% overload</td>

<td>EDTA disodium salt</td><td> 0,01</td><td> 0,01</td><td> 0,01</td>

<td>Hydroxypropyl methylcellulose</td><td> 1,8</td><td> —</td><td> —</td>

<td>Carbopol 974P</td><td> —</td><td> 0,6</td><td> —</td>

Table 3 continued

<td>Poly (vinyl alcohol) (Airvol 205S)</td><td> —</td><td> ---</td><td> 1,8</td>

<td>Sodium chloride</td><td> 0,55</td><td> 0,55</td><td> 0,55</td>

<td>Sodium hydrogen phosphate (anhydrous)</td><td> 0,5</td><td> 0,5</td><td> 0,5</td>

<td>Purified water</td><td>qs 100%</td><td>qs 100%</td><td>qs 100%</td>

Table 4

<td>FORMULATION</td><td>OBSERVATIONS</td>

<td>H.</td><td>Sediment-free after 6 cycles with or without nucleation at all temperatures</td>

<td>AND</td><td>Hazy from cycle 1 with or without nuclei at both temperatures</td>

<td>J.</td><td>Sediment-free after 6 cycles with or without nucleation at all temperatures</td>

Example 7: The compositions shown in Table 5 below were tested for freeze-melt stability under two different conditions (seeded and seedless; seed = same as in Example 4 above) at two temperatures (0 ° C). or -20 ° C). In no event was the polymeric component autoclaved and none of the compositions was filtered through a 0.2 µm filter. Each composition (three vials each) was subjected to six freeze-thaw cycles, one cycle of three days at low temperature (i.e.

0 ° C or -20 ° C), then one day at room temperature. The compositions were visually inspected and the results recorded. The results are shown in Table 6 below.

Table 5

<td>Ingredient</td><td colspan="8">FORMULATION</td><td></td>

<td></td><td colspan="8">Concentration (% w / w)</td><td></td>

<td>Olopatadine HCl</td><td> 0,222</td><td> 0,222</td><td> 0,222</td><td> 0,222</td><td> 0,222</td><td> 0,222</td><td> 0,333</td><td> 0,333</td><td> 0,333</td>

<td>Polyvinylpyrrolidone (average molecular weight MW = 58K)</td><td> 2</td><td> 2</td><td></td><td> 1,8</td><td></td><td></td><td> 2</td><td> 2</td><td></td>

<td>Poly (ethylene glycol) (400)</td><td></td><td> 2</td><td> 2</td><td></td><td></td><td></td><td></td><td> 2</td><td></td>

<td>Polyvinylpyrrolidone (average molecular weight MW = 1300K)</td><td></td><td></td><td></td><td></td><td> 1,8</td><td></td><td></td><td></td><td> 2</td>

PL 205 565 B1 cont. table 5

<td>Chloride benzalkonium</td><td>0.01 + 3% override</td><td> 0,01</td><td>0.0 + 3% override</td><td>0.01 + 3% override</td><td>0.01 + 3% override</td><td>0.01 + 3% override</td><td>0.01 + 3% override</td><td> 0,01</td><td> 0,01</td>

<td>Sodium hydrogen phosphate (anhydrous)</td><td> 0,5</td><td> 0,5</td><td> 0,5</td><td> 0,5</td><td> 0,5</td><td> 0,5</td><td> 0,5</td><td> 0,5</td><td> 0,5</td>

<td>Sodium chloride</td><td> 0,55</td><td> 0,3</td><td> 0,3</td><td> 0,55</td><td> 0,55</td><td> 0,6</td><td> 0,55</td><td> 0,3</td><td> 0,3</td>

<td>Disodium salt EDTA</td><td> 0,02</td><td> 0,01</td><td> 0,01</td><td> 0,02</td><td> 0,02</td><td> ---</td><td> 0,02</td><td> 0,01</td><td> 0,01</td>

<td>Cleared water</td><td>qs 100</td><td>qs 100</td><td>qs 100</td><td>qs 100</td><td>qs 100</td><td>qs 100</td><td>qs 100</td><td>qs 100</td><td>qs 100</td>

Table 6

<td></td><td colspan="5">OBSERVATIONS (number of vials containing sediment)</td>

<td>FORMULATION</td><td># cycles</td><td>The embryos crystallization at 0 ° C</td><td>The embryos crystallization -20 ° C</td><td>Seed free 0 ° C</td><td>Without seeds of crystallization -20 ° C</td>

<td>P.</td><td> 5</td><td> 1/3</td><td>0/3 (6 cycles)</td><td> 2/3</td><td>2/3 (6 cycles)</td>

<td>Q</td><td> 5</td><td> 3/3</td><td>0/3 (6 cycles)</td><td> 3/3</td><td>0/3 (6 cycles)</td>

<td>S.</td><td> 5</td><td>3/3 (3 cycles)</td><td> 3/3</td><td>3/3 (3 cycles)</td><td> 2/3</td>

Example 8: The formulations shown in Table 7 were prepared and subjected to a freeze-melt test for 5.5 cycles. For one set of samples, one cycle was defined as one week at 0 ° C followed by one week at uncontrolled room temperature (approximately 21 ° C). For the second set of samples, one cycle was defined as one week at -20 ° C followed by one week at uncontrolled room temperature (about 21 ° C). The results are presented in Table 8.

PL 205 565 B1

Table 7

<td rowspan="3">INGREDIENT</td><td colspan="2">FORMULATION</td>

<td>Concentration (%</td><td>weight / weight)</td>

<td>Olopatadine HCl</td><td> 0,222</td><td> 0,222</td>

<td>Poly (styrene sulfonic acid) (average molecular weight MW = 1000K)</td><td> 0,25</td><td> 0,5</td>

<td>Benzalkonium chloride</td><td> 0,01</td><td> 0,01</td>

<td>EDTA disodium salt</td><td> 0,05</td><td> 0,05</td>

<td>Mannitol</td><td> 4,4</td><td> 4,4</td>

<td>Boric acid</td><td> 0,45</td><td> 0,45</td>

<td>N-lauroyl sarcosine</td><td> 0,04</td><td> 0,04</td>

<td>Tromethamine / HCl</td><td>qs pH 6.5</td><td>qs pH 6.5</td>

<td>Purified water</td><td>qs 100</td><td>qs 100</td>

Table 8

<td>FORMULATION</td><td>OBSERVATIONS</td>

<td>T.</td><td>No deposit at any temperature</td>

<td>AT</td><td>No deposit at any temperature</td>

Example 9: Seven prepared compositions were subjected to freeze-melt tests. Each of the seven compositions contained purified water, 0.222% w / w. Olopatadine Hydrochloride, 0.01% w / w (+ 3% excess) of benzalkonium chloride, 0.06 wt. sodium chloride, 0.5 wt. Sodium hydrogen phosphate and NaOH to adjust pH = 7. These samples differed in the amount or grade (molecular weight) of polyvinylpyrrolidone they contained, as shown in Table 9. In no event was the polymeric component autoclaved and the compositions were filtered through a 0.2 µm filter. The seven samples were placed in scintillation vials containing stir bars and were subjected to freeze-melt stability studies under two different conditions and at two temperatures (3-4 ° C or -21 ° C). After six cycles of 3 days at low temperature and one day at room temperature (with stirring), the samples were subjected to 3.5 cycles of one week at low temperature followed by one week at room temperature (no stirring). Although fibers were observed in several samples during the test, no crystals were observed in any of the samples by the end of the test. At the end of the test, the stir bars were removed and the samples (samples from parallel determinations of each composition) were visually inspected. The results are presented in Table 9.

Table 9

<td>A sample</td><td>Polyvinylpyrrolidone (% w / w); Wed molecular weight MW</td><td>Particles Constant</td><td>Fibers / particles amorphous</td><td>Clarity</td>

<td colspan="5">Cooling (3-4 ° C)</td>

<td>9.1A</td><td>Lack</td><td>Lack</td><td>Fibers</td><td>Clear</td>

<td>9.1B</td><td>Lack</td><td>Crystals</td><td>amorphous particles</td><td>Hazy</td>

<td>9.2A</td><td>0.01% (58K)</td><td>Lack</td><td>Fibers</td><td>Clear</td>

<td>9.2B</td><td>0.01% (58K)</td><td>Lack</td><td>Fibers</td><td>Clear</td>

<td>9.3A</td><td>0.1% (58K)</td><td>Lack</td><td>Possible fibers</td><td>Clear</td>

PL 205 565 B1 cont. table 9

<td>9.3B</td><td>0.1% (58K)</td><td>Lack</td><td>Lack</td><td>Clear</td>

<td>9.4A</td><td>0.2% (58K)</td><td>Lack</td><td>Lack</td><td>Clear</td>

<td>9.4B</td><td>0.2% (58K)</td><td>Lack</td><td>Lack</td><td>Clear</td>

<td>9.5A</td><td>0.5% (58K)</td><td>Lack</td><td>Lack</td><td>Clear</td>

<td>9.5B</td><td>0.5% (58K)</td><td>Lack</td><td>Lack</td><td>Clear</td>

<td>9.6A</td><td>1.0% (58K)</td><td>Lack</td><td>Lack</td><td>Clear</td>

<td>9.6B</td><td>1.0% (58K)</td><td>Lack</td><td>Lack</td><td>Clear</td>

<td>9.7A</td><td>0.1% (1300K)</td><td>Large particles</td><td>Fibers</td><td>Clear</td>

<td>9.7b</td><td>0.1% (1300K)</td><td>Particles</td><td>Fibers</td><td>Clear</td>

<td colspan="5">Freezing-melting (-21 ° C)</td>

<td>9.1A</td><td>Lack</td><td>Lack</td><td>Fibers</td><td>Clear</td>

<td>9.1B</td><td>Lack</td><td>Lack</td><td>Fibers</td><td>Clear</td>

<td>9.2A</td><td>0.01% (58K)</td><td>Lack</td><td>Fibers</td><td>Clear</td>

<td>9.2B</td><td>0.01% (58K)</td><td>Lack</td><td>Fibers</td><td>Clear</td>

<td>9.3A</td><td>0.1% (58K)</td><td>Lack</td><td>Lack</td><td>Clear</td>

<td>9.3B</td><td>0.1% (58K)</td><td>Lack</td><td>Lack</td><td>Clear</td>

<td>9.4A</td><td>0.2% (58K)</td><td>Lack</td><td>Lack</td><td>Clear</td>

<td>9.4B</td><td>0.2% (58K)</td><td>Lack</td><td>Lack</td><td>Clear</td>

<td>9.5A</td><td>0.5% (58K)</td><td>Lack</td><td>Lack</td><td>Clear</td>

<td>9.5B</td><td>0.5% (58K)</td><td>Lack</td><td>Lack</td><td>Clear</td>

<td>9.6A</td><td>1.0% (58K)</td><td>Lack</td><td>Lack</td><td>Clear</td>

<td>9.6B</td><td>1.0% (58K)</td><td>Lack</td><td>Lack</td><td>Clear</td>

<td>9.7A</td><td>0.1% (1300K)</td><td>Lack</td><td>Fibers</td><td>Clear</td>

<td>9.7b</td><td>0.1% (1300K)</td><td>Lack</td><td>Fibers</td><td>Clear</td>

Example 10: The formulations shown in table 10 were prepared and subjected to temperature cycling and short-term stability tests. For the cycling temperature test, each cycle consisted of 2 days at the first temperature followed by two days at the second temperature (4 days in total). The cycles were repeated three times. Each sample was tested in triplicate. The short-term stability studies were performed under two conditions: 4 ° C and 25 ° C. The results of these studies are presented in Table 11.

Table 10

<td rowspan="2">Ingredient</td><td colspan="6">% wt /. wt.</td>

<td>Olopatadine-HCl</td><td> 0,222</td><td> 0,443</td><td> 0,665</td><td> 0,222</td><td> 0,443</td><td> 0,665</td>

<td>Polyvinylpyrrolidone (average molecular weight MW = 5 8K)</td><td> 1,8</td><td> 1,8</td><td> 1,8</td><td> 0</td><td> 0</td><td> 0</td>

<td>Benzalkonium chloride</td><td>0.01 + 3% overload</td><td>0.01 + 3% overload</td><td>0.01 + 3% overload</td><td>0.01 + 3% overload</td><td>0.01 + 3% overload</td><td>0.01 + 3% overload</td>

PL 205 565 B1 cont. table 10

<td>EDTA disodium salt</td><td> 0,01</td><td> 0,01</td><td> 0,01</td><td> 0,01</td><td> 0,01</td><td> 0,01</td>

<td>Sodium chloride</td><td> 0,55</td><td> 0,55</td><td> 0,55</td><td> 0,55</td><td> 0,55</td><td> 0,55</td>

<td>Hydrogen Phosphate (V) sodium (anhydrous)</td><td> 0,5</td><td> 0,5</td><td> 0,5</td><td> 0,5</td><td> 0,5</td><td> 0,5</td>

<td>Purified water</td><td>Qs 100</td><td>Qs 100</td><td>Qs 100</td><td>Qs 100</td><td>Qs 100</td><td>Qs 100</td>

Table 11

<td rowspan="3">The storage conditions</td><td rowspan="2">Age</td><td colspan="6">FORMULATION</td>

<td>Beginning</td><td></td><td></td><td></td><td></td><td> /</td><td> /</td>

<td rowspan="3">Cycle from 18 ° C to 25 ° C</td><td>4 days</td><td></td><td></td><td> /</td><td></td><td> /</td><td> /</td>

<td rowspan="3">Cycle from 4 ° C to 25 ° C</td><td>4 days</td><td></td><td></td><td> /</td><td></td><td> /</td><td> /</td>

<td>4 weeks</td><td></td><td></td><td>Ppt *</td><td></td><td>Ppt</td><td>Ppt</td>

<td>8 weeks</td><td></td><td></td><td>Ppt</td><td></td><td>Ppt</td><td>Ppt</td>

<td>12 weeks</td><td></td><td></td><td>Ppt</td><td></td><td>Ppt</td><td>Ppt</td>

<td>16 weeks</td><td></td><td></td><td>Ppt</td><td></td><td>Ppt</td><td>Ppt</td>

<td>4 weeks</td><td></td><td></td><td> /</td><td></td><td> /</td><td>Ppt</td>

<td>8 weeks</td><td></td><td></td><td> /</td><td></td><td></td><td>Ppt</td>

<td>12 weeks</td><td></td><td></td><td> /</td><td></td><td>Ppt</td><td>Ppt</td>

<td>16 weeks</td><td></td><td></td><td></td><td></td><td>Ppt</td><td>Ppt</td>

/ = Clear, colorless; Ptp = sediment observed in 3 out of 3 samples; * sediment observed in 2 out of 3 samples (preparation X,

4 ° C, 4 weeks)

Example 11: The formulations shown in Table 12 were prepared and stored at the temperature indicated (T room = room temperature: about 25 ± 4 ° C; chilled = about 3 ± 2 ° C). Observations were made at the indicated time. The results are presented in Table 13.

PL 205 565 B1

Table 12

<td rowspan="3">INGREDIENT</td><td colspan="3">FORMULATION</td>

<td colspan="3">Concentration (% w / w)</td>

<td>Olopatadine ^ HCl</td><td> 0,222</td><td> 0,443</td><td> 0,665</td>

<td>Polyvinylpyrrolidone (Avg molecular MW = 58K)</td><td> 1,8</td><td> 1,8</td><td> 1,8</td>

<td>Benzalkonium chloride</td><td>0.01 ± 3% over</td><td>0.01 ± 3% over</td><td>0.01 ± 3% over</td>

<td>EDTA disodium salt</td><td> 0,01</td><td> 0,01</td><td> 0,01</td>

<td>Sodium chloride</td><td> 0,36</td><td> 0,35</td><td> 0,33</td>

<td>Sodium hydrogen phosphate (anhydrous)</td><td> 0,5</td><td> 0,5</td><td> 0,5</td>

<td>Purified water</td><td>qs 100</td><td>qs 100</td><td>qs 100</td>

Table 13

<td>Conditions storage</td><td>Age / Time Stretch</td><td>Formulation AB</td><td>Formulation AC</td><td>Formulation AD</td>

<td rowspan="4">Tpok.</td><td>One month</td><td>Clear</td><td>Clear</td><td>Clear</td>

<td>2 months</td><td>Clear</td><td>Clear</td><td>Clear</td>

<td>3 months</td><td>Clear</td><td>Clear</td><td>Clear</td>

<td>Four months</td><td>Clear</td><td>Clear</td><td>Clear</td>

<td rowspan="4">chilled</td><td>One month</td><td>Clear</td><td>Clear</td><td>Clear</td>

<td>2 months</td><td>Clear</td><td>Clear</td><td>Clear</td>

<td>3 months</td><td>Clear</td><td>Clear</td><td>Clear</td>

<td>Four months</td><td>Clear</td><td>Clear</td><td>Clear</td>

Patent claims

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Olopatadine formulations for topical administration

Abstract

Term

PL 205 565 B1

PL 205 565 B1

PL 205 565 B1

PL 205 565 B1

PL 205 565 B1

PL 205 565 B1

PL 205 565 B1

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