MXPA00002550A - Prostaglandin product - Google Patents

Abstract

A pharmaceutical product comprising an aqueous prostaglandin formulation and a polypropylene container are disclosed. Aqueous prostaglandin formulations are more stable in polypropylene containers than polyethylene containers.

Description

PROSTAGLANDINE PRODUCT FIELD OF THE INVENTION This invention relates to aqueous pharmaceutical compositions containing prostaglandins. In particular, the present invention relates to aqueous prostaglandin compositions packaged in polypropylene containers.

BACKGROUND OF THE INVENTION As used herein, "LDPE" means low density polyethylene. Prostaglandins have markedly low water solubility, and are generally unstable. Attempts have been made to solubilize and stabilize various prostaglandins by complexing them with different cyclodextrins. See, for example: EP 330 511 A2 (Ueno et al.) And EP 435 682 A2 (Wheeler). These attempts have met with varying successes. Surfactants and / or solubilizers have been used with other types of drugs that have lower solubility in water. However, the addition of surfactants and / or solubilizers may improve or adversely affect the chemical stability of the drug compounds. See Surfactant Systems, Their Chemistry, Pharmacy, and Biology, (eds. Attwood et al., Chapman and Hall, New York, 1983, C. 11, particularly pp. 698-714. The use of nonionic surfactants, such as polyethoxylated castor oils, as solubilizing agents is known. See, for example, US 4,960,799 (Nagy). The use of nonionic surfactants such as polyethoxylated castor oils in stable emulsions is also known. US 4,075,333 (Josse) discloses stable and intravenous emulsion vitamin formulations. El-Sayed et al., Int. J. Pharm., 13: 303-12 (1983) discloses stable oil-in-water emulsions of an antineoplastic drug. US 5,185,372 (Ushio et al.) Discloses topically administrable ophthalmic vitamin A formulations which are stable preparations in which a nonionic surfactant is used to form an emulsion of vitamin A in an aqueous medium. The patent of E.U.A. No. 5,631, 287 (Schneider) discloses storage-stable prostaglandin compositions containing a chemically stabilizing amount of a polyethoxylated castor oil. Currently, there are only two commercially available multi-dose ophthalmic prostaglandin products, Xalatan ™ (latanoprost solution; Unjohn) and Rescula ™ (isopropyl unoprostone; Fujisawa). Xalatan ™ is packed in a polyethylene (LDPE) container. According to the package insert, this product should be stored under refrigeration at 2-8 ° C until it is opened. Once opened, the container can be stored at room temperature up to 25 ° C for six weeks. Rescula ™ is also packed in a polyethylene (LDPE) container.

BRIEF DESCRIPTION OF THE INVENTION The present invention is directed to pharmaceutical products containing an aqueous composition of prostaglandin packed in polypropylene containers. Aqueous compositions of prostaglandin packed in polypropylene containers are more stable than those packed in polyethylene containers.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 compares the stability of Formulation D in bottles of clear glass, low density polyethylene and isotactic polypropylene at 65 ° C. Figure 2 compares the stability of formulation E in transparent glass, low density polyethylene and isotactic polypropylene bottles at 65 ° C. Figure 3 compares the stability of Formulation F in bottles of clear glass, low density polyethylene and isotactic polypropylene at 65 ° C.

Figure 4 compares the stability of Formulation G in bottles of clear glass, low density polyethylene and isotactic polypropylene at 65 ° C.

DETAILED DESCRIPTION OF THE INVENTION As used herein, "aqueous prostaglandin compositions" means aqueous compositions containing at least one prostaglandin and a large amount of water, wherein water constitutes the continuous phase of the composition. As used in the present"polypropylene" means polypropylene, substantially free (ie, less than about 5% by weight) of non-polypropylene olefins. The term "polypropylene" includes, for example, isotactic polypropylene, syndiotactic polypropylene, and mixtures of isotactic and syndiotactic polypropylene. The terms "prostaglandin" and "PG" are generally used to describe a class of compounds that are analogues and derivatives of prostanoic acid (1). PG's can be further classified, for example, according to their 5-member ring structure, using a letter designation; the PG's of the serial A-J are known. The PG's can also be classified based on the number of unsaturated bonds in the side chain, for example, PGi's (13,14-unsaturated), PG2's (13,14 and 5,6-unsaturated) and PG3's (13,14-, 5 , 6- and 17,18-unsaturated). See patent of E.U.A. No. 5,631, 287 . -..., - 'M? ftÍßtll? M * ÍSaftti whose full contents are incorporated herein by way of reference. The prostaglandins that can be used in the present invention include all pharmaceutically acceptable prostaglandins, their derivatives and analogs, and their pharmaceutically acceptable esters and salts. Said prostaglandins include the natural compounds: PGE-i, PGE2, PEG3, PGF1a, PGF2a, PGF3a, PGD2 and PGI2 (prostacyclin), as well as analogs and derivatives of these compounds having similar biological activities of greater or lesser potency. Analogs of the natural prostaglandins include, but are not limited to: alkyl (i.e., 15-methyl or 16,16-dimethyl) substitutions, which confer increased or prolonged potency by reducing biological metabolism, or alter the selectivity of action; saturation (eg, 13,14-dihydro) or unsaturation (eg, 2,3-didehydro, 13,14-didehydro), which confer prolonged potency by reducing biological metabolism or alter selectivity of action; deletions or replacements (eg, 11-deoxy, 9-deoxo-9-methylene), chlorine (or halogen) by oxygen (eg, 9β-chloro), oxygen by carbon (eg, 3-oxa), lower alkyl by oxygen (for example, 9-methyl), hydrogen by oxygen (for example, 1-CH 2 OH, 1-CH 2 OAcyl) which improve the chemical stability and / or selectivity of action; and changes in the chain? (for example, 18,19,20-trinor-17-phenyl, 17,18,19,20-tetranor-16-phenoxy), which improve the selectivity of action and reduce the biological metabolism. Derivatives of these prostaglandins include all pharmaceutically acceptable salts and esters, which can be attached to the 1-carboxyl group of any of the hydroxyl groups of the prostaglandin by use of the corresponding alcohol or organic acid reagent, as appropriate. It is to be understood that the terms "analogues" and "derivatives" include compounds that exhibit functional and physical responses similar to those of the prostaglandins per se. Specific examples of prostaglandins suitable for use in the products of the present invention include the following compounds: Compound No. 1. Acid (5Z) - (9R, 11f?, 15R) -9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor- 5-prostenoic; 2. (5Z) - (9f?, 11R, 15?) - 9-Chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor- isopropyl ester 5-prostenoic; 3. (5Z) - (9R, 11R, 15R) -9-Chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor- 5-prostenoic; 4. (5Z) - (9S, 11R, 15R) -15-cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester; 5. (5Z) - (9f?, 11R, 15S) -9-Chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5 isopropyl ester -prostenoic; 6. (5Z) - (9f?, 11R, 15R) -9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanoride acid amide 5-prostenoic; 7. NN-dimethylamide (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid; 8. (5Z) - (9R, 11R, 15R) -9-Chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanormyl ester 5-prostenoic; 9. Methylcyclopentyl ester of (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5- prostenoic; 10. Cyclopentyl ester of acid (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5- prostenoic; 11. Dimethylpropyl ester of (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5- prostenoic; 12. Adamantyl ester of (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5- prostenoic; 13. (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5- diisopropylphenyl ester prostenoic; 14. Dimethylphenyl ester of (5Z) - (9R, 11, 15R) -9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5- prostenoic; 15. Isopropyl ester (5Z, 13E) - (9S, 11R, 15R) -3-oxa-9,11,15-trihydroxy-16- (3-chlorophenoxy) -17,18,19,20-tetranor- 5,13-prostadienoic; 16. (5Z) - (9R, 11R, 15R) -9-Chloro-15-cyclohexyl-11-hydroxy-15-methoxy-3-oxa-16,17,18,19,20-f-butyl ester pentanor-5-prostenoic; 17. (5Z) - (9R, 11R, 15R) -15-cyclohexyl-3-oxa-9,11, 15-trihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester; 18. Isopropyl ester (5E) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5- prostenoic; 19. Terbutyl ester of (5Z) - (9R, 11R) -9-chloro-15-cyclohexyl-11-dihydroxy-3-oxa-15-oxo-16, 17,18, 19,20-pentanor-5- prostenoic; 20. (5Z) - (9S, 11R, 15R) -3-oxa-17-phenyl-9,11,15-trihydroxy-18,19,20-trinor-5-prostenoic acid isopropyl ester; 21. (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-1- (dimethylamino) -3-oxa-16,17,18,19,20-pentanor-5-prostene-11, 15-diol; 22. (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenol; 23. Acid (9R, 11R, 15R) -9-chloro-15-cyclohexyl-11-hydroxy-3-thia-16,17,18,19,20-pentanor-13-prostinoic acid; 24. Latanoprost (PhXA41); 25. Cloprostenol isopropyl ester; 26. Acid (5Z) - (9R, 11R, 15R) -1-decarboxy-1- (pivaloyloxy) methyl- 9,11,15-trihydroxy-16 - [(3-chlorophenyl) oxy] -17,18,19 , 20-tetranor-5-prostenoic; 27. Acid (5Z) - (9R, 11R, 15R) -1-decarboxy-1- (pivaloyloxy) methyl-9,11,15-trihydroxy-16 - [(3-chlorophenyl) oxy] -17.18, 19,20-tentranor-5,13-prostadienoic; 28. (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-11,15-dihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester; 29. (5Z) - (9S, 11R, 15S) -15-cyclohexyl-9,11, 15-trihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester; . Amide acid (5Z, 13E) - (9S, 11R, 15R) -9,11,15-trihydroxy-16- (3-chlorophenoxy) -17,18,19,20-trentanor-5, 13- prostadienoic; 31. PGF2a isopropyl ester and 32. Fluprostenol isopropyl ester All the above compounds are known. The prostaglandins which are preferred to be used in the compositions of the present invention are compounds 2 and 32 above. The prostaglandin compositions packaged in polypropylene containers according to the present invention can be adapted for any administration route. Preferred are compositions adapted for topical administration to the ears, nose or eyes, with preferred compositions being preferred for topical administration to the eye. In addition to one or more prostaglandins, the aqueous compositions of the present invention also contain at least one surfactant to help solubilize or disperse the prostaglandin in the composition. The surfactants also inhibit or prevent the adsorption of the prostaglandin on the walls of the container. The surfactant may be any pharmaceutically acceptable surface active agent, such as pharmaceutically acceptable cationic, anionic or nonionic surfactants. Examples of suitable surfactants include polyethoxylated castor oils, such as those classified as PEG-2 to PEG-200 castor oils, as well as those classified as hydrogenated castor oils PEG-5 to PEG-200. Such polyethoxylated castor agents include those manufactured by Rhone-Poulenc (Cranbury, New Jersey) under the trademark Alkamuls®, those manufactured by BASF (Parsippany, New Jersey) under the Cremophor® brand and those manufactured by Nikko Chemical Co., Ltd. (Tokyo, Japan) with the Nikkol brand. Preferred polyethoxylated castor oils are those classified as PEG-15 to PEG-50 castor oils, and PEG-30 to PEG-35 castor oils are most preferred. It is more preferred to use the polyethoxylated castor oils known as Cremophor® EL and Alkamuls® EL-620. Preferred hydrogenated polyethoxylated castor oils are those classified as hydrogenated castor oils PEG-25 to PEG-55. The most preferred polyethoxylated hydrogenated castor oil is PEG-40 hydrogenated castor oil, such as Nikkol HCO-40. The aqueous compositions of the present invention optionally comprise other formulatory ingredients, such as antimicrobial preservatives, tonicity agents and pH regulators. Many of these formulatory ingredients are known. Examples of suitable antimicrobial preservatives for topically administrable multi-dose ophthalmic formulations include: benzalkonium chloride, thimerosal, chlorobutanol, methylparaben, propylparaben, phenylethyl alcohol, disodium edetate, sorbic acid, Polyquad® and other agents equally well known to those skilled in the art. Such preservatives, if present, will typically be employed in an amount of between about 0.001 and about 1.0% by weight. Examples of suitable agents that can be used to adjust the tonicity or osmolarity of the formulations include sodium chloride, potassium chloride, mannitol, dextrose, glycerin and propylene glycol. If present, said agents will be employed in an amount of between about 0.1 and about 10.0% by weight. Examples of suitable pH regulating agents include acetic acid, citric acid, carbonic acid, phosphoric acid, boric acid, the pharmaceutically acceptable salts of the foregoing, and tromethamine. Said pH regulators, if present, will be employed in an amount of between about 0.001 and about 1.0% by weight. The compositions of the present invention may further include components to provide prolonged release and / or comfort. Such components include high molecular weight anionic mucomimetic polymers and gelling polysaccharides, such as those described in US 4,861, 760 (Mazuel et al), US 4,911, 920 (Jani et al.) And in the commonly assigned application Serial No. 08 / 108,824 (Lang et al.). The contents of these patents and patent applications relating to the polymers mentioned above are incorporated herein by reference. As will be appreciated by those skilled in the art, the compositions can be formulated in various dosage forms suitable for the delivery of aqueous compositions. In the preferred case of topical ophthalmic delivery, the compositions may be formulated as solutions, suspensions or emulsions, for example. Topically administrable ophthalmic compositions have a pH of between 3.5 to 8.0 and an osmolarity of between 260 to 320 milliOsmoles per kilogram (mOsm / kg). Preferred topically administrable aqueous compositions are preferably packaged in a "small volume" bottle. As used herein, the term "small volume" bottle shall mean a bottle of a size sufficient to hold a quantity of liquid medicine sufficient for 1-3 topical doses per day for 1-2 months, generally about 20 mL or less. For example, small volume containers include bottles with a capacity of 5 mL, 10 mL and 15 mL adapted to administer ophthalmic drops topically. Small volume bottles made of syndiotactic polypropylene are easier to press than those made of isotactic polypropylene, and oval bottles are easier to press than round bottles. Accordingly, aqueous compositions adapted for ophthalmic administration are preferably packaged in oval bottles of syndiotactic polypropylene. The invention will be better illustrated by the following examples, which are designed to be illustrative, but not limiting.

Preparation of Formulations A-G: Formulations A-G shown in Examples 1-7 below were prepared as follows. Approximately 75% of the total volume was added to a transparent glass container of suitable size ^ ^ ^^^^^^^^^^^^^^ faith of water. To this was added sequentially sodium acetate or tromethamine and boric acid, followed by mannitol, EDTA, benzalkonium chloride and Cremophor® EL or HCO-40 so that there would be a complete dissolution of one ingredient before the addition of the next ingredient. Subsequently the pH of the solution was adjusted using NaOH and / or HCl, and the water was added to bring the volume to 100%. In a separate clear glass container, the appropriate amount of prostaglandin was added, followed by the appropriate amount of the vehicle whose preparation was described above. The container was then sealed and sonicated in an ultrasonic bath for one hour or alternatively stirred with a magnetic stirring rod overnight, until the prostaglandin had completely dissolved. The resulting solution was sterile filtered (0.2 μm filter).

EXAMPLE 1 The following topically administrable ophthalmic formulation was prepared in the manner described above.

INGREDIENT FORMULATION A (w / v%) Compound No. 32 0.001 + 5% (prostaglandin) excess Cremophor® EL 0.5 Tromethamine 0.12 Boric acid 0.3 Mannitol 4.6 Disodium EDTA 0.01 Benzalkonium chloride 0.01 + 5% excess 10 NaOH and / or HCl c.b.p. pH 7.4 Purified water c.b.p. 100% The following procedure was used to test the compatibility of formulation A with the packaging materials. Bottles of transparent LDPE sterilized with ETO, transparent LDPE sterilized with rays range and isotactic polypropylene sterilized with ETO were cut into thin rectangular pieces (2 mm x 10 mm). The isotactic polypropylene bottles were made of Rexene ™ isotactic polypropylene (Huntsman Chemical, Inc., Odessa, TX). Approximately 0.5 g of each bottle material was transferred to 10 mL clear glass ampoules (this The amount corresponds approximately to the surface area with which a product with a capacity of 5 mL could interact). Each glass ampule was then filled with 5 mL of Formulation A and sealed. The packaging materials were tested in this way to eliminate the effects ttftÉ j «» &? eS & í evaporation. The sealed ampoules were stored in an oven at 55 ° C and removed at the indicated times for the HPLC analysis. The stability of the prostaglandin in formulation A was evaluated using a semi-radiation CLAR method, using a C-18 Delta-Pak ™ column (150 x 4.6 mm), 5 μm, 100A connected to a C-18 Delta-Pak precolumn ™. The reference standard solution contained the prostaglandin in a water / methanol solution (70:30). Mobile phase A: Sodium salt of 1- octane sulfonic acid (100 mM); pH = 3.7 Mobile phase B: Acetonitrile / methanol (10: 1) Injection volume: 100μL Detector: 220 nm Column temperature 25 ° C Semigradient flow rate 1.6 mL / min The results of the compatibility tests are shown below in table 1.

TABLE 1 Compatibility of Formulation A EXAMPLE 2 The following topically administrable ophthalmic formulation was prepared in the manner described above.

INGREDIENT FORMULATION B (w / v%) Compound No. 32 (prostaglandin) 0.001 + 5% excess Cremofor® EL 0.1 Tromethamine 0.12 Boric acid 0.3 Mannitol 4.6 Disodium EDTA 0.01 Benzalkonium chloride 0.01 + 5% excess NaOH and / or HCl Cbp pH 7.4 Purified water Cbp 100% The compatibility of Formulation B with glass, LDPE and polypropylene containers was monitored by monitoring the stability of the drug in the manner described in Example 1 for formulation A. The results are shown below in Table 2 .

TABLE 2 Compatibility of Formulation B fifteen EXAMPLE 3 The following topically administrable ophthalmic formulation was prepared in the manner described above. ¡^^^^^ i ^^^^ te & ^^^ ig ^.

INGREDIENT FORMULATION C (w / v%) Compound No. 32 (prostaglandin) 0.003 HCO-40 0.5 Tromethamine 0.12 Boric acid 0.3 Mannitol 4.6 Disodium EDTA 0.01 Benzalkonium chloride 0.015 NaOH and / or HCl Cbp pH 6.0 Purified water Cbp 100% The compatibility of Formulation C in unsterilized syndiotactic polypropylene bottles, syndiotactic polypropylene bottles sterilized with ETO and isotactic polypropylene bottles (Rexene®) was determined as follows. The bottles were filled with 5 mL of sterile Formulation C, then stored in an oven at 55 ° C and removed at the indicated time points for the HPLC analysis as described above. Syndiotactic polypropylene bottles were made of FINA 3721 WZ syndiotactic polypropylene (Fina Oil and Chemical Co., Dallas, TX). Compatibility results are shown below in tables 3 and 4. Table 3 compares the compatibility of formulation C in non-sterilized syndiotactic polypropylene bottles. sterilized with ETO. Table 4 compares the compatibility of formulation C in non-sterilized isotactic and syndiotactic polypropylene bottles.

TABLE 3 Compatibility of formulation C in sterilized polypropylene bottles vs. not sterilized TABLE 4 Compatibility of formulation c in isotactic polypropylene bottles against syndiotactic EXAMPLE 4 The following topically administrable ophthalmic formulation was prepared in the manner described above.

INGREDIENT FORMULATION D (w / v%) Compound No. 2 0.012 + 5% (prostaglandin) excess Cremophor® EL 0.5 Sodium acetate (trihydrate) 0.07 Mannitol 4.3 Disodium EDTA 0.1 Benzalkonium chloride 0.01 + 5% excess NaOH and / or HCl cbp pH 5.0 Purified water cbp 100% The stability of the prostaglandin in formulation D in transparent glass bottles, LDPE sterilized with ETO and isotactic polypropylene sterilized with ETO was evaluated as follows. The bottles were filled with sterile D formulation and stored in an oven at 65 ° C, then removed at the indicated times for the CLAR analysis. In this case, the CLAR data was generated using a column for Phenomenex CLAR 150 X 4.6 mm with Spherisorb® 10 ODS packaging (2). The mobile phase was 560 mL of phosphate at 440 mL of acetonitrile, adjusted to a pH of about 8.5. The flow rate was 1 mL / minute, the detection was at 200 nm UV and the injection amount was 20 mcL. The compatibility results are shown in figure 1.

EXAMPLE 5 The following topically administrable ophthalmic formulation was prepared in the manner described above.

INGREDIENT FORMULATION E (w / v%) Compound No. 2 0.012 + 5% (prostaglandin) excess Cremophor® EL 1.5 Sodium acetate (trihydrate) 0.07 Mannitol 4.3 Disodium EDTA 0.1 Benzalkonium chloride 0.01 + 5% excess NaOH and / or HCl cbp pH 5.0 Purified water cbp 100% The stability of the prostaglandin in formulation E was evaluated in transparent glass, LDPE and isotactic polypropylene bottles at 65 ° C according to the procedure described in example 4 for formulation D. The results are shown in figure 2 .

EXAMPLE 6 The following topically administrable ophthalmic formulation was prepared in the manner described above.

INGREDIENT FORMULATION F (w / v%) Compound No. 2 0.012 + 5% (prostaglandin) excess Cremophor® EL 2.0 Sodium acetate (trihydrate) 0.07 Mannitol 4.3 Disodium EDTA 0.1 Benzalkonium chloride 0.01 + 5% excess NaOH and / or HCl cbp pH 5.0 Purified water cbp 100% The stability of the prostaglandin in formulation F was evaluated in transparent glass, LDPE and isotactic polypropylene bottles at 65 ° C according to the procedure described in example 4 for formulation D. The results are shown in figure 3 .

EXAMPLE 7 The following topically administrable ophthalmic formulation was prepared in the manner described above.

INGREDIENT FORMULATION G (w / v%) Compound No. 2 0.012 + 5% (prostaglandin) excess Cremophor® EL 1.0 Sodium acetate (trihydrate) 0.07 Mannitol 4.3 Disodium EDTA 0.1 Benzalkonium chloride 0.01 + 5% excess NaOH and / or HCl cbp pH 5.0 Purified water cbp 100% The stability of the prostaglandin in formulation G was evaluated in transparent glass, LDPE and isotactic polypropylene bottles at 65 ° C according to the procedure described in example 4 for formulation D. The results are shown in figure 4 The invention has been described with reference to certain preferred embodiments; however, it must be understood that it can be incorporated into other forms or specific variations of the same without departing from its spirit or essential characteristics. The embodiments described above are therefore considered illustrative in all respects, and not as restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description. ÍJgi§ É ^

Claims (4)

NOVELTY OF THE INVENTION CLAIMS

1. A prostaglandin product comprising: a) an aqueous composition of prostaglandin comprising a therapeutically effective amount of at least one prostaglandin and a pharmaceutically acceptable surfactant and b) a polypropylene container; wherein the aqueous composition of prostaglandin is packaged in the polypropylene container.

2. The prostaglandin product according to claim 1, further characterized in that the prostaglandin is selected from the group consisting of (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-11, 15 -dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid; isopropyl ester of (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid ester; (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-butyl ester -prostenoic; acid ester (5Z) - (9S, 11R, 15R) -15-cyclohexyl-3-oxa-9,11, 15-trihydroxy-16,17,18,19,20-pentanor-5- prostenoic; isopropyl ester of (5Z) - (9R, 11R, 15S) -9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid ester; acid amide (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid; N, N-dimethylamide of (5Z) - (9R, 11R, 15R) -9- chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-d -prostenoic; 1-Methylcyclohexyl ester of (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5- prostenoic; Methylcyclopentyl ester of (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid ester; Cyclopentyl ester of (5Z) - (9R, 11R, 15R) -9-Chloro-15-cyclohexyl-11,1-d-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5- prostenoic; Dimethylpropyl ester of (dZ) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid ester; adamantyl ester of (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid ester; (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid diisopropylphenyl ester; Dimethylphenyl ester of (5Z) - (9R, 11R, 15R) -9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid ester; acid isopropyl ester (5Z, ISEHTS.I IR.IdRJ-S-oxa-g.l.ld-trihydroxy-ie-IS-chlorophenoxy) -17,18,19,20-tetranor-5,13-prostadienoic acid; f-butyl ester of acid (dZ) - (9R, 11 R, 1 dR) -9-chloro-1 d-cyclohexyl-11-hydroxy-1 d-methoxy-3-oxa-16,17,18,19, 20-pentanor-d-prostenoic; isopropyl ester of acid (dZ) - (9R, 11 R, 1 dR) -1 d-cyclohexyl-3-oxa-9, 11, 1 d-trihydroxy-16,17,18,19,20-pentanor-5- prostenoic; isopropyl ester of (5E) - (9R, 11R, 1dR) -9-chloro-1 d-cyclohexyl-11, 1d-dihydroxy-3-oxa-16,17,18,19,20-pentanor-d -prostenoic; terbutyl ester of acid (dZ) - (9R, 11R) -9-chloro-1d-cyclohexyl-11-dihydroxy-3-oxa-1d-oxo-16, 17,18, 19,20-pentanor-d-prostenoic acid; isopropyl ester of acid (dZ) - ^^^? ^^^ - ^^ r ^ * - ^ • ^ rtj¡ «(9S, 11R, 1 dR) -3-oxa-17-phenyl-9,11, 1d-trihydroxy-18,19, 20-trinor-d-prostenoic; (dZ) - (9R, 11R, 1dR) -9-chloro-1d-cyclohexyl-1- (dimethylammon) -3-oxa-16,17,18,19,20-pentanor-d-prostene-11, 1d-diol; (dZ) - (9R, 11R, 1dR) -9-chloro-1d-cyclohexyl-11,1-dihydroxy-3-oxa-16,17,18,19,20-pentanor-d-prostenol; d (9R, 11R, 1dR) -9-chloro-1 d-cyclohexyl-11-hydroxy-3-thia-16,17,18,19,20-pentanor-13-prostinoic acid; latanoprost (PhXA41); cloprostenol isopropyl ester; acid (dZ) - (9R, 11R, 1 dR) -1-decarboxy-1- (pivaloyloxy) methyl-9,11,15-trihydroxy-16 - [(3-chlorophenyl) oxy] -17,18,19, 20-tetranor-d-prostenoic; acid (dZ) - (9R, 11R, 1dR) -1- decarboxy-1- (pivaloyloxy) methylene-9,11,1d-trihydroxy-16 - [(3-chlorophenyl) oxy] -0.118 , 19,20-tentranor-d, 13-prostadienoic; isopropyl ester of acid (dZ) - (9R, 11 R, 1 dR) -9-chloro-1 d-cyclohexyl-11, 1 d-dihydroxy-16,17,18,19,20-pentanor-d-prostenoic acid; isopropyl ester of (5Z) - (9S, 11R, 15S) -1d-cyclohexyl-9,11, 1d-trihydroxy-16,17,18,19,20-pentanor-d-prostenoic acid ester; acid amide (dZ.ISEHgS.II .IdRJ-TH .I d-trihydroxy-ie-ÍS-chlorophenoxy- ^. ld.ig ^ Od trentanor-d, 13-prostadienoic, isopropyl ester of PGF2a and isopropyl ester of fluprostenol.

3. The prostaglandin product according to claim 3, further characterized in that the prostaglandin is selected from the group consisting of isopropyl ester of acid (dZ) - (9R, 11R, 1dR) -9-0 chloro-1 d- cyclohexyl-11, 1-d-dihydroxy-3-oxa-16,17,18,19,20-pentanor-d-prostenoic acid and fluprostenol isopropyl ester 4.- The prostaglandin product according to claim 1, further characterized because the composition is adapted for topical ophthalmic administration and the surfactant comprises a polyethoxylated castor oil d.- The prostaglandin product according to claim 4, further characterized in that the polyethoxylated castor oil d is selected from the group consisting of of castor oil PEG-2 to PEG-200 and ac Hydrogenated castor eites PEG-d to PEG-200. 6. The prostaglandin product according to claim 1, further characterized in that the polypropylene container is a polypropylene bottle adapted for topical delivery and wherein the polypropylene is selected from the group consisting of isotactic polypropylene, syndiotactic polypropylene and mixtures of isotactic and syndiotactic polypropylene. 7. The prostaglandin product according to claim 1, further characterized in that the aqueous composition of prostaglandin d is adapted for topical ophthalmic administration and the polypropylene container is a small volume bottle adapted for topical ophthalmic delivery. 8. The prostaglandin product according to claim 7, further characterized in that the polypropylene container 0 is an oval bottle of syndiotactic polypropylene. 9. The prostaglandin product according to claim 8, further characterized in that the aqueous composition of prostaglandin is a multiple dose composition comprising an ophthalmically acceptable preservative.