WO1998019707A1 - Polyhydroxy monocarboxylic and dicarboxylic acids and their lactones in ophthalmic compositions - Google Patents

Polyhydroxy monocarboxylic and dicarboxylic acids and their lactones in ophthalmic compositions Download PDF

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Publication number
WO1998019707A1
WO1998019707A1 PCT/US1997/020064 US9720064W WO9819707A1 WO 1998019707 A1 WO1998019707 A1 WO 1998019707A1 US 9720064 W US9720064 W US 9720064W WO 9819707 A1 WO9819707 A1 WO 9819707A1
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WO
WIPO (PCT)
Prior art keywords
acid
weakly basic
group
polyhydroxy
solubility enhancing
Prior art date
Application number
PCT/US1997/020064
Other languages
French (fr)
Inventor
Suketu D. Desai
Original Assignee
Alcon Laboratories, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Alcon Laboratories, Inc. filed Critical Alcon Laboratories, Inc.
Priority to AU51038/98A priority Critical patent/AU5103898A/en
Publication of WO1998019707A1 publication Critical patent/WO1998019707A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears

Definitions

  • the present invention relates to the solubilization of compounds having poor aqueous solubility.
  • this invention relates to the use of mono- and dicarboxylic acids, and their lactones, as solubility-enhancing agents in aqueous ophthalmic pharmaceutical compositions.
  • inorganic or organic acids are used to prepare salts of weakly basic drugs.
  • examples of such acids include hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, oxalic acid, and fumaric acid.
  • Examples of known salts of weakly basic drugs include betaxolol hydrochloride, pilocarpine nitrate,
  • demecarium bromide, ephedrine sulfate, dexbrompheniramine maleate, and ergotamine tartrate demecarium bromide, ephedrine sulfate, dexbrompheniramine maleate, and ergotamine tartrate.
  • 93/05816 discloses the use of an ionic polymer, namely polystyrene sulfonic acid
  • PSSA polymer
  • compositions containing quinolone antibiotics compositions containing quinolone antibiotics.
  • the PSSA-containing aqueous quinolone solutions can be formulated at or near physiological pH.
  • ingredient has a molecular weight in the range of 10,000 to 1.6 million.
  • injectable solutions and contain polyhydroxy monocarboxylic acids or their lactones to
  • compositions are disclosed, however.
  • the present invention provides aqueous ophthalmic pharmaceutical
  • compositions of weakly basic ophthalmic drugs contain, in
  • solubility-enhancing agents selected from
  • solubility enhancing agents are capable of
  • the present invention also relates to methods of increasing the aqueous
  • methods comprise adding to the composition a solubility-enhancing amount of one or
  • agents selected from the group consisting of polyhydroxy monocarboxylic acids are more agents selected from the group consisting of polyhydroxy monocarboxylic acids,
  • Fig. 1 illustrates the aqueous solubility enhancing effect of six polyhydroxy mono-
  • weakly basic means having a pK a of approximately 4 to approximately 8.
  • polyhydroxy dicarboxylic acids and their lactones, are combined with a sparingly soluble, weakly basic ophthalmic drug to increase the drug's aqueous solubility.
  • Suitable polyhydroxy monocarboxylic acids include, but are not limited to, lactic
  • Suitable polyhydroxy dicarboxylic acids include, but are not limited to, glutaric acid, citric acid, a-keto glutaric acid, D-glucaric acid, citramalic acid, fumaric acid, maleic acid, and oxalic acid.
  • Suitable lactones include, but are not limited to gluconolactone, D-glucuronolactone, and D-glucoascorbic acid.
  • polyhydroxy carboxylic acid and/or lactone included in the compositions of the present invention will depend upon the concentration and identity of the chosen weakly basic drug compound, as well as the target solubility. In general,
  • polyhydroxy carboxylic acid and/or lactone will be present in an amount equal to at least one molar equivalent of the chosen drug. Often an excess of polycarboxylic acid and/or lactone will be present to ensure complete dissolution of the
  • compositions of the present invention will generally range from about 0.1 - 5 wt.%.
  • Suitable ophthalmic drugs for use in the compositions of the present invention are Suitable ophthalmic drugs for use in the compositions of the present invention.
  • Suitable ophthalmic drugs include, but are not limited to, weakly basic carbonic anhydrase inhibitors, such as brinzolamide; weakly basic antiallergic
  • the aqueous compositions of the present invention may also contain other ingredients typically present in ophthalmic pharmaceutical compositions. Such ingredients include, but are not limited to, tonicity-adjusting agents,
  • preservatives viscosity enhancing agents, buffers, comfort enhancing agents, agents to provide extended drug release, stabilizing agents, and chelating agents.

Abstract

Polyhydroxy mono- and dicarboxylic acids, and their lactones, are useful as solubility-enhancing agents in aqueous ophthalmic compositions of weakly basic ophthalmic drugs.

Description

POLYHYDROXY MONOCARBOXYLIC AND DICARBOXYLIC ACIDS AND THEIR LACTONES IN OPHTHALMIC COMPOSITIONS
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the solubilization of compounds having poor aqueous solubility. In particular, this invention relates to the use of mono- and dicarboxylic acids, and their lactones, as solubility-enhancing agents in aqueous ophthalmic pharmaceutical compositions.
2. Description of Related Art
It is well known that the aqueous solubility and dissolution rate of drugs having relatively low aqueous solubility can be improved by preparing electrolyte salts of the
drugs. Generally, inorganic or organic acids are used to prepare salts of weakly basic drugs. Examples of such acids include hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, oxalic acid, and fumaric acid. Examples of known salts of weakly basic drugs include betaxolol hydrochloride, pilocarpine nitrate,
demecarium bromide, ephedrine sulfate, dexbrompheniramine maleate, and ergotamine tartrate.
In addition to the acids mentioned above, polymeric agents have also been
employed to increase the aqueous solubility of drug compounds. For example, WO
93/05816 discloses the use of an ionic polymer, namely polystyrene sulfonic acid
polymer (PSSA), as solubility enhancing agents for use in aqueous pharmaceutical
compositions containing quinolone antibiotics. The PSSA-containing aqueous quinolone solutions can be formulated at or near physiological pH. The PSSA
ingredient has a molecular weight in the range of 10,000 to 1.6 million.
EP 0 534 860 A1 and Chemical Abstract CA1 18(20) :198251 d disclose solutions
of sparfloxacin, a quinolone antibiotic. The reference compositions are formulated as
injectable solutions and contain polyhydroxy monocarboxylic acids or their lactones to
enhance the aqueous solubility of sparfloxacin. No topically administrable ophthalmic
compositions are disclosed, however.
SUMMARY OF THE INVENTION
The present invention provides aqueous ophthalmic pharmaceutical
compositions of weakly basic ophthalmic drugs. These compositions contain, in
addition to the ophthalmic drug, one or more solubility-enhancing agents selected from
the group consisting of polyhydroxy monocarboxylic acids, polyhydroxy dicarboxylic
acids, and lactones thereof. These solubility enhancing agents are capable of
increasing the solubility of weakly basic drugs up to 600 - 700 %.
The present invention also relates to methods of increasing the aqueous
solubility of weakly basic drugs in ophthalmic pharmaceutical compositions. The
methods comprise adding to the composition a solubility-enhancing amount of one or
more agents selected from the group consisting of polyhydroxy monocarboxylic acids,
polyhydroxy dicarboxylic acids, and lactones thereof. Without being wishing to be bound to any theory, it is believed that a primary
mechanism by which the polyhydroxy carboxylic acids of the present invention increase the aqueous solubility of weakly basic ophthalmic drugs is the formation of a salt.
DETAILED DESCRIPTION OF THE INVENTION
Fig. 1 illustrates the aqueous solubility enhancing effect of six polyhydroxy mono-
and dicarboxylic acids and lactones on the weakly basic ophthalmic drug, brinzolamide, at pH 7.4.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, "weakly basic" means having a pKa of approximately 4 to approximately 8.
According to the present invention, polyhydroxy monocarboxylic acids,
polyhydroxy dicarboxylic acids, and their lactones, are combined with a sparingly soluble, weakly basic ophthalmic drug to increase the drug's aqueous solubility. Many
polyhydroxy carboxylic acids and lactones are known and are commercially available
from chemical supply sources, such as Sigma Chemical Company, Inc. (St. Louis, MO)
and Aldrich Chemical Company, Inc. (Milwaukee, Wl). Suitable polyhydroxy carboxylic
acids and lactones are those which are pharmaceutically acceptable. Suitable polyhydroxy monocarboxylic acids include, but are not limited to, lactic
acid, D-gulonic acid, 2-keto-L-gulonic acid, glucoheptanoic acid, gluconic acid, b-D- giucuronic acid, and lactobionic acid. Suitable polyhydroxy dicarboxylic acids include, but are not limited to, glutaric acid, citric acid, a-keto glutaric acid, D-glucaric acid, citramalic acid, fumaric acid, maleic acid, and oxalic acid. Suitable lactones include, but are not limited to gluconolactone, D-glucuronolactone, and D-glucoascorbic acid.
The amount of polyhydroxy carboxylic acid and/or lactone to be included in the compositions of the present invention will depend upon the concentration and identity of the chosen weakly basic drug compound, as well as the target solubility. In general,
however, the polyhydroxy carboxylic acid and/or lactone will be present in an amount equal to at least one molar equivalent of the chosen drug. Often an excess of polycarboxylic acid and/or lactone will be present to ensure complete dissolution of the
formed salts in the aqueous ophthalmic formulation. With customary levels of ophthalmic drugs, the total concentration of polyhydroxy carboxylic acid and/or lactone
in the compositions of the present invention will generally range from about 0.1 - 5 wt.%.
Suitable ophthalmic drugs for use in the compositions of the present invention
include any weakly basic ophthalmic drug for which it is desirable to improve aqueous
solubility. Examples of suitable ophthalmic drugs include, but are not limited to, weakly basic carbonic anhydrase inhibitors, such as brinzolamide; weakly basic antiallergic
agents, such as lodoxamide; and weakly basic anticataract agents. In addition to the weakly basic ophthalmic drug and one or more polyhydroxy carboxylic acids and/or lactones, the aqueous compositions of the present invention may also contain other ingredients typically present in ophthalmic pharmaceutical compositions. Such ingredients include, but are not limited to, tonicity-adjusting agents,
preservatives, viscosity enhancing agents, buffers, comfort enhancing agents, agents to provide extended drug release, stabilizing agents, and chelating agents.
Certain embodiments of the present invention are illustrated in the following
examples.
Examples 1 -6
The effect of six polyhydroxy carboxylic acids and lactones on the aqueous solubility of the carbonic anhydrase inhibitor, brinzolamide, was evaluated in eighteen
formulations (six solubilizing agents, three concentrations each) as shown below in
Table 1. Each formulation was evaluated at pH = 7.4 and at room temperature. The aqueous solubility of brinzolamide at room temperature is 0.037%. All concentrations are calculated using a weight percent basis.
TABLE 1
Figure imgf000008_0001
These results are also shown graphically in Figure 1.
The invention has been described by reference to certain preferred embodiments; however, it should be understood that it may be embodied in other specific forms or variations thereof without departing from its spirit or essential characteristics. The embodiments described above are therefore considered to be
illustrative in all respects and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description.

Claims

What is claimed is:
1. A method of increasing the solubility of a weakly basic ophthalmic drug
compound in an aqueous pharmaceutical composition comprising the step of adding to
the aqueous composition an effective amount of an agent selected from the group
s consisting of polyhydroxy monocarboxylic acids; polyhydroxy dicarboxylic acids; lactones of polyhydroxy monocarboxylic acids; and lactones of dicarboxylic acids.
2. The method of Claim 1 wherein the solubility enhancing agent is a polyhydroxy
monocarboxylic acid selected from the group consisting of lactic acid; D-gulonic acid; 2- o keto-L-gulonic acid; glucoheptanoic acid; gluconic acid; b-D-glucuronic acid; and lactobionic acid.
3. The method of Claim 1 wherein the solubility enhancing agent is a polyhydroxy dicarboxylic acids selected from the group consisting of glutaric acid; citric acid; a-keto s glutaric acid; D-glucaric acid; citramalic acid; fumaric acid; maleic acid; and oxalic acid.
4. The method of Claim 1 wherein the solubility enhancing agent is a lactone selected from the group consisting of gluconolactone; D-glucuronolactone; and D- glucoascorbic acid.
0
5. The method of Claim 1 wherein the amount of solubility enhancing agent is equal
to at least one molar equivalent of the weakly basic ophthalmic drug.
6. The method of Claim 5 wherein the amount of solubility enhancing agent is greater than one molar equivalent of the weakly basic ophthalmic drug.
7. The method of Claim 6 wherein the amount of solubility enhancing agent is from
s about 0.1 to about 5 wt.%.
8. The method of Claim 1 wherein the weakly basic ophthalmic drug is selected from the group consisting of weakly basic carbonic anhydrase inhibitors; weakly basic antiallergic agents; and weakly basic anticataract agents.
0
9. The method of Claim 8 wherein the weakly basic ophthalmic drug is selected
from the group consisting of brinzolamide and lodoxamide.
10. An aqueous pharmaceutical composition comprising a weakly basic ophthalmic is drug and a solubility enhancing amount of an agent selected from the group consisting
of polyhydroxy monocarboxylic acids; polyhydroxy dicarboxylic acids; lactones of
polyhydroxy monocarboxylic acids; and lactones of polyhydroxy dicarboxylic acids.
11. The composition of Claim 10 wherein the solubility enhancing agent is a
20 polyhydroxy monocarboxylic acid selected from the group consisting of lactic acid; D-
gulonic acid; 2-keto-L-gulonic acid; giucoheptanoic acid; gluconic acid; b-D-glucuronic
acid; and lactobionic acid.
12. The composition of Claim 10 wherein the solubility enhancing agent is a
polyhydroxy dicarboxylic acids selected from the group consisting of glutaric acid; citric
acid; a-keto glutaric acid; D-glucaric acid; citramalic acid; fumaric acid; maleic acid; and
oxalic acid.
13. The composition of Claim 10 wherein the solubility enhancing agent is a lactone
selected from the group consisting of gluconolactone; D-glucuronolactone; and D- glucoascorbic acid.
14. The composition of Claim 10 wherein the amount of solubility enhancing agent is
equal to at least one molar equivalent of the weakly basic ophthalmic drug.
15. The composition of Claim 14 wherein the amount of solubility enhancing agent is greater than one molar equivalent of the weakly basic ophthalmic drug.
16. The composition of Claim 15 wherein the amount of solubility enhancing agent is from about 0.1 to about 5 wt.%.
17. The composition of Claim 10 wherein the weakly basic ophthalmic drug is
selected from the group consisting of weakly basic carbonic anhydrase inhibitors;
weakly basic antiallergic agents; and weakly basic anticataract agents.
18. The composition of Claim 17 wherein the weakly basic ophthalmic drug is
selected from the group consisting of brinzolamide and lodoxamide.
PCT/US1997/020064 1996-11-05 1997-11-05 Polyhydroxy monocarboxylic and dicarboxylic acids and their lactones in ophthalmic compositions WO1998019707A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU51038/98A AU5103898A (en) 1996-11-05 1997-11-05 Polyhydroxy monocarboxylic and dicarboxylic acids and their lactones in ophthalmic compositions

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US3036496P 1996-11-05 1996-11-05
US60/030,364 1996-11-05

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003015752A1 (en) * 2001-08-14 2003-02-27 Bakulesh Mafatlal Khamar The process for preparing isotonic topical antibiotic ophthalmic formulation with improved therapeutic effect
WO2013114397A2 (en) * 2012-01-16 2013-08-08 Biocon Limited Pharmaceutically acceptable salt of brinzolamide and composition thereof

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE855320A (en) * 1976-06-04 1977-12-02 Continental Pharma PHARMACEUTICAL COMPOSITION BASED ON SUBSTITUTE PHENYL-AMONO-ALCOHOL, PROCESS AND METHOD OF USE OF THIS COMPOSITION.
US4704397A (en) * 1980-03-11 1987-11-03 Warner-Lambert Company Pharmaceutical salts of 4-(9-acridinyl-amino) methanesulfon-m-anisidide
GB2203039A (en) * 1987-03-02 1988-10-12 American Cyanamid Co Ophthalmic local compositions containing acetazolamide
EP0397147A2 (en) * 1989-05-10 1990-11-14 Bristol-Myers Squibb Company Stable solutions of rebeccamycin analog and preparation thereof
EP0433766A1 (en) * 1989-12-18 1991-06-26 Alcon Laboratories, Inc. Compositions of antiallergics and antihistamines and methods for their use
EP0534860A1 (en) * 1991-09-27 1993-03-31 Rhone-Dpc Europe Injectable stabilized solutions containing sparfloxacin or its salts
WO1997002825A1 (en) * 1995-07-12 1997-01-30 Alcon Laboratories, Inc. Thiophene sulfonamides useful as carbonic anhydrase inhibitors

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE855320A (en) * 1976-06-04 1977-12-02 Continental Pharma PHARMACEUTICAL COMPOSITION BASED ON SUBSTITUTE PHENYL-AMONO-ALCOHOL, PROCESS AND METHOD OF USE OF THIS COMPOSITION.
FR2353288A1 (en) * 1976-06-04 1977-12-30 Continental Pharma HYDROSOLUBLE PHARMACEUTICAL COMPOSITION BASED ON AN AMINE COMPOUND AS ACTIVE PRODUCT
US4704397A (en) * 1980-03-11 1987-11-03 Warner-Lambert Company Pharmaceutical salts of 4-(9-acridinyl-amino) methanesulfon-m-anisidide
GB2203039A (en) * 1987-03-02 1988-10-12 American Cyanamid Co Ophthalmic local compositions containing acetazolamide
EP0397147A2 (en) * 1989-05-10 1990-11-14 Bristol-Myers Squibb Company Stable solutions of rebeccamycin analog and preparation thereof
EP0433766A1 (en) * 1989-12-18 1991-06-26 Alcon Laboratories, Inc. Compositions of antiallergics and antihistamines and methods for their use
EP0534860A1 (en) * 1991-09-27 1993-03-31 Rhone-Dpc Europe Injectable stabilized solutions containing sparfloxacin or its salts
WO1997002825A1 (en) * 1995-07-12 1997-01-30 Alcon Laboratories, Inc. Thiophene sulfonamides useful as carbonic anhydrase inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PITRE D. ET AL: "Analytical profile of iodoxamic acid", ANAL. PROFILES DRUG SUBST., vol. 20, 1991, pages 303 - 335, XP002055769 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003015752A1 (en) * 2001-08-14 2003-02-27 Bakulesh Mafatlal Khamar The process for preparing isotonic topical antibiotic ophthalmic formulation with improved therapeutic effect
WO2013114397A2 (en) * 2012-01-16 2013-08-08 Biocon Limited Pharmaceutically acceptable salt of brinzolamide and composition thereof
WO2013114397A3 (en) * 2012-01-16 2013-10-17 Biocon Limited Pharmaceutically acceptable salt of brinzolamide and composition thereof

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Publication number Publication date
AU5103898A (en) 1998-05-29

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