CA2179419C - Sulfated polyvinyl alcohol polymers to stabilize pharmaceutical drug compounds - Google Patents
Sulfated polyvinyl alcohol polymers to stabilize pharmaceutical drug compounds Download PDFInfo
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- CA2179419C CA2179419C CA002179419A CA2179419A CA2179419C CA 2179419 C CA2179419 C CA 2179419C CA 002179419 A CA002179419 A CA 002179419A CA 2179419 A CA2179419 A CA 2179419A CA 2179419 C CA2179419 C CA 2179419C
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- polyvinyl alcohol
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- sulfated polyvinyl
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Abstract
Stable formulations of positively charged, hydrolytically unstable drug comp ounds are obtained by adding a sulfated polyvinyl alcoho l copolymer to the formulations.
Description
. R'O 96115773 PC1'1US95/14956 SULFATED POLYVINYL ALCOHOL POLYMERS TO STABILIZE
PHARMACEUTICAL DRUG COMPOUNDS
BACKGROUND OF THE INVENTION
1. Field of the Invention The present invention relates to stable compositions of hydrolytically unstable ,o pharmaceutical compounds. In particular, this invention relates to stable compositions containing positively charged, hydrolytically unstable drug compounds and sulfated polyvinyl alcohol polymers.
PHARMACEUTICAL DRUG COMPOUNDS
BACKGROUND OF THE INVENTION
1. Field of the Invention The present invention relates to stable compositions of hydrolytically unstable ,o pharmaceutical compounds. In particular, this invention relates to stable compositions containing positively charged, hydrolytically unstable drug compounds and sulfated polyvinyl alcohol polymers.
2. Description of Related Art ,5 Epinephrine is ari ophthalmic drug which has been used for many years in the treatment of glaucoma. When topically administered to the eye, epinephrine can cause irritation, tearing, conjunctival hyperemia, and other side effects. The dipivalyl ester of epinephrine has been developed as a prodrug in an attempt to eliminate zo epinephrine's undesirable side effects. This epinephrine prodrug is known as dipivefrine hydrochloride or dipivalyl epinephrine ("DPE").
One of the problems associated with DPE in solution, however, is its instability due to ester hydrolysis andlor oxidation, causing a relatively short shelf life.
One known method of improving the stability and/or comfort of certain pharmaceutical drug compounds is complexing the drug compound with certain ion-exchange resins. Such a method is disclosed in, for example, U.S. Patent Nos.
4,911,920 and 5,093,126, where sustained release ophthalmic formulations of topical 3o anti-glaucoma drugs include a water insoluble ion-exchange resin such as a sodium ,. ,, WO 96115773 PC'T/US95/14956 a . .
poly(styrenedivinyl benzene) sulfonate, to provide an additional means of sustained release and to improve comfort.
Ophthalmic solutions containing polystyrene sulfonate compounds are disclosed in U.S. Patent No. 3,987,163. The reference solutions can be used to treat ' "dry eye" or as a carrier for ophthalmic medicaments. When used as a carrier, the reference solutions provide prolonged duration of medicament activity.
European Patent Application Publication No. 0 392 487 discloses a stabilized ,° pharmaceutical composition containing an anthracycline antibiotic having an amino sugar residue and a certain kind of water-soluble polyanion capable of at least 40%
interacting with the antibiotic. The water-soluble polyanions are natural and synthetic polymers having negatively charged acidic residues, such as sulfuric or sulfonic acid residues, and have a molecular weight of 500 to 2,000,000. Listed examples of ,5 natural polyanions include polysaccharides preferably having 1.5 to 3 sulfuric acid residues per repeating unit sugar. Dextransulfate is listed as one example of a natural macromolecular polyanion. The synthetic polymers include, among others, polystyrene and polyvinyl alcohol each preferably having 0.2 to 1.0 sulfuric acid residue per monomer unit. The reference anthracycline antibiotic composition ~° possess improved stability in the neutral pH region.
The present invention provides stable compositions of positively charged, hydrolytically unstable drug compounds. The compositions of the present invention comprise one or more sulfated polyvinyl alcohol ("PVS") copolymers and one or more positively charged, hydrolytically unstable drug compounds. ' The present invention also provides for a method of improving the stability of compositions containing positively charged, hydrolytically unstable ophthalmic drug compounds, wherein the method comprises adding one or more PVS copolymers to such compositions.
DETAILED DESCRIPTION OF THL INVENTION
The compositions of the present invention comprise one or more positively charged, hydrolytically unstable drug compounds and one or more PVS copolymers in an amount effective to stabilize such compound or compounds.
The PVS copolymers useful in the compositions and methods of the present invention are block or random copolymers having the formula _((~j2-~i~_(C _ C_}m A Y R
I
wherein n and m are integers that represent degrees of polymerization and n= 5-2,500;
m= 10-7,000;
A= OH;
X and Y independently = H or CH3;
Z= H or Cl - C6 alkyl; and R= a single bond, C1-C6 alkyl, or benzyl; provided that if Z = C1-C6 alkyl, R = a single bond.
One of the problems associated with DPE in solution, however, is its instability due to ester hydrolysis andlor oxidation, causing a relatively short shelf life.
One known method of improving the stability and/or comfort of certain pharmaceutical drug compounds is complexing the drug compound with certain ion-exchange resins. Such a method is disclosed in, for example, U.S. Patent Nos.
4,911,920 and 5,093,126, where sustained release ophthalmic formulations of topical 3o anti-glaucoma drugs include a water insoluble ion-exchange resin such as a sodium ,. ,, WO 96115773 PC'T/US95/14956 a . .
poly(styrenedivinyl benzene) sulfonate, to provide an additional means of sustained release and to improve comfort.
Ophthalmic solutions containing polystyrene sulfonate compounds are disclosed in U.S. Patent No. 3,987,163. The reference solutions can be used to treat ' "dry eye" or as a carrier for ophthalmic medicaments. When used as a carrier, the reference solutions provide prolonged duration of medicament activity.
European Patent Application Publication No. 0 392 487 discloses a stabilized ,° pharmaceutical composition containing an anthracycline antibiotic having an amino sugar residue and a certain kind of water-soluble polyanion capable of at least 40%
interacting with the antibiotic. The water-soluble polyanions are natural and synthetic polymers having negatively charged acidic residues, such as sulfuric or sulfonic acid residues, and have a molecular weight of 500 to 2,000,000. Listed examples of ,5 natural polyanions include polysaccharides preferably having 1.5 to 3 sulfuric acid residues per repeating unit sugar. Dextransulfate is listed as one example of a natural macromolecular polyanion. The synthetic polymers include, among others, polystyrene and polyvinyl alcohol each preferably having 0.2 to 1.0 sulfuric acid residue per monomer unit. The reference anthracycline antibiotic composition ~° possess improved stability in the neutral pH region.
The present invention provides stable compositions of positively charged, hydrolytically unstable drug compounds. The compositions of the present invention comprise one or more sulfated polyvinyl alcohol ("PVS") copolymers and one or more positively charged, hydrolytically unstable drug compounds. ' The present invention also provides for a method of improving the stability of compositions containing positively charged, hydrolytically unstable ophthalmic drug compounds, wherein the method comprises adding one or more PVS copolymers to such compositions.
DETAILED DESCRIPTION OF THL INVENTION
The compositions of the present invention comprise one or more positively charged, hydrolytically unstable drug compounds and one or more PVS copolymers in an amount effective to stabilize such compound or compounds.
The PVS copolymers useful in the compositions and methods of the present invention are block or random copolymers having the formula _((~j2-~i~_(C _ C_}m A Y R
I
wherein n and m are integers that represent degrees of polymerization and n= 5-2,500;
m= 10-7,000;
A= OH;
X and Y independently = H or CH3;
Z= H or Cl - C6 alkyl; and R= a single bond, C1-C6 alkyl, or benzyl; provided that if Z = C1-C6 alkyl, R = a single bond.
According to another aspect of the present invention, there is provided a method of producing a hydrolytically stable composition containing a positively charged, hydrolytically unstable drug compound, wherein the method comprises adding to the composition a sulfated polyvinyl alcohol copolymer of the formula X Z
- (CH2- CH)ri (C- C-~
Y R
wherein n and m are integers that represent degrees of polymerization and n = 5-2,500; m = 10-7,000; A = OH; X
and Y independently = H or CH3; Z = H or C1-C6 alkyl; and R = a single bond, C1-C6 alkyl, or benzyl; provided that if Z = C1-C6 alkyl, R = a single bond.
Suitable PVS copolymers will typically have a molecular weight from 2,000 to 1.2 million and a degree of sulfation of at least 20°s. Preferably, the PVS copolymers will have a molecular weight from 20,000 to 500,000, and most preferably from 100,000 to 300,000.
- 3a -WO 96115773 PC1'/US95/14956 The preferred PVS copolymers are those of the formula listed above wherein, A
= OH; X, Y and Z = H; and R = nothing or benzyl. , The most preferred PVS copolymers for use in the compositions of the present invention are those wherein A = OH; X, Y and Z = H; and R = nothing; such that they have the formula -(CH2-CH),; (CHZ-CH)m '° I I
where n and m have the same values as those above. The degree of sulfation of these most preferred PVS polymers is preferably at least 40% and is most preferably ,5 from 55 to 75%.
PVS may be prepared by sulfating polyvinyl alcohol, a commercially available polymer, using methods known in the art. Generally, PVS is synthesized by partially or completely hydrolyzing polyvinyl acetate to obtain a polyvinyl alcohol. The polyvinyl z° alcohol is then reacted with a sulfuric acid to obtain a PVS
copolymer. Alternatively, certain PVS copolymers are commercially available as a sodium or potassium salt from Aldrich Chemical Company (Milwaukee, Wisconsin) and Eastman Kodak Company (Rochester, New York).
The amount of PVS necessary to enhance the hydrolytic stability of the pharmaceutical compositions of the present invention will depend on a variety of factors, such as the type and amount of positively charged drug compounds) to be stabilized and the target shelf life or degree of stabilization desired.
Typically, the amount of PVS contained in the compositions of the present invention will range from rl .. .
~ WO 96/15773 I ~ 217 9 419 PCT~S95/14956 0.05 to 5.0%. Preferably, the amount will range from 0.1 to 1Ø Most preferred are PVS concentrations ranging from 0.1 to 0.4%.
Suitable drug compounds useful in the compositions of the present invention ' S include any positively charged drug compound capable of complexing with PVS and for which it is desirable to enhance hydrolytic stability. Examples of such positively charged drug compounds include DPE and prodrugs containing esters. DPE is especially preferred.
,° In addition to one or more PVS polymers and one or more positively charged drug compounds, the compositions of the present invention may optionally contain ingredients conventionally employed in pharmaceutical compositions. Examples of such other ingredients include, but are not limited to, preservatives, buffering agents, tonicity agents, chelating agents, viscosity enhancing agents, agents to adjust pH, ,5 antioxidants, ion-exchange resins and the like.
The composition of the present invention may be formulated for a variety of administration routes including, but not limited to, oral, parental, topical and nasal administration routes. Most preferred are compositions formulated for topical z° ophthalmic administration.
Certain embodiments of the present invention are illustrated in the following examples.
' '. 2179419 W096115773 _ ' PCT/1T595/14956 Example 1: Stable. Topical ~hthalmic Solu ion Ingredient % (w/~) .
a DPE 0.22% ' PVS 0.40%
BAC 0.01 Mannitol 0.5%
Boric acid 0.5%
t Antioxidant 0.16%
NaOH/HCl QS pH 3.2 Purified Water QS 100%
t5 In~red!ent / (w/vl DPE 0.11 BAC 0.01 zo EDTA 0.0138 NaCI 0_gg NaOH/HCl QS pH 3.0 Purified Water QS 100%
. WO 96115773 ' ' 217 9 419 PCTIUS9SI14956 Ingredient %(WIV~
DPE 0.11 ' S Betaxolol 0.28 Amberlite~ IRP-69 0.25 PVS 0.20 Boric acid 0.50 Mannitol 4.0 , Carbomer 974P 0.3 Lauroyl sarcosinate 0.03 EDTA 0.01 BAC 0.011 NaOH/HCl pH: 5.5-5.8 ,5 Purified Water QS 100%
omoarative Example 2: Onhtha mic Solution N~thout PVS
Jnqredient ~W/V) DPE 0.1 + 25% excess z Betaxolol 0.28 Amberfite~ IRP-69 0.25 Boric Acid 1.0 Mannitol 0.5 Carbomer 974P 0.35 a Lauroyl sarcosinate 0.03 EDTA 0.01 BAC 0.01 Sodium thiosulfate 0.20 NaOH/HCl OS pH 7.0 Purified Water OS 100%
R'O 96115773 F w 217 9 419 pCT~S95/14956 %(WNl DPE 0.11 Betaxolol 0.28 PVS 0.2 Mannitol 4.0 EDTA 0.01 Lauroyl sarcosinate 0.03 , BAC 0.01 Boric acid 0.5 NaOHIHCI . QS pH 4.5 Purified Water QS 100%
,5 The stability-enhancing effectiveness of the PVS polymers of the present invention was evaluated as follows. The formulations described in Examples 1-3 and Comparative Examples 1 and 2 above were placed in either plastic bottles or glass ampules and placed in controlled temperature ovens (room temperature, 35°C, 45°C, 55°C, and 65°C, 75°C, and 85°C). Samples were pulled at predetermined times (1 z° day to 26 weeks). Arrhenius plots were obtained and shelf life was calculated by extrapolation at the desired temperature.
The results are shown in Table 1 below.
WO 96!15773 PGTIU595/14956 Table 1 Formulation Calculated ShelfFormulation Calculated Life at Shelf-RT (weeks) Life at RT
(weeks) Example 1 465 Comparative Example81 . pH=3.2 pH=3.2 Example 2 132 Comparative Example8 pH=5.8 pH = 7.0 Example 3 125 - -pH = 4.5 As shown in the above table, the shelf-life of DPE is greatly enhanced by the use of PVS in the compositions. The stability enhancement of the formulation of Example 1 was approximately 500%, and the enhancement for the formulation of Example 2 was approximately 1600%.
,° The invention has been described. by reference to certain preferred embodiments; however, it should be understood that it may be embodied in other speck 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 ,5 by the appended claims rather than by the foregoing description.
- (CH2- CH)ri (C- C-~
Y R
wherein n and m are integers that represent degrees of polymerization and n = 5-2,500; m = 10-7,000; A = OH; X
and Y independently = H or CH3; Z = H or C1-C6 alkyl; and R = a single bond, C1-C6 alkyl, or benzyl; provided that if Z = C1-C6 alkyl, R = a single bond.
Suitable PVS copolymers will typically have a molecular weight from 2,000 to 1.2 million and a degree of sulfation of at least 20°s. Preferably, the PVS copolymers will have a molecular weight from 20,000 to 500,000, and most preferably from 100,000 to 300,000.
- 3a -WO 96115773 PC1'/US95/14956 The preferred PVS copolymers are those of the formula listed above wherein, A
= OH; X, Y and Z = H; and R = nothing or benzyl. , The most preferred PVS copolymers for use in the compositions of the present invention are those wherein A = OH; X, Y and Z = H; and R = nothing; such that they have the formula -(CH2-CH),; (CHZ-CH)m '° I I
where n and m have the same values as those above. The degree of sulfation of these most preferred PVS polymers is preferably at least 40% and is most preferably ,5 from 55 to 75%.
PVS may be prepared by sulfating polyvinyl alcohol, a commercially available polymer, using methods known in the art. Generally, PVS is synthesized by partially or completely hydrolyzing polyvinyl acetate to obtain a polyvinyl alcohol. The polyvinyl z° alcohol is then reacted with a sulfuric acid to obtain a PVS
copolymer. Alternatively, certain PVS copolymers are commercially available as a sodium or potassium salt from Aldrich Chemical Company (Milwaukee, Wisconsin) and Eastman Kodak Company (Rochester, New York).
The amount of PVS necessary to enhance the hydrolytic stability of the pharmaceutical compositions of the present invention will depend on a variety of factors, such as the type and amount of positively charged drug compounds) to be stabilized and the target shelf life or degree of stabilization desired.
Typically, the amount of PVS contained in the compositions of the present invention will range from rl .. .
~ WO 96/15773 I ~ 217 9 419 PCT~S95/14956 0.05 to 5.0%. Preferably, the amount will range from 0.1 to 1Ø Most preferred are PVS concentrations ranging from 0.1 to 0.4%.
Suitable drug compounds useful in the compositions of the present invention ' S include any positively charged drug compound capable of complexing with PVS and for which it is desirable to enhance hydrolytic stability. Examples of such positively charged drug compounds include DPE and prodrugs containing esters. DPE is especially preferred.
,° In addition to one or more PVS polymers and one or more positively charged drug compounds, the compositions of the present invention may optionally contain ingredients conventionally employed in pharmaceutical compositions. Examples of such other ingredients include, but are not limited to, preservatives, buffering agents, tonicity agents, chelating agents, viscosity enhancing agents, agents to adjust pH, ,5 antioxidants, ion-exchange resins and the like.
The composition of the present invention may be formulated for a variety of administration routes including, but not limited to, oral, parental, topical and nasal administration routes. Most preferred are compositions formulated for topical z° ophthalmic administration.
Certain embodiments of the present invention are illustrated in the following examples.
' '. 2179419 W096115773 _ ' PCT/1T595/14956 Example 1: Stable. Topical ~hthalmic Solu ion Ingredient % (w/~) .
a DPE 0.22% ' PVS 0.40%
BAC 0.01 Mannitol 0.5%
Boric acid 0.5%
t Antioxidant 0.16%
NaOH/HCl QS pH 3.2 Purified Water QS 100%
t5 In~red!ent / (w/vl DPE 0.11 BAC 0.01 zo EDTA 0.0138 NaCI 0_gg NaOH/HCl QS pH 3.0 Purified Water QS 100%
. WO 96115773 ' ' 217 9 419 PCTIUS9SI14956 Ingredient %(WIV~
DPE 0.11 ' S Betaxolol 0.28 Amberlite~ IRP-69 0.25 PVS 0.20 Boric acid 0.50 Mannitol 4.0 , Carbomer 974P 0.3 Lauroyl sarcosinate 0.03 EDTA 0.01 BAC 0.011 NaOH/HCl pH: 5.5-5.8 ,5 Purified Water QS 100%
omoarative Example 2: Onhtha mic Solution N~thout PVS
Jnqredient ~W/V) DPE 0.1 + 25% excess z Betaxolol 0.28 Amberfite~ IRP-69 0.25 Boric Acid 1.0 Mannitol 0.5 Carbomer 974P 0.35 a Lauroyl sarcosinate 0.03 EDTA 0.01 BAC 0.01 Sodium thiosulfate 0.20 NaOH/HCl OS pH 7.0 Purified Water OS 100%
R'O 96115773 F w 217 9 419 pCT~S95/14956 %(WNl DPE 0.11 Betaxolol 0.28 PVS 0.2 Mannitol 4.0 EDTA 0.01 Lauroyl sarcosinate 0.03 , BAC 0.01 Boric acid 0.5 NaOHIHCI . QS pH 4.5 Purified Water QS 100%
,5 The stability-enhancing effectiveness of the PVS polymers of the present invention was evaluated as follows. The formulations described in Examples 1-3 and Comparative Examples 1 and 2 above were placed in either plastic bottles or glass ampules and placed in controlled temperature ovens (room temperature, 35°C, 45°C, 55°C, and 65°C, 75°C, and 85°C). Samples were pulled at predetermined times (1 z° day to 26 weeks). Arrhenius plots were obtained and shelf life was calculated by extrapolation at the desired temperature.
The results are shown in Table 1 below.
WO 96!15773 PGTIU595/14956 Table 1 Formulation Calculated ShelfFormulation Calculated Life at Shelf-RT (weeks) Life at RT
(weeks) Example 1 465 Comparative Example81 . pH=3.2 pH=3.2 Example 2 132 Comparative Example8 pH=5.8 pH = 7.0 Example 3 125 - -pH = 4.5 As shown in the above table, the shelf-life of DPE is greatly enhanced by the use of PVS in the compositions. The stability enhancement of the formulation of Example 1 was approximately 500%, and the enhancement for the formulation of Example 2 was approximately 1600%.
,° The invention has been described. by reference to certain preferred embodiments; however, it should be understood that it may be embodied in other speck 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 ,5 by the appended claims rather than by the foregoing description.
Claims (26)
1. A hydrolytically stable, pharmaceutical composition comprising a positively charged, hydrolytically unstable drug compound and a sulfated polyvinyl alcohol block or random copolymer in an amount effective to hydrolytically stabilize the drug, wherein the sulfated polyvinyl alcohol copolymer has the formula wherein n and m are integers that represent degrees of polymerization and n = 5-2,500;
m = 10-7,000;
A = OH;
X and Y independently = H or CH3;
Z = H or C1-C6 alkyl; and R = a single bond, C1-C6 alkyl, or benzyl; provided that if Z = C1-C6 alkyl, R = a single bond.
m = 10-7,000;
A = OH;
X and Y independently = H or CH3;
Z = H or C1-C6 alkyl; and R = a single bond, C1-C6 alkyl, or benzyl; provided that if Z = C1-C6 alkyl, R = a single bond.
2. The composition of claim 1 wherein X, Y and Z = H;
and R = the single bond or benzyl.
and R = the single bond or benzyl.
3. The composition of claim 2 wherein R = the single bond.
4. The composition of any one of claims 1 to 3, wherein the sulfated polyvinyl alcohol copolymer has a molecular weight from 2,000 - 1.2 million.
5. The composition of any one of claims 1 to 3, wherein the sulfated polyvinyl alcohol copolymer has a molecular weight from 20,000 - 500,000.
6. The composition of any one of claims 1 to 3, wherein the sulfated polyvinyl alcohol copolymer has a molecular weight from 100,000 - 300,000.
7. The composition of any one of claims 1 to 6, wherein the sulfated polyvinyl alcohol copolymer has a degree of sulfation of at least 20%.
8. The composition of any one of claims 1 to 6, wherein the sulfated polyvinyl alcohol copolymer has a degree of sulfation of at least 40%.
9. The composition of any one of claims 1 to 6, wherein the degree of sulfation is from 55 - 75%.
10. The composition of any one of claims 1 to 9, wherein the amount of sulfated polyvinyl alcohol polymer is from 0.05 to 5% (w/v).
11. The composition of any one of claims 1 to 9, wherein the amount of sulfated polyvinyl alcohol polymer is from 0.1 to 1% (w/v).
12. The composition of any one of claims 1 to 9, wherein the amount of sulfated polyvinyl alcohol polymer is from 0.1 to 0.4% (w/v).
13. The composition of any one of claims 1 to 12, wherein the drug compound is dipivalyl epinephrine and the composition is a topically administrable ophthalmic composition.
14. A method of producing a hydrolytically stable composition containing a positively charged, hydrolytically unstable drug compound, wherein the method comprises adding to the composition a sulfated polyvinyl alcohol copolymer of the formula wherein n and m are integers that represent degrees of polymerization and n = 5-2,500;
m = 10-7,000;
A = OH;
X and Y independently = H or CH3;
Z = H or C1-C6 alkyl ; and R = a single bond, C1-C6 alkyl, or benzyl; provided that if Z = C1-C6 alkyl, R = a single bond.
m = 10-7,000;
A = OH;
X and Y independently = H or CH3;
Z = H or C1-C6 alkyl ; and R = a single bond, C1-C6 alkyl, or benzyl; provided that if Z = C1-C6 alkyl, R = a single bond.
15. The method of claim 14, wherein X, Y and Z = H; and R = the single bond or benzyl.
16. The method of claim 15, wherein R = the single bond.
17. The method of any one of claims 14 to 16, wherein the sulfated polyvinyl alcohol copolymer has a molecular weight from 2,000 - 1.2 million.
18. The method of any one of claims 14 to 16, wherein the sulfated polyvinyl alcohol copolymer has a molecular weight from 20,000 - 500,000.
19. The method of any one of claims 14 to 16, wherein the sulfated polyvinyl alcohol copolymer has a molecular weight from 100,000 - 300,000.
20. The method of any one of claims 14 to 19, wherein the sulfated polyvinyl alcohol copolymer has a degree of sulfation of at least 20%.
21. The method of any one of claims 14 to 19, wherein the sulfated polyvinyl alcohol copolymer has a degree of sulfation of at least 40%.
22. The method of any one of claims 14 to 19, wherein the degree of sulfation is from 55 - 75%.
23. The method of any one of claims 14 to 22, wherein the amount of sulfated polyvinyl alcohol polymer is from 0.05 to 5% (w/v).
24. The method of any one of claims 14 to 22, wherein the amount of sulfated polyvinyl alcohol polymer is from 0.1 to 1% (w/v).
25. The method of any one of claims 14 to 22, wherein the amount of sulfated polyvinyl alcohol polymer is from 0.1 to 0.4% (w/v) .
26. The method of any one of claims 14 to 25, wherein the drug compound is dipivalyl epinephrine and the composition is a topically administrable ophthalmic composition.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/342,523 US5662919A (en) | 1994-11-21 | 1994-11-21 | Sulfated polyvinyl alcohol polymers to stabilize pharmaceutical drug compounds |
| US08/342,523 | 1994-11-21 | ||
| PCT/US1995/014956 WO1996015773A1 (en) | 1994-11-21 | 1995-11-16 | Sulfated polyvinyl alcohol polymers to stabilize pharmaceutical drug compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2179419A1 CA2179419A1 (en) | 1996-05-30 |
| CA2179419C true CA2179419C (en) | 2005-11-15 |
Family
ID=35530860
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002179419A Expired - Fee Related CA2179419C (en) | 1994-11-21 | 1995-11-16 | Sulfated polyvinyl alcohol polymers to stabilize pharmaceutical drug compounds |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2179419C (en) |
-
1995
- 1995-11-16 CA CA002179419A patent/CA2179419C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CA2179419A1 (en) | 1996-05-30 |
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