CA2238872A1 - Stable vancomycin hydrochloride solutions - Google Patents
Stable vancomycin hydrochloride solutions Download PDFInfo
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- CA2238872A1 CA2238872A1 CA 2238872 CA2238872A CA2238872A1 CA 2238872 A1 CA2238872 A1 CA 2238872A1 CA 2238872 CA2238872 CA 2238872 CA 2238872 A CA2238872 A CA 2238872A CA 2238872 A1 CA2238872 A1 CA 2238872A1
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- vancomycin hydrochloride
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
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Abstract
The present invention provides stable solutions of vancomycin hydrochloride comprising between about 0.5 % and about 12 % w/v vancomycin hydrochloride and between about 0.5 % and about 30 % v/v ethanol. These solutions are particularly useful for storage in a liquid state not requiring either freezing or freeze drying in order to maintain stability of the active agent. The present invention also provides a method of inhibiting degradation of vancomycin hydrochloride in a solution containing between about 0.5 % and about 12 % w/v vancomycin hydrochloride, said method comprising including between about 0.5 % and about 30 % v/v ethanol in said solution.
Description
CA 02238872 1998-0~-29 W O 97/19690 PCT~US96/18898 T;tle ST~RT.~ VANCOMYCIN HYDROCHLORIDE SOT.UTIONS
This invention relates to a~ueous solutions of the antibiotic vancomycin hydrochloride and to a method for improving the stability thereof.
Vancomycin is described in U.S. Patent No.
3,067,099. It is a well known antibiotic, often prescribed for the treatment of staphylococcal infections, particularly infections caused by methicillin-resistant strains of staphylococcus. Vancomycin is a fermentation.product isolated from the culture broth of Norcardi~ orl~n~alis, which produces a mixture o~ closely related co-fermentation factors, /'Factor B/' being identi~ied as the major antibacterial agent in the mixture.
Few of the co-fermentation factors have been isolated and characterized due to their unstable nature.
Moreover, vancomycin itself degrades to a number of products including its pre~om;n~nt degradation product, vancomycin - CA 02238872 l998-0~-29 _ WO 97/19690 PCT~US96/18898 CDP-l ~see Sheldrick et. al., Nature 271:223, 1978). It has _ been difficult to differentiate between co-fermentation _ factors and degradation products of vancomycin due to _ complexity of the chromatographic profile.
_ 5 ~ Vancomycin is formulated for pharmaceutical use as the hydrochloride salt, vancomycin hydrochloride, w~ich has - previously been supplied ~or oral and parenteral use as a dry - solid or as a frozen liquid preparation. Heretofore, li~uid _ solutions of vancomycin hydrochloride have been impractical - 10 as ph~rm~ceutical preparations because of the limited _ stability o~ the vancomycin hydrochloride agent in solution.
Nevertheless, it is desirable to provide vancomycin hydrochloride in solution so as to reduce the manufacturing _ costs associated with lyophilization and to reduce hospital labor costs required ~or reconstitution of the lyophilized product and transfer of the reconstituted material.
The present invention provides stable solutions of - vancomycin hydrochloride and a method for inhibiting physical and chemical degradation of vancomycin hydrochloride in a solution.
--- The present invention provides stable solutions of vancomycin hydrochloride comprising between about 0 5% and 2~ about 12% w/v vancomycin hydrochloride and between about 0.5%
and about 30% vJv ethanol. These solutions are particularly useful for storage in a liquid state not re~uiring either CA 02238872 1998-0~-29 W O 97/19~90 PCT~US96/18898 freezing or freeze drying in order to maintain stability of the active agent.
The present invention also provides a method of inhibiting degradation of vancomycin hydrochloride in a solution containing between about 0.5% and about 12% w/v vancomycin hydrochloride, said method comprising including between about 0.5% and about 30% v~v ethanol in said solution.
The vancomycin hydrochloride solutions of this invention comprise between about 0.5% and about 12% w/v vancomycin hydrochloride and between about 0.5% and about 30%
v/v of ethanol. Preferred solutions comprise between about 5% and about 12% w/v vancomycin hydrochloride. Solutions comprising between about 10% and 30% v/v ethanol are likewise preferred. Especially preferred solutions comprise 10% w/v vancomycin hydrochloride with either 10% or 20% v/v ethanol:
The discovery of the benefits provided by inclusion of ethanol in liquid formulations of vancomycin hydrochloride is closely related to a novel method of inhibiting degradation of vancomycin hydrochloride in a solution containing between about 0.5% and about 12% w/v vancomycin t hydrochloride, said method comprising including between about 0.5% and about 30% v/v ethanol in said solution. Preferred methods of the current invention comprise the inclusion of between about 5% and about 12% w/v vancomycin hydrochloride, and in particular about 10% w/v vancomycin hydrochloride.
- CA 02238872 1998-0~-29 _ W O 97/19690 PCT~US96/18898 _ Methods wherein between about 10% and 30~ v/v ethanol are - included in concentrated solutions of vancomycin _ hydrochloride are likewise preferred. Especially preferred methods comprise including either 10% or 20% v/v ethanol with _ 5 10% w/v vancomycin hydrochloride. Cooling vancomycin hydrochloride solutions containing ethanol to 10~C or less - further inhibits degradation of vancomycin and thus results _ in pre~erred methods. Temperatures o~ 0~C to 5~C are _ especially preferred.
Vancomycin hydrochloride solutions of the current invention are prepared by slurrying the calculated amount of vancomycin base in a suitable diluent, for example, water or commercially available preparations used for intravenous administration, in which sufficient alcohol to achieve the - 15 desired concentration has been included. Many other suitable _ diluents are ~nown in the art. Hydrochloric acid is then - added to form the soluble hydrochloride salt. The solution of vancomycin hydrochloride is adjusted to a final pH of 2.5-4.5, preferrably 3.1-3.3 and brought to final volume with the diluent.
Alternatively, a substantial portion of the hydrochloric acid necessary to convert the base to the salt can be added to a suitable diluent containing sufficient alcohol to achieve the desired concentration prior to adding - 25 the vancomycin base. The resulting solution is adjusted to a ~ final pH of 2.5-4.5, preferrably 3.1-3.3, and brought to - final volume with the diluent.
CA 02238872 1998-0~-29 W O 97/19690 PCT~US96/18898 The solutions thus prepared are filtered through 0.2 micron membranes to clarify them and render them particulate free. Filtration may also be used to sterilize i solutions. The filtered solutions can then be filled into a variety of pharmaceutically appropriate packages, such as, for example, ampoules, vials, syringes, and bulk packages.
E~mnle 1 In order to assess the effect of ethanol on stability of vancomycin hydrochloride solutions, three lots of vancomycin base were converted to vancomycin hydrochloride in a 10% w/v concentrate solution according to the procedures outlined above. Varying concentrations of ethanol were included in the solutions, which were then stored either at room (about 23~C) or refrigerated ~about 5~C) temperatures.
The solutions were evaluated for purity, retention o~
potency, appearance of degradation products, and physical stability at various time points.
The amount of Factor B r~m~;n;ng in solutions prepared according to the current invention was measured over time by HPLC and is reported in Table 1 as a percent of total vancomycin-related substances. Stability, as measured by retention of potency is reported in Table 2. Appearance of ? degradation products, recited as related substances, is reported in Table 3.
_ CA 02238872 l998-0~-29 _ WO 97/19690 PCTAJS96/18898 -_ T~RTE 1 - Pexcent Vancomvcin Factor B
in V~nComYCin Hv~Qchloride-Eth~n~l Solutio~c =
- Davs at 23~C Davs at 5~C
-- Lot Ethanol Initial 10-11 24-2835-40 60-70 60-70 >750 _ A 0% 96.0 89.7 83.6 PPT94.6 81.4*
- 2% 96.0 89.7 8S.2 PPT95.2 83 0 - 5% 95.8 90.7 86.1 PPT94.7 83.5 = 10% 95.8 92.2 88.0 85.395.1 84 9 - 20% 97.0 92.8 90.4 86.695.g 87.3 _ 30% 96.1 93.4 91 1 87.895.5 88.4 - B 0% 95.8 94.5 90.2 85.9 PPT95.3 PPT
- 2% 95.9 94.5 90 1 86.3 PPT95 5 PPT
5% 96.1 94.2 90.6 86.8 PPT95.5 PPT
_ 10% 96.3 94.8 91.8 88.3 88.195.8 85.5 - 20% 96.4 95 1 92.7 89.4 89.696.1 87.4 _ 30% 96.4 95.5 93 7 90.5 91.496.1 89.2 _ C 0% 95.4 90.2 PPT 94.6PPT
_ 2% 95.3 90.5 85.1 94.6PPT
= 5~ 95.4 91.8 86.1 94.884.1 _ 10% 95.2 91.9 87.5 95.086.2 - 20% 95.2 94.1 88.8 95.187.2 - 30~ 95.1 94.3 90.0 95.288.4 - * - slight precipitate observed - PPT - precipitate present, no HPLC assay per~ormed _ -CA 02238872 1998-0~-29 - W O 97/19690 PCT~US96/18898 T~RTT~ 2 V~nc~vcin Potencv (ma/ml) of V~ncomvcin Hvdrochloride-Eth~nol Solutions Davs at 23~C Davs at 5~C
Lot Ethanol Initial 10-11 24-28 35-40 60-70 60-70 >750 A 0~100.0 95.6 90.9 87.1 80 8* 99.7 85.4*
2%98.8 95.7 90.3 86.8 82.3* 99.5 87.1 5%99 8 97.4 93.0 89 2 82.4* 99.8 86.6 10%98.5 97 4 93.0 91.0 86.2 97.2 89.1 20%100.0 97.8 95.6 91.5 89.8 99.4 90.1 30%100.0 98.1 96 5 92.4 90.2 98.7 91 1 B 0%100.8 98.2 92.5 90.2 85.5* 98.6 PPT
2%101.8 100.8 93.4 89.8 PPT 99.6 PPT
5%101.3 98.4 92.8 91.0 PPT 100.4 PPT
10%102.0 99.0 94.6 90.6 89.1 99.8 90.7 20~101.7 100.8 94.6 93.8 90.8 99.7 92.6 30%101.5 100.0 97.0 95.2 92.8 101.6 96.2 C 0%101.7 95.6 PPT 101.0 PPT
2%101.6 96.2 91.1 99.8 PPT
5%104.0 98.0 89.0 101.6 90 6 10%102.4 97.8 94.3 100.2 92.3 20%104.0 99.2 93.4 101.4 94.0 30%103.7 97.7 95.8 101.4 95.4 0 * - slight precipitate observed PPT - precipitate present, no HPLC assay per~ormed - CA 02238872 l998-0~-29 _ WO 97/19690 PCTAUS96/18898 - TARr~ 3 - Percent Related Sl~hstances ~%~
in V~ncomvcin ~vdro~hloride-Eth~nol Solution~
_ Dav~ at 23~c Dav~ a~ 5 - Lot Ethanol Initial 10-11 24-28 35-40 60-70 60-70 >750 _ A 0% 0.9 3.3 5.8 PPT 1.6 PPT
- 2% 0.9 3.4 4.9 PPT 1.5 7.6 5~ 0.9 3.2 4.1 PPT 0.9 6.5 _ 10% 0.9 2.7 3.9 3.9 0.9 5.2 - 20~ 0.6 2.4 3.4 3.5 0.9 3.3 - 30~ 0.9 2.1 3.0 3 3 0.9 2.3 - B 0~ 1.3 2.2 3.7 5.0 PPT 1.6 PPT
- 2% 1.3 2.1 3.7 4.5 PPT 1.5 PPT
- 5% 1.2 2.2 3.5 4.3 PPT 1.4 PPT
10% 1.1 1.9 3.2 2.8 3.5 1.3 4.9 _ 20% 0.8 1.7 2.8 2.3 2.g 1.1 3.2 _ 30~ 0.8 1.4 2 3 2.1 1.4 0.9 2.0 - C o% 1.1 3.0 PPT 1.4 PPT
~ 2~ 1.0 2.8 4.5 1.3 PPT
- 5% 0.9 2.7 4.1 1.3 6.1 - 10~ 0.8 2.5 3 5 1.2 4.6 - 20% 0.9 1.1 3.3 1.1 3.2 - 30% 0.8 0.9 2.9 1.1 2.3 _ 10 PPT - precipitate present, no HPLC a~qay per~ormed -_ The results indicate that addition of ethanol to _ solutions of vancomycin hydrochloride greatly extends the _ 15 stability and antimicrobiological activity of the solutions.
- Thus, vancomycin hydrochloride can be formulated according to - the current invention as a liquid that can be easily stored - for immediate use. For example, vancomycin hydrochloride - solutions can be prepared as a concentrate that is readily - 20 diluted or as a solution that is ready for direct _ administration.
~ Since the effect of ethanol is concentration - dependent, including ethanol at concentrations o~ about 10%---CA 02238872 1998-0~-29 30% are pre~erred and concentrations o~ 10% and 20% are especially pre~erred. However, ~ormulations o~ the current invention may be made su~iciently concentrated to eliminate any concern over the ethanolic content o~ the diluted product. For example, a li~uid concentrate containing 100 mg/ml vancomycin hydrochloride and 10% ethanol can be diluted twenty-~old to 5 mg/ml vancomycin hydrochloride and 0.5%
ethanol. A typical 500 mg dose o~ vancomycin hydrochloride could be ~Am; ni stered in a 100 ml intravenous solution containing 0.5 ml ethanol. A 1 g dose o~ vancomycin hydrochloride could be administered in a 200 ml intravenous solution.
The bene~its o~ ethanol occur at very low ethanol concentrations and may be included in concentrations as low as 0.5% to improve stability o~ dilute vancomycin hydrochloride solutions.
This invention relates to a~ueous solutions of the antibiotic vancomycin hydrochloride and to a method for improving the stability thereof.
Vancomycin is described in U.S. Patent No.
3,067,099. It is a well known antibiotic, often prescribed for the treatment of staphylococcal infections, particularly infections caused by methicillin-resistant strains of staphylococcus. Vancomycin is a fermentation.product isolated from the culture broth of Norcardi~ orl~n~alis, which produces a mixture o~ closely related co-fermentation factors, /'Factor B/' being identi~ied as the major antibacterial agent in the mixture.
Few of the co-fermentation factors have been isolated and characterized due to their unstable nature.
Moreover, vancomycin itself degrades to a number of products including its pre~om;n~nt degradation product, vancomycin - CA 02238872 l998-0~-29 _ WO 97/19690 PCT~US96/18898 CDP-l ~see Sheldrick et. al., Nature 271:223, 1978). It has _ been difficult to differentiate between co-fermentation _ factors and degradation products of vancomycin due to _ complexity of the chromatographic profile.
_ 5 ~ Vancomycin is formulated for pharmaceutical use as the hydrochloride salt, vancomycin hydrochloride, w~ich has - previously been supplied ~or oral and parenteral use as a dry - solid or as a frozen liquid preparation. Heretofore, li~uid _ solutions of vancomycin hydrochloride have been impractical - 10 as ph~rm~ceutical preparations because of the limited _ stability o~ the vancomycin hydrochloride agent in solution.
Nevertheless, it is desirable to provide vancomycin hydrochloride in solution so as to reduce the manufacturing _ costs associated with lyophilization and to reduce hospital labor costs required ~or reconstitution of the lyophilized product and transfer of the reconstituted material.
The present invention provides stable solutions of - vancomycin hydrochloride and a method for inhibiting physical and chemical degradation of vancomycin hydrochloride in a solution.
--- The present invention provides stable solutions of vancomycin hydrochloride comprising between about 0 5% and 2~ about 12% w/v vancomycin hydrochloride and between about 0.5%
and about 30% vJv ethanol. These solutions are particularly useful for storage in a liquid state not re~uiring either CA 02238872 1998-0~-29 W O 97/19~90 PCT~US96/18898 freezing or freeze drying in order to maintain stability of the active agent.
The present invention also provides a method of inhibiting degradation of vancomycin hydrochloride in a solution containing between about 0.5% and about 12% w/v vancomycin hydrochloride, said method comprising including between about 0.5% and about 30% v~v ethanol in said solution.
The vancomycin hydrochloride solutions of this invention comprise between about 0.5% and about 12% w/v vancomycin hydrochloride and between about 0.5% and about 30%
v/v of ethanol. Preferred solutions comprise between about 5% and about 12% w/v vancomycin hydrochloride. Solutions comprising between about 10% and 30% v/v ethanol are likewise preferred. Especially preferred solutions comprise 10% w/v vancomycin hydrochloride with either 10% or 20% v/v ethanol:
The discovery of the benefits provided by inclusion of ethanol in liquid formulations of vancomycin hydrochloride is closely related to a novel method of inhibiting degradation of vancomycin hydrochloride in a solution containing between about 0.5% and about 12% w/v vancomycin t hydrochloride, said method comprising including between about 0.5% and about 30% v/v ethanol in said solution. Preferred methods of the current invention comprise the inclusion of between about 5% and about 12% w/v vancomycin hydrochloride, and in particular about 10% w/v vancomycin hydrochloride.
- CA 02238872 1998-0~-29 _ W O 97/19690 PCT~US96/18898 _ Methods wherein between about 10% and 30~ v/v ethanol are - included in concentrated solutions of vancomycin _ hydrochloride are likewise preferred. Especially preferred methods comprise including either 10% or 20% v/v ethanol with _ 5 10% w/v vancomycin hydrochloride. Cooling vancomycin hydrochloride solutions containing ethanol to 10~C or less - further inhibits degradation of vancomycin and thus results _ in pre~erred methods. Temperatures o~ 0~C to 5~C are _ especially preferred.
Vancomycin hydrochloride solutions of the current invention are prepared by slurrying the calculated amount of vancomycin base in a suitable diluent, for example, water or commercially available preparations used for intravenous administration, in which sufficient alcohol to achieve the - 15 desired concentration has been included. Many other suitable _ diluents are ~nown in the art. Hydrochloric acid is then - added to form the soluble hydrochloride salt. The solution of vancomycin hydrochloride is adjusted to a final pH of 2.5-4.5, preferrably 3.1-3.3 and brought to final volume with the diluent.
Alternatively, a substantial portion of the hydrochloric acid necessary to convert the base to the salt can be added to a suitable diluent containing sufficient alcohol to achieve the desired concentration prior to adding - 25 the vancomycin base. The resulting solution is adjusted to a ~ final pH of 2.5-4.5, preferrably 3.1-3.3, and brought to - final volume with the diluent.
CA 02238872 1998-0~-29 W O 97/19690 PCT~US96/18898 The solutions thus prepared are filtered through 0.2 micron membranes to clarify them and render them particulate free. Filtration may also be used to sterilize i solutions. The filtered solutions can then be filled into a variety of pharmaceutically appropriate packages, such as, for example, ampoules, vials, syringes, and bulk packages.
E~mnle 1 In order to assess the effect of ethanol on stability of vancomycin hydrochloride solutions, three lots of vancomycin base were converted to vancomycin hydrochloride in a 10% w/v concentrate solution according to the procedures outlined above. Varying concentrations of ethanol were included in the solutions, which were then stored either at room (about 23~C) or refrigerated ~about 5~C) temperatures.
The solutions were evaluated for purity, retention o~
potency, appearance of degradation products, and physical stability at various time points.
The amount of Factor B r~m~;n;ng in solutions prepared according to the current invention was measured over time by HPLC and is reported in Table 1 as a percent of total vancomycin-related substances. Stability, as measured by retention of potency is reported in Table 2. Appearance of ? degradation products, recited as related substances, is reported in Table 3.
_ CA 02238872 l998-0~-29 _ WO 97/19690 PCTAJS96/18898 -_ T~RTE 1 - Pexcent Vancomvcin Factor B
in V~nComYCin Hv~Qchloride-Eth~n~l Solutio~c =
- Davs at 23~C Davs at 5~C
-- Lot Ethanol Initial 10-11 24-2835-40 60-70 60-70 >750 _ A 0% 96.0 89.7 83.6 PPT94.6 81.4*
- 2% 96.0 89.7 8S.2 PPT95.2 83 0 - 5% 95.8 90.7 86.1 PPT94.7 83.5 = 10% 95.8 92.2 88.0 85.395.1 84 9 - 20% 97.0 92.8 90.4 86.695.g 87.3 _ 30% 96.1 93.4 91 1 87.895.5 88.4 - B 0% 95.8 94.5 90.2 85.9 PPT95.3 PPT
- 2% 95.9 94.5 90 1 86.3 PPT95 5 PPT
5% 96.1 94.2 90.6 86.8 PPT95.5 PPT
_ 10% 96.3 94.8 91.8 88.3 88.195.8 85.5 - 20% 96.4 95 1 92.7 89.4 89.696.1 87.4 _ 30% 96.4 95.5 93 7 90.5 91.496.1 89.2 _ C 0% 95.4 90.2 PPT 94.6PPT
_ 2% 95.3 90.5 85.1 94.6PPT
= 5~ 95.4 91.8 86.1 94.884.1 _ 10% 95.2 91.9 87.5 95.086.2 - 20% 95.2 94.1 88.8 95.187.2 - 30~ 95.1 94.3 90.0 95.288.4 - * - slight precipitate observed - PPT - precipitate present, no HPLC assay per~ormed _ -CA 02238872 1998-0~-29 - W O 97/19690 PCT~US96/18898 T~RTT~ 2 V~nc~vcin Potencv (ma/ml) of V~ncomvcin Hvdrochloride-Eth~nol Solutions Davs at 23~C Davs at 5~C
Lot Ethanol Initial 10-11 24-28 35-40 60-70 60-70 >750 A 0~100.0 95.6 90.9 87.1 80 8* 99.7 85.4*
2%98.8 95.7 90.3 86.8 82.3* 99.5 87.1 5%99 8 97.4 93.0 89 2 82.4* 99.8 86.6 10%98.5 97 4 93.0 91.0 86.2 97.2 89.1 20%100.0 97.8 95.6 91.5 89.8 99.4 90.1 30%100.0 98.1 96 5 92.4 90.2 98.7 91 1 B 0%100.8 98.2 92.5 90.2 85.5* 98.6 PPT
2%101.8 100.8 93.4 89.8 PPT 99.6 PPT
5%101.3 98.4 92.8 91.0 PPT 100.4 PPT
10%102.0 99.0 94.6 90.6 89.1 99.8 90.7 20~101.7 100.8 94.6 93.8 90.8 99.7 92.6 30%101.5 100.0 97.0 95.2 92.8 101.6 96.2 C 0%101.7 95.6 PPT 101.0 PPT
2%101.6 96.2 91.1 99.8 PPT
5%104.0 98.0 89.0 101.6 90 6 10%102.4 97.8 94.3 100.2 92.3 20%104.0 99.2 93.4 101.4 94.0 30%103.7 97.7 95.8 101.4 95.4 0 * - slight precipitate observed PPT - precipitate present, no HPLC assay per~ormed - CA 02238872 l998-0~-29 _ WO 97/19690 PCTAUS96/18898 - TARr~ 3 - Percent Related Sl~hstances ~%~
in V~ncomvcin ~vdro~hloride-Eth~nol Solution~
_ Dav~ at 23~c Dav~ a~ 5 - Lot Ethanol Initial 10-11 24-28 35-40 60-70 60-70 >750 _ A 0% 0.9 3.3 5.8 PPT 1.6 PPT
- 2% 0.9 3.4 4.9 PPT 1.5 7.6 5~ 0.9 3.2 4.1 PPT 0.9 6.5 _ 10% 0.9 2.7 3.9 3.9 0.9 5.2 - 20~ 0.6 2.4 3.4 3.5 0.9 3.3 - 30~ 0.9 2.1 3.0 3 3 0.9 2.3 - B 0~ 1.3 2.2 3.7 5.0 PPT 1.6 PPT
- 2% 1.3 2.1 3.7 4.5 PPT 1.5 PPT
- 5% 1.2 2.2 3.5 4.3 PPT 1.4 PPT
10% 1.1 1.9 3.2 2.8 3.5 1.3 4.9 _ 20% 0.8 1.7 2.8 2.3 2.g 1.1 3.2 _ 30~ 0.8 1.4 2 3 2.1 1.4 0.9 2.0 - C o% 1.1 3.0 PPT 1.4 PPT
~ 2~ 1.0 2.8 4.5 1.3 PPT
- 5% 0.9 2.7 4.1 1.3 6.1 - 10~ 0.8 2.5 3 5 1.2 4.6 - 20% 0.9 1.1 3.3 1.1 3.2 - 30% 0.8 0.9 2.9 1.1 2.3 _ 10 PPT - precipitate present, no HPLC a~qay per~ormed -_ The results indicate that addition of ethanol to _ solutions of vancomycin hydrochloride greatly extends the _ 15 stability and antimicrobiological activity of the solutions.
- Thus, vancomycin hydrochloride can be formulated according to - the current invention as a liquid that can be easily stored - for immediate use. For example, vancomycin hydrochloride - solutions can be prepared as a concentrate that is readily - 20 diluted or as a solution that is ready for direct _ administration.
~ Since the effect of ethanol is concentration - dependent, including ethanol at concentrations o~ about 10%---CA 02238872 1998-0~-29 30% are pre~erred and concentrations o~ 10% and 20% are especially pre~erred. However, ~ormulations o~ the current invention may be made su~iciently concentrated to eliminate any concern over the ethanolic content o~ the diluted product. For example, a li~uid concentrate containing 100 mg/ml vancomycin hydrochloride and 10% ethanol can be diluted twenty-~old to 5 mg/ml vancomycin hydrochloride and 0.5%
ethanol. A typical 500 mg dose o~ vancomycin hydrochloride could be ~Am; ni stered in a 100 ml intravenous solution containing 0.5 ml ethanol. A 1 g dose o~ vancomycin hydrochloride could be administered in a 200 ml intravenous solution.
The bene~its o~ ethanol occur at very low ethanol concentrations and may be included in concentrations as low as 0.5% to improve stability o~ dilute vancomycin hydrochloride solutions.
Claims (18)
1. A solution of vancomycin hydrochloride comprising between about 0.5% and about 12% w/v vancomycin hydrochloride and between about 0.5% and about 30% v/v ethanol.
2. The solution of claim l wherein the concentration of vancomycin hydrochloride is about 5% to about 12% w/v.
3. The solution of claim 1 wherein the concentration of vancomycin hydrochloride is about 10% w/v.
4. The solution of claim 1 wherein the concentration of ethanol is between about 10% and about 30%
v/v .
v/v .
5. The solution of claim 1 wherein the concentration of ethanol is about 10% v/v.
6. The solution of claim 3 wherein the concentration of ethanol is about 10% v/v.
7. The solution of claim 3 wherein the concentration of ethanol is about 20% v/v.
8. A method of inhibiting degradation of vancomycin hydrochloride in a solution containing between about 0.5% and about 12% w/v vancomycin hydrochloride, said method comprising including between about 0.5% and about 30%
v/v ethanol in said solution.
v/v ethanol in said solution.
9. The method of claim 8 wherein the concentration of vancomycin hydrochloride in said solution is about 5% to about 12% w/v.
10. The method of claim 8 wherein the concentration of vancomycin hydrochloride in said solution is about 10% w/v.
11. The method of claim 8 wherein the concentration of ethanol included in said solution is between about 10% and about 30% v/v.
12. The method of claim 8 wherein the concentration of ethanol included in said solution is about 10% v/v.
13. The method of claim 10 wherein the concentration of ethanol is about 10% v/v.
14. The method of claim 10 wherein the concentration of ethanol is about 20% v/v.
15. The method of claim 8 wherein said solution is cooled to 10°C or less.
16. The method of claim 8 wherein said solution is cooled to between about 0°C and about 5°C.
17. The method of claim 13 wherein said solution is cooled to between about 0°C and about 5°C.
18. The method of claim 14 wherein said solution is cooled to between about 0°C and about 5°C.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US782495P | 1995-12-01 | 1995-12-01 | |
| US60/007,824 | 1995-12-01 | ||
| GBGB9600213.4A GB9600213D0 (en) | 1996-01-05 | 1996-01-05 | Stable vancomycin hydrochloride solutions |
| GB9600213.4 | 1996-01-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2238872A1 true CA2238872A1 (en) | 1997-06-05 |
Family
ID=26308428
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2238872 Abandoned CA2238872A1 (en) | 1995-12-01 | 1996-11-25 | Stable vancomycin hydrochloride solutions |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU1407197A (en) |
| CA (1) | CA2238872A1 (en) |
| WO (1) | WO1997019690A1 (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999017793A1 (en) * | 1997-10-03 | 1999-04-15 | Fujisawa Pharmaceutical Co., Ltd. | Hydrochlorides of vancomycin antibiotics and process for producing the same |
| US10959946B2 (en) * | 2014-03-14 | 2021-03-30 | Azurity Pharmaceuticals, Inc. | Composition and method for vancomycin oral liquid |
| SG11201703568WA (en) | 2014-11-06 | 2017-05-30 | Xellia Pharmaceuticals Aps | Glycopeptide compositions |
| WO2016127087A1 (en) * | 2015-02-06 | 2016-08-11 | Latitude Pharmaceuticals, Inc. | Aqueous solution formulations of vancomycin |
| WO2017194385A1 (en) * | 2016-05-09 | 2017-11-16 | Xellia Pharmaceuticals Aps | Stabilized glycopeptide antibiotic formulations |
| AU2020237983A1 (en) | 2019-03-08 | 2021-10-07 | Emphascience, Inc. | Stable pharmaceutical formulations of peptide and protein drugs |
| US11433115B2 (en) | 2020-10-30 | 2022-09-06 | Somerset Therapeutics, Llc | Glycopeptide antibiotics liquid formulations and methods and uses thereof |
| EP4014969A1 (en) | 2020-12-16 | 2022-06-22 | EVER Valinject GmbH | Aqueous solution |
| EP4014965A1 (en) | 2020-12-16 | 2022-06-22 | EVER Valinject GmbH | Aqueous solution |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4885275A (en) * | 1987-10-15 | 1989-12-05 | Eli Lilly And Company | Vancomycin-HCL solutions and the lyophilization thereof |
-
1996
- 1996-11-25 AU AU14071/97A patent/AU1407197A/en not_active Abandoned
- 1996-11-25 WO PCT/US1996/018898 patent/WO1997019690A1/en active Application Filing
- 1996-11-25 CA CA 2238872 patent/CA2238872A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| WO1997019690A1 (en) | 1997-06-05 |
| AU1407197A (en) | 1997-06-19 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Dead |