CA2244213A1 - Buffer systems for stabilizing pharmaceutical preparations - Google Patents
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- 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
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- 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
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- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- 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
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
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- C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
- C07C59/265—Citric acid
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
- C07H5/04—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to nitrogen
- C07H5/06—Aminosugars
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Abstract
The invention concerns buffer systems, consisting of a physiologically tolerable amine and a carboxylic acid, for use in the preparation of pharmaceutical agents.
Description
8chering AG 5132OBDEMlXXoO-P
Buffer 8ystems for Stabilizing Pharmaceutical Preparations Thi-; invention describes complex buffer systems for increasing the stability of pharmaceutical preparations during production and storage. The buffer mixtures according to the invention are especially suitable for parenteral use owing to their special properties. They are particularly suitable for the production of contrast medium solutions.
Prior Ar~
In pharmaceutical practice, buffer solutions are often used in aqueous formulations, which require a certain pH in order to ensure stable storage. Since decomposition processes such as, for example, hydrolysis or oxidation and also solubility can exhibit different pH optima, in most cases an attempt is made to get as c:Lose as possible (= euhydration) to the physiologic pH of 7.4 in the case of ophthalmic pharmaceutical agents and aqueous injection solutions and infusion solutions. Owing to the large buffer capacity of the blood plasma, at least in the case of injection solutions (volume S 20 ml) with a low buffer capacity, quite large deviations from isohydric pH (=7.4) can be accepted in the range of about pH 4-9 (Physikalische Pharmazie [Physical Pharmaceutics], Ed.: H. Stricker, Wissenschaftliche Verlagsgesellschaft mbH [Scientific Publishing, Inc.], Stuttgart, 3rd Edition, 1987). In Table 1, pharmaceutically commonly used buffer systems for parenteral use are listed (Pharmazeutische Technologie [Pharmaceutical Technology], Eds.: H. Sucker, P.
Fuchs and P. Speiser, Georg Thieme Verlag Stuttgart, 1978).
Table 1: Commonly Used Buffer Systems for ParenterAl Use Substance 1 Substance 2 pH-range ~x;rum buffer capacity at pH
Sodium acetate Acetic acid 3.8-5.6 4.7 Sodium Disodium 5-8 6.8 dihydrogen hydrogen phosphate phosphate Glycine Sodium 8.6-12.8 11.2 hydroxide Citric acid Disodium 2.2-7.8 about 5 phosphate Trometamol Hydrochloric 7.2-9.0 about 8 acid Iodine-containing x-ray contrast media, which in most cases are used as infusion solutions, represent an important group of parenterally administered pharmaceutical agents. Here, as buffer substances, in addition to the ones cited in Tab. 1, trometamol [tris(hydroxymethyl)aminomethane, 2-amino-2-(hydroxymethyl)-1,3-propanediol] (contained in, e.g., Ultravist(R), Omnipaque(R) or Solutrast(R)) and sodium dihydrogen phosphate (e.g., in Conray(R)), for example also sodium hydrogen carbonate (e.g, in Isovist(R)), can be used.
Other commonly used buffer systems are, e.g., glutamic acid/NaOH and aspartamic acid/NaOH, as are used in, e.g., European Patent Application EP 437 622. In International Patent Application WO 89/09614, a phosphate buffer is used for stabilizing a pharmaceutical formulation. For biochemical reactions, the introduction of zwitterionic buffers by Good (so-called Good buffers) has proven extraordinarily useful. The zwitterions contain sec- and tert-amino groups as vehicles for positive charges and sulfonic acid groups or carboxy groups as vehicles for negative charges. Examples of this are: ACES, ADA, BES, BIcrNE~ CAPS, HEPES, MES, MOPS, PIPES, TES, TRICINE (see Rompp Chemie Lexikon and CRC Handbook of Chemistry and Physics).
According to a study by Grit et al., J. Pharm. Sci., Vol.
82, No. 4 (1993), p. 362 ff, liposome suspensions are best buffered at pH 6.5. From Chemistry and Physics of Lipids (Vol.
60 (1991), p. 93 ff, it is known that lecithin is less quickly hydrolyzed in a trometamol buffer than in pure water, but the trometamol-buffer buffers at pH 8-9 and is not suitable for stabilizing liposome suspensions.
owing to its good buffering action in the range of 7.2 - 9.0 and the resulting possibility of setting an isohydric pH, the trometamol buffer (= tris) has come to occupy a special position in this regard. In comparison to the phosphate buffer, which covers the pH range from 5 to 8, moreover, no problems are described with respect to possible precipitation with ions from the glass primary container for the trometamol buffer.
Within the framework of DE 2926850, a process for the production or sterilization of special iodine-containing x-ray contrast medium solutions is described, which is based on the temperature-dependent reduction of the pH of amine-buffered solutions. Because the pH values of the trometamol-buffered or meglumine-buffered solutions (pH 7.0 - 7.6) drop to values of between p]~ 3.5 and 5.5 during sterilization, it was possible to achieve a definite reduction in iodide formation during production. After sterilization has been completed, the pH of corresponding solutions is returned again to approximately the starting value.
When stored at room temperature (15-25~C) and away from light, the commonly used x-ray contrast medium solutions (RKM) have a ~;~um shelf life of three years. Prolonged product service lives often cannot be reached because of decomposition processes. The instability reactions that are described for these substance groups can be accompanied by changes in pH and color, as well as a reduction in the active ingredient content.
The contents of iodide and free amine are used as an indicator of the chemical decomposition of such x-ray contrast media (Kontrastmittel [Contrast Media], Ed.: U. Speck, Springer-Verlag Berlin, 3:rd Edition, 1991).
The object of this invention is therefore to make available new buffer systems with good buffering action in the physiologic range in order to reduce the decomposition reactions of pharmaceutical substances in the storage and production --especially heat sterilization -- of pharmaceutical preparations.
This object is achieved by the buffer systems according to the invention, as they are characterized in the claims.
The aqueous buffer systems according to the invention are mixtures that consist of a physiologically compatible amine and a physiologically compatible aliphatic or aromatic organic acid.
Substances that are already approved as pharmaceutical agents or pharmaceutical agent additives and that occur under physiologic conditions in the human or animal organism are defined as physiologically compatible amines or acids.
As amine components of the buffer mixtures according to the invention, all physiologically compatible amines are suitable.
N-methylglucamine (meglumine) and/or trometamol (2-amino-2-(hydroxymethyl)-1,3-propanediol, TRIS) is preferably used, and especially preferably trometamol.
As acid components in the buffer mixtures according to the invention, monovalent or multivalent carboxylic acids (e.g., succinic acid, maleic acid, benzoic acid), hydroxycarboxylic acids (e g., glycolic acid, citric acid, malic acid or lactic acid), keto acids (e.g., ~-ketoglutaric acid) or sulfonic acids (e.g., 2--[4-(2-hydroxyethyl)-1-piperazino]-ethanesulfonic acid (HEPES)),, and amino acids (e.g., glycine, aspartic acid, phenylalanine, lysine, arginine, preferably the naturally occurring L-amino acids) or their salts can be used. Thus, in especially preferred cases, for example, succinic acid is combined with trometamol. The components that are used in the buffer mixtures according to the invention can be mixed in any molar ratios. In addition to the standard molar mixture ratio of 1:1 (e.g., lo mmol of tris and 10 mmol of glycine), other mixture ratios of between 1:99 and 99:1 can also be set. In some cases, very good results are achieved with mixture ratios of 25:75 and 75:25.
To set the pH of buffer mixtures according to the invention, for example, salts of the main buffer components can be used, in addition to the substances that are commonly used by one skilled in the art, such as, for example, a sodium hydroxide solution or hydrochloric acid.
Owing to their adequate buffer capacity in the pH range of between 4 and 9, the buffers according to the invention, in especially suitable cases, offer the possibility of optimized matching of the pH to the stability requirements of the respective pharmaceutical substance while taking physiologic requirements into account. Unlike the conventional trometamol buffer, which has an adequate buffer capacity only in the pH
range of about 7.2 to 9.0, buffer systems according to the invention can, if necessary, optionally also be used effectively below this pH range. Moreover, owing to their special physical and chemical properties, the buffers according to the invention also turn out to be superior to conventional buffer systems in the range of isohydric pH (about 7.4). Thus, certain decomposition processes can often be avoided by using buffers according to the invention under otherwise identical conditions.
In addition, when buffer mixtures according to the invention are used, the addition of additional formulation adjuvants, such as, for example, complexing agents (e.g., sodium calcium edetate) can be partially eliminated since the buffer mixtures according to the invention themselves act in a complexing manner in especially suitable cases. In addition, the formulations according to the invention enhance neither microbial attack nor precipitation reactions with ions from the primary container. The formulations according to the invention are also distinguished by especially good compatibility.
Parenteral preparations (injection and infusion solutions) accordinq to the invention are generally set at pH values of between ~ and 9 or 5 and 8. In special cases, however, pH values of between 6.0 and 8.0 or 5.0 and 6.7 are desired.
The buffer mixtures according to the invention exhibit a marked temperature dependence in terms of their pH. It has turned out, surprisingly enough, that the steepness of the temperature-dependent drop in the pH of the buffer according to the invention has a marked dependence on starting pH. In special cases, the pH of the formulations according to the invention drops during heat sterilization (121~C, 20 minutes) by more than 0.5 or 1 to 3 pH units. By specifically selecting a buffer system according to the invention for a special pharmaceutical substance, the extent of the pH depression and thus optionally occurring decomposition reactions can be controlled during sterilization. Thus, in certain cases, a smaller pH drop during sterilization may be desired with a view to avoiding special decomposition processes.
In the production of formulations according to the invention, osmolality is generally set to values in the range of 200 to 1200 mOsmlkg or 200 to 1,000 mOsm/kg or, in especially preferred cases, between 250 and 850 mOsm/kg.
The buffer systems according to the invention are thus distinguished in that usually small total concentrations can be set in the range of 2 to 40 mmol, but preferably between 10 and 20 mmol or 5 and 15 mmol.
The buffer systems according to the invention are especially suitable for stabilizing contrast media, particularly x-ray contrast media based on iodine-containing aromatic compounds. In this case, on the one hand, during production there is a stabilization that can be only partially attributed to the pH
drop during the sterilization process. In comparison to the trometamol buffer (pH 7.5), a significant reduction in iodide formation in the case of one-time and repeated sterilization (121~C, 20 minutes) in iopromide solutions (300 mg of iodine/ml~
can be detected, for example, when using a trometamol/glycine buffer according to the invention (pH 7.5). This was all the more surprising as at this starting pH the buffer according to the invention shows only a comparatively small temperature-dependent pH drop relative to the trometamol/HCl buffer. Similar results were obtained using a trometamol/succinic acid buffer or trometamol/HEPES buffer (pH 7.5).
Because of the possibility of setting the pH below 7.0 while preserving adequate buffer capacity, the buffer systems according to the invention also potentially allow further stabilization during production. Thus, for example, setting the pH of an iopromide solution (300 mg of iodine/ml) in the trometamol/succinic acid buffer according to the invention at 6.5 results in a further drastic reduction of iodide formation during sterilization (20 minutes, 121~C) compared to a comparable trometamol. This effect was also strongly pronounced in the case of extended sterilization times, so that in especially suitable cases buEfer systems according to the invention also make it possible to repeatedly sterilize x-ray contrast medium solutions.
Compared to the buffers that were previously used, the special advantage of the buffer systems according to the invention lies, however, in the additional increase in the stability of x-ray contrast medium solutions in storage. Thus, by using buffers according to the invention, in general service lives of over 3 years, but preferably 4-6 years or 5 to 10 years, can be achieved because of reduced decomposition reactions. In this case, in addition to the parameters that are familiar to one skilled in the art (e.g., pH and color of the solution), the iodide content and, in special cases, the content of free amine are used as a special measure of the stability of corresponding solutions. Over the entire storage time (service life), for example, the iodide content of x-ray contrast medium solutions (concentration: 300 mg of iodine/ml) is thus below 75 ~g/ml, but preferably below 50 or 30 ~g/ml.
Depending on the starting pH of the x-ray contrast medium solution, in especially suitable cases a reduction in amine formation during storage can also be achieved by using buffers according to the invention. The free amine content of corresponding solutions (e.g., 300 mg of iodine/ml) is generally below 0.3~, but preferably below 0.1 to 0.05%, during the service life.
After as little as three months of storage at an elevated temperature (40~C), it was possible, in especially suitable cases, to detect a significantly reduced iodide formation in x-ray contrast medium solutions (iopromide) that are produced with buffers according to the invention compared to tometamol-buffered solutions (starting pH values = 7.5 and 6.5). Depending on the starting pH, there was also a slight reduction in amine content.
Surprisingly enough, moreover, it was also possible to show that, in the presence of buffers according to the invention, in some cases there was a significant decrease in the reduction of the complexing agent content (sodium calcium edetate) in the contrast medium sclutions that were studied. Consequently, when buffers according to the invention were used for the production of x-ray contrast media solutions, the potential is opened up for greatly reducing the addition of complexing agents or eliminating the latter entirely.
Owing to the above-described properties, the buffers according to the invention are suitable mainly for stabilizing parenterally administered hydrophilic x-ray contrast media, which are generally known from radiological practice. These include, for one thing, x-ray contrast media such as, for example, amidotri~oate, metrizoate, iopromide, N,N'-bis(2,3-dihydroxypropyl)-5-hydroxyacetylamino-2,4,6-triiodo-N-methylisophthalamide, iohexol, iopamidol, iosimide, ioversol, iomeprol/ iopentol, ioxilan, iobitridol, ioxaglate, iotrolan, N,N'-bis[3-carbamoyl-5-(2,3-dihydroxypropylcarbamoyl)-2,4,6-triiodo-phenyl]-N,N'-bis(2,3-dihydroxypropyl)-malonamide and iodixanol, which are also used to some extent in computer tomography (CT). In this case, the x-ray contrast media can also be encapsulated in liposomes.
The buffer systems according to the invention can, moreover, also be used in special cases, independently of the method of application (e.g., parenterally, orally, topically (also ophthalmic pharmaceutical agents)), for stabilizing other aqueous pharmaceutical substance solutions or suspensions (e.g., crystal suspensions, liposomes, micro- or nanoparticles or -capsules).
In this case, mainly therapeutic active ingredients, such as, for example, analgesics/antiphlogistic agents, antibiotics, cytostatic agents, and virustatic agents can be mentioned as nonlimiting examples, in addition to MRT-contrast media, such as, for example, Gd-DTPA, Gd-EOB-DTPA, Gd-DOTA, Gd-BOPTA, Mn-DPDP, gadobutrol, or ultrasonic contrast media. These active ingredient groups can also be present as liposomal formulations.
. . 12 Embodiment3:
The ]purpose of the following examples is to explain the subject of the invention, without intending that it be limited to these examples.
Example 1: 8tability of a Trometamol/HCl-Buffered Iopromide ~olution A trometamol (20 mmol)-buffered iopromide solution (set at about pH ~7.5 or 6.5 with HCl) with an iodine concentration of 300 mg/ml was produced, and aliquots of this solution were autoclaved (121~C) ir.~ sealed 10 ml injection flasks over times that are indicated in the table. The samples that were thus obtained were studied w:ith respect to their pH and iodide and amine contents (free aromatic amine).
Starting Sterilization Change in Iodide Amine pH Time pH Content Content [~
[min] [~g/ml] by weight]
-0.10 8.9 0.019 -0.12 9.5 0.025 7.5 180 -0.18 11.9 0.055 -0.15 8.9 0.010 -0.18 8.7 0.011 6.5 180 -0.22 10.2 0.017 CA 022442l3 l998-07-27 , 13 Example :!: 8tability of Glycine (10 mmol)/Tris (10 mmol) of Buffered Iopromide 8O1utions After the pH values are set (to 7.5 and 6.5), two iopromide solutionC; (300 mg of iodine/ml) that are buffered with glycine (lo mmol~/tris (lo mmol) are autoclaved (121~C) over the times that are indicated in the table, analogously to Example 1. The samples were studied with respect to their pH and iodide and amine contents (free aromatic amine).
pH Sterilization Change in Iodide Amine Time [min] pH Content Content [%
t~g/ml] by weight]
7.5 20 -0.11 5.1 0.016 -0. 13 5.5 0.029 6.5 20 -0.17 6.3 0.010 -0.23 6.5 0.012 CA 022442l3 l998-07-27 ' 14 Example 3: ~tability of Succinic Acid (10 mmol)/tris (10 mmol) of Buffered Iopromide Solutions This test was carried out analogously to Example 2.
pH Sterilization Change in Iodide Amine Time [min] pH Content Content [%
[~g/ml] by weight]
7.5 20 -0.16 1.8 0.021 -0.22 3.6 0.050 6.5 20 -0.17 0.9 0.021 -0.24 1.9 0.033 Example 4: Stability of ~EPE~ (10 mmol)/tris (10 mmol) of Buffered Iopromide Solutions This test was carried out analogously to Example 2.
pH Sterilization Change in Iodide Amine Time [min] pH Content Content [~
[~g/ml] by weight]
7.5 20 -0.09 2.3 0.020 -0.17 5.4 0.049 6.5 20 -0.06 6.2 0.008 -0.11 6.8 0.013 CA 022442l3 l998-07-27 . 15 Example !;: 8tability of Glycine (20 mmol) of Buffered Iopromide 801ution~3 After the pH values are set (to about 7.5 and 6.5), two iopromide solutions (300 mg of iodine/ml) that are buffered with glycine (20 mmol) are treated analogously to Example 1.
Starting Sterilization Change in Iodide Amine pH Time pH Content Content [~
[min] [~g/ml] by weight]
-0.24 2.2 0.025 -0.33 4.0 0.048 7.5 180 -0.68 7. 2 0.092 -0.38 1.0 0.010 -0.66 1.4 0.013 6.5 180 -0.89 2.3 0.021 CA 022442l3 l998-07-27 Example 6: 8tability of ~uccinic Acid (20 mmol) of Buffered Iopromide Solutions This test was carried out analogously to Example 5.
Startingr Sterilization Change in Iodide Amine pH Time pH Content Content [%
[min] [~g/ml] by weight]
-0.27 2.9 0.056 -o. 63 7.2 O. 145 7.5 180 -1.07 16.6 0.348 -0.16 1.4 0.034 -0.25 4.4 0.092 6.5 180 -0.40 11.6 0.229 Example 7: Temperature Dependence of the pH of a Trometamol-buffered Solution A 20 mmol trometamol solution is set at pH 7.5 with O.lN
HCl, and the pH is determined as a function of temperature with a pH-meter 761 from the Knick Company with and without temperature correction or compensation. The results are shown in Figure 1.
CA 022442l3 l998-07-27 . 17 Example ~: Temperature Dependence of the pH of Various Buffer Solution:~
Various aqueous buffer solutions (10 mmol each relative to each buffer component) are produced, and pH is determined as a function of temperature with a pH-meter 761 from the Knick Company. The respective temperatures of the buffer solutions were measured with an external Pt-100 detector, and the temperature on the pH-meter was corrected accordingly. The data that are thus obtained are shown in Figures 2 and 3.
Example '~: Three-Month 8tability of an Iopromide 801ution as a Function of Various Buffers Buffered iopromide solutions (300 mg of iodine/ml) that are produced analogously to Examples 1 and 2 were first autoclaved in 10 ml injection flasks (20 minutes, 121~C) and then stored for three months at 40~C in a climate test chamber. In this case, parallel solutions were stored that were to have been set to a starting pH (before sterilization) of 7.5 or 6.5. The samples that were thus obtained were studied with respect to their contents of iodide, amine (free aromatic amine), and sodium calcium edetate.
CA 022442l3 l998-07-27 Buffer System Iodide t~g/ml] Amine [~ by Sodium Calcium pH = 7.5 weight] Edetate [~g/ml]
Trometamol 11. 8 0.062 90.8 Trometamol/ 8. 2 0.058 92.7 Glycine Trometamol/ 2.6 0.048 93.7 Succinic Acid Trometamol/ 6.6 O. 070 94. 2 HEPES
Buffer ~ystem Iodide [~g/ml] Amine [% by Sodium Calcium pH = 6.5 weight] Edetate [ ~g/ml ]
Trometamol 8.6 0.014 89.9 Trometamol/ 7.1 0.015 89.0 Glycine Trometamol/ 1.4 0.024 93.7 Succinic Acid Trometarnol/ 7.1 0.014 90.9 HEPES
It turned out that the stability of the x-ray contrast medium solution was improved just by using pure trometamol buffer in a pH ral~ge < 6.5. When buffer according to the invention was used, however, it was possible to achieve additional stabilization. This applies especially for the combination of trometamol with succinic acid.
Example 10: Buffer Capacities of Various Buffer 801utions The buffer capacities of various buffer solutions are shown in Figure 4.
Example 11: Stability o~ Buffered Placebo Liposome 501utions Placebo liposome solutions that consist of soybean phosphatidylcholine (150 mg/ml) were produced using continuous high-pressure extrusion (5 passes each through 0.8/0.6/0.4 and 0.2 ~m polycarbonate membrane filter disks) using various buffer systems (setting to pH 6.5), and aliquots of these suspensions in sealed 10 ml injection flasks were autoclaved (121~C) over the times indicated in the table. The samples that were thus obtained were studied with respect to their particle size (photon correlation spectroscopy), as well as their contents of lysophosphatidylcholine (HPLC).
CA 022442l3 l998-07-27 , 21 Buffer 8terili~ation Mean Diameter LPC-Content Time ~min] [nm] tmg/g]
20 mmol of 0 161 1.7 citric acid/ 20 154 2.5 NaOH
161 3.3 20 mmol of 0 164 1.5 phosphate 20 165 2.0 buffer (see Fig. 1) 60 160 3.5 10 mmol of 0 154 0.7 tris/10 mmol 157 0.9 of succinic acid 60 158 1.2 10 mmol of 0 159 0.6 tris/10 mmol 20 153 0.9 of glycine 154 1.3
Buffer 8ystems for Stabilizing Pharmaceutical Preparations Thi-; invention describes complex buffer systems for increasing the stability of pharmaceutical preparations during production and storage. The buffer mixtures according to the invention are especially suitable for parenteral use owing to their special properties. They are particularly suitable for the production of contrast medium solutions.
Prior Ar~
In pharmaceutical practice, buffer solutions are often used in aqueous formulations, which require a certain pH in order to ensure stable storage. Since decomposition processes such as, for example, hydrolysis or oxidation and also solubility can exhibit different pH optima, in most cases an attempt is made to get as c:Lose as possible (= euhydration) to the physiologic pH of 7.4 in the case of ophthalmic pharmaceutical agents and aqueous injection solutions and infusion solutions. Owing to the large buffer capacity of the blood plasma, at least in the case of injection solutions (volume S 20 ml) with a low buffer capacity, quite large deviations from isohydric pH (=7.4) can be accepted in the range of about pH 4-9 (Physikalische Pharmazie [Physical Pharmaceutics], Ed.: H. Stricker, Wissenschaftliche Verlagsgesellschaft mbH [Scientific Publishing, Inc.], Stuttgart, 3rd Edition, 1987). In Table 1, pharmaceutically commonly used buffer systems for parenteral use are listed (Pharmazeutische Technologie [Pharmaceutical Technology], Eds.: H. Sucker, P.
Fuchs and P. Speiser, Georg Thieme Verlag Stuttgart, 1978).
Table 1: Commonly Used Buffer Systems for ParenterAl Use Substance 1 Substance 2 pH-range ~x;rum buffer capacity at pH
Sodium acetate Acetic acid 3.8-5.6 4.7 Sodium Disodium 5-8 6.8 dihydrogen hydrogen phosphate phosphate Glycine Sodium 8.6-12.8 11.2 hydroxide Citric acid Disodium 2.2-7.8 about 5 phosphate Trometamol Hydrochloric 7.2-9.0 about 8 acid Iodine-containing x-ray contrast media, which in most cases are used as infusion solutions, represent an important group of parenterally administered pharmaceutical agents. Here, as buffer substances, in addition to the ones cited in Tab. 1, trometamol [tris(hydroxymethyl)aminomethane, 2-amino-2-(hydroxymethyl)-1,3-propanediol] (contained in, e.g., Ultravist(R), Omnipaque(R) or Solutrast(R)) and sodium dihydrogen phosphate (e.g., in Conray(R)), for example also sodium hydrogen carbonate (e.g, in Isovist(R)), can be used.
Other commonly used buffer systems are, e.g., glutamic acid/NaOH and aspartamic acid/NaOH, as are used in, e.g., European Patent Application EP 437 622. In International Patent Application WO 89/09614, a phosphate buffer is used for stabilizing a pharmaceutical formulation. For biochemical reactions, the introduction of zwitterionic buffers by Good (so-called Good buffers) has proven extraordinarily useful. The zwitterions contain sec- and tert-amino groups as vehicles for positive charges and sulfonic acid groups or carboxy groups as vehicles for negative charges. Examples of this are: ACES, ADA, BES, BIcrNE~ CAPS, HEPES, MES, MOPS, PIPES, TES, TRICINE (see Rompp Chemie Lexikon and CRC Handbook of Chemistry and Physics).
According to a study by Grit et al., J. Pharm. Sci., Vol.
82, No. 4 (1993), p. 362 ff, liposome suspensions are best buffered at pH 6.5. From Chemistry and Physics of Lipids (Vol.
60 (1991), p. 93 ff, it is known that lecithin is less quickly hydrolyzed in a trometamol buffer than in pure water, but the trometamol-buffer buffers at pH 8-9 and is not suitable for stabilizing liposome suspensions.
owing to its good buffering action in the range of 7.2 - 9.0 and the resulting possibility of setting an isohydric pH, the trometamol buffer (= tris) has come to occupy a special position in this regard. In comparison to the phosphate buffer, which covers the pH range from 5 to 8, moreover, no problems are described with respect to possible precipitation with ions from the glass primary container for the trometamol buffer.
Within the framework of DE 2926850, a process for the production or sterilization of special iodine-containing x-ray contrast medium solutions is described, which is based on the temperature-dependent reduction of the pH of amine-buffered solutions. Because the pH values of the trometamol-buffered or meglumine-buffered solutions (pH 7.0 - 7.6) drop to values of between p]~ 3.5 and 5.5 during sterilization, it was possible to achieve a definite reduction in iodide formation during production. After sterilization has been completed, the pH of corresponding solutions is returned again to approximately the starting value.
When stored at room temperature (15-25~C) and away from light, the commonly used x-ray contrast medium solutions (RKM) have a ~;~um shelf life of three years. Prolonged product service lives often cannot be reached because of decomposition processes. The instability reactions that are described for these substance groups can be accompanied by changes in pH and color, as well as a reduction in the active ingredient content.
The contents of iodide and free amine are used as an indicator of the chemical decomposition of such x-ray contrast media (Kontrastmittel [Contrast Media], Ed.: U. Speck, Springer-Verlag Berlin, 3:rd Edition, 1991).
The object of this invention is therefore to make available new buffer systems with good buffering action in the physiologic range in order to reduce the decomposition reactions of pharmaceutical substances in the storage and production --especially heat sterilization -- of pharmaceutical preparations.
This object is achieved by the buffer systems according to the invention, as they are characterized in the claims.
The aqueous buffer systems according to the invention are mixtures that consist of a physiologically compatible amine and a physiologically compatible aliphatic or aromatic organic acid.
Substances that are already approved as pharmaceutical agents or pharmaceutical agent additives and that occur under physiologic conditions in the human or animal organism are defined as physiologically compatible amines or acids.
As amine components of the buffer mixtures according to the invention, all physiologically compatible amines are suitable.
N-methylglucamine (meglumine) and/or trometamol (2-amino-2-(hydroxymethyl)-1,3-propanediol, TRIS) is preferably used, and especially preferably trometamol.
As acid components in the buffer mixtures according to the invention, monovalent or multivalent carboxylic acids (e.g., succinic acid, maleic acid, benzoic acid), hydroxycarboxylic acids (e g., glycolic acid, citric acid, malic acid or lactic acid), keto acids (e.g., ~-ketoglutaric acid) or sulfonic acids (e.g., 2--[4-(2-hydroxyethyl)-1-piperazino]-ethanesulfonic acid (HEPES)),, and amino acids (e.g., glycine, aspartic acid, phenylalanine, lysine, arginine, preferably the naturally occurring L-amino acids) or their salts can be used. Thus, in especially preferred cases, for example, succinic acid is combined with trometamol. The components that are used in the buffer mixtures according to the invention can be mixed in any molar ratios. In addition to the standard molar mixture ratio of 1:1 (e.g., lo mmol of tris and 10 mmol of glycine), other mixture ratios of between 1:99 and 99:1 can also be set. In some cases, very good results are achieved with mixture ratios of 25:75 and 75:25.
To set the pH of buffer mixtures according to the invention, for example, salts of the main buffer components can be used, in addition to the substances that are commonly used by one skilled in the art, such as, for example, a sodium hydroxide solution or hydrochloric acid.
Owing to their adequate buffer capacity in the pH range of between 4 and 9, the buffers according to the invention, in especially suitable cases, offer the possibility of optimized matching of the pH to the stability requirements of the respective pharmaceutical substance while taking physiologic requirements into account. Unlike the conventional trometamol buffer, which has an adequate buffer capacity only in the pH
range of about 7.2 to 9.0, buffer systems according to the invention can, if necessary, optionally also be used effectively below this pH range. Moreover, owing to their special physical and chemical properties, the buffers according to the invention also turn out to be superior to conventional buffer systems in the range of isohydric pH (about 7.4). Thus, certain decomposition processes can often be avoided by using buffers according to the invention under otherwise identical conditions.
In addition, when buffer mixtures according to the invention are used, the addition of additional formulation adjuvants, such as, for example, complexing agents (e.g., sodium calcium edetate) can be partially eliminated since the buffer mixtures according to the invention themselves act in a complexing manner in especially suitable cases. In addition, the formulations according to the invention enhance neither microbial attack nor precipitation reactions with ions from the primary container. The formulations according to the invention are also distinguished by especially good compatibility.
Parenteral preparations (injection and infusion solutions) accordinq to the invention are generally set at pH values of between ~ and 9 or 5 and 8. In special cases, however, pH values of between 6.0 and 8.0 or 5.0 and 6.7 are desired.
The buffer mixtures according to the invention exhibit a marked temperature dependence in terms of their pH. It has turned out, surprisingly enough, that the steepness of the temperature-dependent drop in the pH of the buffer according to the invention has a marked dependence on starting pH. In special cases, the pH of the formulations according to the invention drops during heat sterilization (121~C, 20 minutes) by more than 0.5 or 1 to 3 pH units. By specifically selecting a buffer system according to the invention for a special pharmaceutical substance, the extent of the pH depression and thus optionally occurring decomposition reactions can be controlled during sterilization. Thus, in certain cases, a smaller pH drop during sterilization may be desired with a view to avoiding special decomposition processes.
In the production of formulations according to the invention, osmolality is generally set to values in the range of 200 to 1200 mOsmlkg or 200 to 1,000 mOsm/kg or, in especially preferred cases, between 250 and 850 mOsm/kg.
The buffer systems according to the invention are thus distinguished in that usually small total concentrations can be set in the range of 2 to 40 mmol, but preferably between 10 and 20 mmol or 5 and 15 mmol.
The buffer systems according to the invention are especially suitable for stabilizing contrast media, particularly x-ray contrast media based on iodine-containing aromatic compounds. In this case, on the one hand, during production there is a stabilization that can be only partially attributed to the pH
drop during the sterilization process. In comparison to the trometamol buffer (pH 7.5), a significant reduction in iodide formation in the case of one-time and repeated sterilization (121~C, 20 minutes) in iopromide solutions (300 mg of iodine/ml~
can be detected, for example, when using a trometamol/glycine buffer according to the invention (pH 7.5). This was all the more surprising as at this starting pH the buffer according to the invention shows only a comparatively small temperature-dependent pH drop relative to the trometamol/HCl buffer. Similar results were obtained using a trometamol/succinic acid buffer or trometamol/HEPES buffer (pH 7.5).
Because of the possibility of setting the pH below 7.0 while preserving adequate buffer capacity, the buffer systems according to the invention also potentially allow further stabilization during production. Thus, for example, setting the pH of an iopromide solution (300 mg of iodine/ml) in the trometamol/succinic acid buffer according to the invention at 6.5 results in a further drastic reduction of iodide formation during sterilization (20 minutes, 121~C) compared to a comparable trometamol. This effect was also strongly pronounced in the case of extended sterilization times, so that in especially suitable cases buEfer systems according to the invention also make it possible to repeatedly sterilize x-ray contrast medium solutions.
Compared to the buffers that were previously used, the special advantage of the buffer systems according to the invention lies, however, in the additional increase in the stability of x-ray contrast medium solutions in storage. Thus, by using buffers according to the invention, in general service lives of over 3 years, but preferably 4-6 years or 5 to 10 years, can be achieved because of reduced decomposition reactions. In this case, in addition to the parameters that are familiar to one skilled in the art (e.g., pH and color of the solution), the iodide content and, in special cases, the content of free amine are used as a special measure of the stability of corresponding solutions. Over the entire storage time (service life), for example, the iodide content of x-ray contrast medium solutions (concentration: 300 mg of iodine/ml) is thus below 75 ~g/ml, but preferably below 50 or 30 ~g/ml.
Depending on the starting pH of the x-ray contrast medium solution, in especially suitable cases a reduction in amine formation during storage can also be achieved by using buffers according to the invention. The free amine content of corresponding solutions (e.g., 300 mg of iodine/ml) is generally below 0.3~, but preferably below 0.1 to 0.05%, during the service life.
After as little as three months of storage at an elevated temperature (40~C), it was possible, in especially suitable cases, to detect a significantly reduced iodide formation in x-ray contrast medium solutions (iopromide) that are produced with buffers according to the invention compared to tometamol-buffered solutions (starting pH values = 7.5 and 6.5). Depending on the starting pH, there was also a slight reduction in amine content.
Surprisingly enough, moreover, it was also possible to show that, in the presence of buffers according to the invention, in some cases there was a significant decrease in the reduction of the complexing agent content (sodium calcium edetate) in the contrast medium sclutions that were studied. Consequently, when buffers according to the invention were used for the production of x-ray contrast media solutions, the potential is opened up for greatly reducing the addition of complexing agents or eliminating the latter entirely.
Owing to the above-described properties, the buffers according to the invention are suitable mainly for stabilizing parenterally administered hydrophilic x-ray contrast media, which are generally known from radiological practice. These include, for one thing, x-ray contrast media such as, for example, amidotri~oate, metrizoate, iopromide, N,N'-bis(2,3-dihydroxypropyl)-5-hydroxyacetylamino-2,4,6-triiodo-N-methylisophthalamide, iohexol, iopamidol, iosimide, ioversol, iomeprol/ iopentol, ioxilan, iobitridol, ioxaglate, iotrolan, N,N'-bis[3-carbamoyl-5-(2,3-dihydroxypropylcarbamoyl)-2,4,6-triiodo-phenyl]-N,N'-bis(2,3-dihydroxypropyl)-malonamide and iodixanol, which are also used to some extent in computer tomography (CT). In this case, the x-ray contrast media can also be encapsulated in liposomes.
The buffer systems according to the invention can, moreover, also be used in special cases, independently of the method of application (e.g., parenterally, orally, topically (also ophthalmic pharmaceutical agents)), for stabilizing other aqueous pharmaceutical substance solutions or suspensions (e.g., crystal suspensions, liposomes, micro- or nanoparticles or -capsules).
In this case, mainly therapeutic active ingredients, such as, for example, analgesics/antiphlogistic agents, antibiotics, cytostatic agents, and virustatic agents can be mentioned as nonlimiting examples, in addition to MRT-contrast media, such as, for example, Gd-DTPA, Gd-EOB-DTPA, Gd-DOTA, Gd-BOPTA, Mn-DPDP, gadobutrol, or ultrasonic contrast media. These active ingredient groups can also be present as liposomal formulations.
. . 12 Embodiment3:
The ]purpose of the following examples is to explain the subject of the invention, without intending that it be limited to these examples.
Example 1: 8tability of a Trometamol/HCl-Buffered Iopromide ~olution A trometamol (20 mmol)-buffered iopromide solution (set at about pH ~7.5 or 6.5 with HCl) with an iodine concentration of 300 mg/ml was produced, and aliquots of this solution were autoclaved (121~C) ir.~ sealed 10 ml injection flasks over times that are indicated in the table. The samples that were thus obtained were studied w:ith respect to their pH and iodide and amine contents (free aromatic amine).
Starting Sterilization Change in Iodide Amine pH Time pH Content Content [~
[min] [~g/ml] by weight]
-0.10 8.9 0.019 -0.12 9.5 0.025 7.5 180 -0.18 11.9 0.055 -0.15 8.9 0.010 -0.18 8.7 0.011 6.5 180 -0.22 10.2 0.017 CA 022442l3 l998-07-27 , 13 Example :!: 8tability of Glycine (10 mmol)/Tris (10 mmol) of Buffered Iopromide 8O1utions After the pH values are set (to 7.5 and 6.5), two iopromide solutionC; (300 mg of iodine/ml) that are buffered with glycine (lo mmol~/tris (lo mmol) are autoclaved (121~C) over the times that are indicated in the table, analogously to Example 1. The samples were studied with respect to their pH and iodide and amine contents (free aromatic amine).
pH Sterilization Change in Iodide Amine Time [min] pH Content Content [%
t~g/ml] by weight]
7.5 20 -0.11 5.1 0.016 -0. 13 5.5 0.029 6.5 20 -0.17 6.3 0.010 -0.23 6.5 0.012 CA 022442l3 l998-07-27 ' 14 Example 3: ~tability of Succinic Acid (10 mmol)/tris (10 mmol) of Buffered Iopromide Solutions This test was carried out analogously to Example 2.
pH Sterilization Change in Iodide Amine Time [min] pH Content Content [%
[~g/ml] by weight]
7.5 20 -0.16 1.8 0.021 -0.22 3.6 0.050 6.5 20 -0.17 0.9 0.021 -0.24 1.9 0.033 Example 4: Stability of ~EPE~ (10 mmol)/tris (10 mmol) of Buffered Iopromide Solutions This test was carried out analogously to Example 2.
pH Sterilization Change in Iodide Amine Time [min] pH Content Content [~
[~g/ml] by weight]
7.5 20 -0.09 2.3 0.020 -0.17 5.4 0.049 6.5 20 -0.06 6.2 0.008 -0.11 6.8 0.013 CA 022442l3 l998-07-27 . 15 Example !;: 8tability of Glycine (20 mmol) of Buffered Iopromide 801ution~3 After the pH values are set (to about 7.5 and 6.5), two iopromide solutions (300 mg of iodine/ml) that are buffered with glycine (20 mmol) are treated analogously to Example 1.
Starting Sterilization Change in Iodide Amine pH Time pH Content Content [~
[min] [~g/ml] by weight]
-0.24 2.2 0.025 -0.33 4.0 0.048 7.5 180 -0.68 7. 2 0.092 -0.38 1.0 0.010 -0.66 1.4 0.013 6.5 180 -0.89 2.3 0.021 CA 022442l3 l998-07-27 Example 6: 8tability of ~uccinic Acid (20 mmol) of Buffered Iopromide Solutions This test was carried out analogously to Example 5.
Startingr Sterilization Change in Iodide Amine pH Time pH Content Content [%
[min] [~g/ml] by weight]
-0.27 2.9 0.056 -o. 63 7.2 O. 145 7.5 180 -1.07 16.6 0.348 -0.16 1.4 0.034 -0.25 4.4 0.092 6.5 180 -0.40 11.6 0.229 Example 7: Temperature Dependence of the pH of a Trometamol-buffered Solution A 20 mmol trometamol solution is set at pH 7.5 with O.lN
HCl, and the pH is determined as a function of temperature with a pH-meter 761 from the Knick Company with and without temperature correction or compensation. The results are shown in Figure 1.
CA 022442l3 l998-07-27 . 17 Example ~: Temperature Dependence of the pH of Various Buffer Solution:~
Various aqueous buffer solutions (10 mmol each relative to each buffer component) are produced, and pH is determined as a function of temperature with a pH-meter 761 from the Knick Company. The respective temperatures of the buffer solutions were measured with an external Pt-100 detector, and the temperature on the pH-meter was corrected accordingly. The data that are thus obtained are shown in Figures 2 and 3.
Example '~: Three-Month 8tability of an Iopromide 801ution as a Function of Various Buffers Buffered iopromide solutions (300 mg of iodine/ml) that are produced analogously to Examples 1 and 2 were first autoclaved in 10 ml injection flasks (20 minutes, 121~C) and then stored for three months at 40~C in a climate test chamber. In this case, parallel solutions were stored that were to have been set to a starting pH (before sterilization) of 7.5 or 6.5. The samples that were thus obtained were studied with respect to their contents of iodide, amine (free aromatic amine), and sodium calcium edetate.
CA 022442l3 l998-07-27 Buffer System Iodide t~g/ml] Amine [~ by Sodium Calcium pH = 7.5 weight] Edetate [~g/ml]
Trometamol 11. 8 0.062 90.8 Trometamol/ 8. 2 0.058 92.7 Glycine Trometamol/ 2.6 0.048 93.7 Succinic Acid Trometamol/ 6.6 O. 070 94. 2 HEPES
Buffer ~ystem Iodide [~g/ml] Amine [% by Sodium Calcium pH = 6.5 weight] Edetate [ ~g/ml ]
Trometamol 8.6 0.014 89.9 Trometamol/ 7.1 0.015 89.0 Glycine Trometamol/ 1.4 0.024 93.7 Succinic Acid Trometarnol/ 7.1 0.014 90.9 HEPES
It turned out that the stability of the x-ray contrast medium solution was improved just by using pure trometamol buffer in a pH ral~ge < 6.5. When buffer according to the invention was used, however, it was possible to achieve additional stabilization. This applies especially for the combination of trometamol with succinic acid.
Example 10: Buffer Capacities of Various Buffer 801utions The buffer capacities of various buffer solutions are shown in Figure 4.
Example 11: Stability o~ Buffered Placebo Liposome 501utions Placebo liposome solutions that consist of soybean phosphatidylcholine (150 mg/ml) were produced using continuous high-pressure extrusion (5 passes each through 0.8/0.6/0.4 and 0.2 ~m polycarbonate membrane filter disks) using various buffer systems (setting to pH 6.5), and aliquots of these suspensions in sealed 10 ml injection flasks were autoclaved (121~C) over the times indicated in the table. The samples that were thus obtained were studied with respect to their particle size (photon correlation spectroscopy), as well as their contents of lysophosphatidylcholine (HPLC).
CA 022442l3 l998-07-27 , 21 Buffer 8terili~ation Mean Diameter LPC-Content Time ~min] [nm] tmg/g]
20 mmol of 0 161 1.7 citric acid/ 20 154 2.5 NaOH
161 3.3 20 mmol of 0 164 1.5 phosphate 20 165 2.0 buffer (see Fig. 1) 60 160 3.5 10 mmol of 0 154 0.7 tris/10 mmol 157 0.9 of succinic acid 60 158 1.2 10 mmol of 0 159 0.6 tris/10 mmol 20 153 0.9 of glycine 154 1.3
Claims (12)
1. Buffer solution, characterized in that it contains at least one physiologically compatible amine and at least one physiologically compatible organic acid.
2. Buffer solution according to claim 1, wherein it contains 2-amino-2-(hydroxymethyl)-1,3-propanediol as an amine component.
3. Buffer solution according to claim 1, wherein it contains N-methylglucamine as an amine component.
4. Buffer solution according to claim 1, wherein it contains a monovalent or multivalent carboxylic acid, a hydroxycarboxylic acid, a keto acid, a sulfonic acid, or an amino acid as an acid component.
5. Buffer solution according to claim 1, wherein it contains benzoic acid, succinic acid, maleic acid, glycolic acid, citric acid, malic acid, lactic acid, .alpha.-ketoglutaric acid, 2-[4-(2-hydroxyethyl)-1-piperazino]-ethanesulfonic acid, glycine, aspartic acid, phenylalanine, lysine, or arginine as an acid component.
6. Buffer solution according to claim 1, wherein it contains 2-amino-2-(hydroxymethyl)-1,3-propanediol and glycine.
7. Buffer solution according to claim 1, wherein it contains 2-amino-2-(hydroxymethyl)-1,3-propanediol and HEPES.
8. Buffer solution according to claim 1, wherein it contains 2-amino-2-(hydroxymethyl)-1,3-propanediol and succinic acid.
9. Use of buffer solution according to claim 1 for the production of pharmaceutical agents.
10. Use of buffer solution according to claim 1 for the production of x-ray contrast media, MRT-contrast media, radiodiagnostic agents, or radiotherapeutic agents.
11. Use of buffer solution according to claim 1 for the production of liposome suspensions.
12. Use of buffer solution according to claim 1 for the production of contrast medium-containing liposome suspensions.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19604230.5 | 1996-01-29 | ||
| DE19604230 | 1996-01-29 |
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| CA002244213A Abandoned CA2244213A1 (en) | 1996-01-29 | 1996-12-20 | Buffer systems for stabilizing pharmaceutical preparations |
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| EP (1) | EP0877628A2 (en) |
| JP (1) | JP2000504334A (en) |
| AU (1) | AU1870497A (en) |
| CA (1) | CA2244213A1 (en) |
| DE (1) | DE19648650C2 (en) |
| NO (1) | NO983464D0 (en) |
| WO (1) | WO1997028104A2 (en) |
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| US10383822B2 (en) | 2012-08-10 | 2019-08-20 | Taiho Pharmaceutical Co., Ltd. | Stable oxaliplatin-encapsulating liposome aqueous dispersion and method for stabilizing same |
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| US11998580B2 (en) | 2018-01-31 | 2024-06-04 | Akamis Bio Limited | Group B adenovirus-containing formulation |
| US12049513B2 (en) | 2016-08-29 | 2024-07-30 | Akamis Bio Limited | Oncolytic group B adenovirus expressing a stroma-targeted bispecific t-cell engager |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7250153B2 (en) | 2002-12-12 | 2007-07-31 | Biophysica Research, Inc. | Contrast media formulations having improved biological tolerance |
| JP2005170923A (en) * | 2003-10-21 | 2005-06-30 | Konica Minolta Medical & Graphic Inc | Liposome-containing X-ray contrast medium and method for producing the same |
| JP2005170928A (en) * | 2003-10-21 | 2005-06-30 | Konica Minolta Medical & Graphic Inc | Lyposome-containing x ray-imaging agent and method for producing the same |
| JP2005220034A (en) * | 2004-02-03 | 2005-08-18 | Konica Minolta Medical & Graphic Inc | Method for producing contrast medium for X-ray examination |
| JP4654590B2 (en) * | 2004-03-31 | 2011-03-23 | コニカミノルタエムジー株式会社 | Contrast composition for X-ray CT and method for producing the same |
| EP1772156A1 (en) * | 2004-07-21 | 2007-04-11 | Konica Minolta Medical & Graphic, Inc. | Liposome-containing x-ray radiopaque dye and process for producing the same |
| RU2012138280A (en) * | 2010-03-23 | 2014-04-27 | ДжиИ Хелткер АС | OBTAINING A STABILIZED DIAGNOSTIC COMPOSITION FOR X-RAY STUDY |
| JP6867639B2 (en) * | 2016-10-11 | 2021-05-12 | 学校法人 聖マリアンナ医科大学 | Combined nonionic iodine contrast agent |
| EP4011369A1 (en) | 2020-12-14 | 2022-06-15 | G.L. Pharma GmbH | Aqueous pharmaceutical composition comprising tapentadol tartrate |
| JP7372429B1 (en) | 2022-10-31 | 2023-10-31 | キユーピー株式会社 | Emulsion and its manufacturing method |
| JP7353453B1 (en) | 2022-10-31 | 2023-09-29 | キユーピー株式会社 | Emulsion and its manufacturing method |
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| CH649469A5 (en) * | 1978-07-04 | 1985-05-31 | Nyegaard & Co As | SOLUTION OF AN X-RAY CONTRAST AND A BUFFER AND THE USE THEREOF FOR PRODUCING A STERILE INJECTABLE PHYSIOLOGICALLY ACCEPTABLE SOLUTION OF AN X-RAY CONTRAST. |
| GB9020091D0 (en) * | 1990-09-14 | 1990-10-24 | Nycomed As | Contrast media |
| DE4121568C2 (en) * | 1991-04-22 | 1997-07-03 | Schering Ag | Method and device for producing a contrast medium from a concentrate |
| IT1256248B (en) * | 1992-12-24 | 1995-11-29 | Bracco Spa | WATER INJECTABLE FORMULATIONS FOR RADIODIAGNOSTICS INCLUDING MIXTURES OF IODURATED AROMATIC COMPOUNDS USEFUL AS X-RAY MATTING AGENTS |
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1996
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- 1996-12-20 AU AU18704/97A patent/AU1870497A/en not_active Abandoned
- 1996-12-20 EP EP96946112A patent/EP0877628A2/en not_active Withdrawn
- 1996-12-20 CA CA002244213A patent/CA2244213A1/en not_active Abandoned
- 1996-12-20 JP JP9527225A patent/JP2000504334A/en active Pending
- 1996-12-20 WO PCT/DE1996/002488 patent/WO1997028104A2/en not_active Application Discontinuation
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- 1998-07-28 NO NO983464A patent/NO983464D0/en not_active Application Discontinuation
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10383822B2 (en) | 2012-08-10 | 2019-08-20 | Taiho Pharmaceutical Co., Ltd. | Stable oxaliplatin-encapsulating liposome aqueous dispersion and method for stabilizing same |
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| US11938159B2 (en) | 2013-10-25 | 2024-03-26 | Akamis Bio Limited | Oncolytic adenoviruses armed with heterologous genes |
| US11970536B2 (en) | 2015-12-17 | 2024-04-30 | Akamis Bio Limited | Group B adenovirus encoding an anti-TCR-complex antibody or fragment |
| US12049513B2 (en) | 2016-08-29 | 2024-07-30 | Akamis Bio Limited | Oncolytic group B adenovirus expressing a stroma-targeted bispecific t-cell engager |
| US12258417B2 (en) | 2016-08-29 | 2025-03-25 | Akamis Bio Limited | Adenovirus armed with bispecific T cell engager |
| US11998580B2 (en) | 2018-01-31 | 2024-06-04 | Akamis Bio Limited | Group B adenovirus-containing formulation |
Also Published As
| Publication number | Publication date |
|---|---|
| DE19648650C2 (en) | 1998-07-02 |
| WO1997028104A8 (en) | 1997-12-18 |
| EP0877628A2 (en) | 1998-11-18 |
| JP2000504334A (en) | 2000-04-11 |
| WO1997028104A2 (en) | 1997-08-07 |
| NO983464L (en) | 1998-07-28 |
| AU1870497A (en) | 1997-08-22 |
| DE19648650A1 (en) | 1997-08-07 |
| WO1997028104A3 (en) | 1997-09-12 |
| NO983464D0 (en) | 1998-07-28 |
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