DE19648650A1 - Buffer solution for stabilising pharmaceutical compositions - Google Patents

Abstract

New buffer solution (I) comprises: (A) at least one physiologically compatible amine; and (B) at least one physiologically compatible organic acid.

Description

The present invention describes complex buffer systems to increase the stability of pharmaceutical preparations during manufacturing and storage. The invention Buffer mixes are special due to their Properties for parenteral use especially suitable. They are particularly suitable for production of contrast media solutions.

State of the art

Buffer solutions are often used in pharmaceutical practice used in aqueous formulations, the Storage stability requires a certain pH. There Decomposition processes such as hydrolysis or Oxidation as well as the solubility different pH Optima can be used in ophthalmic drugs and watery Injection and infusion solutions mostly one as close as possible to the physiological pH of 7.4 sought (= euhydria). Because of the big Buffer capacity of the blood plasma can at least in the case of injection solutions (volume 20 ml) with lower Buffer capacity quite large deviations from that  isohydric pH (= 7.4) in the range of about pH 4-9 accepted (Physical Pharmacy, Ed .: H. Stricker, Scientific Publishing Company mbH Stuttgart, 3rd ed., 1987). In Table 1 are pharmaceutical Common buffer systems for parenteral use listed (Pharmaceutical Technology, Eds .: H. Sucker, P. Fuchs and P. Speiser, Georg Thieme Verlag Stuttgart, 1978).

Table 1

Common buffer systems for parenteral use

A significant group of medicines used parenterally X-ray contrast media containing iodine represent which are mostly used as infusion solutions. Here find as buffer substances in addition to those listed in Tab. 1 Trometamol [tris (hydroxymethyl) aminomethane, 2-amino-2- (hydroxymethyl) -1,3-propanediol] (e.g. contained in Ultravist®, Omnipaque® or Solutrast®) and sodium dihydrogen phosphate (e.g. in Conray®) for example Sodium bicarbonate (e.g. in Isovist®) use.  

Because of its good buffering effect in the range of pH 7.2-9.0 and the associated possibility of hiring The trometamol buffer (= Tris) achieved a special position here. Compared to Phosphate buffers that cover the pH range of 5-8 no further problems for the trometamol buffer with regard to a possible precipitation with ions from the Glass primary container described.

In the context of DE 29 26 850 a method for the production or sterilization of special x-ray contrast containing iodine medium solutions described, which depends on the temperature dependent lowering of the pH of amine-buffered Solutions based. As a result of the drop in the pH of Trometamol or meglumine buffered solutions (pH 7.0-7.6) to pH values between 3.5 and 5.5 during the Sterilization could thus significantly reduce the Iodide formation can be achieved during manufacture. After after sterilization, the pH value changes accordingly Solutions almost return to the initial value.

The most common X-ray contrast media (RKM) solutions are when stored at room temperature (15-25 ° C) and under light exclusion mostly stable over three years. Longer product run times can often be due to decomposition processes cannot be reached. The one for this group of substances described instability reactions can with Changes in pH and color, as well as one Decrease in the active ingredient content go hand in hand. As an indicator of The chemical decomposition of such RKM becomes the content of Iodide and free amine (contrast medium, Ed .: U. Speck, Springer-Verlag Berlin, 3rd edition, 1991).

The object of the present invention is therefore to create new ones Buffer systems with a good buffer effect in the physiological To provide the decomposition reactions area of drugs during storage and manufacture - especially heat sterilization - from reduce pharmaceutical preparations.

This object is achieved by the buffer systems according to the invention solved as they are characterized in the claims.

The aqueous buffer systems according to the invention are are mixtures of a physiologically compatible amine and a physiologically acceptable aliphatic or aromatic organic acid.

Such are physiologically compatible amines or acids To understand substances that are used as medicinal products or Drug additives are already approved or under physiological conditions in human or animal Organism occur.

As an amine component of the buffer mixtures according to the invention all physiologically compatible amines are suitable. N-methylglucamine (meglumine) and / or is preferred Trometamol (2-amino-2- (hydroxymethyl) -1,3-propanediol, TRIS) used, particularly preferably trometamol.

As an acid component in the buffer mixtures according to the invention can be mono- or polyvalent carboxylic acids (e.g. amber acid, maleic acid, benzoic acid), hydroxycarboxylic acids (e.g. Glycolic acid, citric acid, malic acid or lactic acid), Keto acids (e.g. α-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, preferred the naturally occurring L-amino acids) or their salts will. This is the case in particularly preferred cases For example, succinic acid combined with trometamol. The used in the buffer mixtures according to the invention  Components can be in any molar ratio be mixed. In addition to the standard molar Mixing ratio of 1: 1 (e.g. 10 mM Tris and 10 mM Glycine) can also mix other ratios can be set between 1:99 and 99: 1. In some cases become very great at mixing ratios of 25: 75 and 75: 25 achieved good results.

To adjust the pH according to the invention Buffer mixtures can be used in addition to those customary for the expert Substances such as caustic soda or hydrochloric acid for example, salts of the main buffer components be used.

Because of their sufficient buffer capacity in the pH range between 4 and 9, the buffers according to the invention offer in the possibility of a particularly suitable case optimized adjustment of the pH value to the stability requirements of the respective drug under Consideration of physiological requirements. In contrast to the conventional Trometamol buffer, which is only in the pH range sufficient buffer capacity from about 7.2 to 9.0 can have buffer systems according to the invention if required effective even below this pH range if necessary be used. In addition, the buffers according to the invention because of their special physical and chemical properties also in the area of the isohydric pH (approx. 7.4) compared to conventional ones Buffer systems as superior. So through use buffer according to the invention under otherwise identical conditions often avoid certain decomposition processes. In addition can when using buffer mixtures according to the invention partly on the addition of further formulation aids such as complexing agents (e.g. sodium calcium edetate) can be dispensed with, since the inventive Buffer mixtures themselves in particularly suitable cases appear complex. In addition, the Formulations according to the invention are neither a microbial  Infested precipitation reactions with ions from the Primary container. Furthermore, the invention Formulations through a particularly good tolerance out.

Parenteral preparations according to the invention (injection and Infusion solutions) are usually adjusted to pH values between 4 and 9 or 5 and 8 set. In special cases however, pH values will be between 6.0 and 8.0 or 5.0 and 6.7 sought.

The buffer mixtures according to the invention show a noticeable Temperature dependence with regard to their pH value. Surprisingly, it could be shown that the slope the temperature-dependent drop in pH fiction appropriate buffer a clear dependence on the initial pH. In special cases the pH drops Formulations according to the invention during the heat sterilization (121 ° C, 20 min) by more than 0.5 or 1 to 3 pH units. By specifically selecting a he buffer system according to the invention for a special Drug can measure the extent of pH depression and thus any decomposition reactions that may occur during the Control sterilization. So in certain cases less pH drop during sterilization in terms wanted to avoid special decomposition processes be.

In the preparation of formulations according to the invention the osmolality usually to values in the range from 200 to 1200 mOsm / kg or 200 to 1000 mOsm / kg or in particular preferred cases between 250 and 850 mOsm / kg.

The buffer systems according to the invention are characterized by this from that usually low total concentrations in Range from 2 to 40 mM, but preferably between 10 and 20 mM or 5 and 15 mM can be used.  

The buffer systems according to the invention are suitable in special way to stabilize contrast media, especially X-ray contrast media based aromatics containing iodine. Here comes on the one hand Stabilization in the manufacture to be carried only for Part of the pH reduction during the sterilization process is due. Compared to trometamol buffer (pH 7.5), for example, when using a trometamol / glycine buffer according to the invention (pH 7.5) significant reduction in iodide formation with single and repeated sterilization (121 ° C, 20 min) in iopromide Detect solutions (300 mg iodine / ml). This was all the more More surprising than the buffer according to the invention in this Initial pH compared to Trometamol / HCl buffer only one comparatively low temperature-dependent pH reduction shows. Similar results were obtained using a Trometamol / succinic acid buffers or Trometamol / HEPES Buffers (pH 7.5) can be obtained.

Due to the possibility of setting pH values below 7.0 while maintaining a sufficient The buffer systems according to the invention allow buffer capacity furthermore potentially further stabilization during the production. For example, that resulted Adjustment of the pH of an iopromide solution (300 mg Iodine / ml) in the trometamol / succinic acid according to the invention Buffer to pH 6.5 in a further drastic reduction iodide formation during sterilization (20 min, 121 ° C) compared to a comparable trometamol buffered Solution. This effect was also with longer ones Sterilization times are very pronounced, so that buffer systems according to the invention in particularly suitable Repeated sterilization of cases Enable X-ray contrast media solutions.

The particular advantage of buffer systems according to the invention compared to the buffers used up to now the additional increase in the stability of  X-ray contrast media solutions during storage. Let it be as a result of using buffers according to the invention reduced decomposition reactions usually Terms of over 3 years, but preferably 4 - 6 years or 5 to reach 10 years. As a special measure of stability Corresponding solutions are in addition to the expert common parameters (e.g. pH value and color of the solution) the iodide content and in special cases the content of free amine. For example, the Iodide content of X-ray contrast media solutions (Concentration: 300 mg iodine / ml) over the entire period Storage period (running time) below 75 µg / ml is preferred however below 50 or 30 µg / ml.

Depending on the initial pH value of the X-ray contrast medium solution can be particularly in suitable cases by using buffers according to the invention a reduction in amine formation during storage to reach. The content of corresponding solutions (e.g. 300 mg Iodine / ml) of free amine is usually during the term below 0.3% but preferably below 0.1 or 0.05 %.

After just three months of storage at an elevated temperature (40 ° C) could be used in particularly suitable cases significantly reduced iodide formation in the invention X-ray contrast medium solutions produced in buffers (Iopromide) versus trometamol buffered solutions Detect (initial pH values = 7.5 and 6.5). Furthermore could depending on the initial pH value, a slight one in some cases Reduction of the amine content can be found. Surprisingly, it was also possible to show that in the presence of buffers according to the invention in some cases a significant reduction in the decrease in the complexing agent content (sodium calcium edetate) in the examined Contrast media solutions resulted. This opens up the potential possibility when using inventive Buffer for the production of X-ray contrast medium solutions  To reduce the addition of complexing agents greatly or this to eliminate entirely.

The buffers according to the invention are suitable on the basis of the above described properties especially for stabilization of parenterally applied hydrophilic X-ray contrast media derived from radiological practice are generally known. This includes the X-ray contrast media such as amidotrizoate, Metrizoate, iopromide, N, N′-bis (2,3-dihydroxypropyl) -5- hydroxyacetylamino-2,4,6-triiodo-N-methylisophthalamide, Iohexol, iopamidol, iosimide, ioversol, iomeprol, iopentol, Ioxilan, Iobitridol, Ioxaglat, Iotrolan, N, N′-Bis [3- carbamoyl-5- (2,3-dihydroxypropylcarbamoyl) -2,4,6-triiodo phenyl] -N, N'-bis (2,3-dihydroxypropyl) malonamide and Iodixanol, some of which is also used in computer tomography (CT) Find use. The X-ray contrast media can also encapsulated in liposomes.

In addition, the buffer systems according to the invention, in special cases, regardless of the method of application (e.g. parenterally, orally, topically (including ophthalmic drugs)) too to stabilize other aqueous drug solutions or suspensions (e.g. crystal suspensions, liposomes, micro- or nanoparticles or capsules) are used. Here are non-limiting examples in addition to MRI Contrast agents such as Gd-DTPA, Gd-EOB-DTPA, Gd- DOTA, Gd-BOPTA, Mn-DPDP, Gadobutrol or ultrasound contrast agents, especially therapeutic agents such as for example analgesics / anti-inflammatory drugs, antibiotics, To name cytostatics and antivirals. This too Active ingredient groups can be used as liposomal formulations available.

Embodiments

The following examples are intended to illustrate the subject matter of the invention explain without wishing to restrict him to these.

example 1 Stability of a trometamol / HCl buffered Iopromide solution

A trometamol ( 20 mM) buffered iopromide solution (adjusted to approximately pH 7.5 or 6.5 with HCl) with an iodine concentration of 300 mg / ml was prepared and aliquots of this solution in sealed 10 ml injection bottles for the period specified in the table autoclaved (121 ° C). The samples thus obtained were examined for their pH, iodide and amine content (free aromatic amine).

Example 2 Stability Glycine (10 mM) / Tris (10 mM) buffered iopromide solutions

After adjusting the pH values (to 7.5 and 6.5) two iopromide buffered with glycine (10 mM) / Tris (10 mM) solutions (300 mg iodine / ml) above those in the table autoclaved period specified analogously to Example 1 (121 ° C). The samples were analyzed for their pH, iodide and Amine content (free aromatic amine) examined.

Example 3 Stability succinic acid (10 mM) / Tris (10 mM) buffered iopromide solutions

This experiment was carried out analogously to Example 2.

Example 4 Stability HEPES (10 mM) / Tris (10 mM) buffered iopromide solutions

This experiment was carried out analogously to Example 2.

Example 5 Stability Glycine (20 mM) buffered Iopromide solutions

After adjusting the pH values (to about 7.5 and 6.5) two iopromide solutions buffered with glycine (20 mM) (300 mg Iodine / ml) treated analogously to Example 1.

Example 6 Stability succinic acid (20 mM) buffered Iopromide solutions

This experiment was carried out analogously to Example 5.

Example 7 Temperature dependence of the pH of one Trometamol buffered solution

A 20 mM trometamol solution is adjusted to pH 7.5 with 0.1 N HCl and the pH is determined as a function of temperature using a Knick 761 pH meter with and without temperature correction or compensation. The results are shown in Fig. 1.

Example 8 Temperature dependence of the pH value various buffer solutions

Various aqueous buffer solutions (each 10 mM based on each buffer component) are prepared and the pH is determined as a function of the temperature using a 761 pH meter from Knick. The respective temperature of the buffer solutions was measured with an external Pt-100 sensor and the temperature on the pH meter was corrected accordingly. The data thus obtained are shown in FIGS. 2 and 3.

Example 9 Three months stability of an iopromide solution in Dependence on different buffers

Buffered prepared analogously to Examples 1 and 2 Iopromide solutions (300 mg iodine / ml) were initially in 10 ml injection bottles autoclaved (20 min, 121 ° C) and then over three months at 40 ° C in a climatic cabinet stored. Solutions were stored in parallel, the to an initial pH value (before sterilization) of 7.5 or 6.5 had been set. The samples thus obtained were determined with regard to their iodide, amine (free aromatic amine) and sodium calcium edetate.

It was shown that the stability of the x-ray contrast medium solution by using pure trometamol buffer was already improved in the pH range 6.5. Using However, the buffer according to the invention could be another Stabilization can be achieved. This applies in particular to the combination of trometamol with succinic acid.  

Example 10 Buffer capacities of different buffer solutions

The buffer capacities of various buffer solutions are shown in Fig. 4.

Example 11 Stability of buffered placebo liposomes solutions

Placebo liposome solutions consisting of Soybean phosphatidylcholine (150 mg / ml) was analyzed using continuous high pressure extrusion (5 passages each 0.8 / 0.6 / 0.4 and 0.2 µm polycarbonate membrane filter discs) made using different buffer systems (Adjustment to pH 6.5) and aliquots of these suspensions in sealed 10 ml injection bottles over the in the Autoclaved period given in the table (121 ° C). The so Samples obtained were for their particle size (Photon correlation spectroscopy) and their content Lysophosphatidylcholine (HPLC) examined.

Claims (12)

1. buffer solution, characterized in that it contains at least one physiologically acceptable amine and at least one physiologically acceptable organic acid. 2. Buffer solution according to claim 1, characterized in that that as the amine component 2-amino-2- (hydroxymethyl) - Contains 1,3-propanediol. 3. Buffer solution according to claim 1, characterized in that it contains N-methylglucamine as the amine component. 4. Buffer solution according to claim 1, characterized in that that they are a mono- or polyvalent as an acid component Carboxylic acid, a hydroxycarboxylic acid, a keto acid, contains a sulfonic acid or an amino acid. 5. buffer solution according to claim 1, characterized in that as an acid component, benzoic acid, Succinic acid, maleic acid, glycolic acid, Citric acid, malic acid, lactic acid, α-keto glutaric acid, 2- [4- (2-hydroxyethyl) -1-piperazino] - ethanesulfonic acid, glycine, aspartic acid, phenylalanine Contains lysine or arginine. 6. Buffer solution according to claim 1, characterized in that that they are 2-amino-2- (hydroxymethyl) -1,3-propanediol and Contains glycine. 7. buffer solution according to claim 1, characterized in that they are 2-amino-2- (hydroxymethyl) -1,3-propanediol and HEPES contains. 8. buffer solution according to claim 1, characterized in that that they are 2-amino-2- (hydroxymethyl) -1,3-propanediol and Contains succinic acid.   9. Use of buffer solution according to claim 1 for the Manufacture of pharmaceutical products. 10. Use of buffer solution according to claim 1 for the Production of X-ray contrast media, MRI contrast means, radio diagnostics or radiotherapeutics. 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 agent-containing liposomes suspensions.