HK1061811B - Stable salts of o-acetylsalicyclic with basic amino acids - Google Patents

Description

Stable salts of O-acetylsalicylic acid with basic amino acids

The invention relates to stable salts of O-acetylsalicylic acid with basic amino acids, to a process for their preparation, and to their use as medicaments.

O-acetylsalicylic acid (Aspirin)^*) The analgesic effect of (b) has been utilized therapeutically for a long time. Thus, O-acetylsalicylic acid is used as an analgesic, anti-pyretic, anti-rheumatic, and non-steroidal anti-inflammatory agent to treat, for example, arthritis, neuropathic pain, and myalgia.

However, O-acetylsalicylic acid has only limited solubility and is therefore suitable only for oral administration. However, it has been disclosed that ｃA salt of O-acetylsalicylic acid with ｃA basic amino acid is suitable for parenteral administration (see JP-A-48056815). L-lysine, D, L-lysine and arginine are used in particular as basic amino acids. Glycine may also be added in a certain proportion.

Salts of O-acetylsalicylic acid with basic amino acids have long been used for a variety of different indications, for example for the indications mentioned above. The good solubility of these O-acetylsalicylates is an advantage compared to O-acetylsalicylic acid, especially for parenteral administration. Furthermore, the good tolerance of O-acetylsalicylate for longer term oral administration is of particular importance.

To date, some of the disadvantages of O-acetylsalicylates are their inadequate stability. On the one hand, the shelf life of pharmaceutical preparations made from these salts is thus limited. On the other hand, sterilization of the active compounds, which may be necessary, cannot be carried out by heat sterilization, but must be carried out by other routes, for example by introducing ethylene oxide gas, because of the inadequate thermal stability of these salts.

The low stability of O-acetylsalicylate can be attributed to the product undergoing a reverse reaction to produce O-acetylsalicylic acid and the corresponding amino acid, as is known to those skilled in the art. The amino acid is then reacted with O-acetylsalicylic acid to remove the acetyl group (amidolysis) and release the salicylic acid. However, the presence of salicylic acid in pharmaceutical compositions is disadvantageous and should therefore be limited to low acceptable values. This degradation reaction is known to be pH-dependent (F.Moll, Arch.Pharm.318(1985), 120-127). Lowering the pH increases the protonation of the released amino acids, so that no or only very limited reaction with O-acetylsalicylic acid takes place. The decomposition of the amide and thus the release of salicylic acid is thereby inhibited.

In order to improve the stability of pharmaceutical formulations containing O-acetylsalicylate, it has been proposed in the past to add "acidic stabilizers" such as calcium chloride (see US-A-4265888). However, for the treatment of cardiovascular diseases, the presence of Ca ions in the product is unacceptable.

It has also been postulated that the moisture content of the O-acetylsalicylate product has a significant effect on its stability. Thus, another way to increase the stability of O-acetylsalicylate is to reduce the residual moisture content by drying under vigorous conditions. However, as mentioned above, due to the instability of the salt at the temperatures required for this, sufficient drying at elevated temperatures can only achieve the intended purpose to a limited extent or not at all.

The object of the present invention was therefore to obtain compositions comprising salts of O-acetylsalicylic acid with basic amino acids, having improved stability and therefore not having the disadvantages of the O-acetylsalicylic acid salts known hitherto in terms of storage and/or stability.

The object of the invention is achieved by a composition comprising a salt of O-acetylsalicylic acid with a basic amino acid, the salt having a mean particle size of more than 160 μm, more than 60% of the particles having a particle size of 100-200 μm in terms of the particle size distribution as determined under standard conditions with a Malvern 2600D apparatus.

According to the invention, compositions are preferred in which the average particle size of the salt of O-acetylsalicylic acid with a basic amino acid contained in the composition is greater than 170 μm, more than 70% of the particles having a particle size of 100-200 μm in terms of the particle size distribution determined under standard conditions with a Malvern 2600D apparatus.

The invention is illustrated in more detail by the accompanying drawings, in which:

FIG. 1 shows the reaction of a commercially available O-acetylsalicylate (Aspiosol)^*) Particle size distribution of (a) compared to the particle size distribution of the O-acetylsalicylate prepared according to example 1.

FIG. 2 shows embodiment 1 and Aspiosol of the invention shown in FIG. 1^*Integral of the curve of the particle size distribution of (a).

FIGS. 3 and 4 show the crystals of O-acetylsalicylate of example 1 of the present invention.

FIGS. 5 and 6 show Aspiosol^*The crystal of (4). The particle size analyses shown in FIGS. 1 and 2 were performed using the same crystals.

FIG. 7 is a graph showing stability at different temperatures. In which the O-acetylsalicylate and Aspiosol of example 3 of the present invention are shown^*The salicylic acid content (in%) of (c).

The O-acetylsalicylate of the present invention is significantly different from the heretofore known O-acetylsalicylate in terms of its particle size analysis and is advantageous for the O-acetylsalicylate of the present invention, the particle size distribution is narrower and the average particle size is shifted to a larger particle size (see FIGS. 1 and 2). This means that the O-acetylsalicylate of the present invention is composed of larger and more uniformly shaped (growing) crystals. In addition to a narrower particle size distribution and a larger average particle size, the O-acetylsalicylate of the present invention also exhibits a highly defined crystal structure (see FIGS. 3 and 4). In contrast, the commercial O-acetylsalicylate Aspiosol^*Clearly with a more undefined crystal structure (see fig. 5 and 6).

The advantageous properties of the O-acetylsalicylate mentioned above surprisingly lead to the fact that the residual moisture content of the O-acetylsalicylate of the invention can be kept at an extremely low level and thus the above-mentioned reverse reaction of the O-acetylsalicylate to O-acetylsalicylic acid and the corresponding amino acid can be suppressed. This is all the more surprising since it is described that O-acetylsalicylate is hygroscopic per se. Surprisingly, however, the O-acetylsalicylate of the present invention has reduced hygroscopicity. The O-acetylsalicylate of the present invention is significantly more stable at the same temperature than the known acetylsalicylates with a higher residual moisture content.

The residual moisture content of the salts according to the invention is less than 0.4%, preferably less than 0.3%, in particular less than 0.15%.

It can be seen from fig. 7 that the O-acetylsalicylate of the present invention having a residual moisture content of less than 0.3% remains almost unchanged in terms of its free salicylic acid ratio after a period of 8 weeks at a temperature of 25 c, whereas the O-acetylsalicylate having a residual moisture content of, for example, more than 0.4% undergoes significant degradation and the free salicylic acid ratio increases. Thus, it was confirmed that the O-acetylsalicylate of the present invention is stable over a long period of time at room temperature or under cooling.

The O-acetylsalicylate of the present invention can be prepared by the following method. All starting materials are commercially available. The amino acids which can be used according to the invention can be in the L or D configuration or else be a mixture of the D and L forms. According to the invention, the term "amino acid" refers in particular to naturally occurring alpha-amino acids, but also to homologues, isomers and derivatives thereof. Examples of isomers that may be mentioned are enantiomers. The derivative may be, for example, an amino acid having a protecting group. Typical examples of basic amino acids which may be mentioned are: lysine, arginine, histidine, ornithine, diaminobutyric acid.

According to the invention, the reactants, i.e. the solution of O-acetylsalicylic acid and the corresponding amino acid, are combined as quickly as possible at a temperature below 30 c, preferably 20-25 c, under normal pressure, and mixed to form a homogeneous phase. Suitable solvents for the reactants are water or water-miscible organic solvents, for example alcohols such as methanol, ethanol or isopropanol, in particular ethanol, ethers such as Tetrahydrofuran (THF), or ketones such as acetone.

The reactants are used in such an amount that the basic amino acid is slightly in excess. According to the invention, a ratio of O-acetylsalicylic acid to amino acid of from 1: 1.05 to 1: 1.5 is preferred, with a ratio of O-acetylsalicylic acid to amino acid of from 1: 1.05 to 1: 1.2 being particularly preferred.

According to the invention, the O-acetylsalicylic acid solution should contain 1 to 10% by weight, preferably 5 to 10% by weight, particularly preferably 6 to 8% by weight, of O-acetylsalicylic acid. The basic amino acid solution should contain 10 to 40% by weight, preferably 15 to 35% by weight, particularly preferably 20 to 30% by weight, of amino acid.

The homogeneous mixture obtained in this way is then used to carry out the crystallization of the composition according to the invention, optionally seeded, with the addition of a substantial excess of acetone compared to the reactants, for example an excess of 20 to 50%, preferably 30 to 40%. According to the invention, it is very important to keep the temperature of the crystalline phase within as narrow limits as possible. The temperature must not exceed 40 ℃ and should preferably be kept below 35 ℃. According to the invention, temperatures below 25 ℃ are preferred, in particular temperatures of 0 ℃. As a seed crystal, the seed crystal is,crystals of the desired product may be used, for example Aspiosol^*And (4) crystals. The crystallization is carried out at normal pressure.

In the process of the present invention, it is also important to maintain a specific stirring energy during the crystallization. The homogeneous mixture of the starting materials can be stirred only slightly. The stirring energy applied should not exceed 0.1W/l of reaction medium. According to the invention, it is preferred to apply an agitation energy of from 0.04 to 0.06W per liter of reaction medium. Possible stirrers are all conventional stirrers which can be controlled accordingly, for example stirrer vessels with baffles.

For crystallization, the solution should be maintained under the above conditions for no more than 20 hours. According to the invention, a crystallization time of less than 10 hours is preferred under the above-mentioned conditions, a time of from 1 to 8 hours being particularly preferred.

The composition of the present invention may further contain glycine, as required. The amount of glycine is freely selectable. According to the invention, the proportion of glycine in the reaction solution is 5 to 30% by weight, particularly preferably 5 to 15% by weight, particularly preferably 10% by weight.

According to the invention, a solution of glycine in water or a water-miscible organic solvent may be added to the reaction mixture of the reactants, wherein the above-mentioned solvents may be used as organic solvents. Glycine behaves inertly to these reactants. Under the inventive conditions described above, a process for the crystallization of the two solids (O-acetylsalicylic acid) from the homogeneous phase (co-crystallization) can be carried out.

However, according to the invention, it is also possible to add glycine in the form of a suspension to the already crystallized suspension of O-acetylsalicylate. The glycine suspension can be prepared in a conventional manner. According to the invention, it is preferred to prepare the glycine suspension with a solvent mixture of water and an alcohol, e.g. ethanol.

The manner in which glycine is added does not have any effect on the properties of the composition of the present invention. It should be noted that the addition of glycine to the compositions of the present invention is not essential. In particular, the presence of glycine does not have any effect on the stability of the composition of the invention.

The crystals are then separated by conventional means, for example by filtration or centrifugation. The solid is washed several times in accordance with the invention with an organic solvent, preferably an alcohol, such as ethanol, and/or a ketone, such as acetone, or a mixture of alcohols or ketones, for example a mixture of ethanol and acetone, or a different such solvent is used.

The solid was then dried under reduced pressure. The temperature should be kept below 50 ℃, preferably below 40 ℃ and particularly preferably below 35 ℃. A pressure of less than 50 mbar, preferably less than 30 mbar, should be applied to the solid. The drying can be carried out under conventional conditions, for example in a drying apparatus.

The process of the invention can also be carried out under sterile conditions at all times. For the aseptic conditions, the differences from the above-described operations, such as sterilization of the raw materials and the equipment used, are known to those skilled in the art.

The compositions of the invention are useful as analgesics, anti-pyretic agents, anti-rheumatic agents and non-steroidal anti-inflammatory agents for the treatment of, for example, rheumatic diseases, neuropathic pain, myalgia and migraine. However, they can also be used in particular as platelet aggregation inhibitors for the prophylaxis and treatment of cardiovascular and cerebrovascular diseases (e.g. ischemic heart disease, stroke, stable and unstable angina pectoris, acute myocardial infarction, bypass surgery, PTCA, stent implantation). Other fields of application are the stimulation of the immune system and the prevention of tumors (e.g. colon, esophageal or lung cancer) in HIV patients, the delay of cognitive decline in dementia syndromes (e.g. alzheimer's disease), the inhibition of gallstone formation and the treatment of diabetes.

The invention also includes pharmaceutical formulations comprising the compositions of the invention and a non-toxic inert pharmaceutically acceptable carrier, and methods of making such formulations.

The compositions of the present invention may also optionally be present in microencapsulated form in one or more of the above-mentioned carriers.

The composition of the present invention should be present in the above-described pharmaceutical formulation at a concentration of about 0.1 to 99.5%, preferably about 0.5 to 95%, by weight of the total mixture.

In a particular embodiment of the invention, the above-mentioned pharmaceutical preparations may also comprise an effective amount of one or more other pharmaceutically active compounds than the composition according to the invention, in particular one or more ADP receptor antagonists (such as ticlopidine and clopidogrel), GPIIb/IIIa receptor antagonists (such as abciximab, epilabide, tirofiban, orofiban, xemilofiban and sibrafiban), phosphodiesterase inhibitors (such as dipyridamole), thrombin receptor antagonists (such as hirudin, hirulog and argatroban), factor Xa inhibitors (such as antistatin, DX-9065 and pentose), HMG-CoA receptor antagonists (such as simvastatin and cerivastatin) and/or calcium antagonists (such as nifedipine).

In general, it has been demonstrated that in human medicine and veterinary medicine, in order to obtain the desired therapeutic effect, the active compounds according to the invention are administered in a total amount of from about 0.5 to about 500, preferably from 5 to 100, mg/kg of body weight per 24 hours, optionally in the form of several single doses. A single dose contains from about 1 to about 80, in particular from 3 to 30, mg of the active compound according to the invention per kg of body weight.

The active compound may act systemically and/or locally. For this purpose, administration can be by any suitable means, for example, by the oral or parenteral route. For these administration routes, the active compounds can be administered in suitable administration forms.

For oral administration, known administration forms and/or modified forms which rapidly release the active compound are suitable, such as tablets (uncoated and coated tablets, for example gastric juice-resistant coated tablets, FDT (fast-dissolving tablets), effervescent tablets, chewable tablets), capsules, sugar-coated tablets, granules, pills, powders, emulsions, suspensions and solutions.

Parenteral administration can be used to bypass the absorption step (intravenous, intra-arterial, intracardiac, intraspinal, intramedullary) or to intervene in absorption (intramuscular, subcutaneous, intradermal or intraperitoneal). For parenteral administration, suitable administration forms are solutions, suspensions, emulsions, lyophilisates and injections and infusions in the form of sterile powders.

Topical application in the form of suppositories or transdermal systems (e.g. patches, ETS systems) as well as creams, ointments, gels, sprays or dissolved in organic or inorganic solvents is also a possible mode of administration.

The active compounds can be converted into the administration forms described by known methods. This is done with inert, non-toxic pharmaceutically acceptable excipients. Such excipients include carriers (e.g. microcrystalline cellulose), solvents (e.g. liquid polyethylene glycol), emulsifiers (e.g. sodium lauryl sulphate), dispersants (e.g. polyvinylpyrrolidone), synthetic and natural biopolymers (e.g. albumin), stabilisers (e.g. antioxidants such as ascorbic acid), colourants (e.g. inorganic pigments such as iron oxide) or taste and/or odour correctors.

Examples

The invention is described in more detail by means of non-limiting preferred embodiments. All quantitative data are in weight percent unless otherwise indicated.

Example 1: lysine acetylsalicylate

A pyrogen-free solution of 9.9kg of O-acetylsalicylic acid in 120kg of ethanol was added via a sterile filter to a sterile pyrogen-free stirred apparatus vessel with baffles. A pyrogen-free solution of 9.0kg of lysine hydrate sterile-filtered in 26.5kg of pyrogen-free water was added at 20-25 ℃ for a short time and the solution was mixed so that the temperature did not exceed 30 ℃. Seed crystals of 50g were added and the mixture which had crystallized was mixed with 120kg of sterile filtered acetone with cooling to 0 ℃. The mixture is allowed to crystallize for 1-8 hours at 0 ℃ with gentle stirring. The crystals are separated under aseptic conditions using a filter or centrifuge. The moist product is washed several times with ethanol in a separation unit. The moist product is transferred under aseptic conditions to a dryer and dried at a pressure of less than 30 mbar at a temperature of not more than 40 ℃.

The desired product is obtained in an amount of 89 to 94% and has a residual water content of 0.10 to 0.15%.

Example 2: d, L-lysine acetylsalicylate with 10% glycine

A pyrogen-free solution of 9.9kg of O-acetylsalicylic acid in 145kg of ethanol was added via a sterile filter to a sterile pyrogen-free stirred apparatus vessel with baffles. A pyrogen-free solution of 9.0kg of D, L-lysine hydrate and 2.4kg of glycine in 35kg of pyrogen-free water which had been subjected to sterile filtration was added in a short time at 20 to 25 ℃ and the solution was mixed so that the temperature did not exceed 30 ℃. Seed crystals of 50g were added and the mixture which had crystallized was mixed with 120kg of sterile filtered acetone with cooling to 0 ℃. The mixture is allowed to crystallize for 1-8 hours at 0 ℃ with gentle stirring. The crystals are separated under aseptic conditions using a filter or centrifuge. The moist product is washed in a separate unit with ethanol and acetone in succession. The moist product is transferred under aseptic conditions to a dryer and dried at a pressure of less than 30 mbar at a temperature of not more than 40 ℃.

90-95% of the desired product is obtained, with a residual water content of 0.10-0.15%.

Example 3: d, L-lysine acetylsalicylate with 10% glycine

A pyrogen-free solution of 9.9kg of O-acetylsalicylic acid in 120kg of ethanol was added via a sterile filter to a sterile pyrogen-free stirred apparatus vessel with baffles. A pyrogen-free solution of 9.0kg of lysine hydrate sterile-filtered in 26.5kg of pyrogen-free water was added at 20-25 ℃ for a short time and the solution was mixed so that the temperature did not exceed 30 ℃. Seed crystals of 50g were added and the mixture which had crystallized was mixed with 120kg of sterile filtered acetone with cooling to 0 ℃. The mixture is allowed to crystallize for 1-8 hours at 0 ℃ with gentle stirring. A sterile suspension of 2.1kg glycine in 8kg pyrogen-free water and 25kg ethanol was prepared in a separate sterile and pyrogen-free stirred vessel. This suspension was added to the salicylate suspension. The crystallization mixture is separated under aseptic conditions with a filter or centrifuge. The moist product is washed several times with ethanol in a separation unit. The moist product is transferred under aseptic conditions to a dryer and dried at a pressure of less than 30 mbar at a temperature of not more than 40 ℃.

89-94% of the desired product is obtained, with a residual moisture content of 0.10-0.15%.

Determination of particle size distribution

The compositions according to the invention and the commercially available Aspiosol were determined under the following standard conditions using a Malvern 2600D measuring device from Malvern^*(sold by Bayer AG).

The Malvern 2600 assay device consists of a He/Ne laser, a measurement cuvette with a constant temperature reservoir system, a fourier lens and a multi-component detector. The measured optical density is converted into a particle size distribution. The alignment of the laser and lens was adjusted by hand before each measurement and the measurement set up was checked by blank measurement. The blank pulse must not exceed the maximum value of 20 for each detector element.

Shaking the sample to be assayed by hand for about 15 seconds; then, a spatula was used to take a sample. The amount of sample depends on the allowable shielding area (0.1-0.3) of the assay device. Using conventional dispersants such as Baysilon M10^*(Bayer AG) the samples taken were slightly pre-dispersed in a beaker (stirred with a glass rod) and then filled into the reservoir of the assay device, which was also filled with the dispersant. The beaker was washed thoroughly with dispersant to ensure representative samples.

The measurement was carried out using a focal length of 300mm, a constant temperature of 20 ℃ and a mask area of 0.1 to 0.3.

The products were measured after 0, 15 and 60 seconds of sonication. For this, an ultrasonic needle was placed in the reservoir of the product circuit. The suspension was pumped through the assay cuvette in a closed cycle. The signal recorded with the detector is analyzed and converted into a particle size distribution.

The results are shown in FIGS. 1 and 2.

Claims (21)

1. Composition comprising a salt of O-acetylsalicylic acid with a basic amino acid, characterized in that the average particle size of the salt is greater than 160 μm, more than 60% of the particles having a particle size of 100-200 μm in terms of particle size distribution.

2. Composition according to claim 1, characterized in that the average particle size of the salt is greater than 170 μm, more than 70% of the particles having a particle size of 100-200 μm in terms of particle size distribution.

3. The composition of claim 1, characterized in that the basic amino acid is selected from the group consisting of lysine, arginine, histidine, ornithine and diaminobutyric acid.

4. Composition according to claim 3, characterized in that the basic amino acid is lysine.

5. The composition of claim 1, characterized in that the composition further comprises glycine.

6. A process for the preparation of a composition according to any one of claims 1 to 5, which comprises rapidly combining O-acetylsalicylic acid with a solution of a basic amino acid in water or a water-miscible organic solvent at a temperature of less than 30 ℃ and atmospheric pressure, wherein the amino acid is in slight excess in the reaction solution, adding acetone and optionally seed crystals at a temperature of less than 40 ℃ and atmospheric pressure, stirring for not more than 20 hours with a stirring energy of not more than 0.1W per liter of reaction medium, separating off the solid, washing with an organic solvent, drying at a temperature of less than 50 ℃ and a pressure of less than 50 mbar, optionally adding a solution of 5 to 30% by weight of glycine in water or a water-miscible organic solvent to the reaction solution or as a suspension to a crystalline suspension of O-acetylsalicylic acid salt.

7. The method of claim 6, characterized in that the solution of O-acetylsalicylic acid and the basic amino acid is combined at a temperature of 20-25 ℃ and atmospheric pressure.

8. The process as claimed in claim 6, wherein the ratio of O-acetylsalicylic acid to amino acid in the reaction solution is from 1: 1.05 to 1: 1.2.

9. The process as claimed in claim 6, characterized in that an excess of 30 to 40% by weight of acetone is added.

10. The process as claimed in claim 6, characterized in that the temperature during and after the addition of acetone is 0 ℃.

11. The process as claimed in claim 6, characterized in that, after the addition of acetone, the mixture is stirred for 1 to 8 hours.

12. The process as claimed in claim 6, wherein the stirring energy is from 0.04 to 0.06W/l of reaction medium.

13. The method of claim 6, characterized in that the drying is carried out at a temperature below 35 ℃.

14. The method according to claim 6, characterized in that the drying is carried out at a pressure below 30 mbar.

15. The method of claim 6, characterized in that 10% by weight of glycine is added.

16. The method according to any one of claims 6 to 15, characterized in that the method is carried out under sterile conditions.

17. Medicament comprising at least one composition according to any one of claims 1 to 5.

18. Medicament according to claim 17, characterized in that it further comprises one or more additional pharmaceutically active components.

19. Pharmaceutical according to claim 18, characterized in that the additional pharmaceutical active ingredient is selected from the group consisting of ADP receptor antagonists, GPIIb/IIIa receptor antagonists, phosphodiesterase inhibitors, thrombin receptor antagonists, factor Xa inhibitors, HMG-CoA receptor antagonists and calcium antagonists.

20. Use of a composition according to any one of claims 1 to 5 in the manufacture of a medicament for the treatment of arthritis, neuralgia, myalgia and/or migraine.

21. Use of a composition according to any one of claims 1 to 5 in the manufacture of a medicament for the treatment of myocardial infarction, stroke, ischemic heart disease, angina pectoris, bypass surgery, PTCA and/or stent implantation.