DE102017007385A1 - Maleate-free solid dosage forms - Google Patents

Abstract

The invention relates to the use of maleate-free preparations of triaminopyridines for the long-term treatment of diseases and disorders of the nervous system.

Description

The most prominent example of triaminopyridine-based drugs is flupirtine. Flupirtin is the international generic name (INN) of 2-amino-3-carbethoxyamino-6- (4-fluorobenzylamino) -pyridine and may be represented by the following structural formula (II): 1 ) being represented:

Flupirtin is a centrally active non-opioid analgesic that does not cause addiction or tolerance. It is also a muscle relaxant. Although flupirtine does not appear to bind to any of the previously identified NMDA receptor complex-associated binding sites, it has several functional NMDA antagonistic properties. It has also been shown that flupirtine inhibits the expression of the protein Bcl-2, which is known to inhibit apoptosis (programmed cell death) and necrosis ( WO 97/49398 A1 ), elevated. Flupirtin is the prototype of the substance class SNEPCO (Selective Neuronal Potassium Channel Opener).
Because of these diverse activities, flupirtine has a unique pharmacological activity spectrum. Flupirtin is useful in the treatment and prevention of acute and chronic pain ( WO 97/14415 A1 ), including neuropathic pain, nerve pain, cancer pain, vasomotor and migraine headache, postoperative pain, post-traumatic pain, burn pain, erosion pain, toothache, fibromyalgia ( WO 00/59487 A2 ) and the pain associated with degenerative and inflammatory joint disease.

Flupirtin shows advantages over opioids. Long-term use of opioids to treat pain results in constipation, nausea, sedation, confusion, itching, urinary retention, tolerance and dependence. Comparative studies of flupirtine with tramadol and pentazocine showed that it is equally effective, but without side effects of opioids. ( Harish S, Bhuvana K, Bengalorkar GM, Kumar T. Flupirtine: Clinical pharmacology. Journal of Anesthesiology, Clinical Pharmacology. 2012; 28 (2): 172-177. doi: 10.4103 / 0970-9185.94833)

Flupirtine is also used to treat and prevent muscle tension, muscle cramps, muscle stiffness and movement disorders such as dystonia ( WO 2007/128462 A1 and DE 4122166 A1 and EP 0467164 A2 ). It is especially useful in the treatment of back pain. In addition, flupirtine also exerts potent cytotoxic and neuroprotective effects and is useful in the treatment and prevention of neurodegenerative disorders ( WO 95/05175 A1 ), such as Parkinson's disease, dementia including Alzheimer's disease, Huntington's chorea, multiple sclerosis, amyotrophic lateral sclerosis, encephalopathy including AIDS-related encephalopathy, Creutz-Feldt-Jakob disease including classical and new variants and Batten disease, also neuronal ceroid Called lipofuscinosis, ( WO 01/39760 A2 ). Flupirtin is also used in the treatment and prevention of ocular diseases such as maculopathy including senile macular degeneration, diabetic retinopathy, glaucoma and retinitis pigmentosa. Flupirtine is also used in the treatment and prevention of myocardial ischemia and infarction, cerebral ischemia and infarction, shock and tinnitus ( WO 02/15907 A1 ).

Other triaminopyridines have been used to treat epilepsy ( WO 95/005175 A1 and Sheridan PH et al. Pilot Study of Flupirtine in Refractory Seizures. Neurology, Vol. 36, 1986, p. 85 ) and as anti-inflammatory agents ( DE 1795858 B1 )

DE 1795858 B1 and DE 1795499 A disclose triaminopyridines as free bases and as their hydrochlorides. However, these compounds are of little commercial interest because they are very sensitive to oxidation and therefore have poor storage stability. From the EP 0160865 B1 Flupirtine gluconate is known to be somewhat more stable against oxidation. However, it is not suitable for a solid oral dosage form and must be used as an injection.

Flupirtin-maleate polymorphs may be prepared according to EP 199951 A2 and EP 977736 A1 getting produced.

As described above, flupirtine has been proposed for the treatment of acute and chronic pain, nerve disorders, normalization of muscle tone, tinnitus, overactive bladder, multiple sclerosis, fibromyalgia, etc. The approved use of flupirtine in Europe is for the treatment of back pain. Experience has shown that such a disease requires treatment for longer periods of time. This can vary from weeks to months or even years. Some cases of liver disease have been observed some time after the product was launched and a link with the use of flupirtin is suspected. This is a complex area as this medicine is often used concomitantly with other medicines for the treatment of pain known to have liver effects. Therefore, in the initial stages, it was not understood what effect flupirtine has on the liver.

In the year 2012 a 12-week, double-blind, three-arm study was conducted on 207 double-blind patients with flupirtine extended-release dose (400 mg / day, titrated to 600 mg / day) with prolonged-release tolterodine (4 mg / day). and with placebo. There were larger increases in liver enzymes (more than three times the upper limit of normal). Following this demonstration in multiple flupirtine-exposed patients, the study was prematurely discontinued due to these effects. Based on data at the end of the study, hepatotoxicity was detected in 31% of patients who received flupirtin for ≥6 weeks. Michel, Martin C., et al. "Journal of clinical pharmacology 73.5 (2012): 821-825.

In June 2013, the Coordination Group for Mutual Recognition and Decentralized Procedures - Human (CMDh) restricted the use of oral flupirtine drugs and suppositories to contraindicated the use of other analgesics, the lowest possible dose, the analgesic effect and the Duration of treatment and limited to a maximum of two weeks. The indication was therefore changed to acute pain and the use for the treatment of chronic pain was removed (combined with the need for analgesics for more than 3 months). In addition, patients should be checked for liver function after each full week of treatment and discontinued as soon as a patient shows any signs of liver problems. Flupirtine must not be used in patients with pre-existing liver disease or alcohol problems, or in patients taking other medicines known to cause liver problems. Consequently, the initially promising use of flupirtine in a number of diseases has been eliminated, especially in chronic diseases lasting more than 2 weeks.
The recommendations follow a review by the Pharmaceutical Safety Assessment Committee of the EMA, Pharmacovigilance Risk Assessment Committee (PRAC), which reviewed the reported liver problems with flupirtine, ranging from elevated liver enzymes (elevated levels of transaminase) to drug-induced hepatitis or even liver failure. The PRAC evaluated the available data on liver safety and found that no cases of liver failure or liver transplantation were reported in patients taking the drug for two weeks or less.

Triaminopyridines are highly electron-rich aromatic amines. These compounds are sensitive to oxidation and show a high redox potential, as measured by cyclic voltammetry. Triaminopyridines can be metabolized oxidatively to azaquinonediimines, which might be involved in the hepatotoxic effect of flupirtine ( Lemmerhirt, Christian J .; Rombach, Mirko; Bodtke, Anja; Bednarski, Patrick J .; Link, Andreas, ChemMedChem (2015), 10 (2), 368-379 )

Idiosyncratic drug-induced liver injury (DILI) is a common cause of market withdrawal of a drug, and although rare, DILI can lead to serious clinical consequences such as acute liver failure and the need for liver transplantation. Avoidance of iatrogenic "damage" caused by a therapeutic intention is a priority in patient care ( Minjun Chen, Ayako Suzuki, Jurgen Borlak, Raúl J. Andrade, M Isabel Lucena, Journal of Hepatology 2015 vol. 63, p 503-514 )

DE 102011006425 A1 discloses a combination of flupirtine and N-acetylcysteine to avoid side effects on the liver. However, further studies have shown that the required daily dose of the drug combination exceeds 1000-5000 mg to suppress the hepatotoxic effects. These high daily doses result in decreased patient compliance and are not practical.

We have found that the effects of flupirtine on the liver are adversely increased by the presence of the maleic acid salt used in all solid dosage forms of commercially available triaminopyridines. This is surprising since maleic acid and maleate show very low toxicity. A hepatotoxic effect of this compound is not known in the medical literature.

The object of the present invention is to provide stable and solid addition salts of triaminopyridines and in particular compounds containing a 2,3,6-triaminopyridine core such as flupirtine, which are distinguished by an improved balanced mixture of oxidation stability and long-term compatibility. Long-term compatibility means treatment for more than 14 days without hepatotoxic effects or reduced effects compared to the same dose of the maleate salt of the corresponding triaminopyridine. In addition, it is the object of the present invention to provide pharmaceutical compositions comprising triaminopyridines such as flupirtine addition salts as the active ingredient, methods of preparing the salts and pharmaceutical compositions, and therapeutic uses thereof. Solid flupirtin formulations that have prolonged therapeutic activity and are effective as products for the treatment of nerve disorders such as pain, muscle tension, neurodegenerative diseases, or inflammatory conditions are desirable. In particular, oral or rectal or topical flupirtine formulations that can be administered for more than 2 weeks without exhibiting negative liver effects such as hepatotoxicity or excessive liver enzyme levels for the treatment of nerve diseases are desirable.
It has now surprisingly been found that the avoidance of maleate in combination with triminopyridines such as flupirtine (D 9998) or D 10527 or D 10527, as in DE 1795858 B1 described, does not lead to elevated liver enzyme levels. Drug-induced liver damage can be avoided. This was demonstrated by comparing triaminopyridine maleate salts and its corresponding non-maleate salt using a cell-based assay system:

Liver damage:

The degree of liver damage was determined by increasing the serum concentration levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) relative to the standard levels as measured by an optimized UV method with the HITACHI automatic analyzer (Model 7050 ). These enzymes are released upon cell damage in membrane leakage and their increase in plasma is characteristic of liver damage ( Borlak, J .; Chougule, A .; Singh, PK Toxicol. Vitro 2014, 28, 784-795. AND: Laine, L .; Goldkind, L .; Curtis, SP; Connors, LG; Yanqiong, Z .; Cannon, CP Am. J. Gastroenterol. 2009, 104, 356-362 ).
A 50% reduction in serum level increase of ALT and AST using the non-maleate derivatives relative to the maleate salts is considered significant. Table 1 Enzyme activity of LDH, ALT and AST in serum medium 24 hours after treatment with F-Mal or F-Mes and increasing amounts of HRP in HepG2 or Huh7 cells HepG2 cells DMSO 30x Cmax F-times + 10U / ml HRP 30x Cmax F-times + 30U / ml HRP 30xCmax F-times + 90U / ml HRP H2O2 H2O2 + 90U / ml HRP LDH 1 1 1 1 2 1 OLD 1 3 10 39 1 9 AST 1 4 9 25 2 7 DMSO 30x Cmax F-Mes + 10U / ml HRP 30x Cmax F-Mes + 30U / ml HRP 30xCmax F-Mes + 90U / ml HRP H2O2 H2O2 + 90U / ml HRP LDH 1 1 1 1 2 1.5 OLD 1 4 8th 15 1 9 AST 1 2.5 14 11 2 7 Huh7 Cells DMSO 30x Cmax F-times + 10U / ml HRP 30x Cmax F-times + 30U / ml HRP 30xCmax F-times + 90U / ml HRP H2O2 LDH 1 1 1 2 1 OLD 1 3 9 36 1 AST 1 3 6 22 1 DMSO 30x Cmax F-Mes + 10U / ml HRP 30x Cmax F-Mes + 30U / ml HRP 30xCmax F-Mes + 90U / ml HRP H2O2 LDH 1 1 1 1.5 1.5 OLD 1 3 7 15 1 AST 1 2 5 7 1.5

Description of the experiments

Cells and media: HepG2 cells, a well-defined human hepatoblastoma cell line, were maintained in Dulbecco's modified Eagle's medium (DMEM / F12, Gibco BRL, USA) containing 10% fetal bovine serum (FBS, Gibco BRL, USA). , The cells were cultured based on standard protocols at 37 ° C in the incubator under 5% CO 2 and 95% humified air until the experiment. LDH assay: HepG2 cells were grown in 96-well dishes to evaluate the release of LDH (lactate dehydrogenase) from necrotic cells using the cytotoxicity detection guide (Roche, Mannheim, Germany).

Description of the drawings

The accompanying drawings, which are incorporated in and constitute a part of the specification, illustrate only certain preferred embodiments of the present invention. Together with the rest of the description, they are intended to illustrate preferred embodiments of the invention to those skilled in the art.

1 Figure 13 is a bar graph showing the effects of the increase of transaminases in HepG2 cells after treatment with F-Mal in the presence of an increasing amount of HRP (horseradish peroxidase).
Human liver epithelial cells (HepG2) were treated with F-Mal (flupirtine maleate) or F-Mes (flupirtine mesilate). To demonstrate an effect in this in vitro test for liver toxicity, serum levels of transaminases ALT and AST were assayed using the 30-fold dose of the normal therapeutic dose (30xCmax) of the triaminopyridines. First, HepG2 cells were treated with F-Mal and increasing amounts of HRP: 10 U / ml, 30 U / ml, 90 U / ml. As in 1 shown a strong increase in the enzyme activity of aminotransferase ALT and AST can be observed. Depending on the HRP dose, the activity of ALT increased by a factor of 3, 10 or 39 and by 4, 9 or 25 for AST levels relative to the level with DMSO only (standard = 1). Treatment with H ₂ O ₂ or HRP alone only leads to a very slight increase in enzyme activity.

2 Figure 4 is a bar graph showing the effects of transaminase uptake in HepG2 cells after treatment with F-Mes in the presence of an increasing amount of HRP (horseradish peroxidase).
Similar to the previous experiment, HepG2 was treated with F-Mes and increasing amounts: 10 U / ml, 30 U / ml, 90 U / ml HRP. As in 2 a moderate increase in the enzyme activity of the aminotransferase ALT and AST can be observed. Depending on the HRP dose, the activity of ALT increased by the factor 4 . 8th or 14 and the AST levels around 3, 14 or 11 relative to the DMSO concentration (standard = 1).

3 Fig. 12 is a bar graph showing the effects of increasing transaminases in Huh7 cells after treatment with F-Mal in the presence of an increasing amount of HRP (horseradish peroxidase).
Analogous to the previous experiments, Huh7 cells were treated with F-Mal and increasing amounts of HRP: 10 U / ml, 30 U / ml, 90 U / ml. As in 3 can show a strong increase in the enzyme activity of Aminotransferase ALT and AST are observed. Depending on the HRP dose, the activity of ALT increased by the factor 3 . 9 or 36 and that of the AST by 3, 6 or 22 compared to the DMSO concentration (standard = 1).

4 Figure 13 is a bar graph showing the effects of transaminase uptake in Huh7 cells after treatment with F-Mes in the presence of an increasing amount of HRP (horseradish peroxidase).
Analogous to the previous experiment, Huh7 cells were treated with F-Mes and increasing amounts: 10 U / ml, 30 U / ml, 90 U / ml HRP. As in 4 a moderate increase in the enzyme activity of the aminotransferase ALT and AST can be observed. Depending on the HRP dose, the activity of ALT increased by the factor 3 . 7 or 15 and that of the AST by 2.5, 5 or 7 compared to the DMSO concentration (standard = 1).

Compared to F-Mes, the enzyme levels of ALT and AST are almost doubled using F-Mal after treatment of HepG2 or Huh7 cells with increasing amounts of HRP in the presence of water peroxide.

It is concluded that by avoiding maleate, the sharp increase of ALT and AST in hepatocytes, exemplified by HepG2 and Huh7 cells, can be avoided after treatment with triaminopyridines and HPO. The hepatotoxic effect of Triaminopyridinen after prolonged treatment can be avoided.

In contrast to other acids, such as hydrochloric acid, di- and tricarboxylic acids and more complex hydroxyl-containing monocarboxylic acids, such as gluconic acid, the sulfonic acid addition salts of triaminopyridines show a significantly improved stability to oxygen ( EP 2350009A1 ).

Tabelle. 2: Strukturen von Triaminopyridinen, die als Maleat und als Nicht-Maleat zur Untersuchung der Transaminaseaktivität in Gegenwart von HRP verwendet wurden D 9998: R1=H, R2= 4-F D10081: R1= benzyl, R2= 4-F D10081: R1=H; R2=3-OCH₃ The avoidance of a combination with maleate is not only advantageous for flupirtine, but also for the group of 2,3,6-triaminopyridines in general (Structures Table 2).

Table. Figure 2: Structures of triaminopyridines used as maleate and as non-maleate to study transaminase activity in the presence of HRP D 9998: R1 = H, R2 = 4-F D10081: R1 = benzyl, R2 = 4-F D10081: R1 = H; R2 = _3-OCH3

The present invention is particularly useful for triaminopyridine acid addition salts represented by the following formula (2) wherein R represents an optionally substituted C ₁ -C ₁₂ alkyl or C ₆ -C ₁₀ aryl group.

Suitable C ₁ -C ₁₂ alkyl groups for R include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, cyclohexyl , Heptyl, octyl, nonyl, decyl and dodecyl radicals.
Suitable C ₆ -C ₁₀ aryl groups for R include phenyl and naphthyl. The C ₁ -C ₁₂ alkyl or C ₆ -C ₁₀ aryl groups may optionally be substituted. Suitable substituents are known in the art and include hydroxyl, C ₁ -C ₄ alkoxy, phenoxy, halo, COOH, C ₁ -C ₄ alkyl, and phenyl.

Pharmaceutical formulations

The salts of the invention may also be used to advantage in solid and liquid pharmaceutical formulations.

The salts of the invention are particularly well suited for solid pharmaceutical formulations. Solid pharmaceutical compositions can be defined as those compositions that are in a non-liquid state. Alternatively, solid pharmaceutical compositions may be defined as pharmaceutical compositions which are administered orally or rectally into the gastrointestinal tract. Alternatively, solid pharmaceutical compositions may be defined as pharmaceutical compositions that are not suitable for direct parenteral administration.

Examples of solid pharmaceutical compositions include tablets, film-coated tablets, hard gelatin capsules, soft gelatin capsules, pellets, granules, dragees, suppositories, microcapsules and lyophilisates.
However, it is preferred that solid pharmaceutical formulations comprising flupirtine salts of formula (2) are not lyophilizates when the flupirtine salt is selected from the methanesulfonate, ethanesulfonate, hydroxyethanesulfonate, halobenzenesulfonate, toluenesulfonate and naphthalenesulfonate salts means "lyophilisate" in the WO 2004/112754 described material, ie a material which is obtained by drying in the frozen state under high vacuum by freezing the solvent which evaporates in the frozen state. A freeze-dried material obtained in this way is very porous and retains its original volume. Such a lyophilisate is an amorphous material. The salts of the invention are also suitable for liquid pharmaceutical formulations. Liquid pharmaceutical compositions can be defined as those compositions which are in a liquid or semi-liquid state. The term "semi-liquid" or "semi-liquid state" is to be understood as described in the textbook Rudolf Voigt, "Pharmaceutical Technology", 10th ed., 2006, p. 373.

Examples of liquid formulations include solutions, emulsions, suspensions, creams, ointments, pastes, gels. In addition, the present invention also relates to pharmaceutical compositions combining solid and liquid state characteristics, such as encapsulated gels or "liquid capsules", in which a liquid or semi-liquid is encapsulated by a suitable material to obtain a formulation suitable for orally is administration. Suitable materials for the preparation of gels are known in the art and include, among others, fatty acid esters of sucrose or glycerin.

The salts of the present invention are also particularly useful for the preparation of controlled release pharmaceutical compositions. In one aspect of the controlled release formulations, the crystals of the invention may also be more readily coated, thus overcoming the formulation difficulties inherent in prior sustained release formulations using acicular flupirtine salts.

Furthermore, the improved solubility of some of the salts of the invention allows to modulate the release properties of the formulation. Thus, by combining salts of different solubility, it is possible to control flupirtine release profiles. With respect to the above-mentioned pharmaceutical compositions, the present invention is therefore also directed to those embodiments in which the above-mentioned pharmaceutical compositions are controlled release pharmaceutical compositions comprising a mixture of flupirtic acid addition salts.
In this context, a controlled-release pharmaceutical composition means a composition in which the pharmaceutical agent is released at a controlled rate over an extended period of time. The rate of release may vary over time.

The pharmaceutical compositions of the invention may also comprise one or more excipients, such as carriers, diluents, binders, lubricants, surfactants, disintegrants, plasticizers, tackifiers, opacifiers, dyes, antioxidants, and the like. As will be apparent to those skilled in the art, the exact choice of additives and their relative amounts will depend on the type of pharmaceutical composition, active ingredient, dosage and other factors.

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• WO 9749398 A1 [0002]
• WO 9714415 A1 [0002]
• WO 0059487 A2 [0002]
• WO 2007/128462 A1 [0004]
• DE 4122166 A1 [0004]
• EP 0467164 A2 [0004]
• WO 9505175 A1 [0004]
• WO 01/39760 A2 [0004]
• WO 0215907 A1 [0004]
• WO 95/005175 A1 [0005]
• DE 1795858 B1 [0005, 0006, 0015]
• DE 1795499 A [0006]
• EP 0160865 B1 [0006]
• EP 199951 A2 [0007]
• EP 977736 A1 [0007]
• DE 102011006425 A1 [0013]
• EP 2350009 A1 [0025]
• WO 2004/112754 [0031]

Cited non-patent literature

• Harish S, Bhuvana K, Bengalorkar GM, Kumar T. Flupirtine: Clinical pharmacology. Journal of Anesthesiology, Clinical Pharmacology. 2012; 28 (2): 172-177. doi: 10.4103 / 0970-9185.94833) [0003]
• PH et al. Pilot Study of Flupirtine in Refractory Seizures. Neurology, Vol. 36, 1986, p. 85 [0005]
• Lemmerhirt, Christian J .; Rombach, Mirko; Bodtke, Anja; Bednarski, Patrick J .; Link, Andreas, ChemMedChem (2015), 10 (2), 368-379 [0011]
• Minjun Chen, Ayako Suzuki, Jurgen Borlak, Raúl J. Andrade, M Isabel Lucena, Journal of Hepatology 2015 vol. 63, p 503-514 [0012]
• Borlak, J .; Chougule, A .; Singh, P.K. Toxicol. Vitro 2014, 28, 784-795. AND: Laine, L .; Goldkind, L .; Curtis, S.P .; Connors, L.G .; Yanqiong, Z .; Cannon, C.P. At the. J. Gastroenterol. 2009, 104, 356-362 [0016]

Claims (10)

A pharmaceutical composition for use in long-term therapy of a patient comprising a triaminopyridine compound stabilized in the form of a pharmaceutically acceptable salt other than the maleate or hydrogenalate salt, all other components of said composition being used for long-term therapy or one of the additional uses Components are also free of maleate or hydrogen maleate. Pharmaceutical composition according to Claim 1 wherein the triaminopyridine compound is 2-amino-3-carbethoxyamino-6- (4-fluoro-benzylamino) -pyridine. Pharmaceutical composition according to Claim 2 wherein the compound is flupirtine mesilate salt. Pharmaceutical composition according to one of Claims 1 to 3 for the treatment or prevention of acute and chronic pain, neuropathic pain, nerve pain, fibromyalgia, cancer pain, vasomotor and migraine headaches, postoperative pain, post-traumatic pain, burning pain, erosive pain, toothache, and pain associated with degenerative and inflammatory joint disease and for the treatment of inflammatory diseases. Pharmaceutical composition according to Claim 3 for the treatment or prevention of abnormal muscle tension, muscle spasms, muscle stiffness, dystonia, overactive bladder and tinnitus. Pharmaceutical composition according to Claim 3 for the treatment or prevention of neurodegenerative diseases such as Parkinson's disease, dementia including Alzheimer's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, encephalopathy including AIDS-related encephalopathy, Creutzfeldt Jakob including classical and novel variants and neuronal ceroid lipofuscinosis. Pharmaceutical composition according to Claim 3 for the treatment or prevention of diseases of the eye, such as maculopathy including senile macular degeneration, diabetic retinopathy, glaucoma and retinitis pigmentosa. Pharmaceutical composition according to Claim 3 for use in the long-term therapy of a chronic disease. Pharmaceutical composition according to Claim 8 , where the chronic disease is back pain. Pharmaceutical composition according to Claim 8 , where the chronic disease is epilepsy.

Images