Summary of the invention
The present inventors have unexpectedly found that L-lactic acid addition salt (= L-lactate), D-lactic acid addition salt (= D-lactate) and DL-lactic acid addition salt (= DL-lactate) of 1- [2- (2, 4-dimethylphenylsulfanyl) phenyl ] piperazine have high solubility. Accordingly, the present invention relates to a liquid formulation comprising the L-lactic acid addition salt, the D-lactic acid addition salt and/or the DL-lactic acid addition salt of 1- [2- (2, 4-dimethylphenylsulfanyl) phenyl ] piperazine.
In one embodiment, the present invention relates to compounds which are the L-lactic acid addition salts of 1- [2- (2, 4-dimethylphenylsulfanyl) phenyl ] piperazine.
In one embodiment, the present invention relates to compounds which are the D-lactic acid addition salts of 1- [2- (2, 4-dimethylphenylsulfanyl) phenyl ] piperazine.
In one embodiment, the present invention relates to a method of treatment, comprising: the liquid formulation of the present invention is administered to a patient in need thereof.
In one embodiment, the invention relates to the use of a salt of the invention for the preparation of a liquid pharmaceutical composition for the treatment of certain diseases.
In one embodiment, the present invention relates to a salt of the present invention for use in the treatment of certain diseases, wherein the salt is in the form of a liquid formulation.
In one embodiment, the present invention relates to a container comprising the liquid formulation of the present invention, wherein said container is equipped with a drop collector (aggregate).
Drawings
FIG. 1 XRPD of anhydrous L-lactate 1(AH1)
FIG. 2 XRPD of L-lactate monohydrate 1(MH1)
FIG. 3 XRPD of L-lactate monohydrate 2(MH2)
FIG. 4 XRPD of DL-lactate form alpha (alpha)
FIG. 5 XRPD of DL-lactate form beta (. beta.)
FIG. 6 XRPD of DL-lactate Monohydrate (MH) (with alpha-form inclusions)
FIG. 7 XRPD of DL-lactate gamma form (gamma), with inclusions of alpha-form.
Detailed description of the invention
The formulations relevant to the present invention are all pharmaceutical compositions.
In WO 2008/113359, 1- [2- (2, 4-dimethylphenylthio) phenyl has been described]The crystalline base of piperazine and the previously known salts. The water solubility of these salts is shown in table 2. Table 1 gives XRPD reflectance, melting point and solubility data for the salts of the invention. The data in tables 1 and 2 show that the beta-form of the DL-lactic acid addition salt and the L-lactic acid addition salt MH2 have a particularly high solubility. Thus, these salt forms are suitable for use in compositions comprising 1- [2- (2, 4-dimethylphenylthio) phenyl]In liquid formulations of piperazine. According to table 2, the mesylate salts also benefit from an extremely high solubility. However, the use of methanesulfonic acid (methanesulfonate) in combination with an alcoholic solvent in the synthesis of pharmaceutical compositions involves the risk of obtaining an alkyl methanesulfonate impurity, which is genotoxic: (Mutat. Res. 581(2005)23-34;Eur. J. Pharm. Sci. 28(2006)1-6). Therefore, lactate salts are preferred over mesylate salts for use in pharmaceutical compositions.
For convenience, the L-lactic acid addition salt, D-lactic acid addition salt and DL-lactic acid addition salt of 1- [2- (2, 4-dimethylphenylsulfanyl) phenyl ] piperazine are referred to as the salts of the present invention. Both the L-lactic acid addition salt and the DL-lactic acid addition salt exist in some polymorphic forms, as shown in the examples. Specifically mentioned is the beta form of the DL-lactic acid addition salt as a salt according to the invention. For convenience, the lactic acid addition salt is also referred to as the lactate salt.
The polymorphic forms are characterized by their corresponding XRPD reflections as listed in table 1 and depicted in figures 1-7.
In this context, the AH1 form of L-lactate represents the anhydrous form, characterized by: XRPD reflections at 4.65, 10.96 and 13.97(° 2 θ), and are further characterized by fig. 1.
Herein, MH1 form of L-lactate represents the first monohydrate form characterized by: XRPD reflections at 4.36, 8.73, 11.18, 11.81, 12.78 and 13.11(° 2 θ), and are further characterized by fig. 2.
Herein, the MH2 form of L-lactate represents the second monohydrate form characterized by: XRPD reflections at 5.33, 9.75, 10.10, 14.44 and 14.63(° 2 θ), and is further characterized by fig. 3.
Herein, the alpha form of DL-lactate represents the first polymorph characterized by: XRPD reflections at 6.67, 8.33, 9.44, 11.82 and 15.35(° 2 θ), and further characterized by fig. 4.
Herein, the β form of DL-lactate represents a second polymorph characterized by: XRPD reflections at 6.01, 10.10, 10.32, 12.06, 12.84, 13.08 and 13.58(° 2 θ), and further characterized by fig. 5.
Herein, MH form of DL-lactate represents the monohydrate form, characterized by: XRPD reflections at 4.37, 8.73, 11.14, 11.78, 12.75 and 13.11(° 2 θ), and further characterized by fig. 6.
Herein, the gamma form of DL-lactate represents a third polymorph characterized by: XRPD reflections at 4.63, 10.94, 11.65 and 13.93(° 2 θ), and further characterized by fig. 7.
Lactic acid is also known as 2-hydroxypropionic acid and forms a 1:1 acid addition salt with 1- [2- (2, 4-dimethylphenylsulfanyl) phenyl ] piperazine used in the present invention.
1- [2- (2, 4-dimethylphenylsulfanyl) phenyl ] piperazine may be prepared according to the procedures disclosed in WO 03/029232 and WO 2007/144005. The examples disclose specific routes to obtain the salts of the invention. Briefly, the L-lactate AH1 and DL-lactate α forms can be prepared as follows: l-lactic acid or DL-lactic acid is added to 1- [2- (2, 4-dimethylphenylsulfanyl) phenyl ] piperazine, respectively, in a suitable anhydrous organic solvent, such as ethyl acetate, and vice versa, followed by precipitation, which may be formed, for example, by cooling, removal of the solvent, addition of another anhydrous solvent, or a combination thereof.
L-lactate MH1 can be formed directly as follows: the L-lactate AH1 was exposed to elevated relative humidity. L-lactate MH2 is the more stable form of L-lactate monohydrate and was formed as follows: 1 mL of water was added to 100 mg of L-lactate MH 1. The water solubility of L-lactate MH2 was 26 mg/mL. The DL-lactate β form is obtained from an aqueous slurry of the DL-lactate α form. The β form is a more stable polymorphic variant of DL-lactate and has a solubility of 8 mg/mL. DL-lactate MH was obtained as follows: the DL-lactate alpha form is exposed to high relative humidity. The DL-lactate γ form was obtained by heating DL-lactate MH 1. Throughout this document (unless stated otherwise), an indication of the concentration of a salt of the invention, for example 5 mg/ml, means a concentration equivalent to that expressed by the amount of free base specified, for example 5 mg/ml.
The present inventors have noted that the presence of lactic acid in the formulation of the present invention improves the solubility of the salt of the present invention. The presence of lactic acid, whether in the form of D-, L-or DL-lactic acid, may increase the solubility of the salts of the invention to 20-25 mg/mL.
Only salts of L-lactic acid and DL-lactic acid were prepared; however, 1- [2- (2, 4-dimethylphenylsulfanyl) phenyl ] piperazine is not chiral and the L-lactate and D-lactate are enantiomers, so that the D-lactate is present (in mirror image form) in the same crystalline form with the same XRPD pattern, melting point and solubility as the L-lactate. The X-ray powder diffraction (XRPD) of the various forms of L-lactate and DL-lactate are depicted in FIGS. 1-7.
The liquid formulations may be for oral or parenteral administration. Parenteral administration liquid formulations, including infusion solutions, are similar in many respects to other liquid formulations, but are otherwise characterized by sterility and isotonicity.
The liquid oral preparations of the present invention may be provided in the form of syrups, elixirs, oral solutions, suspensions or concentrated oral preparations. One advantage of these administration forms is that the patient does not have to swallow the solid form, which can be difficult especially for elderly and pediatric patients or patients with oral or throat impairments.
Syrups and elixirs are typically sweetened, flavored liquids containing the active pharmaceutical ingredient. Syrups typically have a higher sugar content, and elixirs often contain alcohol. Oral solutions are solutions of the active ingredient. Suspensions are two-phase systems comprising solid particles dispersed in a liquid. Administration of syrups, elixirs, oral solutions and suspensions typically involves the ingestion of a relatively large quantity of liquid, i.e. 10-50 mL.
In contrast, the concentrated oral formulations of the present invention can be administered to a patient by metering a pre-measured volume of the formulation from a suitable dispenser and adding the resulting volume to a glass containing a liquid (water, juice or the like) with which the patient drinks. For convenience, a small volume is measured, for example less than 2 mL, for example less than 1 mL, for example less than 0.5 mL. As an example of such a product, the United kingdom Regulatory authorities (MHRA) have approved a concentrated oral formulation containing 40 mg/ml of the antidepressant citalopram.
In one embodiment, the concentrated oral formulation of the invention may be administered to a patient by metering a predetermined number of drops of said formulation from a suitable dispenser, e.g. a container containing a drop collector (aggregate), and adding the drops to a glass containing a liquid (water, juice or the like) with which the patient drinks. In this context, a drop collector (aggregate) is a container-mounted collector (aggregate) that enables liquid within the container to be dispensed from the container in the form of discrete droplets.
Preliminary results have shown that the concentrated oral formulations of the present invention tend to be unstable when exposed to light. To overcome this potential problem, the formulation may be stored in a dark place, for example, in an opaque container, or in a container that is protected from light by a box.
In an oral concentrate formulation, the concentration of the salt of the invention is determined by the number (or volume) of droplets desired to be collected, and the amount of salt desired to be administered. Measuring about 5-20 droplets is generally considered to be the best compromise between therapeutic safety/efficacy on the one hand and convenience on the other. If the concentration of the salts of the invention is too high, i.e. if only small droplets are intended to be measured out, the safety or effectiveness of the treatment may be compromised. Because of the small number of drops, one or two drops more or less than the target number, the uncertainty in the delivered dose will be significantly increased. On the other hand, if the concentration of the salt of the present invention is too low, the number of drops to be measured is high, which is too troublesome for the patient or the manager.
For a daily dose of 2.5 mg, a concentrated oral formulation with an active ingredient concentration of 2.5 mg/mL may be suitable. A concentration of 2.5 mg/mL and a number of droplets of 20 droplets/mL, 20 droplets may be administered for a dose of 2.5 mg.
For a daily dose of 2.5 mg, a concentrated oral formulation with an active ingredient concentration of 5 mg/mL may be suitable. A concentration of 5 mg/mL and a number of droplets of 20 droplets/mL, for a dose of 2.5 mg, 10 droplets may be administered.
For a daily dose of 2.5 mg, a concentrated oral formulation with a concentration of 10 mg/mL of active ingredient may be suitable. A concentration of 10 mg/mL and a number of droplets of 20 droplets/mL, 5 droplets may be administered for a dose of 2.5 mg.
For a daily dose of 5 mg, a concentrated oral formulation with a concentration of 5 mg/mL of active ingredient may be suitable. A concentration of 5 mg/mL and a number of droplets of 20 droplets/mL, 20 droplets may be administered for a dose of 5 mg.
For a daily dose of 5 mg, a concentrated oral formulation with a concentration of 10 mg/mL of active ingredient may be suitable. A concentration of 10 mg/mL and a number of droplets of 20 droplets/mL, for a dose of 5 mg, 10 droplets may be administered.
For a daily dose of 5 mg, a concentrated oral formulation with an active ingredient concentration of 20 mg/mL may be suitable. A concentration of 20 mg/mL and a number of droplets of 20 droplets/mL, for a dose of 5 mg, 5 droplets may be administered.
For a daily dose of 10 mg, a concentrated oral formulation with a concentration of 10 mg/mL of active ingredient may be suitable. A concentration of 10 mg/mL and a number of droplets of 20 droplets/mL, 20 droplets may be administered for a dose of 10 mg.
For a daily dose of 10 mg, a concentrated oral formulation with an active ingredient concentration of 20 mg/mL may be suitable. A concentration of 20 mg/mL and a number of droplets of 20 droplets/mL, for a dose of 10 mg, 10 droplets may be administered.
For a daily dose of 20 mg, a concentrated oral formulation with an active ingredient concentration of 20 mg/mL may be suitable. A concentration of 20 mg/mL and a number of droplets of 20 droplets/mL, 20 droplets may be administered for a dose of 20 mg.
Thus, in one embodiment, the concentrated oral formulation of the invention comprises about 2.5-20 mg/mL of the salt of the invention. Specific examples include about 5-20 mg/mL, about 5-15 mg/mL, about 5-10 mg/mL and about 2.5, 5, 7.5, 10, 15 or 20 mg/mL.
In one embodiment, the concentrated oral formulation of the invention comprises at least 2.5 mg/mL of the salt of the invention.
In one embodiment, the concentrated oral formulation of the invention comprises at least 5 mg/mL of the salt of the invention.
In one embodiment, the concentrated oral formulation of the invention comprises at least 10 mg/mL of the salt of the invention.
In one embodiment, the concentrated oral formulation of the invention comprises at least 20 mg/mL of the salt of the invention.
In addition to the salts of the present application, the oral formulations of the present application, particularly concentrated oral formulations, may contain solvents, buffers, surfactants, surface tension modifiers, viscosity modifiers, preservatives, antioxidants, coloring agents, taste masking agents, flavoring agents, and the like.
Examples of solvents include water and other solvents that are miscible with water or solubilizing agents and suitable for oral purposes. Examples of suitable solvents are ethanol, propylene glycol, glycerol, polyethylene glycol, poloxamers, sorbitol and benzyl alcohol. The water solubility of the active ingredient may be further enhanced by the addition of a pharmaceutically acceptable co-solvent, cyclodextrin or derivative thereof to the solution.
The buffer system may be used to maintain the pH of the formulation in an optimal pH range. The buffer system is a mixture of a suitable amount of a weak acid, such as acetic acid, phosphoric acid, succinic acid, tartaric acid, lactic acid or citric acid, and conjugate bases thereof. Ideally, the buffer system has sufficient capacity to remain within the target pH range when diluted with a neutral, slightly acidic or slightly basic beverage.
Surfactants are substances that solubilize active compounds, which are not sufficiently soluble in aqueous media, usually to form micelles. Preferably, the surfactant used should be non-ionic (due to less toxicity). High concentrations of surfactant may be used to allow dilution during administration without precipitation. Examples of surfactants include tweens (tweens), spans (spans), and mono-and diglycerides.
Surface tension modifiers may be included to adjust the number of droplets of the concentrated oral formulation. An example of a surface tension modifier is ethanol, which can reduce surface tension and increase the number of droplets.
Viscosity modifiers may be included to adjust the droplet rate of the concentrated oral formulation. The drop rate of the formulation in the form of discrete droplets metered from a container equipped with a droplet collector (aggregate) should preferably not exceed 2 drops per second. Examples of viscosity modifiers include ethanol, hydroxyethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene glycol and glycerol.
Preservatives may be added to prevent the growth of microorganisms (e.g., bacteria, yeast and fungi) in the liquid formulation, which may require repeated use. Suitable preservatives should be pharmaceutically acceptable, physicochemically stable and effective at the target pH range. Examples of preservatives include ethanol, benzoic acid, sorbic acid, methyl paraben, propyl paraben and benzyl alcohol.
In dissolved form, drugs are typically more susceptible to chemical degradation than solid forms; it is therefore desirable to include an antioxidant in the liquid formulation. Examples of antioxidants include propyl gallate, ascorbyl palmitate, ascorbic acid, sodium sulfite, citric acid and EDTA.
In some formulations, a colorant may be used so that the product has a uniform appearance. Some active ingredients may further be sensitive to light, and it may prove necessary to add colorants to the droplet formulation in order to protect it from light and for stability purposes. Suitable colorants include, for example, tartrazine and sunset yellow.
Sweeteners may mask the unpleasant taste associated with some formulations or impart a target taste. Examples of sweetening agents are saccharin, the sodium salt of saccharin, dextrose, sorbitol, glycerol, acesulfame potassium and neohesperidin dihydrochalcone. The taste can be further optimized by the addition of one or more flavoring agents. Suitable flavouring agents are fruit flavours such as cherry, raspberry, red currant, lemon or strawberry flavour, or other flavours such as licorice (liquuorish), anise, peppermint, caramel and the like. Specific examples of concentrated oral formulations of the lactic acid addition salt of compound I that can be administered using a drop collector (aggregate) are the following. Further examples are provided in the examples section. The active compound is the DL-lactate, L-lactate or D-lactate of compound I. 1% of compound I in free base form corresponds to 1.3% of active compound. 2% of compound I in free base form corresponds to 2.6% of active compound. These examples are intended to illustrate the invention and should not be construed as limiting.
0.33% active compound
0.08% of methylparaben
0.02% propyl p-hydroxybenzoate
0.2% hydroxyethyl cellulose
Adding water to 100%
0.65% active compound
5% hydroxypropyl beta-cyclodextrin
0.02% propyl gallate
0.2% sorbinsyre
Adding water to 100%
1.3% active Compound
0.1% hydroxyethyl cellulose
Adding water to 100%
2.6% active Compound
10% hydroxypropyl beta-cyclodextrin
Water is added to 100%.
The pharmacological profile of compound I is disclosed in WO 03/029232, WO 2007/144005 and WO 2008/113359. Briefly, Compound I is an inhibitor of the serotonin transporter, 5-HT3Antagonists of receptors and 5-HT1AAgonists of the receptor. Compound I causes an increase in extracellular levels of serotonin, norepinephrine, dopamine and acetylcholine in the rat brain [ Moore et al,Eur. Neuropsychopharmacol., 18, suppl 4, s321, 2008]. The' 359 application also discloses the results of a clinical trial of depressed patients using the corresponding HBr addition salt, showingUnexpectedly low levels of sleep and sexually related adverse conditions.
Based on this background, the salts of the present invention are expected to be effective in the treatment of mood disorders, for example, major depressive disorder, generalized anxiety disorder, panic disorder, post traumatic stress disorder and anxiety-related depression, i.e., co-existing depression and anxiety disorders. The effect on extracellular acetylcholine levels is expected to translate into an effect on cognitive ability, see: use of an inhibitor of acetylcholinesterase in the treatment of alzheimer's disease. Thus, the salts of the present invention may also be used to treat depression associated with cognitive impairment and alzheimer's disease.
A subset of patients with major depressive disorders may respond to treatment with, for example, a selective serotonin transport inhibitor, but still maintain other symptoms, such as cognitive and/or sleep symptoms, in the sense of improving clinically relevant scales (e.g., HAMD or MADRS). These patients are referred to herein as depression with residual symptoms. It is expected that the salts of the present invention will be effective in treating such patients.
The preclinical data provided, for example, in WO 2008/113359, support the notion that compound I may be used to treat pain. In one embodiment, the pain is chronic pain or pain associated with chronic pain, the chronic pain comprising: artificial limb pain, neuropathic pain, diabetic neuropathy, post-herpetic neuralgia (PHN), Carpal Tunnel Syndrome (CTS), HIV neuropathy, complex regional pain syndrome (CPRS), trigeminal neuralgia, surgical interventions (e.g., post-operative analgesia), diabetic vasculopathy, capillary resistance, diabetic symptoms associated with insulitis, pain associated with menstruation, pain associated with cancer, dental pain, headache, migraine, tension-type headache, trigeminal neuralgia, Korston's syndrome, myofascial pain, myofibrillary injury, fibromyalgia syndrome, skeletal and joint pain (osteoarthritis), rheumatoid arthritis and edema due to injury associated with burning, sprain or fracture pain due to osteoarthritis, osteoporosis, skeletal metastasis or unknown reasons, gout, fibrositis, myofascial pain, thoracic outlet syndrome, upper or lower back pain (where back pain is caused by systemic, regional, or primary spine disease (radiculopathy)), pelvic pain, cardiac chest pain, non-cardiac chest pain, Spinal Cord Injury (SCI) -related pain, central post-stroke pain, cancer neuropathy, AIDS pain, sickle cell pain, or geriatric pain. In one embodiment, the pain is Irritable Bowel Syndrome (IBS).
Based on the pharmacological profile, it is also contemplated that the salts of the invention may be useful in the treatment of eating disorders, such as obesity, binge eating, anorexia and binge eating disorders, and substance abuse, such as alcohol, nicotine and drug abuse.
Thus, in one embodiment, the invention relates to a method of treating a disease selected from the group consisting of: mood disorders; major depressive disorder; generalized anxiety disorder; panic disorder; post traumatic stress disorder; depression associated with cognitive impairment, alzheimer's disease or anxiety; melancholia with residual symptoms; chronic pain; an eating disorder or phenomenon of abuse, the method comprising: administering to a patient in need thereof a therapeutically effective amount of a liquid formulation of the invention.
Due to the extremely low levels of adverse conditions observed during treatment with 1- [2- (2, 4-dimethylphenylsulfanyl) phenyl ] piperazine, the liquid formulation of the present invention may also be used as a second-line treatment for patients who cannot use other drugs (due to sleep or sex-related adverse conditions), such as other antidepressants, e.g., Selective Serotonin Reuptake Inhibitors (SSRIs), selective Norepinephrine Reuptake Inhibitors (NRIs), norepinephrine/serotonin reuptake inhibitors (SNRIs) or Tricyclic Compounds (TCAs). In this embodiment, the patient to be treated has received another drug (or is still receiving), and such a drug is stopped or reduced (or must be stopped or reduced) due to sleep or sex-related adverse conditions. In one embodiment, the liquid formulation is a concentrated oral formulation.
In one embodiment, the patient to be treated has been diagnosed with the disease being treated by the patient.
Typical oral dosages are in the range of about 0.01 to about 5 mg/kg body weight per day, preferably about 0.01 to about 1 mg/kg body weight per day, and are administered in one or more doses, e.g., 1 to 3 doses. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the patient being treated, the nature and severity of the condition being treated and any concomitant diseases to be treated and other factors known to those skilled in the art.
Typical oral dosages for adults are in the range of 0.5-50 mg per day of the salts of the invention, e.g. 1-10 mg per day. This may typically be achieved by administering 0.5-50 mg of a salt of the invention, e.g. 0.5, 1, 2.5, 5, 10, 15, 20, 25, 30 or 40 mg of a salt of the invention, once or twice daily. In the case of pediatric treatment, the dosage may be reduced according to age and/or body weight.
As used herein, a "therapeutically effective amount" of a compound refers to an amount sufficient to cure, alleviate or partially inhibit the clinical manifestations of a given disease and its complications in a therapeutic intervention involving the administration of the compound. An amount sufficient to achieve this goal is defined as a "therapeutically effective amount". The term also includes: an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications in a treatment comprising administration of the compound. The effective amount for each purpose will depend on the severity of the disease or injury and the weight and general state of the patient. It will be appreciated that the appropriate dosage can be determined using routine experimentation, by constructing a valuable model (matrix) and testing different points in the model (matrix), all within the routine skill of a trained physician.
The terms "treatment" and "treating" as used herein refer to the management and care of a patient for the purpose of combating a condition (e.g., a disease or disorder). The term includes the full spectrum of treatments for a given condition from which a patient is suffering, for example, administration of active compounds in order to alleviate symptoms or complications, delay the progression of a disease, disorder, or condition, alleviate or eliminate symptoms and complications, and/or cure or eliminate a disease, disorder, or condition, as well as prevent a condition, wherein prevention is to be understood as: management and care of the patient for the purpose of combating the disease, condition or disorder, and comprises administering the active compound so as to prevent the onset of symptoms or complications. Nevertheless, prophylactic (prevention) and therapeutic (treatment) treatment are two separate aspects of the invention. Preferably, the patient to be treated is a mammal, especially a human.
In one embodiment, the present invention relates to the use of a salt of the invention for the preparation of a liquid formulation for the treatment of a disease selected from the group consisting of: mood disorders; major depressive disorder; generalized anxiety disorder; panic disorder; post traumatic stress disorder; depression associated with cognitive deficits, alzheimer's disease, or anxiety; melancholia with residual symptoms; chronic pain; eating disorders or abuse phenomena.
In one embodiment, the salt is selected from the beta form of DL-lactate and the MH2 form of L-lactate.
In one embodiment, the liquid formulation is a concentrated oral formulation.
In one embodiment, the present invention relates to a salt of the invention for use in the treatment of a disease selected from the group consisting of: mood disorders; major depressive disorder; generalized anxiety disorder; panic disorder; post traumatic stress disorder; depression associated with cognitive deficits, alzheimer's disease, or anxiety; melancholia with residual symptoms; chronic pain; eating disorders or abuse phenomena, wherein said salt is in the form of a liquid formulation.
In one embodiment, the salt is selected from DL-lactate and L-lactate.
In one embodiment, the liquid formulation is a concentrated oral formulation.
In one embodiment, the present invention relates to a liquid formulation comprising a salt of 1- [2- (2, 4-dimethylphenylsulfanyl) phenyl ] piperazine selected from the DL-lactic acid addition salt, the L-lactic acid addition salt and/or the D-lactic acid addition salt. In particular, the liquid formulation is a concentrated oral formulation.
In one embodiment, the present invention relates to compounds which are the L-lactic acid addition salts of 1- [2- (2, 4-dimethylphenylsulfanyl) phenyl ] piperazine. Of particular mention are the MH2 form.
In one embodiment, the invention relates to a compound which is an L-lactic acid addition salt of 1- [2- (2, 4-dimethylphenylsulfanyl) phenyl ] piperazine with XRPD reflections at about 5.33, 9.75, 10.10, 14.44 and 14.63(° 2 Θ), e.g. with the XRPD pattern depicted in figure 3.
In one embodiment, the present invention relates to compounds which are the D-lactic acid addition salts of 1- [2- (2, 4-dimethylphenylsulfanyl) phenyl ] piperazine.
In one embodiment, the invention relates to a compound which is the β form of the DL-lactic acid addition salt, having XRPD reflections at about 6.01, 10.10, 10.32, 12.06, 12.84, 13.08, 13.58(° 2 Θ), e.g. having the XRPD pattern depicted in figure 5.
The salts of the present invention may be administered alone or in combination with other therapeutically active compounds, wherein both compounds may be administered simultaneously or sequentially. Examples of therapeutically active compounds which may advantageously be combined with the salts of the present invention include: sedatives or hypnotics, e.g. benzodiazepines(ii) a Anticonvulsants such as lenoda, valproic acid, topiramate, gabapentin, carbamazepine; mood stabilizers such as lithium; dopaminergic agents, such as dopamine agonists and L-Dopa; medicaments for treating ADHD, such as atomoxetine (atomoxetine); psychostimulants such as modafinil (modafinil), ketamine, ritalin and amphetamine; other antidepressants, e.g. mirtazapine (mirtazapine), mianserin andbupropion (buproprion); hormones, such as T3, estrogen, DHEA and testosterone; atypical antipsychotics, such as olanzapine and aripiprazole; typical antipsychotics, such as haloperidol; drugs for the treatment of alzheimer's disease, such as cholinesterase inhibitors and Memantine (Memantine), folic acid; s-adenosylmethionine; immunomodulators, such as interferon; opiates, such as buprenorphine (buprenorphine); angiotensin II receptor 1 antagonists (AT1 antagonists); an ACE inhibitor; statins (statins); and alpha1 adrenergic antagonists, such as prazosin.
All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference in their entirety and to the same extent as if each reference were individually indicated to be incorporated by reference and were specifically indicated to be incorporated by reference and were set forth in its entirety herein (to the maximum extent permitted by applicable law), regardless of the incorporation of individual documents by separate provision made elsewhere herein.
The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention, are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. For example, the phrase "the compound" will be understood to refer to various "compounds" of the invention or the specifically described aspects, unless otherwise stated.
Unless otherwise indicated, all exact values provided herein are representative of corresponding approximate values (e.g., all exact exemplary values provided for a particular factor or assay can be considered to also provide a corresponding approximate measure, modified by "about," if appropriate).
The description of any aspect or aspect of the invention herein uses terms such as "comprising," "having," "including," or "containing" an element or elements for the purpose of providing support for similar aspects or aspects of the invention that "consist of," "consist essentially of," or "consist essentially of" the element or elements, unless otherwise stated or clearly contradicted by context (e.g., a composition described herein as comprising a particular element should be understood as also describing a composition consisting of that element unless otherwise stated or clearly contradicted by context).
Examples
Analysis of
X-ray powder diffraction (XRPD) using CuKa1Radiation, measured on a PANalytical X' Pert PRO X-ray diffractometer. Samples were measured in reflection mode in the 2 theta range at 5-40 deg.C using an X' celerator detector. Throughout this document, diffraction data are indicated at ± 0.1(° 2 θ).
EXAMPLE 1.1- [2- (2, 4-dimethyl-phenylsulfanyl) -phenyl]AH1 form of piperazine, L-lactate
1- [2- (2, 4-dimethyl-phenylsulfanyl) -phenyl ] -piperazine base (5.00 g) was dissolved in ethyl acetate (50 mL) at 50 ℃. The solution was somewhat cloudy and filtered through a paper filter. L- (+) -lactic acid (1.84 g) was added to the solution, and stirred at room temperature. Precipitation began, the suspension was stirred at room temperature for two hours, and the product was isolated by filtration. The solid was dried in a vacuum oven at 40 ℃ overnight. The water solubility of AH1 cannot be determined because when this material comes into contact with water, it transforms into a monohydrate.
Example 2.1- [2- (2, 4-dimethyl-phenylsulfanyl) -phenyl]MH1 form of piperazine, L-lactate
100 mg of the AH1 form of 1- [2- (2, 4-dimethyl-phenylsulfanyl) -phenyl ] piperazine, L-lactate of example 1 were placed in an open container under ambient conditions (22 ℃, 30% RH). The solubility of MH1 could not be determined because the compound was converted to MH2 in an aqueous slurry.
Example 3.1- [2- (2, 4-dimethyl-phenylsulfanyl) -phenyl]MH2 form of piperazine, L-lactate
To 100 mg of 1- [2- (2, 4-dimethyl-phenylsulfanyl) -phenyl ] piperazine of example 2 in the form of MH1 of L-lactate was added 1 mL of water and the mixture was left overnight. The precipitate (MH 2-form) was filtered.
Example 4.1- [2- (2, 4-dimethyl-phenylsulfanyl) -phenyl]Alpha form of piperazine, DL-lactate
1- [2- (2, 4-dimethyl-phenylsulfanyl) -phenyl ] -piperazine base (5.00 g) was dissolved in ethyl acetate (50 mL) at 50 ℃. The solution was somewhat cloudy and filtered through a paper filter, which became clear. DL-lactic acid (1.68 g) was added to the solution, and stirred at room temperature. Precipitation started after two hours. The suspension was stirred at room temperature for two hours and the product isolated by filtration. The solid was dried in a vacuum oven at 40 ℃ overnight. The solubility of the alpha form in water cannot be determined because the compound is converted to the beta form in an aqueous slurry.
Example 5.1- [2- (2, 4-dimethyl-phenylsulfanyl) -phenyl]Beta form of piperazine, DL-lactate
To 100 mg of the alpha form of 1- [2- (2, 4-dimethyl-phenylsulfanyl) -phenyl ] piperazine, DL-lactate from example 5, 1 mL of water was added and the mixture was left overnight. The precipitate (. beta. -form) was filtered.
Example 6.1- [2- (2, 4-dimethyl-phenylsulfanyl) -phenyl]MH form of piperazine, DL-lactate
10 mg of the alpha form of 1- [2- (2, 4-dimethyl-phenylsulfanyl) -phenyl ] piperazine, DL-lactate from example 5 were contacted with high relative humidity (25 ℃, 95% RH) for 4 hours. The solubility of MH in water cannot be determined because it is converted to the beta form in the aqueous slurry.
Example 7.1- [2- (2, 4-dimethyl-phenylsulfanyl) -benzeneBase of]Gamma forms of piperazine, DL-lactate
10 mg of the MH form of 1- [2- (2, 4-dimethyl-phenylsulfanyl) -phenyl ] piperazine, DL-lactate from example 7 were heated to 50 ℃. The water solubility of the gamma form cannot be determined because it is converted to the beta form in an aqueous slurry.
Example 8.1- [2- (2, 4-dimethyl-phenylsulfanyl) -phenyl]Beta form of piperazine, DL-lactate
200 g of 1- [2- (2, 4-dimethyl-phenylsulfanyl) -phenyl ] piperazine, HBr (526 mmol) in Me-THF (3.5L) were stirred and 1M NaOH (1L) was added. The suspension was stirred for 15 minutes, after which all the solid dissolved. The phases were separated and the Me-THF phase was reduced to half the volume after blank filtration. After cooling to room temperature, DL-lactic acid (1.5 eq. to 789 mmol) was added and the solution seeded with 0.5% beta. After 5 minutes, precipitation started and the suspension was stirred at ambient temperature overnight. The suspension was then cooled on ice, filtered, and washed with 200 mL Me-THF, dried overnight under vacuum at 50 ℃.
TABLE 1 summary of selected reflectance, melting point and room temperature solubility for XRPD patterns of various forms of 1- [2- (2, 4-dimethyl-phenylsulfanyl) -phenyl ] piperazine, lactate
na = unsuitable.
TABLE 2 Room temperature solubility of previously known salt forms of 1- [2- (2, 4-dimethyl-phenylsulfanyl) -phenyl ] piperazine
Example 9.1- [2- (2, 4-Dimethylphenylthio) phenyl]Synthesis of piperazine D, L-lactate
50 g (132 mmol) of HBr salt are suspended in 800 mL of toluene and 250 mL (250 mmol; 1.9 eq) of 1M aqueous NaOH are added. The biphasic mixture was heated to 65 ℃ until all solids dissolved and then cooled to room temperature. The phases were separated and the organic phase was evaporated in vacuo to give a slightly yellow solid. 125 mL of ethanol and 20 mL (269 mmol; 2.0 eq) of DL-lactic acid (90%) were added and the suspension was heated until all the solid dissolved and then cooled to room temperature. The solution was seeded with a little crystals of the beta form of 1- [2- (2, 4-dimethylphenylsulfanyl) phenyl ] piperazine D, L-lactate and the suspension was stirred at room temperature overnight and subsequently cooled with an ice bath. The precipitate was filtered, washed with ethanol and dried in a vacuum oven to give 36.5 g of 1- [2- (2, 4-dimethylphenylsulfanyl) phenyl ] piperazine D, L-lactate β form (71% yield).
Example 10 concentrated oral formulations
The concentrated oral formulations shown below were prepared and stability tests were performed under the conditions shown. 25/60 for 25 ℃ and 60% RH, 40/75 for 40 ℃ and 75% RH, 60 for 60 ℃. The numbers indicate the amount of residual active compound after the test time.
The residual amount of 1- [2- (2, 4-dimethylphenylsulfanyl) phenyl ] piperazine in the oral droplet formulation was determined using gradient reverse phase HPLC. The mobile phase consisted of a mixture of water and acetonitrile (TFA added). At 226 nm, detection was by UV.
a)
1.3% active compound-1% free base
0.08% of methylparaben
0.02% propyl p-hydroxybenzoate
Adding water to 100%
b)
1.3% active compound-1% free base
5% hydroxypropyl beta-cyclodextrin
Adding water to 100%
c)
1.3% active compound-1% free base
0.1% hydroxyethyl cellulose
Adding water to 100%
d)
1.3% active compound-1% free base
1.1% L-lactic acid
0.1% hydroxyethyl cellulose
Adding water to 100%
e)
2.6% active compound-2% free base
10% hydroxypropyl beta-cyclodextrin
Adding water to 100%
。
f)
2.6% active compound-2% free base
10% hydroxypropyl beta-cyclodextrin
96% of 10% ethanol
Adding water to 100%
g)
2.6% active compound-2% free base
10% methyl beta-cyclodextrin
Adding water to 100%
h)
2.6% active compound-2% free base
10% methyl beta-cyclodextrin
96% of 10% ethanol
Adding water to 100%