39 results about "Cariprazine" patented technology

The present invention provides 1-hydroxy-2-naphthoate or pamoate of cariprazine, and / or its new solid forms, as well as its pharmaceutical compositions, preparation methods and uses. The salts and solid forms of cariprazine provided by the present invention, especially cariprazine 1-hydroxy-2-naphthoate among the poorly soluble salts of cariprazine, conform to the advantages of long-acting sustained-release preparations, can be developed into suspension injections, and at the same time can overcome the risks of dissociation of existing salt forms such as cariprazine hydrochloride or the problem of not having a sustained-release effect, can achieve the effect of long-term drug administration, and greatly improve the compliance of patients as well as the bioavailability and drug safety of the drug.

This invention belongs to the technical field of medicinal chemistry, specifically relating to a novel crystal form of cariprazine, specifically the cariprazine-4-hydroxybenzoic acid-methanol-hemihydrate crystal form and its preparation method. The novel cariprazine-fumaric acid crystal form provided by this invention comprises a basic unit of one molecule of cariprazine, one molecule of 4-hydroxybenzoic acid, one molecule of methanol, and 0.5 molecules of water. Its preparation method is simple to operate, the crystallization process is easy to control, and it has good reproducibility. The formation of a eutectic significantly enhances the solubility of cariprazine, exhibiting strong pharmaceutical value.

Provided are methods and compositions for enhancing radiotherapy in various cancers by administering dopamine receptor (DRD2)‐binding phenylpiperazine derivatives such as brexpiprazole, cariprazine, pipamperone, and perospirone. In vitro studies show that combining these agents with ionizing radiation (e.g., 5 Gy) significantly reduces cancer cell survival, suppresses metastatic and stemness markers (e.g., CD44, MMP‑2, Snail, Nanog), and promotes apoptosis. Fractionated or single‐fraction radiation regimens can be paired with DRD2 antagonists to lower treatment‐resistant phenotypes, decrease the likelihood of recurrence, and potentially reduce necessary radiation dosages. The approach applies to breast, prostate, lung, pancreatic, and brain cancers, among others. Depending on tumor characteristics, additional chemotherapeutic or immunotherapeutic agents may further improve outcomes.

A method for treating a mental disorder in a subject, comprising the step of normalizing the expression of both DRD1 and DRD5 belonging to the DRD1-like family of the subject to a preset standard level. The DRD1 / 5 level and expression can be increased or decreased bidirectionally by targeting the upstream promoter sequence of DRD1 / 5. The promoter activity of DRD1 / 5 can be attenuated by using antipsychotic drugs that directly target the DRD1 / 5 promoter. The antipsychotic drugs used are typical and / or atypical antipsychotic drugs such as haloperidol, risperidone, clozapine, and cariprazine. This treatment is also useful for subjects in whom the constitutive expression of the DRD1 / 5 gene is impaired. This method can be used to treat schizophrenia, autism, depression, mania, and bipolar disorder by normalizing the DRD1 / 5 expression level. The promoter gene sequencing of DRD1 and / or DRD5 can also be used for quantitative mental health screening by comparing with a standard sequence database.

The invention belongs to the technical field of medicines, and particularly relates to a cariprazine sustained-release microsphere preparation and a preparation method thereof. The preparation comprises an active component cariprazine base or a pharmaceutically acceptable salt thereof, a biocompatible polymer carrier material and an antioxidant. The obtained sustained-release microsphere preparation has the excellent characteristics of round shape, uniform and controllable particle size, high stability, low organic solvent residual quantity, high drug loading capacity and the like; and the sustained and slow release can be realized as long as 3 months in vivo, so that the requirement of long-term treatment is effectively met. In addition, the preparation method provided by the invention is simple in process and easy to operate, and has a good industrial large-scale production prospect.

The present invention provides a long-acting parenteral pharmaceutical composition comprising a therapeutically effective amount of cariprazine or a salt thereof in a depot form suitable for administration to a medically acceptable location in a subject in need thereof. The depot composition is preferably in the form of an in situ implant suitable for subcutaneous or intramuscular administration and provides sustained release of the cariprazine active ingredient and / or its metabolites desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR) for at least four weeks after a single administration. The present invention further provides methods of using the depot composition for the treatment of schizophrenia, major depressive disorder, and bipolar disorder.

The invention provides an oral soluble film containing cariprazine or pharmaceutically acceptable salts thereof and a preparation method of the oral soluble film. The prepared oral soluble film has excellent effects of taste masking, stability, dissolution and the like, is convenient to take, can effectively improve the compliance of schizophrenia patients, and avoids behaviors of medicine hiding, medicine vomiting and the like.

The object of the present invention is an improved process for the preparation of cariprazine of formula (I) comprising the conversion of an imino-piperazine intermediate to an amino-piperazine intermediate by reaction with formic acid.

The invention discloses a method for continuously preparing a key intermediate of cariprazine hydrochloride, which is based on a micro-channel modular reaction device, adopts a red aluminum toluene solution as a reducing agent, has the advantages of high reaction safety, mild conditions, high reaction speed, high product purity and no quenching flushing risk, and is suitable for industrial production.

The invention relates to the technical field of pharmaceutical co-crystals, and particularly discloses a cariprazine and quercetin pharmaceutical co-crystal and a preparation method and application thereof.The cariprazine and quercetin pharmaceutical co-crystal is prepared by mixing cariprazine and quercetin according to the proportion, adding a good solvent n-propyl alcohol till complete dissolution, dropwise adding a poor solvent into the mixed solvent till the mixed solvent is in a supersaturated state to obtain a mixed solution, and then adding the mixed solution into a reaction kettle to obtain the cariprazine and quercetin pharmaceutical co-crystal. And volatilizing the solvent in the mixed solution by adopting a solvent evaporation crystallization method, so that the cariprazine and the quercetin form intermolecular hydrogen-bond interaction, and the cariprazine and quercetin pharmaceutical co-crystal is obtained. A powder dissolution experiment result of the cariprazine and quercetin eutectic crystal shows that the dissolution rate of the cariprazine is reduced compared with the release rate of a free drug under a neutral condition, and a potential slow release effect is shown, so that the cariprazine and quercetin pharmaceutical eutectic crystal can be prepared into a muscle injection, and the clinical application prospect is broad. The traditional Chinese medicine composition has the potential of treating schizophrenia for a long time and reducing muscle stimulation.

The present application relates to the technical field of pharmaceutical cocrystal, and specifically discloses a callylazine and quercetin pharmaceutical cocrystal, a preparation method and application thereof, wherein callylazine and quercetin are mixed in proportion, a good solvent n-propanol is added until complete dissolution, a poor solvent is added drop by drop into the mixed solvent until a supersaturated state, a mixed solution is obtained, solvent in the mixed solution is volatilized by using a solvent evaporation crystallization method, intermolecular hydrogen bonding of callylazine and quercetin is formed, and a callylazine and quercetin pharmaceutical cocrystal is obtained. The powder dissolution experiment result of the callylazine and quercetin cocrystal shows that the dissolution rate of callylazine decreases under neutral conditions compared with the release rate of free drug, and potential sustained release effect is shown, so that the callylazine and quercetin pharmaceutical cocrystal can be prepared into a muscle injection, and has potential for long-acting treatment of schizophrenia and reduction of muscle stimulation.

The invention discloses a quantitative analysis method of potential genotoxic impurities in cariprazine hydrochloride, which adopts a liquid chromatography-mass spectrometry method, takes a 20mM ammonium acetate aqueous solution as a mobile phase A, takes acetonitrile as a mobile phase B, and adopts a reversed-phase liquid chromatographic column with octadecylsilane bonded silica gel filler as a filler for elution. According to the method, bis (2-chloroethyl) amine can be effectively eluted, separated and quantitatively analyzed, the quality of a cariprazine hydrochloride product can be better controlled, and a simple, convenient, accurate, rapid and reliable detection method is provided for industrial production.

The patent discloses long-term injectable formulations and delivery systems of cariprazine and related salts and derivatives in the prevention and treatment of various psychotic diseases, such as schizophrenia, mania, and bipolar disorder. The dosage forms are either microsphere, microparticle, nanoparticle drug delivery systems in a pharmaceutically acceptable carrier, or devices that contain long-term injectable formulation of such cariprazine and related salts and derivatives.

The present invention relates to a 1-hydroxy-2-naphthoate or pamoate salt of cariprazine, a new solid form thereof, and a pharmaceutical composition, preparation method and use thereof. The salt of cariprazine and the solid form thereof, particularly the cariprazine 1-hydroxy-2-naphthoate salt in the poorly soluble cariprazine salt, have the characteristics of a long-acting sustained-release preparation and can be developed into a suspension injection, while at the same time overcoming the problems of the conventional salt-type dissociation risk or lack of sustained release effect such as cariprazine hydrochloride, and can achieve the effect of long-acting administration, greatly improving the patient compliance and the bioavailability and administration safety of the drug.

According to the method for detecting the cariprazine hydrochloride intermediate and the related substances thereof, the sample solubility is high, the separation degree is good, the detection efficiency and the detection precision can be improved, and a method guarantee is provided for guaranteeing the medicine quality and the medication safety.

The object of the present invention is to provide an improved process for the preparation of cariprazine compounds of formula (1): which comprises the step of adding a base to a mixture comprising phosgene or a carbonate derivative and an aminopiperazine compound of formula (3) in salt form: to obtain an isocyanate compound of formula (2): and / or a compound of formula (11):

The present invention provides a method for preparing cariprazine microspheres, comprising the steps of: (a) preparing a dispersed phase by dissolving or dispersing cariprazine or a pharmaceutically acceptable salt thereof and at least one biocompatible polymer in a mixed solvent of methanol and dichloromethane, (b) adding the prepared dispersed phase to the continuous phase and stirring to form microspheres, and (c) removing the solvent; microspheres prepared by the method; and a pharmaceutical composition comprising the microspheres.

The present invention relates to a sustained release pharmaceutical composition in the form of a solution or suspension for use in the treatment of psychotic disorders comprising cariprazine, a biocompatible organic solvent and optionally additional excipients.

This invention provides a cariprazine orally disintegrating film composition, its preparation method, and its application. The orally disintegrating film composition comprises an active ingredient, a film-forming material, and a plasticizer, wherein the active ingredient is selected from one or more mixtures of cariprazine, pharmaceutically acceptable salts of cariprazine, and their inclusion compounds. The orally disintegrating film composition of this invention has the advantages of thin thickness, good taste, stable properties, immediate dissolution in the oral cavity without water, and rapid oral absorption. It also features a simple process, high drug loading capacity, and good drug content uniformity. The orally disintegrating film composition of this invention helps improve medication compliance, medication retention, and vomiting in patients with schizophrenia, and is particularly suitable for patients with swallowing difficulties, showing promising market prospects.

The invention belongs to the technical field of pharmaceutical preparations, and particularly discloses an anti-schizophrenia lyotropic liquid crystal long-acting injection and a preparation method and application thereof, and the anti-schizophrenia lyotropic liquid crystal long-acting injection is composed of an anti-schizophrenia drug, an amphiphilic compound and an organic solvent; the anti-schizophrenia medicine is selected from any one of brexpiprazole, cariprazine and aripiprazole; the amphiphilic compound is selected from any one or more of soybean phosphatidylcholine, egg yolk phosphatidylcholine, glyceryl monooleate, glyceryl monopalmitate, glyceryl dioleate, glyceryl trioleate, vitamin E acetate and phytantriol; the organic solvent is selected from one or more of ethanol, N-methyl pyrrolidone, dimethyl sulfoxide and 1, 2-propylene glycol. The anti-schizophrenia lyotropic liquid crystal in-situ gel long-acting injection forms a stable semi-solid drug reservoir through solvent exchange after administration so as to play a therapeutic effect in long-acting treatment of positive schizophrenia and negative schizophrenia and prevention of schizophrenia relapse.

The present invention provides long-acting parenteral pharmaceutical compositions comprising a therapeutically effective amount of Cariprazine or salts thereof, in a depot form suitable for administering at a medically acceptable location in a subject in need thereof. The depot compositions are preferably in the form of in situ implants suitable for subcutaneous or intramuscular administration and provide prolonged release of the Cariprazine active ingredient and / or its metabolites desmethyl Cariprazine (DCAR) and didesmethyl Cariprazine (DDCAR) for a period of at least 4 weeks following a single administration. The present invention further provides methods of use of the depot compositions for the treatment of schizophrenia, major depressive disorder, and bipolar disorder.

Disclosed herein is an injectable depot formulation and use thereof for treating a mental disorder. The injectable depot formulation comprises cariprazine free base particles and a pharmaceutically acceptable carrier. The cariprazine free base particles have a median particle size by volume (Dv50) ranging from 0.5 μm to 100 μm.

An orally disintegrating pharmaceutical tablet comprising: between 0.1 and 21 wt % of cariprazine or its pharmaceutically acceptable salts, between 0.1 and 15 wt % of a disintegrant, between 0.1 and 5 wt % of colloidal silicon dioxide, between 0.1 and 10 wt % of a taste masking agent, between 0.1 and 5 wt % of a lubricant, and up to 100 wt % of a diluent, the percentage being expressed with regard to the total weight of the pharmaceutical tablet. Said composition for use in the treatment and / or prevention of pathological conditions which require the modulation of dopamine receptors, selected from the group of psychoses, drug abuse, cognitive impairment accompanying schizophrenia, mild-to-moderate cognitive deficits, dementia, psychotic states associated with dementia, eating disorders, attention deficit disorders, hyperactivity disorders in children, psychotic depression, bipolar disorder, paranoid and delusional disorders, dyskinetic disorders, anxiety, sexual dysfunction, sleep disorders, emesis, aggression and autism.

A method of treatment of mental disorder of a subject includes the steps of: normalizing an expression of both DRD1 and DRD5, which belong to DRD1-like family, of the subject to a preset standard level. The DRD1 / 5 level and expression can be increased or decreased bidirectionally by targeting an upstream promoter sequence of DRD1 / 5. The promoter activity of DRD1 / 5 can be attenuated by using an antipsychotic which directly targets the DRD1 / 5 promoter. The antipsychotics being used are typical and / or atypical antipsychotic medications such as Haloperidol,Risperidone, Clozapine and Cariprazine. The treatment is also useful for the subject with an impaired constitutive expression of DRD1 / 5 gene. The method can be used to treat schizophrenia, autism, depression, mania and bipolar disorders by normalizing the DRD1 / 5 expression level. The promoter gene sequencing of DRD1 and / or DRD5 can also be used for quantitative mental health screening through comparing with a standard sequence database.

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a novel crystal form of cariprazine, in particular to a cariprazine-5-sulfosalicylic acid crystal form as well as a preparation method and application thereof. The novel crystal form of cariprazine-5-sulfosalicylic acid provided by the invention contains basic units of one molecule cariprazine and 5-sulfosalicylic acid, so that the stability, solubility and the like are greatly improved, and the preparation method is simple to operate, good in reproducibility and suitable for industrial production.

The invention discloses a preparation method of cariprazine, which comprises the following steps: reacting a compound shown as a formula III with a compound shown as a formula IV or hydrochloride thereof to obtain a compound shown as a formula II, and reducing the compound shown as the formula II to obtain a compound shown as a formula I (namely cariprazine). The preparation method disclosed by the invention is mild in reaction condition, simple and convenient in process, few in side reaction, high in yield and suitable for industrial production.

The present invention relates to an orally disintegrating pharmaceutical tablet comprising between 0.1 and 21% by weight of cariprazine or a pharmaceutically acceptable salt thereof, between 0.1 and 15% by weight of a disintegrating agent, between 0.1 and 5% by weight of colloidal silica, between 0.1 and 10% by weight of a taste masking agent, between 0.1 and 5% by weight of a lubricant, and up to 100% by weight of a diluent, the percentage being expressed relative to the total weight of the pharmaceutical tablet. The present invention relates to a composition for use in the treatment and / or prevention of pathological conditions requiring modulation of dopamine receptors, the composition is selected from the group consisting of psychosis, drug abuse, cognitive impairment associated with schizophrenia, mild to moderate cognitive deficits, dementia, psychotic states associated with dementia, eating disorders, attention deficit disorders, hyperactivity disorders in children, psychotic depression, bipolar disorders, paranotic and delusional disorders, dyskinesia, anxiety, sexual dysfunction, sleep disorders, vomiting, or the like. And attacking behaviors and autism.

To provide a compound for use in the treatment of general symptoms of autism spectrum disorder.SOLUTION: Provided are trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N',N'-dimethylurea (cariprazine), its salts, close analogs, derivatives, pharmaceutical compositions, metabolites, and combinations for treating one or more symptoms of autism. These are also suitable for the treatment of conditions such as Asperger's syndrome, atypical autism (otherwise known as pervasive developmental disorder not otherwise specified; PDD-NOS), Rett syndrome, childhood disintegrative disorder, attention deficit hyperactivity disorder (ADHD), and sensory integration dysfunction.SELECTED DRAWING: None