pharmaceutical compositions comprising sorbitan esters and use thereof

专利摘要:
"PHARMACEUTICAL COMPOSITIONS UNDERSTANDING SORBITAN ESTERS". The present invention relates to a pharmaceutical composition comprising sorbitan esters of carboxylic acids that are useful for the application of antipsychotic drugs.
公开号:BR112013023847B1
申请号:R112013023847-0
申请日:2012-03-19
公开日:2021-02-23
发明作者:B. Hickey Magali；M. Perry Jason；Daniel R. Deaver；Julius F. Remenar；Jennifer VANDIVER
申请人:Alkermes Pharma Ireland Limited；
IPC主号:

专利说明:

RELATED ORDER
[001] This application claims the priority of Provisional Application No. US 61 / 454,008, Legal Registration No. 513352, entitled "Formulations Having Improved Site Reactions", filed on March 18, 2011. The contents of any patents, applications for patent, and references cited throughout this specification are hereby incorporated by reference in their entirety. TECHNICAL FIELD
[002] The present invention relates to an injectable pharmaceutical composition comprising sorbitan esters of carboxylic acids that are useful for the application of antipsychotic drugs. BACKGROUND OF THE INVENTION
[003] The patent Nos. US 4,734,416 and 5,006,528 describes aripi-prazole, 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -3,4-dihydro-2 (1H) - quinolinone or 7- {4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy} -3,4-dihydro-carbostyryl, as an atypical antipsychotic agent useful in the treatment of schizophrenia, bipolar disorder, depression and others CNS disorders. Aripiprazole has the following chemical structure:

[004] Aripiprazole is sold under the brand name Abilify®. This acts as a partial dopamine D2 agonist, 5-HT1A serotonin receptor agonist and is a 5-HT2A serotonin receptor antagonist. Abilify® is currently administered orally in a daily dosing program such as Abilify® Tablets (aripiprazole), Abilify Discmelt® Oral Disintegration Tablets (aripiprazole) and Abilify® Oral Solution (aripiprazole). In one embodiment, the Abilify® Injection for intramuscular use is a fast-acting solution product to treat agitation associated with schizophrenia and bipolar disorder. Unsatisfactory and variable patient adherence to a daily psychiatric drug dosing program has been reported.
[005] Efforts have been made to provide drug dosage forms that can increase patient compliance and then reduce the rate of relapse in the treatment of schizophrenia. U.S. Patent No. 7,807,680 and U.S. No. Publication 2005/0032811 describe sterile injectable formulations of long-acting aripiprazole. Studies on aripiprazole-free injections have shown a prolonged pharmacokinetic profile, but occurrences of unacceptable (moderate to severe) tissue irritation after IM and SC injection have also been reported.
[006] U.S. Patent No. 7,115,587 describes an injectable formulation that releases a solution of aripiprazole complexed with a substituted β-cyclodextrin at the muscle site with reduced irritation as compared to injectable suspensions containing non-complexed aripiprazole. The injection of Abilify® for intramuscular use is a single dose, ready-to-use vial consisting of 9.75 mg / 1.3 ml of aripiprazole and 150 mg / ml of sulfobutylether β-cyclodextrin. Formulation challenges due to drug loading and unsatisfactory solubility of aripiprazole in β-cyclodextrin at neutral pH have been reported.
[007] Olanzapine (1,2-methyl-4- (4-methyl-1-piperazinyl) -10H- thieno [2,3-b] [1,5] benzodiazepine) is a second generation antipiscotic drug sold as Zyprexa ®. It is useful to treat disorders such as schizophrenia, bipolar disorder, psychotic depression and Tourette's syndrome. This active pharmaceutical ingredient acts as an antagonist on 5-HT2 serotonin receptors as well as dopamine D1 / D2 receptors, while also exhibiting anticholinergic and antimuscarinic properties. Olanzapine belongs to the benzodiazepine family, and has the following structure:

[008] This compound is described, for example, in U.S. Patent Nos. 5,229,382 and 6,169,084. A prolonged-release intramuscular injection product that contains the water-insoluble olanzapine pamoate salt insoluble is approved for use in schizophrenia. Like aripiprazole, olanzapine can cause local adverse reactions when injected into an individual. SUMMARY OF THE INVENTION
[009] There is a need for enhanced pharmaceutical compositions of aripiprazole, olanzapine, prodrugs of these, and other antipsychotic agents, for the use of prolonged release, thus increasing patient compliance and optimizing the pharmacological profile of the active agent.
[0010] Pharmaceutical compositions are provided herein comprising (a) a water-insoluble antipsychotic agent, and (b) sorbitan esters of a carboxylic acid, wherein the carboxylic acid comprises 8 to 14 carbon atoms. In a particular embodiment, the sorbitan ester is sorbitan laurate (SML). In one embodiment, the composition may be in the form of an aqueous, flocculated injectable suspension. The composition may comprise additional components, such as a polyoxyethylene derivative of a carboxylic acid sorbite ester, wherein the carboxylic acid comprises 8 to 14 carbon atoms (for example, polysorbate 20). The pharmaceutical composition can be injectable.
[0011] These pharmaceutical compositions can take a variety of forms. These forms include, but are not limited to, completely dispersed and flocculated systems.
[0012] As described below, the pharmaceutical compositions described here have numerous advantages. For example, compositions can be easily resuspended by the user, for example, through manual agitation, in a short period of time before administration.
[0013] The water-insoluble antipsychotic agents that can be used in the pharmaceutical compositions described here include aripiprazole, as well as prodrugs thereof, and olanzapine, as well as prodrugs thereof. Particular aripiprazole prodrugs include compounds of formula (I) or formula (II), for example, compounds of formula (I '), for example, compounds A-4 and A-7:

[0014] Particular olanzapine prodrugs include the compounds of the formula (III) or (IV):

[0015] In another aspect, a pharmaceutical composition is provided here which comprises: (a) a water-insoluble antipsychotic agent; (b) sorbitan esters of a carboxylic acid, wherein the carboxylic acid comprises 8 to 14 carbon atoms; (c) a polyoxyethylene derivative of a carboxylic acid sorbitan ester, wherein the carboxylic acid comprises 8 to 14 carbon atoms; and (d) an aqueous vehicle;
[0016] wherein the composition forms an aqueous injectable suspension, flocculated.
[0017] The composition comprising the components (a) - (d) can have components in different reasons. For example, in a composition embodiment comprising components (a) - (d), the composition comprises components (b) and (c) in a ratio that results in flakes comprising component (a), in which the flakes sediment at a predetermined sediment bed height, so that components (a), (b) and (c) can be resuspended for injection. In one embodiment, the bed height is comprised of at least a 20 to 80% increase in sediment height compared to a non-flocculated suspension after 24 hours of uninterrupted rest, and, in another embodiment, the components (a ), (b) and (c) can be resuspended for injection within 1 to 60 seconds of manual agitation. In another embodiment, the ratio of components (b) to (c) is such that the composition can be injected using a 20 to 25 gauge needle.
[0018] In a particular embodiment, the ratio of components (b) to (c) is approximately 5 to 2, by weight.
[0019] When component (b) is sorbitan laurate, the composition may comprise about 0.2 to 1 percent by weight, about 0.4 to 0.7 percent by weight or about 0.5 percent by weight of sorbitan laurate.
[0020] When component (c) is polysorbate 20, the composition may comprise about 0.05 to 0.8 percent by weight of polysorbate 20, about 0.1 to 0.3 percent by weight of polysorbate 20, or about 0.2 percent by weight of polysorbate 20.
[0021] In one embodiment, the pharmaceutical composition flakes have the following sizes: Dv [10]: 2-10μm, Dv [50]: 10-30μm, and Dv [90]: less than 80 μm (for example, approximately 65 um). In another modality, the flakes are Dv [10]: 1-10μm, Dv [50]: 5-30μm, and Dv [90]: less than 65 μm.
[0022] The compositions may have varying amounts of antipsychotic agent in the pharmaceutical composition. For example, the composition can be comprised of 15 to 35 percent by weight, for example, 20 to 30 percent by weight, for example, 20 to 26 percent by weight of aripiprazole, or olanzapine, or a compound of formula I, II, III, IV or V (lurasidone).
[0023] In another aspect, an aqueous injectable suspension is provided here comprising: (a) aripiprazole, or olanzapine, or a compound of formula I, II, III, IV or V, pharmaceutically acceptable salts, hydrates, or solvates of that,
[0024] in which component (a) is in a weight ratio of approximately 15 to 35%; (b) sorbitan laurate at a weight ratio of approximately 0.2 - 1% (c) polysorbate 20 at a weight ratio of approximately 0.05 - 0.8%; and (d) an aqueous vehicle.
[0025] In an aqueous injectable suspension embodiment, the components are as follows: (a) aripiprazole, or olanzapine, or a compound of formula I, II, III, IV or V in a weight ratio of approximately 20- 26%; (b) sorbitan laurate at a weight ratio of approximately 0.5%; (c) polysorbate 20 at a weight ratio of approximately 0.2%; and (d) an aqueous vehicle.
[0026] In one embodiment, the pharmaceutical composition is formulated for use in releasing a water-insoluble antipsychotic agent in a host. In a preferred embodiment, the host is human. The composition can be intended for parenteral administration (for example, intramuscular, intradermal or subcutaneous). In some embodiments, the composition is formulated for delivery via a needle to a host. Consequently, the composition can be formulated for release for injection through a syringe equipped with a needle, where the end user resuspends the composition before use.
[0027] In one embodiment, the antipsychotic agent (eg, aripiprazole, or olanzapine, or a compound of formula I, II, III, IV or V) can be formulated to modulate the tissue reaction associated with the release of an insoluble antipsychotic agent in water. The pharmaceutical composition that has a reduced injection site reaction may comprise (a) an antipsychotic agent, and (b) sorbitan esters of a carboxylic acid, wherein the carboxylic acid comprises 8 to 14 carbon atoms. In a particular embodiment, the sorbitan ester is sorbitan laurate. In one embodiment, the injection site modulation composition may comprise additional components, such as a polyoxyethylene derivative of a carboxylic acid sorbitan ester, wherein the carboxylic acid comprises 8 to 14 carbon atoms (for example, polysorbate 20) .
[0028] In another modality, the modulation of the tissue reaction is a reduction in irritation at the injection site. In another modality, the modulation of the tissue reaction is a reduction in irritation after the injection of IM or SC. In some embodiments, the tissue reaction is reduced by at least 20 percent by weight. In other embodiments, the tissue reaction is reduced by at least about 10 percent by weight.
[0029] In one embodiment, the antipsychotic agent is selected from the group consisting of aripiprazole, or olanzapine, or a compound of formula I, II, III, IV or V and pharmacologically active salts, hydrates or solvates thereof.
[0030] In some embodiments, the pharmaceutical composition for modulating the injection site reaction further comprises a buffer. The buffer can be selected from a phosphate, citrate, tartrate or acetate buffer. In a particular embodiment, the buffer is a phosphate buffer.
[0031] In a particular embodiment of the above compositions, the composition comprises a water-insoluble antipsychotic agent, about 0.1 to 2% percent sorbitan laurate, about 0.05-1% percent polysorbate 20 and buffer of phosphate. In a particular embodiment, the phosphate buffer comprises isotonic saline with 5-50 mM phosphate buffer at pH 5.0 - 7.5.
[0032] In another aspect, an injectable composition is provided here comprising sorbitan laurate, polysorbate 20, phosphate buffer and aripiprazole, or pharmacologically active salts, hydrates or solvates or prodrugs thereof.
[0033] In yet another aspect, an injectable composition is provided here comprising sorbitan laurate, polysorbate 20, phosphate buffer and olanzapine, or salts, hydrates or solvates or pharmacologically active prodrugs thereof.
[0034] In yet another aspect, an injectable composition is provided herein comprising sorbitan laurate, polysorbate 20, phosphate buffer and Compound A-7, or pharmacologically active salts, hydrates or solvates or prodrugs thereof.
[0035] A method for treating disorders of the central nervous system is also provided herein, which comprises administering an effective amount of any of the above compositions to an individual in need of such treatment.
[0036] In one embodiment, the disorder is anxiety or depression. In another embodiment, the disorder is bipolar disorder. In yet another modality, the disorder is irritability related to autism. In yet another modality, the disorder is a psychotic condition. The psychotic condition can be schizophrenia or schizophreniform diseases. Alternatively, the psychotic condition can be acute mania.
[0037] In yet another aspect, a method of modulating tissue reaction associated with the application of a water-insoluble antipsychotic agent through a needle in a hospe-deiro, which comprises a water-insoluble antipsychotic agent and water laurate, is provided here. sorbitan. In one embodiment of the method, the composition is administered parenterally. In some modalities, the composition is administered intradermally, subcutaneously or intramuscularly. In another modality of the method, the modulation of the tissue reaction is a reduction in irritation and the formation of a subsequent granuloma at the injection site. In certain embodiments, the tissue reaction is reduced by at least about 20 percent. In other embodiments, the tissue reaction is reduced by at least about 10 percent. In yet another embodiment of the method, the composition comprises a water-insoluble antipsychotic agent, about 0.1-2% percent sorbitan laurate, about 0.05-1% percent polysorbate 20 and buffer buffer. phosphate. BRIEF DESCRIPTION OF THE FIGURES
[0038] Figure 1 shows the results of sediment bed height assessments described in the experimental section. The data indicate that pharmaceutical compositions containing sorbitan laurate and polysorbate 20 have significantly higher sediment bed heights than compositions without sorbitan laurate.
[0039] Figure 2 shows a positive effect of sorbite laurate on the sedimented bed height in pharmaceutical compositions of antipsychotic drugs.
[0040] Figure 3 shows an exemplary photograph that illustrates the measure of sediment height in a bottle of the pharmaceutical compositions described here.
[0041] Figure 4 shows microscopic images of three suspensions made with pharmaceutical compositions containing polysorbate 20 and increasing amounts of sorbitan laurate. It is visually clear that flocculation is occurring as the SML content in the vehicle increases.
[0042] Figure 5 shows bottles containing pharmaceutical compositions after sedimentation with sediment height calculations.
[0043] Figure 6 shows graphs of pharmaceutical composition vs. resuspension time. drug particle size. Larger measured suspension particle sizes, caused by flocculation, facilitate faster resuspension than smaller ones.
[0044] Figure 7 is a contour graph that shows amounts of polysorbate 20 and sorbitan laurate needed for proper wetting and resuspension capacity.
[0045] Figures 8A and 8B demonstrate the reduction of tissue reaction associated with antipsychotic drugs when the drugs are formulated with sorbitan laurate.
[0046] Figure 9 demonstrates the results of solubility studies that comprise varied ratios of active agent, component (b), and component (c). DETAILED DESCRIPTION OF THE INVENTION Pharmaceutical compositions
[0047] An injectable pharmaceutical composition comprising an antipsychotic agent and a sorbitan ester of a carboxylic acid is provided herein, wherein the carboxylic acid comprises 8-14 (e.g. 11-13) carbon atoms. A preferred sorbitan ester is sorbitan laurate. This composition is particularly useful for formulating a water-insoluble antipsychotic agent in a pharmaceutical injectable composition. In addition to a carboxylic acid sorbitan ester, the pharmaceutical composition may further comprise a polyoxyethylene derivative of a carboxylic acid sorbitan ester, wherein the carboxylic acid comprises 8-14 carbon atoms. In one embodiment, the polyoxyethylene derivative is polysorbate 20. The pharmaceutical composition can further comprise an aqueous carrier, such as phosphate buffered saline, as well as any pharmaceutical components described herein.
[0048] The compositions described here have numerous advantages. For example, the compositions offer reduced excipient levels while co-optimizing acceptable resuspension capacity and injection capacity, and maintain satisfactory physico-chemical attributes of the antipsychotic agent. As described in the experimental section, these properties were discovered based on comparisons of vehicle performance based on sediment bed height and qualitative resuspension facility. Briefly, the redispersibility of pharmaceutical compositions was evaluated by preparing numerous different formulations (antipsychotic agent with a variety of excipients), and comparing the relative height of sedimented beds. In general, higher sediment bed heights are indicative of flocculated particles, or freely aggregated. These suspensions settle faster initially, but their freely aggregated state allows for easier redispersion and better physical stability since the particles cannot settle as firmly as completely dispersed suspensions, thus resulting in reduced resuspension times using, for example, agitation manual. In one embodiment, the pharmaceutical compositions, for example, a pharmaceutical composition of components (a) and (b), or (a), (b) and (c), can be resuspended for injection within 1 to 60 seconds of stirring. manual.
[0049] As used here, the term "flocculation" refers to the formation of a free aggregation of distinct particles held together in a network-like structure by physical adsorption of macromolecules, bonding during chemical interaction (precipitation), or when forces van der Waals' long range of attraction exceed the shortest range of attraction. (See Pharmaceutical dosage forms: Disperse systems Volume 2. Edited by Herbert A. Lieberman, Martin M. Rieger, and Gilbert S. Banker. (1996) Pg. 18). The "loose aggregation of discrete particles" can be referred to herein as "flocs".
[0050] As shown in Figure 1, pharmaceutical compositions containing component (b) (for example, sorbitan laurate) and component (c) (for example, polysorbate 20) have significantly higher sediment bed heights than compositions without component (b), regardless of the presence of additional additives (for example, polymers) or salts (for example, phosphate buffer, saline). In addition, the induced flocculation is exclusive to component (b) / component (c), as evidenced by comparison with compositions containing sorbitan monopalmitate, sodium docusate, or polysorbate 20 individually. As described below, the flocculation phenomenon is exclusively attributed to the additional influence of component (b), for example, sorbitan laurate.
[0051] Consequently, in one embodiment, a composition is provided here which comprises components (a), (b) and (c) in a ratio that results in flakes, in which the flakes settle beyond a bed height of predetermined sediment, so that components (a), (b) and (c) can be resuspended for injection. The flakes can be comprised of component (a), components (a) and (b), or components (a), (b) and (c). A predetermined sediment bed height refers to a bed height that is greater than the bed height of a comparative pharmaceutical composition that does not have component (b), or none of the components (b) or (c). In one embodiment, the height of the bed is comprised of at least an increase of 10, 20, 30, 40, 50, 60, 70 or 80% in height of sediment compared to a non-flocculated pharmaceutical composition after 24 hours of rest not interrupted. In another embodiment, the bed height is comprised of at least a 20 to 80% increase in sediment height compared to a non-flocculated pharmaceutical composition after 24 hours of uninterrupted rest.
[0052] The flakes formed can have any number of sizes. Non-limiting examples of sizes include Dv [10]: 2-10μm, Dv [50]: 10-30μm, and Dv [90]: less than 80 μm (for example, approximately 65 µm). In another modality, the flakes are Dv [10]: 1-10μm, Dv [50]: 5-30μm, and Dv [90]: less than 65 μm.
[0053] In addition to the advantages of resuspension capacity and injection capacity described above, the pharmaceutical compositions provided here result in reduced tissue reactions. Typically, flocculated pharmaceutical suspensions have an increased viscosity and reduced flow properties, which confer the ability to inject or administer the product to the patient. This in turn can have a negative impact on the local tissue response; therefore, it is surprising that the formulations described here result in an increased tissue response.
[0054] Consequently, in one embodiment, a method of modulating tissue reactions associated with the release of a water-insoluble antipsychotic agent in a host is provided, comprising the water-insoluble antipsychotic agent and component (b) , for example, sorbitan laurate. In another embodiment, the antipsychotic agent / component composition (b) is applied to the host via a needle.
[0055] Surprisingly, it was found that the composition provided here results in a reduced tissue reaction normally associated with antipsychotic agents, such as aripiprazole, olanzapine, derivatives of these, prodrugs of these, and salts of these. As demonstrated in the experimental section, an injectable composition comprising an antipsychotic agent and a sorbitan ester of a carboxylic acid, wherein the carboxylic acid comprises 8-14 carbon atoms (eg, sorbitan laurate), demonstrated an unexpected improvement in tissue reaction compared to similar compositions that comprise a sorbitan ester of a carboxylic acid outside that range (eg, sorbitan monopalmitate). Without sticking to the theory, it is believed that a favorable surface interaction between the sorbitan ester of a carboxylic acid (e.g., sorbitan laurate) and the antipsychotic drug (e.g., aripiprazole or olanzapine) reduces the tissue reaction.
[0056] Furthermore, due to the increased interaction between these with components, the injectable composition provided here can be formulated and kept in suspension with ease. Surprisingly, it has been found that it is easier to formulate the antipsychotic drugs described here using a sorbitan ester of a carboxylic acid, where the carboxylic acid comprises 8-14 carbon atoms (eg, sorbitan laurate) compared to other esters of sorbitan outside this range (for example, sorbitan monopalmitate). This was also unexpected. Without sticking to the theory, it is believed that the sorbitan ester component of the injectable composition provided here improves the hydrophilicity of the drug through surface interactions of the various components. It is further observed that the formulation vehicles containing sorbitan laurate and polysorbate 20 form visible emulsions without lubrication for each surfactant. In contrast, formulations containing sorbitan palmitate do not form consistent emulsions, even with the addition of a second nonionic surfactant, with undissolved material visible at the bottom of the material.
[0057] As used here, the term "tissue reaction" (TR) refers to foreign body responses to a drug product (active agent and / or vehicle used for administration). For example, the local tissue reaction to the drug product results in the influx of immune cells, the subsequent encapsulation of the drug product, and generally the development of a fluid-filled central cavity. The presence of fibroblasts, neutrophils, macrophages and giant cells is usually observed through histological examination. The term “in-due TR” or “unacceptable TR” refers to moderate to severe TR that is unacceptable by the patient and thus has an unfavorable impact on patient comfort and compliance. The term “reduced TR” generally refers to the minimum to mild TR that is acceptable to the patient and therefore does not cause a related adverse event or cause an unfavorable impact on patient compliance. As a result, the injectable composition provided here is characterized by a reduced undue TR and a more acceptable TR after injection of drug product. As used here, "tissue reaction" can also refer to an "injection site reaction".
[0058] The modulation of tissue response after SC administration is described by the reduction of the local injection weight (which comprises the deposit of drug and surrounding tissue) that provides a quantitative assessment of the severity of the response. The modulation of the tissue response after IM administration is described by the spreadability of the drug and the resulting deposit morphology; spreading of the drug along the planes of the muscle fascia is desired rather than the formation of a concentrated mass of drug in a small area.
[0059] The deposit morphology resulting from the MI injection of aripiprazole and aripiprazole prodrugs has been described. Injections of slow-release drug formulations, including aripiprazole commonly result in the formation of “cyst-like structures”, characterized by a vascularized capsule of approximately spherical shape and comprising various types of cells, with or without a fluid compartment central serous. Tissue responses to slow-release formulations occur as the body produces an immune response to remove material from the injection site; this reaction is commonly referred to as a foreign body response. The spherical nature of these reactions can result in localized discomfort and pain, since the FBR increases in size by compressing nerve fibers, innervating muscle tissue and by releasing pro-inflammatory cytokines from the site.
[0060] In a particular modality, the modulation of the tissue reaction is the reduction in tissue reaction at the injection site. In one embodiment, the injection site reaction is reduced by a particular amount, for example, about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5 %, etc.
[0061] When the antipsychotic agent / sorbitan ester composition is used as an injectable composition, including, but not limited to, injection through a needle or injection without a needle, it can be formulated in a conventional injectable vehicle. Suitable vehicles include biocompatible and pharmaceutically acceptable solutions.
[0062] Representative drawings of the sorbitan esters used in the pharmaceutical compositions described here are provided below. Sorbitan laurel can also be referred to as "sorbitan monolaurate":

[0063] As described above, the pharmaceutical composition comprising components (a) and (b) can further comprise component (c): a polyoxyethylene derivative of a sorbite ester of a carboxylic acid, wherein the acid carboxylic acid comprises 814 carbon atoms. In a particular embodiment, component (c) is polysorbate 20, sold under the trade name TWEEN ®. Polysorbate can be added in an amount that reduces the surface tension of a drug product or aids in the stability of drug product suspension.
[0064] Representative drawings of the polyoxyethylene derivative of a sorbitan ester of a carboxylic acid used in pharmaceutical compositions are provided below:

[0065] For compositions comprising components (a), (b), and (c), or (a), (b), (c) and (d), the reasons for (b) and (c) can vary. In one embodiment, the ratio of components (b) to (c) is approximately 10 to 0.5, for example, 10 to 1, for example, 8 to 1, for example, 5: 2, by weight. In another embodiment, the ratio of components (b) to (c) is approximately 5 to 2, by weight. In yet another embodiment, the composition comprises component (a), sorbitan laurate, and polysorbate 20, wherein the ratio of sorbitan laurate to polysorbate 20 is approximately 5 to 2, by weight. In yet another embodiment, the composition comprises component (a), sorbitan laurate, and polysorbate 20, wherein the ratio of sorbite laurate to polysorbate 20 is approximately 3 to 1, by weight. In another embodiment, the composition comprises component (a), sorbitan laurate, and polysorbate 20, wherein the ratio of sorbitan laurate to polysorbate 20 is approximately 2 to 1, by weight. In yet another embodiment, the composition comprises component (a), sorbitan laurate, and polysorbate 20, where the ratio of sorbite laurate to polysorbate 20 is within the range of approximately 3 to 1 - 2 to 1, for example. Weight.
[0066] As described in Table 3, the sorbite laurate / polysorbate 20 ratio can be approximately 0.625, 1, 1.25, 2, 2.5, or 5, representing a range of 0.625 - 5.
[0067] For compositions comprising components (a) and (b), (a), (b), and (c), or (a), (b), (c) and (d), the percentage by weight of (b) and (c) may vary. In one embodiment, the composition comprises about 0.2 - 1 percent by weight of component (b), for example, sorbitan laurate. In another embodiment, the composition comprises about 0.4 - 0.7 percent by weight of component (b), for example, sorbitan laurate. In yet another embodiment, the composition comprises about 0.5 percent by weight of component (b), for example, sorbitan laurate.
[0068] In another embodiment, the composition comprises about 0.05 - 0.8 percent by weight of component (c), for example, polysorbate 20. In yet another embodiment, the composition comprises about 0.1 - 0, 3 percent by weight of component (c), for example, polysorbate 20. In yet another embodiment, the composition comprises about 0.2 percent by weight of polysorbate 20.
[0069] In one embodiment, the component ratio (b) to (c) is such that the composition can be injected using a 20-25 gauge needle. For example, the needle can be a 20, 21, or 23.5 gauge needle.
[0070] The compositions provided here may also have varying amounts of antipsychotic agent. The antipsychotic agent can be aripiprazole, or olanzapine, salts of these compounds, hydrates of these compounds, and / or prodrugs of these compounds. In one embodiment, the composition comprises approximately 15 - 35 percent by weight of aripiprazole, or olanzapine, or a compound of formula I, II, III, IV or V (lurasidone), or pharmaceutically acceptable salts, hydrates, or solvates thereof. In another embodiment, the composition comprises approximately 20 - 30 percent by weight of aripiprazole, or olanzapine, or a compound of formula I, II, III, IV or V, or pharmaceutically acceptable salts, hydrates, or solvates thereof. In yet another embodiment, the composition comprises approximately 20 - 26 percent by weight of aripiprazole, aripiprazole, or olanzapine, or a compound of formula I, II, III, IV or V, or pharmaceutically acceptable salts, hydrates, or solvates thereof. . In another embodiment, the composition comprises approximately 24-26 percent by weight of aripiprazole, or olanzapine, or a compound of formula I, II, III, IV or V, or pharmaceutically acceptable salts, hydrates, or solvates thereof.
[0071] The aqueous carrier of the pharmaceutical compositions provided herein can be a buffer. The buffer can be selected from a phosphate, citrate, tartrate or acetate buffer. In a particular embodiment, the buffer is a phosphate buffer.
[0072] The pharmaceutical compositions provided here may further comprise additional components. For example, the use of additional wetting agents or surfactants in a pharmaceutical composition can promote one or more of the following: (1) Reduction of surface tension, which can assist in wetting, as a 'lower surface tension' liquid will wet the surfaces or particles faster than a high surface tension liquid. Reducing the surface tension of a liquid can also reduce the incidence of foaming. The surface tension of a liquid will be less as more tensors are added; (2) Formation of micelles (that is, spherical or non-spherical surfactant structures in solution that have the ability to dissolve non-soluble components); and / or (3) Increased physical stability of the suspension.
[0073] Pharmaceutical compositions can also contain an aqueous vehicle, which is a vehicle that dilutes and suspends the drug. The diluent of interest here is one that is pharmaceutically acceptable (safe and non-toxic for administration to a human) and is useful for the preparation of a reconstituted formulation. Exemplary diluents include sterile water, sterile water for injection (WFI), bacteriostatic water for injection (BWFI), a pH buffered solution (for example, phosphate buffered saline), sterile saline, Ringer's solution or dextrose solution . The buffer can be phosphate, citrate, tartrate or acetate. In a particular embodiment, the diluent is phosphate-buffered saline, which is a water-based saline solution containing sodium chloride or potassium chloride, and sodium phosphate or potassium phosphate. In one embodiment, the phosphate buffer comprises isotonic saline with 5-50 mM phosphate buffer at pH 4.0 - 9.0, for example, 5.0 - 8.0, for example, 5.0 - 7, 5.
[0074] The pharmaceutical compositions may also contain an additional surfactant which is preferably adsorbed on an interface between two immiscible phases, such as the interface between water and an organic polymeric solution, a water / air interface or an organic solvent / air. Suitable surfactants include, but are not limited to, fatty alcohols such as polyethylene glycols (PEGs) and cetyl alcohol.
[0075] Optionally, the pharmaceutical compositions can further comprise a dispersant, such as, for example, carboxymethyl cellulose (CMC), sodium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, and low-content aluminum and magnesium silicate hydroxypropyl cellulose substituted aluminum, or a mixture thereof. In a particular embodiment, the pharmaceutical composition comprises carboxymethyl cellulose.
[0076] Pharmaceutical compositions may also optionally comprise an antioxidant to inhibit oxidation of ingredients. Some examples of antioxidants include, but are not limited to, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisol, a mixture of 2 and 3 hydroxyanisol-butyl-4-tertiary, butylated hydroxytoluene, sodium iso-ascorbate, dihydroguaretic acid , potassium sorbate, sodium bisulfate, sodium metabisulphate, sorbic acid, potassium ascorbate, vitamin E, butyphenol 4-chloro-2,6-dithercary, alpha-tocopherol, and propylgalate.
[0077] The pharmaceutical compositions can further include a lipid, for example, a neutral lipid. Neutral lipids include any lipid that remains neutrally charged at a pH between about 4 and 9. Neutral lipids include, without limitation, cholesterol, other sterols and derivatives thereof, phospholipids, and combinations of these and other neutral lipids. Phospholipids include any phospholipid or combination of phospholipids capable of forming liposomes. These include phosphatidylcholines, phosphatidylethanamine, lecithin and fractions thereof, phosphatidic acid, phosphatidyl glycerols, phosphatidylinositols, phosphatidyl serines, plasmalogens and sphingomyelins. Phosphatidylcholines include, without limitation, those obtained from eggs, soy beans or other vegetable sources or those that are partially or totally synthetic or of variable lipid chain length and unsaturation, POPC, OPPC, natural soy bean PC or hydrogenated, PC, DMPC, DPPC, DSPC, natural or hydrogenated egg DOPC and derivatives thereof. In one embodiment, phosphatidylcholines are POPC, non-hydrogenated soy bean PC and non-hydrogenated egg PC. Phosphatidylethanolamines include, without limitation, DOPE, DMPE and DPPE and derivatives thereof. Phosphatidyl glycerols include, without limitation, DMPG, DLPG, DPPG, and DSPG. Phosphatidic acids include, without limitation, DSPA, DMPA, DLPA and DPPA.
[0078] The pharmaceutical compositions can also advantageously employ a density enhancing agent, such as a sugar, for example, mannitol, or sorbitol and / or a tonicity adjusting agent, such as sodium chloride or glycerol.
[0079] Other pharmaceutical carriers that could be used in the pharmaceutical compositions provided here also include water, aqueous methylcellulose solutions, saline, dextrose solutions, fructose solutions, ethanol, or oils of animal, vegetable or synthetic origin. The pharmaceutical carrier can also contain preservatives, and buffers as known in the art.
[0080] The terms "pharmaceutical composition", "formulation", "injectable composition," etc. are used synonymously throughout the order.
[0081] The pharmaceutical compositions described here can also be in the form of an emulsion. The term “emulsion” as used in this specification denotes a two-phase system in which one phase is finely dispersed in the other phase. An emulsifier can be used in pharmaceutical compositions to form the emulsion. The term emulsifier, as used by this invention, denotes an agent that can reduce and / or eliminate surface and interfacial tension in a two-phase system. This agent has hydrophilic and lipophilic groups in the emulsifying agent.
[0082] The pharmaceutical compositions described here can also be in the form of a dispersion. As used here, the term "dispersion" will be understood as a mixture in which the fine particles of one substance (for example, a drug) are spread on the other substance (for example, a liquid). Dispersions include suspensions and colloids.
[0083] The methods of the invention include administering the compositions described here, thereby obtaining a sustained or sustained release profile in the patient. "Prolonged release" or "sustained release" includes dosage forms whose characteristics of time course and / or drug delivery site are selected to achieve therapeutic or convenience objectives not offered by conventional dosage forms as a solution or form of immediate release dosage. An extended release profile includes releases that reach a therapeutically effective amount of the antipsychotic agent, for example, aripiprazole, or olanzapine, or a compound of formula I, II, III, IV or V, is present in the individual's plasma for at least at least about 7 days, preferably at least about 14 days, or more preferably, at least about 21 days alternatively for at least 2, 3, 4, 6 or 8 weeks or three months.
[0084] In one embodiment, the pharmaceutical compositions can be administered as a single or individual dose (not divided). However, the composition is also useful for those individuals who require constant or chronic therapy, such as those who receive repeated doses over several hours, days, weeks, months, or more. In such dosage regimes, the method may comprise a first administration of a first extended release composition and a second administration of a second prolonged release composition. The second composition can be the same, substantially the same or different from the first and can include the same active agent or a different active agent. For example, the second composition can be administered in about 7 days, or more, such as at least about 14 days, or at least about 17 days, after the first administration, where the first administration results in the release of agent over a period of time. period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 days, or more.
[0085] The injectable pharmaceutical compositions described here can be injected into a patient in a number of ways. The term “injectable” as used here refers to a composition that is suitable to be applied to an individual in an injection, as with an injection device, including one that uses a syringe or cartridge, which can be housed in a device manual injection or a self-injection device, for example. Specifically, the injectable composition is suitable for parenteral administration. As used here, the term "parenteral administration" refers to administration by injection or infusion. Parenteral administration includes, but is not limited to, intravenous administration, intradermal administration, subcutaneous administration or intramuscular administration. The term "intravenous administration" means administration into a vein. “Intradermal administration” is an injection into the upper layer of the skin (ie, the dermis), just below the epidermis. “Subcutaneous administration” refers to the administration just under the skin. “Intramuscular administration” is the injection directly into a muscle. Antipsychotic agents
[0086] As discussed above, the pharmaceutical compositions provided here are useful for the administration of antipsychotic drugs to an individual. As used here, the term "antipsychotic" refers to all drugs used to treat psychosis. Common conditions for which antipsychotics are prescribed include schizophrenia, mania and delusional disorder, although antipsychotics are also used to combat psychosis associated with a wide range of other diagnoses. Antipsychotics also act as mood stabilizers making them suitable for the treatment of bipolar disorder (even when no symptoms of psychosis are present). The pharmaceutical compositions provided here are particularly useful for formulating a water-insoluble antipsychotic in an injectable composition.
[0087] The pharmaceutical compositions described here are useful for the administration of water-insoluble antipsychotic agents. As used here, a water-insoluble antipsychotic agent is one that dissolves in less than 100% of water. The term "insoluble in water" does not necessarily refer to insolubility in total or 100% water. In some embodiments, the water-insoluble material dissolves at a level of less than 50%. In other embodiments, the water-insoluble material dissolves at a level of less than 10%. In a particular embodiment, the water-insoluble material dissolves at a level of less than 1%. The term "water insoluble" can refer to solubility as prescribed in United States Pharmacopoeia.
[0088] In one embodiment, the antipsychotic drug in the pharmaceutical composition is aripiprazole. The drug substance aripiprazole may comprise, consist essentially of, or consist of aripiprazole (in a crystalline, non-crystalline or amorphous form), an aripiprazole salt, an aripiprazole solvate (including ethanolates and hydrates), or other aripiprazole polymorphs. Preferred salts include those salts insoluble in an aqueous vehicle. Pharmaceutical salts such as hydrochloride and various pharmaceutically acceptable carboxylate salts are suitable.
[0089] The aripiprazole drug substance can also include aripiprazole prodrugs. The term "prodrug" is recognized in the art and is intended to include compounds that, under physiological conditions, are converted into active compounds, for example, those described here. A common method for producing a prodrug is to select portions that are hydrolyzed or otherwise cleaved under physiological conditions to provide the desired compound. In other modalities, the prodrug is converted by an enzymatic activity of the host animal.
Preferred aripiprazole prodrugs that can be used in pharmaceutical compositions include the prodrugs described in Publication No. U.S. 2011/0003828, which is incorporated herein by reference in its entirety.
[0091] In a particular embodiment, the aripipra-zol prodrug is a compound of formula (I) or formula (II):

[0092] where
[0093] Ra is absent, and Rb is -CH2OC (O) R1, -CH2OC (O) OR1, -CH2OC (O) N (R1) 2 or -C (O) R1;
[0094] or
[0095] Rb is absent, and Ra is -CH2OC (O) R1, -CH2OC (O) OR1, -CH2OC (O) N (R1) 2 or -C (O) R1;
[0096] Rc is -CH2OC (O) R1, -CH2OC (O) OR1, -CH2OC (O) N (R1) 2or -C (O) R1;
[0097] in which each R1 is independently selected from the group consisting of hydrogen, substituted or unsubstituted aliphatic, and substituted or unsubstituted aryl; and
[0098] in which each R2 is selected from the group consisting of substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
[0099] where YΘ is a pharmaceutically acceptable counterion; and
[00100] where it represents a single or double bond.
[00101] Suitable counterions include, for example, chloride, bromide, iodine, sulfate, phosphate, acetate, benzoate, tartrate, citrate, propionate, gluconate, lactate, maleate, fumarate, cansilate, glucopath, mesylate, napsylate, pamoate , conjugated bases of organic carboxylic acids, and the like.
[00102] In an embodiment of formula (I), the aripipprazole prodrug is a compound of formula (I '):

[00103] where Ra is CH2OC (O) R1 and where R1 is selected from substituted or unsubstituted aliphatic.
[00104] In a particular embodiment of the formula (I '), R1 is - CH2OC (O) - (CH2) 4CH3 (Compound A-4). In another particular embodiment of the formula (I '), R1 is -CH2OC (O) - (CH2) 10CH3 (Compound A-7). Compounds A-4 and A-7 are shown below:

[00105] In another embodiment, the antipsychotic drug in the pharmaceutical composition is olanzapine. The olanzapine drug substance may comprise, consist essentially of, or consist of olanzapine (in a crystalline, non-crystalline or amorphous form), an olanzapine salt, an olanzapine solvate (including, for example, ethanolates and hydrates) , or other olanzapine polymorphs. A preferred olanzapine salt is olanzapine pamoate. The antipsychotic drug can also be an olznapine prodrug.
[00106] The olanzapine drug substance can also include olanzapine prodrugs of Formula (III), or (IV):

[00107] where
[00108] R3 is -CH2OC (O) R1, -CH2OC (O) OR1, -CH2OC (O) N (R1) 2 or -C (O) R1;
[00109] R4 is -CH2OC (O) R1, -C ^ OC (O) OR1, -CH2OC (O) N (R1) 2 or -C (O) R1;
[00110] in which each R1 is independently selected from the group consisting of hydrogen, substituted or unsubstituted aliphatic, and substituted or unsubstituted aryl; and
[00111] where Y θ is a pharmaceutically acceptable counterion.
[00112] Suitable counterions include, for example, chloride, bromide, iodine, sulfate, phosphate, acetate, benzoate, tartrate, citrate, propionate, gluconate, lactate, maleate, fumarate, cansilate, glucepate, mesylate, napsylate, pamoate, bases conjugates of organic carboxylic acids, and the like.
[00113] In another embodiment, the antipsychotic drug in the pharmaceutical compositions is lurasidone. Lurasidone is an atypical antipsychotic that is useful for the treatment of a variety of psychiatric disorders, including schizophrenia and bipolar disorder. Such a compound is described, for example, in U.S. Patent No. 5,532,372, which is incorporated herein by reference. Lurasidone is the generic name of the compound (3aR, 4S, 7R, 7aS) -2 - [((1R, 2R) -2 - {[4- (1,2-benzisothiazol-3-yl) -piperazin-1-yl ] methyl} cyclohexyl) methyl] hexahydro-1H-4,7-methanisoindol-1,3-dione:

[00114] The lurasidone drug substance may comprise, consist essentially of, or consist of a lurasidone free base (in a crystalline, non-crystalline or amorphous form), a lurasidone salt, a lurasidone solvate (including ethanolates and hydrates), or other polymorphs of lurasidone. The lurasidone drug substance can also include lurasidone prodrugs.
Consequently, aripiprazole, or olanzapine, or a compound of formula I, II, III, IV, or V can be referred to as an "antipsychotic agent" or "water insoluble antipsychotic agent".
[00116] An "aliphatic group" or "aliphatic" is a non-aromatic portion that can be saturated (for example, single bond) or contains one or more units of unsaturation, for example, double and / or triple bonds. An aliphatic group can be linear, branched or cyclic, contains carbon, hydrogen or, optionally, one or more heteroatoms and can be substituted or unsubstituted.
[00117] An aliphatic group, when used as a binder, preferably, contains between about 1 and about 24 atoms, more preferably, between about 4 to about 24 atoms, more preferably, between about 4 to about 12 atoms, more typically between about 4 and about 8 atoms. An aliphatic group, when used as a substituent, preferably contains between about 1 and about 30 atoms, more preferably, between about 4 to about 19 atoms. In addition to aliphatic hydrocarbon groups, aliphatic groups include, for example, polyalkoxyalkyls, such as polyalkylene glycols, polyamines, and polyimines, for example. These aliphatic groups can be additionally replaced. It is understood that the aliphatic groups can include alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl groups described herein.
[00118] In some embodiments, the aliphatic groups of the present invention are alkyl chains containing from 5 to 11 carbon atoms. In other embodiments, aliphatic groups are alkyl chains that contain 15 to 19 carbon atoms.
[00119] The term "aryl", individually or in combination, means a carbocyclic aromatic system that contains one, two or three rings in which these rings can be attached pendently or can be fused. The term "aryl" includes aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. In one embodiment, aryl is unsubstituted or independently substituted one or more times by halogen, C1-6 alkyl, or O-C1-6 alkyl.
[00120] The term "heteroaryl" includes unsaturated heterocyclyl radicals. Examples of heteroaryl radicals include a 3- to 6-membered unsaturated heteromono-cyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (eg 4H -1,2,4- triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.) tetrazolyl (e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc. .; an unsaturated condensed heterocyclyl group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl (eg, tetrazole [1,5-b] pyridazinyl, etc.), etc .; a 3- to 6-membered unsaturated heteromonocyclic group containing an oxygen atom, for example, pyranyl, furyl, etc .; a 3- to 6-membered unsaturated heteromonocyclic group containing a sulfur atom, for example, methylene, etc .; a 3- to 6-membered unsaturated heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl (eg 1,2,4- oxadiazolyl, 1,3,4 -oxadiazolyl, 1,2,5-oxadiazolyl, etc.) etc .; an unsaturated condensed heterocyclyl group that contains 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (eg benzoxazolyl, benzoxadiazolyl, etc.); a 3- to 6-membered unsaturated heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl (eg 1,2,4-thiadiazolyl, 1,3,4 -thiadiazolyl, 1,2,5-thiadiazolyl, etc.) etc .; an unsaturated condensed heterocyclyl group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (eg, benzothiazolyl, benzothiadazolyl, etc.) and the like.
[00121] The term "substituted" refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent that includes, but is not limited to: halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylamino-carbonyl, arylaminocarbonyl, alkoxycarbonyl, alkylamino, aryloxycarbonyl, alkylamino, aryloxy alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, araloxycarbonyl, carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl, heterohalic, heterohalic, hetero- the substituent can be additionally replaced.
[00122] For simplicity, the chemical portions that are defined and referred to can be univalent chemical portions (for example, alkyl, aryl, etc.) or multivalent portions under the appropriate structural circumstances evident for the elements skilled in the art. For example, an "alkyl" moiety may refer to a monovalent radical (for example, CH3-CH2-), or in other cases, a divalent moiety may be "alkyl," in which case the elements skilled in the art will understand that alkyl is a divalent radical (for example, -CH2-CH2-), which is equivalent to the term "alkylene". Similarly, in cases where divalent moieties are required and are determined as "alkoxy", "alkylamino", " aryloxy ”,“ alkylthio ”,“ aryl ”,“ hetero-aryl ”,“ heterocyclic ”,“ alkyl ”,“ alkenyl ”,“ alkynyl ”,“ aliphatic ”, or“ cycloalkyl ”, the elements versed in the technique will understand that the terms alkoxy "," alkylamino "," aryloxy "," alkylthio "," aryl "," heteroaryl "," heterocyclic "," alkyl "," alkenyl "," alkynyl "," aliphatic ", or" cycloalpha " - quila ”refer to the corresponding divalent portion.
[00123] The term "compound" is defined here to include salts, solvates, hydrates, polymorphs, enantiomers, diastereoisomers, pharmaceutically acceptable racemates and the like of compounds having a formula shown here. Treatment Methods
[00124] The pharmaceutical compositions provided here can be used to treat a variety of disorders in an individual in need of it. For example, the described compositions can be used to treat conditions selected from: disorders such as brain deficit following cardiac and graft surgery, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal injury, dementia (including AIDS-induced dementia), Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, eye injury, retinopathy, cognitive disorders, idiopathic disease and drug-induced Parkinson's disease, muscle spasms and disorders associated with muscle spasticity including tremors, epilepsy, seizures, brain deficits secondary to prolonged status epilepticus, headache (including migraine), urinary incontinence, substance tolerance, substance withdrawal (including substances such as opiates, nicotine, products tobacco, alcohol, benzodiazepines, cocaine, tranquilizers, hypnotics, etc. ), psychosis, schizophrenia, anxiety (including generalized anxiety disorder, panic disorder, social phobia, obsessive-compulsive disorder, and post-traumatic stress syndrome (PTSD)), attention deficit disorder (ADD), deficit disorder attention and hyperactivity disorder (ADHD), mood disorders (including depression, mania, bipolar disorders), circadian rhythm disorders (including dyssynchrosis and shift work), trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye , vomiting, cerebral edema, pain (including acute and chronic pain states, severe pain, intractable pain, neuropathic pain, inflammatory pain, and post-traumatic pain), tardive dyskinesia, sleep disorders (including narcolepsy), attention / hyperactivity, and conduct disorder.
[00125] In another embodiment, the present invention provides a method for treating cardiac and cardiovascular diseases such as angina, arrhythmia, and hypertension, in a patient in need thereof. The method comprises administering to the individual a therapeutically effective amount of a composition of the invention or a pharmaceutically acceptable salt thereof.
[00126] The invention further relates to the treatment of fever, diabetes, allergy, asthma, infection, inflammation, and ulcers in a patient in need thereof, which comprises administering to the individual a therapeutically effective amount of a composition of the invention or a pharmaceutically acceptable salt thereof.
[00127] The invention also relates to the treatment of sleep modulation which comprises the administration of a composition of the invention. Sleep modulation includes decreasing sleep onset time, increasing average sleep duration, and increasing maximum sleep duration.
[00128] In a particular embodiment, the pharmaceutical compositions described here can be used to treat anxiety, depression, bipolar disorder, autism-related irritability, and psychotic conditions that include acute mania, schizophrenia and schizophreniform diseases in an individual.
[00129] The term "treated", "treat" or "treatment" includes the reduction or relief of at least one symptom associated with psychosis or a related CNS disorder. The term "treated", "treat" or "treatment" as used in reference to a disease or condition must indicate the intervention of that disease or condition to prevent or slow down development, prevent or slow down progress, halt progress, or eliminate the disease or condition.
[00130] As used here, the term "modulation" or "modular" refers to an effect of altering a biological activity, especially a biological activity associated with an injection site reaction.
[00131] The term "individual" is intended to include animals, which may suffer or be afflicted with dementia associated with psychosis or a related CNS disorder, including, without limitation, psychotic conditions including acute mania, schizophrenia and schizophrenic disorders, disorder bipolar, anxiety and depression. Examples of individuals include mammals, for example, humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In some modalities, the individual is a human, for example, a human who suffers, is at risk of suffering, or potentially capable of suffering from any of the diseases described here.
[00132] The term "about" or "approximately" generally means within 20%, more preferably within 10%, and even more preferably within 5% of a given value or range. Alternatively, especially in biological systems, the term "about" means within about a log (that is, an order of magnitude), preferably within a factor of two of a given value.
[00133] In one embodiment, a therapeutically effective amount of the agent is administered to an individual using the pharmaceutical compositions provided here. The term “therapeutically effective amount” also serves to define an amount resulting in the improvement of any clinical parameters or symptoms. The actual dose may vary with each patient and does not necessarily indicate a complete elimination of all symptoms of the disease. In the case of antipsychotics, the management of exacerbations and maintaining the maintenance of remission of psychiatric symptoms are the main objectives of therapy, and the selection of the appropriate drug and dosage in a particular disease balances these objectives with the reduction of adverse events attributable to the treatment. drug.
[00134] A therapeutically effective amount of the compound used in the treatment described here can be easily determined by the present diagnostician, as an element skilled in the art, by using conventional techniques and observing the results obtained under similar circumstances. When determining the therapeutically effective dose, a number of factors are considered by the present diagnostician, including, but not limited to: the species of mammal; their size, age, and general health; the specific disease involved; the degree or involvement or the severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristic of the preparation administered; the selected dose regimen; the use of concomitant medication; and other relevant circumstances.
[00135] Preferred suitable dosages of the compounds used in the treatment described here are in the range of about 1 mg to about 600 mg, preferably about 3, 5, 10, 15, 20, 25, 30, 35, 40 , 45, 50, 55, 60, 65, 70, 75, 80, 90, 95, 100, 120, 140, 160, 180, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380 , 400, 420, 440, 460, 480, 500, 520, 540, 560, 580 to about 600 mg of total active agent. Dosing programs can be adjusted to provide the optimal therapeutic response. For example, administration can be from one to three times a day over a period of time from one day to several days, weeks, months, and even years, and throughout the patient's life. In a practical way, a unit dose of any supplied composition used in the treatment described here can be administered in a variety of dosing programs, depending on the physician's judgment, the patient's needs, and so on. The specific dosing program will be known to those skilled in the art or can be determined experimentally using routine methods. Exemplary dosing programs include, without limitation, administration five times a day, four times a day, three times a day, twice a day, once a day, every other day, three times a week, twice a week , once a week, twice a month, once a month, and so on. The unit dose preparations provided here may contain aripiprazole, a Formula I compound or a Formula II compound in the range of about 20 to about 900, for example, 60 to about 800, mg (aripiprazole base equivalents) . The unit dose preparations provided here may contain olanzapine, a Formula III compound, or a Formula IV compound in the range of 40 to about 500 mg (olanzapine base equivalents). The unit dose preparations provided here may contain a compound of Formula V in the range of 160 to about 1000 mg (lurasidone base equivalents).
[00136] The preferred amounts according to the selected mode of administration are capable of being determined by an element skilled in the art. Pharmaceutical compositions can be manufactured using known techniques. Typically, the therapeutically effective amount of the compound will be mixed with a pharmaceutically acceptable carrier. EXAMPLE OF THE INVENTION
[00137] The invention is further illustrated by the following examples. The examples are not to be construed as limiting. EXAMPLE I - Optimization of Antipsychotic Drug Product Formulation
[00138] This study describes the development of Compound A-7 drug product formulation for use in further studies. The development was focused on improving the wetting and redispersibility characteristics of the injection vehicle, with the ultimate intention of increasing the physical stability of the suspension. The optimization experiments identified a formulation comprising a drug substance of a crystallized raw material of Compound A-7 (256 mg / mL) suspended in a 10 mM phosphate buffer injection vehicle containing sorbitan laurate (0.5% by weight), polysorbate 20 (0.2% by weight), and sodium chloride, (0.8% by weight).
[00139] Although the early clinical formulation is considered acceptable for short-term study, there is a desire to improve the physical properties of the drug product suspension (i.e. ease of manufacture, and resuspension capacity with increased drug loads) for long-term use. Optimizing these properties could also increase the likelihood of success in a pre-filled syringe, in the event that a system becomes a desired container closure configuration. The formulation development strategy consists of a two-tiered approach designed to classify a wide variety of injection vehicles and to identify promising candidates for further optimization. The first series of experiments evaluated the wettability characteristics, specifically the immersion-free energy and spreading coefficient, of several vehicles with Compound A-7. The immersion of a solid in a liquid (humectant) begins with the displacement of the solid-air interface with a solid-liquid interface. The immersion-free energy in this solid / liquid / air system describes how the exchange of these interfaces is thermodynamically favorable (or unfavorable). The scattering coefficient predicts whether this exchange will occur spontaneously, or whether it will require additional energy input. Thus, these parameters were selected for study as these could be satisfactory indicators of vehicle favorability to moisten the hydrophobic drug substance, and the relative difficulty in doing so. Classified excipients were first limited to materials that were used in approved drug products (although not necessarily limited to parenteral routes of administration) with acceptable safety profiles [Rowe, Raymond C., Paul J. Sheskey, and Paul J Weller. Handbook of Pharmaceutical Excipients, 4th Ed. New York, Pharmaceutical Press. 2003]. The classified excipients represent numerous functionalities in the formulation of stable suspensions, including suspending agents, surfactants / wetting agents, viscosity modifiers, co-solvents and flocculants. The injection vehicles that were considered to have favorable wetting characteristics with Compound A-7 then moved on to the second series of experiments. Description of Excipients Used
* A tablet dissolved in 200 ml of deionized water produces 0.01 M of phosphate buffer, 0.0027 M of potassium chloride and 0.137 M of sodium chloride, pH 7.4, at 25 ° C. 5.2 METHODS 5.2.2 Injection Vehicle Formulation
[00140] Injection vehicles were made by weighing the appropriate mass of excipient in a measured volume of water for injection (WFI) to provide the desired weight-by-volume percentage. Since the amounts of excipient are typically low (<1%), the change in volume from addition was considered insignificant. In those cases where several surfactants are added, more water-soluble surfactants were added first to help disperse less soluble surfactants. The vehicle formulations were then stirred with a magnetic stirrer until all solids were dissolved and the vehicle appeared visually homogeneous. 5.2.3 Composition of Compound A-7 drug product
[00141] The suspension was formed by adding the crystallized Compound A-7 to the injection vehicle formulated with mixture to obtain the desired drug concentration. On the bench scale, this was done on a bottle-by-bottle basis. The appropriate mass of Compound A-7 was weighted in a 5 ml siliconized glass vial and the appropriate volume of vehicle was added to obtain the desired suspension concentration. The flask was then corked / sealed and mixed alternating between a vortex mixer and a 60 second sonication bath. This procedure was typically repeated 7 times (total of 7 minutes). After composition, the absence of aggregates or unincorporated powder was visually confirmed. 5.2.5 Wettability Characterization
[00142] A surface energy measurement methodology has been developed to allow easy classification of formulation candidates with minimal use of drug substance. These experiments use the surface tension of the injection vehicle and the surface energy of the solid to predict the immersion-free energy and the scattering coefficient between the liquid and the solid. 5.2.6 Liquid Surface Tension Analysis
[00143] A force balance tensiometer (Attension Sigma® 701) with a platinum Wilhelmy plate was used to measure the surface energy (tension) of the vehicle of interest. This was done using a 30 mL sample of the vehicle of interest and performing 8 individual surface tension measurements. The first 3 measurements were discarded as not representative of equilibrium conditions, and the remaining measurements were calculated to obtain the surface tension value. The vehicle sample contained a small stirring bar (approx. 10 mm) and the magnetic stirrer on the tensiometer was turned to the lowest setting to allow mixing without significant interruption of the measurement. All measurements were performed under ambient conditions. To then obtain the polar and non-polar (dispersive) components of the surface tension, a polytetrafluoroethylene (PTFE) contact angle pattern (Rame-Hart) was added to the tensiometer and the dynamic contact angle was measured. Since the desired measurement is the static contact angle, a very slow measurement speed was used (0.001 m / min) allowing the approximation of the condition t ^ »(infinite time). This was done using a 30 mL sample of the vehicle of interest and averaging 3 individual contact angle measurements. The vehicle sample contained a small stirring bar (approx. 10 mm) and the magnetic stirrer on the tensiometer was turned to the lowest setting to allow mixing without significant interruption of the measurement. All measurements were performed under ambient conditions.
[00144] With the total surface tension of the liquid, and the angle of contact of the liquid on a non-polar surface with known surface energy attributes, the polar and dispersive components of the surface tension were calculated. 5.2.7 Solid Surface Energy Analysis
[00145] A force balance tensiometer (Kruss K100) with a Washburn powder measuring device (Kruss FL12) was used to obtain the polar and dispersive surface energy components of the Compound A-7 sample. This was done using probe liquids with precisely characterized surface tensions (diiodomethane and ethylene glycol) and measuring the rate at which probe liquids emerge in a 125 mg compressed bed of the powder per capillary action. Contact angle experiments were carried out on the samples according to the Washburn method for the determination of contact angles for porous liquid wetting materials. The contact angle data with diiodomethane and ethylene glycol were used together with Fowkes' theory to obtain the surface energy data. 5.2.8 Characterization of Redispersibility / Bed Height Settled
[00146] The redispersibility of drug products was evaluated by creating suspensions of low concentration and comparing the relative height of the sedimented beds. Higher heights of sedimented bed are indicative of flocculated particles, or freely aggregated. These suspensions settle faster initially, but their freely aggregated state allows for easier redispersion and better physical stability since the particles cannot accumulate as firmly as the fully dispersed suspensions.
[00147] The experiments were carried out using a concentration of 220 ± 22 mg of Compound A-7 in 3 ml of the vehicle of interest (73.3 mg / ml). The lower concentration was used to allow for easier sorting of sediment bed heights as well as for material conservation. An important assumption is that this ranking order could be equal in total concentration. This suspension was composed in a 5 mL vial, deposited in a 3 mL BD plastic syringe using an encapsulated 18G needle, placed upright and left to sediment. Initial experiments showed that the suspensions were completely sedimented after approximately 10 hours, and that subsequently they did not result in any discernible amount of additional bed compaction. With that, all tested suspensions were allowed to sediment for a minimum of 16 h and a maximum of 48 h before being characterized.
[00148] The heights of sedimented bed were evaluated by qualitatively recording the height of the bed at rest without interruption and the total height of the liquid using the graduations in the 3 mL syringes. Formulations that look promising (higher bed heights) at lower concentrations were also evaluated at total concentration (810 mg in 3 mL - equivalent to 270 mg per mL of vehicle) to qualitatively assess redispersibility. 6.0 RESULTS AND DISCUSSIONTable 1: Free Immersion Energy and Spreading Coefficient of Compound A-7 in Various Formulations


[00149] As shown in Table 1, the immersion-free energy for all formulations tested against all samples of recrystallized Compound A-7 was considered negative, with the exception of pure water. Immersion-free energy describes the energy acquired or lost when moving the air-solid interface with a liquid-solid interface. If the signal is negative, the liquid-solid interface (created by wetting) is more energetically favorable, and if the signal is positive, the air-solid interface is more energetically favorable. Examination of the data shows that formulations containing sorbitan laurate, polysorbate 20 and polysorbate 80 are the most favored (free energy most negative of immersion value).
[00150] Although all vehicle formulations tested have thermodynamically favorable immersion-free energies, the data in Table 1 illustrates that the formulations are differentiated by their spreading coefficients. The scattering coefficient value indicates that the replacement of the air-solid interface with the liquid-solid interface will occur spontaneously. The results show that vehicle formulations containing sodium docusate and sorbitan laurate / polysorbate 20 combinations have positive spreading coefficients, which means that they will replace the solid-air interface with the solid-liquid interface without the addition of work (ie scattering occurs spontaneously). A positive spreading coefficient is desired due to an increased likelihood of complete disintegration / wetting of the powder during the suspension composition resulting in total processing ease.
[00151] In short, although the analysis of the wetting data shows that practically all formulations expected to be moistened, with the most favored formulations containing a surfactant such as polysorbate 20, polysorbate 80, sorbite laurate or sodium docusate, a Analysis of the scattering coefficient data identified the formulations that are spontaneously humectant. The latter has positive implications for ease and robustness of processing. As a result, these materials were selected as the area of concentration in the subsequent redispersibility studies discussed in Section 6.4. 6.4 Redispersibility / Sediment Bed Height
[00152] The results of the sedimented bed height evaluations are shown in Figure 1. The data indicate that the formulations containing sorbitan laurate and polysorbate 20 have significantly higher sedimented bed heights than the formulations without sorbitan laurate, regardless of the presence additional polymers (CMC, PEG 3350) or salts (phosphate buffer, saline). In addition, the induced flocculation is exclusive to sorbitan / polysorbate laurate 20, as evidenced by comparison with formulations containing sorbitan monopalmitate, sodium document, or polysorbate 20 individually.
[00153] Experiments were also carried out to assess whether the induced flocculation could be exclusively attributed to the presence of sorbitan laurate, or whether this is the result of an increase in the total surfactant load. The suspensions were made with a load of equivalent mass of polysorbate 20 and polysorbate 80 (1.3% by weight) and a load of equivalent molar content of polysorbate 20 (3.1% by weight) to the total load of surfactants of suspension of 0.5% sorbitan laurate / 0.2% polysorbate 20. Suspensions with increased polysorbate 20 were considered to have sediment bed heights similar to 0.2% by weight of polysorbate formulations, showing the phenomenon of flocculation as exclusively attributed to the additional influence of sorbitan laurate.
[00154] Compared to other formulations, the sorbitan laurate / polysorbate 20 formulations were more easily resuspended after sedimentation, and with that these suspensions were prepared at a total concentration of 21% by weight. At sediment bed heights, the total concentration could not be measured since the flocculated bed fills the entire volume of the syringe. The qualitative evaluation of redispersibility showed the sedimented bed as easily ruptured with moderate manual agitation of the vials.
[00155] In an effort to optimize the ratio of sorbitan laurate to polysorbate 20, suspensions were prepared in 0.2% polysorbate 20 with phosphate buffered saline and the amount of sorbitan laurate varied between 0.2% and 0.6% (representing the ratios of sorbitan laurate: polysorbate 20 1: 1 to 3: 1). The results are shown in Figure 2. The height of the sedimented bed increases to maximum in a 2: 1 ratio, after which, the increase in the concentration of sorbitan laurate has no effect on the height of the bed. To select a formulation in a robust formulation space, the 10 mM phosphate buffer vehicle containing sorbitan laurate (0.5% by weight), polysorbate 20 (0.2% by weight), and sodium chloride , (0.8% by weight) was selected as the main candidate and proposed in further studies. 7.0 Completion of Example I
[00156] The optimized Compound A-7 drug product (Compound A-7 recrystallized raw material drug substance suspended in a 10 mM phosphate buffer injection vehicle containing sorbitan laurate (0.5% per weight), polysorbate 20 (0.2% by weight), and sodium chloride, (0.8% by weight)) was identified for meeting all the desired criteria and exhibiting improved physical attributes (redispersibility, ease of wetting) when compared with the drug substance of recreated raw material of Compound A-7 (21% by weight) suspended in a vehicle of injection of 5 mM of phosphate buffer containing sodium carboxymethyl cellulose (2% by weight), polysorbate 20 (0.2% by weight), and sodium chloride, (0.7% by weight). The optimized formulation is physically and chemically stable when composed as a suspension of 21% by weight (approximately 221 mg / mL) and as a suspension of 25.6% by weight (approximately 270 mg / mL). EXAMPLE II - Performance Evaluation of Compound A-7 Suspensions Containing Varying Amounts of Sorbitan Laurate and Polysorbate 20: Optimization of Excipient Concentrations and Ratio of Sorbitan Laurate to Polysorbate 20
[00157] The purpose of this study is to evaluate the performance of formulating suspensions of Compound A-7 containing varying amounts and ratios of sorbitan laurate and polysorbate 20 in an attempt to establish a robust region for the drug product that meets all the desired product attributes.
[00158] A variety of vehicle formulations have been evaluated and a leading drug product candidate consisting of the recrystallized raw material drug substance from Compound A-7 (25.6% by weight) suspended in an injection vehicle. 10 mM phosphate buffer containing sorbitan laurate (0.5% by weight), polysorbate 20 (0.2% by weight), and sodium chloride, (0.8% by weight) was identified.
[00159] During development, the height of the sedimented bed and the qualitative easiness of resuspension were evaluated and used to identify a main formulation. Increases in these properties are associated with flocculation, a common mechanism used to increase the physical stability of pharmaceutical suspensions [Akers, M., Fites, A. and Robison, R. Formulation Design and Development of Parenteral Suspensions. Journal of Parenteral Science and Technology Vol. 41, No.3 (pp. 88-96), 1987; and Lieberman, Herbert A., Martin M. Reiger and Gilbert S. Banker. Pharmaceutical Dosage Forms: Disperse Systems Volume 2. (pp 18-22, 285-301) 2nd Ed. New York: Marcel Dekker, 1996.]. Flocculation refers to the formation of free aggregates held together by interparticular forces. The sediment layer in a flocculated suspension is freely free-compacted and more easily re-dispersed compared to non-flocculated formulations in which a dense mass can form. Additional experiments to quantify flocculation and formulation performance with vehicles containing varying amounts of sorbitan laurate and polysorbate 20 were designed, executed and analyzed. These follow-up experiments are detailed below. 5.2 METHODS Table 2: Quantities and ratios of surfactant components in examined vehicles
5.2.2 Composition of Compound A-7 Drug product
[00160] Compound A-7 suspensions (265 mg / mL ± 10%) were prepared by adding 3 mL of injection vehicles recorded in Table 1 to 1032 mg of drug substance from recrystallized Compound A raw material -7 in a 5ml siliconized glass bottle. Each bottle was sealed with a rubber stopper and an aluminum seal. Vials of suspensions were mixed by vortexing and tapping to facilitate the initial wetting of the solids. Each vial was then sonicated in a sonicator bath for 10 minutes, with ~ 5 seconds of vortexing every minute. 5.2.4 Measurement of suspension particle size
[00161] The formulated suspension particle size distribution was measured on a Horiba LA910 laser diffraction particle size analyzer equipped with a continuous flow sampling cell using a 0.1% polysorbate 20 solution as means of measurement. The suspension samples were prepared for measurement by resuspending the vial containing the drug product and then adding 0.1 ml of suspension to 10 ml of 0.1% polysorbate 20 solution. A sample was then added by dripping onto the cell. continuous flow sampling until dispersion transmittance drops below 95%. The particle size metric examined is the volume diameter where 10%, 50%, and 90% of the particle size distribution are smaller than the diameter (Dv [10]. Dv [50], and Dv [90]) . 5.2.5 Sediment Height Measurements
[00162] The sediment height was measured after allowing the bottles to rest uninterrupted for at least 24 hours. An approximate photo of all the flasks together was taken using a digital camera, with lighting so that the sediment layer can be clearly seen in the photo. The distance from the bottom of the flask to the surface of the liquid layer and to the surface of the sediment layer was measured from each photo. The ratio of line lengths for each bottle was calculated and reported as the sediment height in percentage, as shown in Figure 3. A sediment height of 100% could indicate that no sediment layer is visible. Injection capacity
[00163] The injection capacity was conducted to assess the capacity of the suspension that will pass through a 20 G needle or larger without obstruction, with minimal resistance applied through the use of a mesh screen. 5.2.7 Resuspension time
[00164] The resuspension time was measured using a Burrel pulse shaker. The flasks were then shaken at max amplitude on the shaker with a pulse motion in an inverted orientation (lid down) for 5-second intervals. The resuspension time is recorded when no visual mass or aggregate material is observed at the bottom of the flask. 5.2.8 Microscopy
[00165] For microscopic analysis, 5 μL of suspension was placed on a glass slide and then diluted with 20 μL of the same vehicle used to produce the suspension. The sample was covered with a glass cover and examined in 10x magnification using an Olympus BX60 microscope. Pictures were taken using an AxioCam MRc camera. 5.3 DESIGN OF EXPERIMENT
[00166] Using JMP 9 software, central composite expe- riment planning (DOE) was initiated with the concentration factors of SML (0 - 1% w / v) and polysorbate 20 (0.1 - 0 , 8% w / v). Previous experiments have shown that at least 0.1% polysorbate 20 is required to properly moisten a 25.6% load by weight of recrystallized Compound A-7 volume drug substance, therefore the lower limit of 0.1% is considered to be the lowest possible level of surfactants required to wet the highly hydrophobic crystals of Compound A-7. The final DOE factors are summarized in Table 3.Table 3: Design of Experiment Factors to consider varying concentrations of SML and polysorbate 20


[00167] The measured responses were: sediment height, resuspension time, particle size distribution (Dv [10], Dv [50], and Dv [90]), and injection capacity. Microscopy was also performed on each sample. 6.1 RESULTS AND DISCUSSION 6.2 Microscopy and Visual Observations
[00168] Microscopy of three suspensions made with vehicle containing 0.2% polysorbate 20 and increasing amounts of SML is shown in Figure 4. It is visually clear that flocculation is occurring as the SML content in the vehicle increases. PSD of measured suspension, recorded below each image in units of microns, increases in relation to the variability of the PSD method (approx. 2-3 microns) with an increased degree of flocculation. This observation is supported by using suspension particle size measurements to quantify the flocculation in which the method preparation maintains the vehicle-induced flocculation. The methodologies established by this type of pilot experiment facilitated the beginning of DOE experimentation. 6.3 DOE Answers
[00169] The desired Compound A-7 drug product formulation attributes include maximum ease of resuspension and injection capacity, the capacity of the suspension that will be passed through a 20 gauge needle or larger without obstruction with minimal resistance applied through the use of a mesh screen. Resuspension time, sediment height, and suspension particle size distribution are all physical measures of the formulated suspension used to assess resuspension ease. These responses are related since the particle size of the suspension can be a measure of flocculation, this increases the sediment height and reduces the resuspension time. A summary of all measured responses is recorded in Table 4.Table 4
6.4 Resuspension Time, Sediment Height and Particle Size Responses
[00170] A photograph of bottles containing suspension after sedimentation with sediment height calculations is shown in Figure5. In the two panels of Figure 6 are shown the observed resuspension time vs. Dv [10] and Dv [50] values for each suspension. The measured resuspension time and the particle size metric show an inverse relationship of suspensions with smaller measured particle size (below 11 and 32 microns for Dv [10] and Dv [50], respectively). Larger sizes of measured suspension particles, probably caused by flocculation, facilitate faster resuspension than smaller ones.
[00171] Particle size trends (Dv [10] and Dv [50]) with the vehicle composition were displayed resulting in surface graphics (not shown). Since the SML concentration increased and the polysorbate 20 concentrations decreased, the suspension particle size reflected by Dv [10] and Dv [50] increased. The smaller Dv [10] and Dv [50] were measured from suspensions containing polysorbate 20 without the addition of SML. For suspensions containing 0.1% polysorbate 20, Dv [10] and Dv [50] increased rapidly with the increase in SML. These data are compatible with the understanding that SML is required for the flocculation of the drug product, this results in an increase in the apparent suspension particle size and, therefore, in a reduction in the resuspension time. 6.5 Formulation Space
[00172] The desired Compound A-7 drug product is comprised of an injection vehicle that facilitates resuspension with optimum ease without decreasing the injection capacity of the suspension to an unacceptable level. Increases in measured suspension particle size parameters are directly correlated to the ease of resuspension, but inversely correlated to the injection capacity. So, a formulation with high% by weight of SML and low% by weight of polysorbate 20 could have the shortest resuspension time, but it could also have the worst injection capacity. The optimal vehicle composition is one where a balance between resuspension facility and injection capacity is achieved by balancing the amounts and ratios of SML and polysorbate 20. The profiles in Figure 6 show that when the measured suspension Dv [ 10] is greater than 11 μm or the measured suspension Dv [50] is greater than 32 microns, the optimal resuspension time is obtained. The values of 11 and 32 microns for Dv [10] and Dv [50], respectively, were used to impose limits within the modeled data to define the acceptable formulation space.
[00173] Previous experiments have shown that at least 0.1% of polysorbate 20 is required to properly wet a concentration of 25.6% by weight 256 mg / mL ± 10% of drug substance from recrystallized raw material from Compound A-7. To explain the small changes in the surface area of recrystallized Compound A-7 volume drug substance as well as the potential loss of polysorbate 20 in stability, at least 0.2% polysorbate 20 is recommended for the vehicle composition. In this concentration of polysorbate 20, a concentration of 0.5% of SML minimizes the levels of excipient while still increasing the resuspension capacity with acceptable injection capacity. This combination of surfactant is indicated in Figure 7 by the intersection of horizontal and vertical lines. 7.0 Completion of Example II
[00174] The formulation performance of Compound A-7 suspensions containing varying amounts and ratios of SML and polysorbate 20 was evaluated and a robust region for the drug product that fulfills all the desired product attributes was established. The suspension drug product of Compound A-7 formulated in an injection vehicle containing 0.5% SML and 0.2% polysorbate 20 is within the robust region of the formulation space, as derived from the DOE analysis performed. This vehicle composition minimizes excipient levels while co-optimizing resuspendability and acceptable injection. EXAMPLE III - INJECTION SITE REACTION MODULATION Subcutaneous Injection Site Reaction Model Protocol and Data
[00175] The following data and experimental protocol refer to the vehicle effect on the ISRs caused by subcutaneous administration (SC) of aripiprazole free base (ARP) in rats. Description of Experimental Planning:
[00176] Overview of experimental planning: There are 7 groups (n = 6) in this study that evaluate the ISRs caused by ARP formulated in 7 different vehicles; a standard vehicle was used as the control with which other vehicle compositions were compared. All groups received a single SC injection of ARP in a dose of 30 mg in a dose volume of 1 mL. A 1 inch 21 gauge needle attached to a 1 cc syringe was used to deliver the drug. Ten days after injection with ARP, the animals were euthanized by CO2 asphyxiation, and the ISR was excited and weighted. The weights of the ISRs were plotted against the administered dose. Materials and methods: Dose of Aripiprazole (ARP) 30 mg; Control Vehicle: 0.1% Polysorbate 20 (Tween® 20) /, 3% CMC, 0.9% NaCl in water Vehicle A: 0.2% Polysorbate 20 (Tween® 20) / 0.5 % sorbitan laurate (Span® 20) in PBS buffer (10 mM, pH ~ 7) Vehicle F: 0.2% Polysorbate 40 (Tween® 40) / 0.5% sorbitan monopalmitate (Span® 40) in PBS buffer (10 mM, pH ~ 7) RELPREVV® vehicle: CMC, mannitol, polysorbate 80, sodium hydroxide and / or hydrochloric acid for pH adjustment, and water for injection Number of study animals: 42 ; age: at least 6 to 8 weeks; Body weight range: 300-350 grams upon prescription from the supplier. Description of experiment, animal allocation and procedures:
[00177] Test Period Procedures: The animals were dosed with ARP on Day 0. On the 10th study day, all animals were euthanized, and the injection site reaction tissue / material was recovered surgically and immediately heavy.
[00178] Figures 8A and 8B demonstrate that formulations comprising sorbitan laurate demonstrated a significant reduction in injection site reaction compared to formulations without sorbitan laurate. Figure 8A shows results of experiments with aripiprazole (free base), and Figure 8B shows the results of experiments with olanzapine pamoate. EXAMPLE IV - A-7 COMPOUND SOLUBILITY IN VEHICLES CONTAINING VARIOUS QUANTITIES OF SORBITAN MONOLAND - Sample preparation: a. Injection vehicles comprised of ca. 10 mM phosphate buffer, 0.2% polysorbate 20, saline and varying amounts of sorbitan laurate (0% -0.75%) were prepared. The injection vehicles were agitated for 4 hours before preparing the suspension preparation. B. Approximately 1.25 ± 0.05 g of Compound A-7 was added to 15 mL of injection vehicles in a 20-mL glass scintillation vial with a 7/8 ”X 5/16” stir bar. The suspension was vigorously stirred on a hot glass Chem-glass CG-1990-T-50 at 25 oC which was controlled using a thermal sensor. ç. At each time point, a total of 3 mL of mixed suspension were transferred to two 1.5mL centrifugal tubes using a plastic pipette. The tubes were centrifuged at 14,000 rpm for 4 minutes. The supernatant from both tubes was combined and centrifuged again at 14,000 rpm for 4 minutes. The HPLC sample was then prepared with a final centrifuged supernatant (2nd) by diluting 0.4 ml of supernatant with 0.6 ml of THF. d. The concentration of dissolved Compound A-7 was determined using HPLC.
[00179] The data illustrated in Figure 9 highlights the trends in concentration of Compound A-7 in solution as a function of SML content in the injection vehicle. Surprisingly, the addition of a second surfactant, SML, reduces the solubility by 0.5% by weight of SML with the solubility increasing again above 0.5% by weight (for example, 0.75% by weight) (intermediate line ). EXAMPLE V - PROPHARMACEUTICAL SYNTHESIS PROCEDURES Synthesis of Aripiprazole Prodrugs
Compound A-1: Preparation of 7- (4- (4- (2,3-dichlorophenyl) piperazin-1-yl) butoxy) -1- (hydroxymethyl) -3,4-dihydroquinolin-2 (1H) - ona
[00180] A mixture of Aripiprazole (20g, 45 mmol), triethylamine (1mL, 7.1 mmol), formaldehyde (37% aqueous solution, 70 mL) and dimethylformamide (200 mL) was heated at 80 ° C for 20 h . The reaction mixture was cooled, diluted with ethyl acetate (400 ml) and washed with water / brine (1: 1, 3 x 500 ml). The organic phase was dried over MgSO4, filtered and evaporated to dryness in vacuo to obtain hemiaminal A-1 as a white solid (18.6 g, containing 25% Aripiprazole, 65% yield based on A-1). 1: (7- (4- (4- (2,3-dichlorophenyl) piperazin-1-yl) butoxy) -2-oxo-3,4-dihydroquinolin-1 (2H) -yl) methyl acetate

[00181] A solution of Compound A-1 (50.63 g, 0.105 mol) in anhydrous tetrahydrofuran (THF, 80 ml) was treated with acetic anhydride (15.3 ml, 0.16 mol) and heated for 2 hours. 60oC (oil bath). To the above solution, triethylamine (2.0 mL, 0.014 mol) was added and stirred for 16 hours at 60 ° C. The solvent was removed using a rotary evaporator. To the resulting crude mixture, ethyl acetate (150 ml) and heptane (50 ml) were added. The solution was washed with NaHCO3 (5% aqueous solution, 250 ml). After separating the two layers, the pH of the aqueous layer was adjusted to above 7. The aqueous layer was further extracted using the organic mixture. The organic layer was separated and washed with 5% NaHCO3 solution, followed by deionized water, and brine. The solution was dried using anhydrous MgSO4, filtered and evaporated in vacuo. The resulting product was purified using silica gel column chromatography using ethanol: ethyl acetate (5:95) as the eluant. The fractions containing the desired product were combined and d-tartaric acid (12.5 g dissolved in 60: 5 ethanol: water) was added, resulting in the precipitation of the desired product (48.78 g, 89% yield), 1H NMR (CDCl3, 300MHz) δ 1.73 (m, 2H), 1.84 (m, 2H), 2.12 (s, 3H), 2.50 (t, 2H), 2.68 (m, 6H), 2.87 (dd, 2H), 3.08 (m, 4H), 3.98 (t, 2H), 5.91 (s, 2H), 6.59 (m, 2H), 6, 96 (dd, 1H), 7.08 (dd, 1H), 7.15 (m, 2H). Compound A-7: (7- (4- (4- (2,3-dichlorophenyl) piperazin dodecanoate) 1-yl) butoxy) -2-oxo-3,4-dihydroquinolin-1 (2H) -yl) methyl

[00182] Compound A-7 was prepared analogously to Compound 1. The desired product was isolated as a crystalline solid (0.3 g, 21% yield). The molecular weight was confirmed by mass spectrometry analysis. Figure 2-6 shows the PXRD, IR, Raman, TGA spectrum of the desired product. 1H NMR (CDCl3, 300MHz) δ 0.87 (t, 3H), 1.24 (m, 16H), 1.62 (m, 2H), 1.83 (m, 2H), 1.86 (m, 2H), 2.36 (t, 2H), 2.49 (t, 2H), 2.68 (m, 6H), 2.86 (dd, 2H), 3.08 (m, 4H), 3, 97 (t, 2H), 5.91 (s, 2H), 6.59 (m, 2H), 6.96 (dd, 1H), 7.07 (dd, 1H), 7.14 (m, 2H ). Compound A-28: (7- (4- (4- (2,3-dichlorophenyl) piperazin-1-yl) butoxy) -2-oxo-3,4-dihydroquinolin-1 (2H) benzylcarbamate - il) methyl

[00183] To a solution of hemi-aminal A1 (4 g, 8.4 mmol), 4-dimethylaminopyridine (0.15 g, 1.3 mmol) and triethylamine (1.1 mL, 7.5 mmol) in dichloromethane ( 30 ml) benzylisocyanate (1.03 ml, 8.3 mmol) was added and the reaction mixture stirred for 24 hours. The reaction mixture was then heated to 35 ° C for 20 hours, cooled and washed with water / brine (1: 1, 50 ml). The organic phase was dried over MgSO4, filtered and evaporated in vacuo. The residue was further purified by chromatography on silica elution with ethyl acetate / dichloromethane / methanol (1: 1: 0.1) to obtain the desired product as an off-white foam (530 mg, 14% yield). 1H NMR (CDCl3, 300MHz) δ 1.58-1.88 (m, 4H), 2.48 (t, 2H), 2.60-2.72 (m, 6H), 2.85 (m, 2H ), 300-3.12 (m, 4H), 3.96 (t, 2H), 4.40 (d, 2H), 5.13 (NH), 5.96 (s, 2H), 6.58 (dd, 1H), 6.79 (d, 1H), 6.92-6.98 (m, 1H), 7.04 (d, 1H), 7.12-7.16 (m, 1H), 7.23-7.35 (m, 6H); m / z (M + H) 611.12 and 613.10. Compound A-4: (7- (4- (4- (2,3-dichlorophenyl) piperazin-1-yl) butoxy) -2- hexanoate oxo-3,4-dihydroquinolin-1 (2H) -yl) methyl

[00184] Compound A-4 was prepared in a similar manner to Compound A-28. The desired product was isolated as a yellow solid (3.69g, 87% yield). 1H NMR (CDCl3, 300MHz) δ 0.78 (t, 3H), 1.11-1.28 (m, 4H), 1.40-1.78 (m, 6H), 2.20-2.40 (m, 4H), 2.40-2.60 (m, 6H), 2.73-2.81 (m, 2H), 2.85-3.00 (m, 4H), 3.88-4 .00 (m, 2H), 5,755.83 (m, 2H), 6.55-6.62 (m, 2H), 7.03-7.12 (m, 2H), 7.20-7.26 (m, 2H), m / z (M + H) 576.4 and 578.4.

权利要求:
Claims (26)
[0001]
1. Pharmaceutical composition, characterized by the fact that it comprises: (a) a compound A-7:
[0002]
2. Composition according to claim 1, characterized by the fact that the composition comprises components (b) and (c) in a ratio that results in flakes comprising component (a), in which the flakes sediment beyond a predetermined sediment bed height, so that components (a), (b) and (c) can be resuspended for injection.
[0003]
3. Composition according to claim 2, characterized by the fact that the bed height is comprised of at least a 20 to 80% increase in sediment height compared to a non-flocculated composition after 24 hours of uninterrupted rest .
[0004]
4. Composition according to claim 2, characterized by the fact that components (a), (b) and (c) can be resuspended for injection within 1 to 60 seconds of manual agitation.
[0005]
5. Composition according to claim 1, characterized by the fact that the ratio of components (b) to (c) is such that the composition can be injected using a 20 to 25 gauge needle.
[0006]
6. Composition according to claim 2, characterized by the fact that (a), (b), and (c) form flakes that have the following sizes: Dv [10]: 2-10μm, Dv [ 50]: 10-30μm, and Dv [90]: less than 65 μm.
[0007]
7. Composition according to claim 1, characterized by the fact that the ratio of components (b) to (c) is 5 to 2, by weight.
[0008]
8. Composition according to claim 1, characterized by the fact that it comprises 0.2 to 1 percent by weight of sorbitan laurate.
[0009]
9. Composition according to claim 1, characterized by the fact that it comprises 0.05 to 0.8 percent by weight of polysorbate 20.
[0010]
10. Composition according to claim 1, characterized by the fact that it comprises 0.1 to 0.3 percent by weight of polysorbate 20.
[0011]
11. Composition according to claim 1, characterized by the fact that it comprises from 15 to 35 percent by weight of compound A-7.
[0012]
12. Composition according to claim 1, characterized by the fact that it comprises from 20 to 30 percent by weight of compound A-7.
[0013]
13. Composition according to claim 1, characterized by the fact that it is an injectable pharmaceutical composition comprising: (a) compound A-7:
[0014]
14. Composition according to claim 1, characterized by the fact that it is an injectable composition comprising: (a) compound A-7:
[0015]
15. Composition according to claim 14, characterized by the fact that the composition is formulated to modulate the tissue reaction associated with the application of a water-insoluble antipsychotic agent.
[0016]
16. Composition according to claim 15, characterized by the fact that the modulation of the tissue reaction is a reduction in irritation at the injection site.
[0017]
17. Composition according to claim 14, characterized in that the composition additionally comprises a plug.
[0018]
18. Composition according to claim 17, characterized by the fact that the buffer is a phosphate, citrate, tartrate or acetate buffer.
[0019]
19. Composition according to claim 1, characterized by the fact that it is a pharmaceutical composition that comprises: (a) 24 to 30 weight percent of compound A-7
[0020]
20. Use of compound A-7, sorbitan laurate and polysorbate 20, characterized by the fact that it is in the preparation of a pharmaceutical composition, as defined in any of claims 1 to 18, for the treatment of disorders of the central nervous system, in which disorders of the central nervous system are selected from the group consisting of anxiety, depression, bipolar disorder and irritability related to autism; or disorders of the central nervous system are a psychotic condition selected from the group consisting of schizophrenia, schizophreniform diseases and acute mania.
[0021]
21. Use according to claim 19, characterized by the fact that the disorder is anxiety or depression.
[0022]
22. Use according to claim 19, characterized by the fact that the disorder is bipolar disorder.
[0023]
23. Use according to claim 19, characterized by the fact that the disorder is irritability related to autism.
[0024]
24. Use according to claim 19, characterized by the fact that the disorder is a psychotic condition.
[0025]
25. Use according to claim 24, characterized by the fact that the psychotic condition is schizophrenia or schizophreniform diseases.
[0026]
26. Use according to claim 24, characterized by the fact that the psychotic condition is acute mania.

类似技术:

---

公开号 | 公开日 | 专利标题

---

US10226458B2|2019-03-12|Pharmaceutical compositions comprising sorbitan esters

---

US9999670B2|2018-06-19|Pharmaceutical compositions comprising benzyl alcohol

---

ES2792149T3|2020-11-10|Pharmaceutical Compositions Having Improved Storage Stability

---

US9993556B2|2018-06-12|Pharmaceutical compositions comprising fatty glycerol esters

---

CN109922808A|2019-06-21|Liposomal formulation for treating cancer

---

NZ733047B2|2019-03-22|Pharmaceutical compositions comprising sorbitan esters

---

NZ713984B2|2018-01-04|Pharmaceutical compositions comprising sorbitan esters

---

NZ615513B2|2016-05-03|Pharmaceutical compositions comprising sorbitan esters

同族专利:

---

公开号 | 公开日

---

SI2685979T1|2017-04-26|

---

AU2012231160B2|2017-04-06|

---

JP2017141292A|2017-08-17|

---

RS55434B1|2017-04-28|

---

NZ733047A|2018-12-21|

---

EP3156056A1|2017-04-19|

---

US20170196856A1|2017-07-13|

---

CN107252414A|2017-10-17|

---

AU2017204486A1|2017-07-20|

---

AU2012231160A1|2013-10-03|

---

CN107252414B|2020-11-24|

---

EP2685979B1|2016-08-24|

---

IL253221D0|2017-08-31|

---

US20160038508A1|2016-02-11|

---

CY1118252T1|2017-06-28|

---

US9034867B2|2015-05-19|

---

HRP20161549T1|2016-12-30|

---

PT2685979T|2016-12-02|

---

MX358344B|2018-08-15|

---

RU2017126606A|2019-02-01|

---

JP2014508176A|2014-04-03|

---

JP6138703B2|2017-05-31|

---

US20190216805A1|2019-07-18|

---

IL228298A|2018-01-31|

---

BR112013023847A2|2016-12-13|

---

PL2685979T3|2017-02-28|

---

RU2627469C2|2017-08-08|

---

CN103561746B|2018-05-29|

---

RU2013146542A|2015-04-27|

---

IL276012D0|2020-08-31|

---

EP2685979A1|2014-01-22|

---

JP6765464B2|2020-10-07|

---

RU2017126606A3|2020-11-12|

---

AU2020250309A1|2020-11-05|

---

RU2757859C2|2021-10-21|

---

HUE032109T2|2017-08-28|

---

WO2012129156A1|2012-09-27|

---

IL253221A|2020-09-30|

---

AU2019202633A1|2019-05-09|

---

US9351976B2|2016-05-31|

---

ES2604558T3|2017-03-07|

---

JP2019085417A|2019-06-06|

---

US10226458B2|2019-03-12|

---

LT2685979T|2016-12-12|

---

NZ615513A|2016-01-29|

---

US20120238552A1|2012-09-20|

---

CN103561746A|2014-02-05|

---

NZ713984A|2017-09-29|

---

DK2685979T3|2016-12-19|

---

CN112451477A|2021-03-09|

---

SMT201600423B|2017-01-10|

---

AU2017204486B2|2019-01-17|

---

CA2830511A1|2012-09-27|

---

US20150258115A1|2015-09-17|

---

MX2013010471A|2014-03-05|

---

CA2830511C|2021-09-14|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

US2418499A|1944-06-20|1947-04-08|Du Pont|2-alkoxymethylmercapto-thiazoles and thiazolines and a process for preparing the same|

---

GB849541A|1956-02-23|1960-09-28|Rohm & Haas|Preparation of unsaturated cyclic urea derivatives|

---

DE1273533B|1962-09-08|1968-07-25|Hoechst Ag|Process for the preparation of N- -carboxylic acid amides|

---

NL128370C|1964-08-28|

---

US3452034A|1967-03-09|1969-06-24|American Cyanamid Co|Substituted 2--4-nitroimidazoles|

---

US3573308A|1969-04-03|1971-03-30|Hoffmann La Roche|3-lower alkoxy methyl-3,4-dihydro-4-hydroxy-4-aryl quinazolin-2 ones and related compounds|

---

US3957808A|1969-09-03|1976-05-18|Rohm And Haas Company|3-alkoxyisothiazoles|

---

US4727151A|1974-06-24|1988-02-23|Interx Research Corporation|Labile quaternary ammonium salts as prodrugs|

---

US3998815A|1974-06-24|1976-12-21|Interx Research Corporation|1-hydrocarbonoyloxymethyl-3-carbamoyl or 3-carboethoxy-pyridinium salts|

---

US4204065A|1975-09-22|1980-05-20|Interx Research Corporation|Soft quaternary surface active agents and method of using same|

---

US4260769A|1977-04-22|1981-04-07|Interx Research Corporation|5,5-Diphenylhydantoins|

---

JPS6223750B2|1978-03-30|1987-05-25|Otsuka Pharma Co Ltd|

---

JPS568318A|1979-06-28|1981-01-28|Janssen Pharmaceutica Nv|Non oral long acting composition of haloperidol and bromperidol derivative|

---

DE3149010A1|1981-12-10|1983-07-07|A. Nattermann & Cie GmbH, 5000 Köln| - 2- -ETHYL) -1,3- DIAZACYCLOPENT-2-EN, THE PRODUCTION AND THEIR USE IN PHARMACEUTICAL PREPARATIONS|

---

US4428935A|1982-05-24|1984-01-31|Pfizer Inc.|Penicillanic acid dioxide prodrug|

---

IT1212743B|1983-05-17|1989-11-30|Dompe Farmaceutici Spa|QUATERNARY SALTS OF BENZO DERIVATIVES [1,4] DIAZEPINONICS, PYRID [1,4] BENZODIAZEPINONICS, PRIDO [1,5] BENZODIAZEPINONICS AND THEIR PHARMACOLOGICAL LIFE ACTS|

---

JPH0422687B2|1983-06-20|1992-04-20|Yoshino Kogyosho Co Ltd|

---

US4760057A|1983-06-23|1988-07-26|Merck & Co., Inc.|carbonyl derivatives as bioreversible prodrug moieties for primary and secondary amine functions in drugs|

---

DK302883D0|1983-06-30|1983-06-30|Hans Bundgaard|ALLOPURINOL PRODUCTS|

---

DE3544134C2|1984-12-15|1991-06-06|Mitsubishi Kasei Corp., Tokio/Tokyo, Jp|

---

GB8513754D0|1985-05-31|1985-07-03|Jones T R|Anti-cancer quinazoline derivatives|

---

DK588486A|1985-12-09|1987-06-10|Otsuka Pharma Co Ltd|USE OF A COMPOUND TO TREAT HYPOXY|

---

GB8607683D0|1986-03-27|1986-04-30|Ici Plc|Anti-tumor agents|

---

US4925860A|1987-08-05|1990-05-15|E. I. Du Pont De Nemours And Company|Stable pharmaceutical composition of 3--5,5-diphenylhydantoin disodium phosphate ester|

---

US5006528A|1988-10-31|1991-04-09|Otsuka Pharmaceutical Co., Ltd.|Carbostyril derivatives|

---

WO1991000863A1|1989-07-07|1991-01-24|Pfizer Inc.|Heteroaryl piperazine antipsychotic agents|

---

US5350747A|1989-07-07|1994-09-27|Pfizer Inc|Heteroaryl piperazine antipsychotic agents|

---

US5229382A|1990-04-25|1993-07-20|Lilly Industries Limited|2-methyl-thieno-benzodiazepine|

---

JP2800953B2|1990-07-06|1998-09-21|住友製薬株式会社|New imide derivatives|

---

US5206386A|1991-03-20|1993-04-27|Isp Investments Inc.|Controlled release N-substituted pyrrolidone esters and process for the use thereof|

---

AU645681B2|1991-05-02|1994-01-20|John Wyeth & Brother Limited|Piperazine derivatives|

---

TW226016B|1991-12-30|1994-07-01|Sterling Winthrop Inc|

---

US5462934A|1992-03-09|1995-10-31|Takeda Chemical Industries|Condensed heterocyclic ketone derivatives and their use|

---

AU4534593A|1992-06-12|1994-01-04|Affymax Technologies N.V.|Compositions and methods for enhanced drug delivery|

---

JP3526575B2|1993-03-08|2004-05-17|エーザイ株式会社|Phosphonic acid derivatives|

---

TW376319B|1993-04-28|1999-12-11|Janssen Pharmaceutica Nv|Pharmaceutical composition containing risperidone pamoate and having a long acting activity for treating psychoses induced by the release of dopamine|

---

DE4439493A1|1994-10-25|1996-05-02|Schering Ag|New quinoxalinedione derivatives, their production and use in pharmaceuticals|

---

JP3571795B2|1995-04-18|2004-09-29|株式会社日本触媒|Catalyst for gas-phase intramolecular dealcoholation reaction of N- carbamates and method for producing N-vinyl carbamates|

---

US7833543B2|1995-06-07|2010-11-16|Durect Corporation|High viscosity liquid controlled delivery system and medical or surgical device|

---

CA2250187A1|1996-03-25|1997-10-02|Eli Lilly And Company|Composition comprising olanzapine and a drug useful in the treatment of pain for use in the treatment of pain|

---

DE19619819A1|1996-05-16|1997-11-20|Boehringer Mannheim Gmbh|New thiazolidinediones, process for their preparation and medicaments containing them|

---

HU226608B1|1996-08-22|2009-04-28|Rtp Pharma Corp|Compositions comprising microparticles of water-insoluble substances and method for preparing same|

---

EP0986403B1|1997-06-13|2003-11-12|Cydex Inc.|Composition with extended shelf-life storage comprisingcyclodextrin and drugs or prodrugs that decompose to water-insoluble components|

---

JP4503826B2|1997-09-30|2010-07-14|イーライリリーアンドカンパニー|2-Methyl-thieno-benzodiazepine formulation|

---

AP1228A|1997-11-17|2003-11-12|Janssen Pharmaceutica Nv|Aqueous suspensions of submicron 9-hydroxyrisperidone fatty acid esters.|

---

US6180095B1|1997-12-17|2001-01-30|Enzon, Inc.|Polymeric prodrugs of amino- and hydroxyl-containing bioactive agents|

---

AT261730T|1997-12-31|2004-04-15|Univ Kansas|WATER-SOLUBLE MEDICINE PRE-STAGES OF TERTICAL AMINE-CONTAINING MEDICINES AND METHOD FOR THE PRODUCTION THEREOF|

---

EP1114028B1|1998-08-26|2006-11-29|Aventis Pharma Limited|Aza-bicycles which modulate the inhibition of cell adhesion|

---

FR2783519B1|1998-09-23|2003-01-24|Sod Conseils Rech Applic|NOVEL AMIDINE DERIVATIVES, THEIR PREPARATION, THEIR USE AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|

---

US7374779B2|1999-02-26|2008-05-20|Lipocine, Inc.|Pharmaceutical formulations and systems for improved absorption and multistage release of active agents|

---

US20060034937A1|1999-11-23|2006-02-16|Mahesh Patel|Solid carriers for improved delivery of active ingredients in pharmaceutical compositions|

---

CA2311734C|2000-04-12|2011-03-08|Bristol-Myers Squibb Company|Flash-melt oral dosage formulation|

---

MY128450A|2000-05-24|2007-02-28|Upjohn Co|1--3--2-indolinone derivatives|

---

US6656505B2|2000-07-21|2003-12-02|Alpharma Uspd Inc.|Method for forming an aqueous flocculated suspension|

---

US20030049320A1|2000-12-18|2003-03-13|Wockhardt Limited|Novel in-situ forming controlled release microcarrier delivery system|

---

US7053092B2|2001-01-29|2006-05-30|Otsuka Pharmaceutical Co., Ltd.|5-HT1a receptor subtype agonist|

---

WO2002064578A1|2001-02-14|2002-08-22|Warner-Lambert Company Llc|Benzo thiadiazine matrix metalloproteinase inhibitors|

---

JP2005511477A|2001-03-19|2005-04-28|プラエシスファーマシューティカルズインコーポレーテッド|Pharmaceutical formulations for sustained release|

---

US20060293217A1|2001-03-19|2006-12-28|Praecis Pharmaceuticals, Inc.|Pharmaceutical formulations for sustained release|

---

US6686377B2|2001-04-03|2004-02-03|Aryx Therapeutics|Ultrashort-acting opioids for transdermal application|

---

MY129350A|2001-04-25|2007-03-30|Squibb Bristol Myers Co|Aripiprazole oral solution|

---

AR033485A1|2001-09-25|2003-12-26|Otsuka Pharma Co Ltd|MEDICINAL SUBSTANCE OF ARIPIPRAZOL OF LOW HYGROSCOPICITY AND PROCESS FOR THE PREPARATION OF THE SAME|

---

AU2003245773A1|2002-02-15|2003-09-04|Glaxo Group Limited|Vanilloid receptor modulators|

---

ES2294330T3|2002-08-02|2008-04-01|MERCK &amp; CO., INC.|FURO DERIVATIVES SUBSTITUTED PYRIDINE.|

---

CA2495864C|2002-08-20|2011-09-27|Bristol-Myers Squibb Company|Aripiprazole complex formulation and method|

---

OA12923A|2002-09-17|2006-10-13|Warner Lambert Co|Heterocyclic substituted piperazines for the treatment of schizophrenia.|

---

US7148211B2|2002-09-18|2006-12-12|Genzyme Corporation|Formulation for lipophilic agents|

---

EA011708B1|2002-12-18|2009-04-28|Алгоркс Фармасьютикалз, Инк.|Administration of trans capsaicin|

---

EP1587506B1|2002-12-18|2008-07-23|Algorx|Administration of capsaicinoids|

---

DE10303669A1|2003-01-28|2004-07-29|Hans-Knöll-Institut für Naturstoff-Forschung e.V.|New quaternary ammonioalkyl carbonate esters useful for treating bacterial and fungal infections and potentially useful for regulating cholesterol biosynthesis|

---

MXPA05010471A|2003-04-03|2006-05-25|Semafore Pharmaceuticals Inc|Pi-3 kinase inhibitor prodrugs.|

---

MXPA05012538A|2003-05-23|2006-02-22|Otsuka Pharma Co Ltd|Carbostyril derivatives and mood stabilizers for treating mood disorders.|

---

AT392905T|2003-07-24|2008-05-15|Merial Ltd|VACCINE FORMULATIONS WITH OIL-IN-WATER EMULSION|

---

US20050032811A1|2003-08-06|2005-02-10|Josiah Brown|Methods for administering aripiprazole|

---

US6987111B2|2003-08-06|2006-01-17|Alkermes Controlled Therapeutics, Ii|Aripiprazole, olanzapine and haloperidol pamoate salts|

---

US7160888B2|2003-08-22|2007-01-09|Warner Lambert Company Llc|[1,8]naphthyridin-2-ones and related compounds for the treatment of schizophrenia|

---

WO2005022155A1|2003-08-29|2005-03-10|Kabushiki Kaisha Toshiba|Color reagent, concentration measuring kit, method of concentration measuring and sensor chip for use therein|

---

NZ546063A|2003-10-23|2009-05-31|Otsuka Pharma Co Ltd|Controlled release sterile injectable aripiprazole -1-piperazinyl]-butoxy]-3,4-dihydro-2-quinolinone) formulation and method|

---

EP1701954A1|2003-12-31|2006-09-20|Warner-Lambert Company LLC|N-substituted piperidine and piperazine derivatives|

---

WO2005079807A1|2004-02-13|2005-09-01|Pfizer Products Inc.|Therapeutic combinations of atypical antipsychotics with corticotropin releasing factor antagonists|

---

US7169803B2|2004-03-15|2007-01-30|Bristol-Myers Squibb Company|N-substituted prodrugs of fluorooxindoles|

---

US7119214B2|2004-04-13|2006-10-10|Cephalon France|Thio-substituted tricyclic and bicyclic aromatic methanesulfinyl derivatives|

---

GB2413795A|2004-05-05|2005-11-09|Cipla Ltd|Process for the preparation of rosiglitazone|

---

WO2006037090A2|2004-09-28|2006-04-06|Purdue Research Foundation|Drug-phosphate conjugates as prodrugs|

---

CN101106972A|2004-11-16|2008-01-16|伊兰制药国际有限公司|Injectable nanoparticulate olanzapine formulations|

---

EP1848541A4|2005-02-07|2013-01-16|Pharmalight Inc|Method and device for ophthalmic administration of active pharmaceutical ingredients|

---

WO2006090273A2|2005-02-22|2006-08-31|Warner-Lambert Company Llc|[1,8]naphthyridin-2-ones and related compounds with keto or hydroxyl linkers for the treatment of schizophrenia|

---

WO2006134864A1|2005-06-13|2006-12-21|Dainippon Sumitomo Pharma Co., Ltd.|Solubilization preparation|

---

WO2007035348A2|2005-09-15|2007-03-29|Elan Pharma International, Limited|Nanoparticulate aripiprazole formulations|

---

EP1777222A1|2005-09-22|2007-04-25|Galantos Pharma GmbH|Cholinergic enhancers with improved blood-brain barrier permeability for the treatment of diseases accompanied by cognitive impairment|

---

WO2007059111A2|2005-11-14|2007-05-24|Entremed, Inc.|Anti-angiogenic activity of 2-methoxyestradiol in combination with anti-cancer agents|

---

US20090068290A1|2006-08-31|2009-03-12|Michel Bourin|Bifeprunox doses for treating schizophrenia|

---

CL2007002684A1|2006-09-15|2008-06-27|Astrazeneca Ab Targacept Inc|COMBINATION THAT INCLUDES AN ANTIPSYCHOTIC AND - -N-METIL-5- [3- IL] -4-PENTEN-2-AMINA; PHARMACEUTICAL COMPOSITION THAT UNDERSTANDS IT; PHARMACEUTICAL KIT; AND USE TO TREAT COGNITIVE INJURY AND / OR PSYCHOTIC DISORDER.|

---

WO2008041246A2|2006-10-05|2008-04-10|Panacea Biotec Ltd.|Injectable depot composition and its' process of preparation|

---

US20090291134A1|2006-11-21|2009-11-26|Jina Pharmaceuticals, Inc.|Endoxifen methods and compositions in the treatment of psychiatric and neurodegenerative diseases|

---

EP2121029A2|2006-12-05|2009-11-25|Neurogesx, Inc.|Prodrugs and methods of making and using the same|

---

CA2672270A1|2006-12-15|2008-06-26|Gennadi V. Glinksy|Treatments of therapy resistant diseases and drug combinations for treating the same|

---

EP1961412A1|2006-12-27|2008-08-27|LEK Pharmaceuticals D.D.|Self-microemulsifying drug delivery systems|

---

US20080186971A1|2007-02-02|2008-08-07|Tarari, Inc.|Systems and methods for processing access control lists in network switches using regular expression matching logic|

---

JP2010522198A|2007-03-19|2010-07-01|アカドイアプハルマセウチカルスインコーポレーテッド|Combination of 5-HT2A inverse agonists and antagonists with antipsychotics|

---

KR101562835B1|2007-04-04|2015-10-23|머크 샤프 앤드 돔 코포레이션|Therapeutic agents|

---

US20100292316A1|2007-07-18|2010-11-18|Research Development Foundation|Improved therapeutic methods and compositions comprising chroman ring compounds|

---

TW201402117A|2007-08-02|2014-01-16|Targacept Inc|-N-methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide, novel salt forms, and methods of use thereof|

---

WO2009052467A1|2007-10-19|2009-04-23|Board Of Regents Of The University Of Texas System|Methods of identifying pi-3-kinase inhibitor resistance|

---

CL2008003305A1|2007-11-06|2009-06-05|M/S Panacea Biotec Ltd|Injectable composition comprising an active agent selected from a defined group; at least one bioerodible polymer, at least one non-toxic solvent and optionally one or more excipients; Preparation process; use to treat mental illness or cancer.|

---

EP2234617B1|2007-12-19|2021-03-31|Janssen Pharmaceutica NV|Dosing regimen associated with long acting injectable paliperidone esters|

---

CA2709784A1|2007-12-21|2009-07-09|University Of Rochester|Method for altering the lifespan of eukaryotic organisms|

---

US9161943B2|2007-12-31|2015-10-20|Industrial Technology Research Institute|Sustained release composition and manufacturing method thereof|

---

US8138169B2|2008-04-11|2012-03-20|Comgenrx, Inc.|Combination therapy for bipolar disorder|

---

CN101345838A|2008-08-04|2009-01-14|华为技术有限公司|TV program navigation method, apparatus and system|

---

JP2012501971A|2008-09-03|2012-01-26|バーテックスファーマシューティカルズインコーポレイテッド|Co-crystals and pharmaceutical formulations containing co-crystals|

---

US20100203129A1|2009-01-26|2010-08-12|Egalet A/S|Controlled release formulations with continuous efficacy|

---

US20100286136A1|2009-05-08|2010-11-11|Simon Jones|Dihydronaphthyridinyl and related compounds for use in treating ophthalmological disorders|

---

PT2445502T|2009-06-25|2017-09-22|Alkermes Pharma Ireland Ltd|Heterocyclic compounds for the treatment of neurological and psychological disorders|

---

CA2766033C|2009-06-25|2016-09-20|Alkermes, Inc.|Prodrugs of nh-acidic compounds|

---

MX2012005083A|2009-10-30|2012-09-28|Janssen Pharmaceutica Nv|Dosing regimen associated with long-acting injectable paliperidone esters.|

---

AU2010339691B2|2010-01-07|2015-04-02|Alkermes Pharma Ireland Limited|Prodrugs of heteraromatic compounds|

---

WO2011084850A1|2010-01-07|2011-07-14|Alkermes, Inc.|Prodrugs for the treatment of schizophrenia and bipolar disease|

---

JP6076740B2|2010-01-07|2017-02-08|アルカーメス ファーマ アイルランド リミテッド|Quaternary ammonium salt prodrug|

---

US20110166128A1|2010-01-07|2011-07-07|Alkermes, Inc.|Diaryldiazepine Prodrugs for the Treatment of Neurological and Psychological Disorders|

---

US20110166194A1|2010-01-07|2011-07-07|Alkermes, Inc.|Asenapine Prodrugs|

---

CN104111233B|2010-02-16|2017-09-15|浜松光子学株式会社|Gas concentration calculates device and gas concentration measurement module|

---

US8536328B2|2010-05-04|2013-09-17|Alkermes Pharma Ireland Limited|Process for synthesizing oxidized lactam compounds|

---

AU2011270701B2|2010-06-24|2015-05-14|Alkermes Pharma Ireland Limited|Prodrugs of NH-acidic compounds: ester, carbonate, carbamate and phosphonate derivatives|

---

EP2685979B1|2011-03-18|2016-08-24|Alkermes Pharma Ireland Limited|Injectable pharmaceutical compositions comprising a water-insoluble anti-psychotic, sorbitan laurate and polysorbate 20|

---

CA2867137C|2012-03-19|2020-12-08|Alkermes Pharma Ireland Limited|Pharmaceutical compositions comprising aripiprazole prodrugs and benzyl alcohol|

---

AU2013235523B9|2012-03-19|2018-01-04|Alkermes Pharma Ireland Limited|Pharmaceutical compositions comprising glycerol esters|

---

US10004807B2|2012-03-19|2018-06-26|Alkermes Pharma Ireland Limited|Pharmaceutical compositions comprising fatty acid esters|

---

NZ748572A|2012-09-19|2020-07-31|Alkermes Pharma Ireland Ltd|Pharmaceutical compositions having improved storage stability|

---

CN110368360A|2014-03-20|2019-10-25|奥克梅斯制药爱尔兰有限公司|Aripiprazole formulations with increased injection speed|PT2445502T|2009-06-25|2017-09-22|Alkermes Pharma Ireland Ltd|Heterocyclic compounds for the treatment of neurological and psychological disorders|

---

EP2685979B1|2011-03-18|2016-08-24|Alkermes Pharma Ireland Limited|Injectable pharmaceutical compositions comprising a water-insoluble anti-psychotic, sorbitan laurate and polysorbate 20|

---

JO3227B1|2011-09-08|2018-03-08|Otsuka Pharma Co Ltd|Piperazine-substituted benzothiophene deriveatives as antipsychotic agents|

---

AU2013235523B9|2012-03-19|2018-01-04|Alkermes Pharma Ireland Limited|Pharmaceutical compositions comprising glycerol esters|

---

US10004807B2|2012-03-19|2018-06-26|Alkermes Pharma Ireland Limited|Pharmaceutical compositions comprising fatty acid esters|

---

CA2867137C|2012-03-19|2020-12-08|Alkermes Pharma Ireland Limited|Pharmaceutical compositions comprising aripiprazole prodrugs and benzyl alcohol|

---

AR090775A1|2012-04-23|2014-12-03|Otsuka Pharma Co Ltd|INJECTABLE PREPARATION|

---

US10052319B2|2012-04-26|2018-08-21|Sumitomo Dainippon Pharma Co., Ltd.|Medicament for treating mental and behavioural disorders|

---

NZ748572A|2012-09-19|2020-07-31|Alkermes Pharma Ireland Ltd|Pharmaceutical compositions having improved storage stability|

---

CA2942638A1|2013-03-15|2014-09-18|Demerx, Inc.|Method for noribogaine treatment of addiction in patients on methadone|

---

US9561232B2|2014-02-18|2017-02-07|Demerx, Inc.|Low dose noribogaine for treating nicotine addiction and preventing relapse of nicotine use|

---

US9591978B2|2014-03-13|2017-03-14|Demerx, Inc.|Methods and compositions for pre-screening patients for treatment with noribogaine|

---

CN110368360A|2014-03-20|2019-10-25|奥克梅斯制药爱尔兰有限公司|Aripiprazole formulations with increased injection speed|

---

US9549935B2|2014-07-14|2017-01-24|Demerx, Inc.|Methods and compositions for treating migraines using noribogaine|

---

US10016415B2|2014-08-18|2018-07-10|Alkermes Pharma Ireland Limited|Aripiprazole prodrug compositions|

---

EP3182958B1|2014-08-18|2019-02-27|Alkermes Pharma Ireland Limited|Aripiprazole prodrug compositions|

---

CN111454207A|2014-08-25|2020-07-28|奥克梅斯制药爱尔兰有限公司|Crystallization method of aripiprazole derivatives in sustained-release preparation for treating schizophrenia|

---

EP3223906B1|2014-11-26|2021-01-06|DemeRx, Inc.|Methods and compositions for potentiating the action of opioid analgesics using iboga alkaloids|

---

CN107920989A|2015-06-08|2018-04-17|考里安国际公司|Preparation for transdermal delivery Aripiprazole|

---

US20170196802A1|2016-01-08|2017-07-13|Abon Pharmaceuticals, Llc|Long Acting Injectable Formulations|

---

ES2893973T3|2016-02-17|2022-02-10|Alkermes Pharma Ireland Ltd|Aripiprazole Multiple Prodrug Compositions|

---

TWI730087B|2016-04-25|2021-06-11|日商大塚製藥股份有限公司|Composition and apparatus for ingestible administration of pharmaceutical product with ingestible event marker|

---

CN110025572A|2018-01-11|2019-07-19|四川科伦药物研究院有限公司|Lauroyl Aripiprazole suspension and preparation method thereof|

---

WO2019173230A1|2018-03-05|2019-09-12|Alkermes Pharma Ireland Limited|Aripiprazole dosing strategy|

---

CN109984999B|2019-04-28|2021-12-24|重庆仁泽医药科技有限公司|Pharmaceutical composition and preparation method and application thereof|

法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

---

2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

---

2020-05-26| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

---

2020-06-02| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

---

2020-09-08| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|

---

2020-12-22| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

---

2021-02-23| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 19/03/2012, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

---

申请号 | 申请日 | 专利标题

---

US201161454008P| true| 2011-03-18|2011-03-18|

---

US61/454,008|2011-03-18|

---

PCT/US2012/029625|WO2012129156A1|2011-03-18|2012-03-19|Pharmaceutical compositions comprising sorbitan esters|

---