TW202313047A - Antipsychotic injectable depot composition - Google Patents

Abstract

A long-acting injectable depot composition having at least drug, solvent, and PLGA copolymer is provided. The composition exhibits improved pharmaceutic performance due to the use of advantageous grades of PLGA polymer with improved particle size distribution.

Description

Antipsychotic injectable depot composition

This patent relates to an injectable depot composition for the administration of the antipsychotic drug risperidone and for the treatment of diseases responsive to risperidone or paliperidon. The composition is particularly suitable for intramuscular administration and forms an implant in situ for sustained release of risperidone for a period of about 28 days or more. When reconstituted, the composition exhibited reduced caking, shortened reconstitution time and consisted of PLGA defined as a beneficial grade in terms of particle size distribution.

Risperidone and its main active metabolite 9-OH-risperidone (paliperidone) (9-OH-risperidone (paliperidone)) are suitable for the treatment of mental diseases, such as schizophrenia, schizophrenia affective disorder, Bipolar disorder and bipolar mania. Risperidone can be administered orally as commercially available lozenges, liquid or orally disintegrating lozenges.

Known LAI depot compositions: US 8,221,778 to Siegel et al. (corresponding to WO 2005/070332), US 5,688,801, US 6,803,055, US 5,770,231, US 7,118,763, US 4,389,330 to Dunn, US 4,530,840 , US 6,673,767 to Brodebeck, US 6,143,314 to Chandrashekar, WO 2004/081196, WO 2001/035929, WO 2008/153611 A2 awarded to QLT USA, WO 2000/024374, WO 2002/038185, WO 2008/100576, WO 2011/151355 A1 awarded to Laboratorios Far maceuticos ROVI, S.A., WO 2011 /42453, US 10085936 to Gutierro Aduriz, US 10463607 to Gutierro Aduriz, US 10182982 to Gutierro Aduriz, US 2020/0085728 A1 to Gutierro Aduriz, EP 2394664 A1 to Laboratorios Farmaceuticos ROVI, S .A., WO 2011/151355 A1 awarded to Laboratorios Farmaceuticos ROVI, S.A., US 10058504 Gutierro Aduriz, US 10881605 Gutierro Aduriz, US 10195138 Gutierro Aduriz, US 2021/0077380 A1 awarded to Laboratorios Farmaceuticos ROVI, S.A., EP 2394663 A1 awarded to Laboratorios Farmaceuticos ROVI , S.A., WO 2011/151356 A2 awarded to Laboratorios Farmaceuticos ROVI, S.A. , US 10350159 awarded to Gutierro Aduriz, US 2019/0328654 A1 awarded to Laboratorios Farmaceuticos ROVI, S.A., EP 2529757 A1 awarded to Laboratorios Farmaceuticos ROVI, S.A., WO 2013/178811 A1 awarded to Laboratorios Farmaceuticos ROVI, S.A., US 10335366 awarded to Gutierro Aduriz, US 2019/ 0254960 A1 awarded to Laboratorios Farmaceuticos ROVI, S.A., US 11007139 awarded to Gutierro Aduriz, EP 2529756 A2 awarded to Laboratorios Farmaceuticos ROVI, S.A., WO 2013/178812 A1 awarded to Laboratorios Farmaceuticos ROVI, S.A., US 2 008/0287464 A1 awarded to Wright, US 2009/0264491 A1 to McKay, US 2004/0010224 A1 to Bodmeier, US 2007/0077304 A1 to Luk, US 2010/0015195 A1 to Jain, US 2010/0266655 A1 to Dadey, WO 95/29664 to Alkermes, WO 2004/011 054 A2 awarded to Alza, WO 2007/041410 A2 to Luk, WO 2008/059058 A1 to Bourges, WO 2010/018159 A1 to Schoenhammer.

Two such LAI products containing risperidone have been approved by the U.S.F.D.A.

RISPERDAL CONSTA ^® (NDA N021346; dosage strengths - 12.5mg/vial, 25mg/vial, 37.5mg/vial and 50mg/vial; US 6596316, US 6379703, US 6194006, WO 2000/40221) is a PLGA containing risperidone Microparticle formulation for intramuscular injection with the aim of maintaining therapeutic risperidone concentrations by biweekly administration. However, since most microparticulate products inherently exhibit a lag period, patients require daily oral supplementation of risperidone, an oral supplement, for the first week after the first dose. After approximately three weeks of a single intramuscular injection of RISPERDAL CONSTA® combined with a daily oral dose of risperidone, the microparticles release sufficient risperidone into the systemic circulation to allow patients to discontinue daily oral supplemental therapeutic doses. However, oral supplementation during this period may present a risk factor for non-compliance. Furthermore, the simultaneous presence of both doses in the body may pose a potential risk of adverse events such as irregular formulation behavior and toxicity.

PERSERIS® (NDA N210655: Dosage Strength - 90 mg and 120 mg per dose; US 9180197, US 9186413, US 9597402, US 10010612, US 10058554, US 10376590, US 10406160) is a depot formulation containing risperidone available in Administered subcutaneously in adipose tissue.

Another LAI product containing risperidone is still undergoing clinical evaluation for the treatment of schizophrenia: Correll et al (NPJ Schizophrenia (Nov. 25, 2020), 6:37), Edison Investment Research Limited (“Doria Phase Phase III trial hits primary endpoint, Laboratorios Farmaceuticos ROVI, S.A. March 19, 2019, www.edisongroup.com/publication/doria-phase-iii-trial-hits-primary-endpoint/23705/), NCT02086786, NCT03160521, NCT01788774, NCT 01320410 , NCT03870880, NCT03160521, NCT01788774, and Anta et al (New dosage forms of risperidone: a review of risperidone ISM in CNS Drugs (September 5, 2020; doi.org/10.1007/s40263-020-00762-0) The composition of this product is not disclosed in these publications.

U.S. 6,331,311 patent to Brodbeck also discloses injectable depot compositions containing biocompatible polymers such as PLGA, solvents such as N-methyl-2-pyrrolidone and beneficial agents such as pharmaceuticals, and contain emulsifiers such as polyols. However, when the beneficial agent is risperidone, the disclosed composition cannot exert satisfactory effects.

U.S. 4,938,763 to Dunn et al discloses a means of injectable in situ implant formation. A biodegradable polymer or copolymer that is soluble in a water-soluble solvent containing a bioactive agent will dissolve or disperse in a polymer solution. Once the polymer solution is exposed to body fluids, the solvent diffuses, the polymer solidifies and the drug remains in the user's body: the polymer matrix. Even though Dunn et al. disclosed the use of water-soluble solvents to obtain polymeric implants formed in situ, they also revealed that many polymers and solvents and the ratio between different components did not produce satisfactory implants. Appropriate release profile, especially when the implant contains risperidone as active ingredient.

The particle size of PLGA copolymer for injectable depot compositions has not been recognized to be relevant for the preparation of LAI depot compositions by reformulating powders, i.e. by mixing solvents with powdered drug and powdered PLGA copolymers to prepare LAI storage composition.

During reformulation and clinical evaluation against a control group of a depot composition containing DMSO, PLGA, and risperidone LAI, the present inventors identified an important potential limitation of the drug in unpublished work. We found that reconstitution of powders by mixing DMSO with PLGA and risperidone powders resulted in agglomeration of the powder, thus leading to potential disadvantages in the clinical setting, such as increased dosing time and/or PLGA polymer in the Problems such as inability to completely dissolve before administration. The inability of PLGA to dissolve completely within the target mixing time prior to clinical administration is a primary concern, as it may ultimately negatively affect the drug release from individual solid implants, which may alter the distribution of the active moiety in plasma and affect drug delivery. effect.

It would be desirable to provide a kit for forming an injectable depot composition which reduces or eliminates clumping of powdered PLGA when mixed with risperidone and DMSO and which increases the dissolution rate of the PLGA powder (speed) to reach the fastest. In other words, the time required to fully dissolve PLGA is reduced or minimized. Such a kit and corresponding powder material would help to reduce, or minimize as much as possible, the associated disadvantages in a clinical setting.

The object of the present invention is to seek to overcome the disadvantages and/or provide improvements of other injectable depot compositions containing risperidone and/or paliperidone. The present invention comprises injectable depot compositions, implants formed from said injectable depot compositions, methods of forming (preparing) said implants, medicaments for forming said injectable depot compositions Kits and components, methods of preparing said injectable depot compositions, methods of administering risperidone and/or paliperidone by administering said injectable depot compositions, and by administering said Injectable depot compositions for the treatment of diseases, symptoms or disorders responsive to risperidone and/or paliperidone. The present invention provides an improved long-acting injectable (LAI) depot composition for the delivery of risperidone or other antipsychotic drugs. The composition comprises an improved grade of PLGA polymer with a beneficial particle size distribution (showing improved efficacy) compared to PLGA grades used in other injectable depot compositions.

The present invention relates to risperidone-containing or paliperidone-containing compositions that facilitate the formation of one or more in situ intramuscular implants and sustainably maintain the desired active moieties (i.e. risperidone and/or Paliperidone) plasma concentration up to 28 days or 28+/-5 days or 28+/-4 days or 28+/-3 days or 28+/-2 days or 28+/-1 days or about 26- 33 days or about 28-33 days. In addition, the composition also exhibits enhanced efficacy.

Following administration, the injectable depot composition provides initial plasma concentrations of the therapeutic active moiety and sustained efficacy for a period of at least about 28 days. It does not require additional oral supplementation of risperidone or paliperidone, nor an increase in the oral loading dose of risperidone or paliperidone to achieve a target steady state plasma concentration of the active moiety. Unlike the use of other LAI (Long Acting Injectable) depot compositions containing risperidone, the method of use of the present invention also provides the advantage that after the oral risperidone dosing regimen is terminated, the Therapeutic plasma concentrations of the active moiety can continue to be maintained by the methods described herein for administration of LAI depot compositions. In addition, unlike the use of other LAI depot compositions containing risperidone, the method of use of the present invention also provides the advantage that after the dosing regimen of the LAI depot composition is terminated, the daily A single oral dose of risperidone continues to maintain therapeutic plasma concentrations of the active moiety. Therapeutic concentrations of the active moiety are sustained from the first day to the last day of the administration period.

The present invention employs an intramuscular administration of 75-100 mg or 25-150 mg of risperidone approximately every 28 days (administered as the LAI depot composition described herein). Unlike RISPERDAL CONSTA, no oral supplementation of risperidone is required. Unlike RISPERDAL CONSTA and PERSERIS, this depot composition provides Therapeutically effective risperidone plasma concentrations.

Improved performance of kits, injectable depot compositions and individual implants is achieved by controlling the particle size distribution of the PLGA polymer. The particle size distribution was predicted a priori to be irrelevant to the effectiveness of the kit, LAI depot composition or implants formed therefrom, since the polymer is arguably completely dissolved in the solvent when the injectable composition is prepared prior to administration. However, the inventors found that the particle size of the polymer actually has an impact on the dissolution profile of the PLGA/drug mixture and the clinical applicability of the LAI depot composition, and that individual implants may form after administration of the LAI depot composition. The effect of drug release in the drug will be affected. It must be noted that these types of compositions require rapid and complete reconstitution prior to administration.

The PLGA (poly(lactic-glycolic acid copolymer)) copolymer used in the present invention has the following particle size distribution: a) particle size mass distribution above 300 microns when measured by sieve analysis according to USP <786> more than 10%, preferably not more than 250 microns; b) when measured by laser light diffraction analysis, the particle size volume distribution of D90 is not more than 300 microns, preferably not more than 280 microns; c) according to USP <786> using When measured by sieve analysis, the mass distribution of particle sizes above 300 microns does not exceed 10%, preferably not more than 250 microns, of which less than 70% of the particles have a particle size of less than 150 microns; d) When measured by sieve analysis according to USP<786> , less than 70% of the particle mass distribution particle size is less than 150 microns; e) when measured by laser light diffraction analysis, the particle size volume distribution of D90 is not more than 300 microns, preferably not more than 280 microns, and the particle size distribution is not more than 280 microns, and the laser light diffraction When measured analytically, the particle size volume distribution of D80 is not less than 135 microns; f) when measured by laser light diffraction analysis, the particle size volume distribution of D80 is not less than 135 microns; g) D50 is about 50-150 microns; h) D10 about 10-50 microns; i) D90 about 170-300 microns; and/or j) D50 about 50-150 microns, D10 about 10-50 microns and D90 about 170-300 microns. The present invention contemplates the use of PLGA grades having combinations of two or more of these particle size distributions.

Preferred embodiments of the present invention comprise PLGA having a particle size mass distribution having a D10 in the range of about 10 microns to about 50 microns, a D50 in the range of about 50 microns to about 150 microns, and a D90 in the range of about 170 microns to about 300 microns .

In some embodiments, the PLGA copolymer has been sieved, ie, sieved and/or pulverized, to obtain a desired particle size distribution. Suitable comminution means include, for example, micronizing, milling, hammering, crushing, grinding, milling and/or pressing the PLGA into a powder.

The present invention also provides a powder mixture of a drug and a PLGA copolymer, wherein the drug is risperidone, paliperidone or a mixture thereof, and the PLGA copolymer has a particle size mass distribution and/or a particle size volume distribution as defined herein . The powder mixture can be stored in a sealed container which can be further placed in the kit. The mixture may be sterilized, for example by beta or gamma radiation.

The mixture of drug and PLGA can be about 25 mg to about 150 mg, about 25 mg to about 125 mg, about 25 mg to about 100 mg, about 50 mg to about 150 mg, about 50 mg to about 125 mg, about 50 mg About 100 mg, about 75 mg to about 150 mg, about 75 mg to about 125 mg, about 75 mg to about 100 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, or about 150 The drug in mg, the drug can be risperidone, paliperidone or a combination thereof.

PLGA can be a sterile, biodegradable thermoplastic copolymer containing lactic acid to glycolic acid (i.e., lactide to glycolide) in a monomer ratio of about 50:50 to about 75:25, about 45:55 to about 75 :25, about 45:55 to about 80:20, about 65:35 to about 80:20, about 70:30 to about 80:20; about 50:50 to about 65:35, or about 65:35 to about 75:25, about 45:55 to about 55:45, or about 48:52 to about 52:48, or about 50:50, that is, 50:50 ± 10%, or 75:25 ± 10%. PLGA contains acid end groups or may be capped. The capping can be an ester group. PLGA can be sterilized by beta or gamma radiation or, if sterilized in solution, by filtration.

The PLGA of the composition will have an intrinsic viscosity in the range of 0.20-0.60 dl/g, about 0.3-0.58 dl/g, measured using an Ubbelhode size 0b glass capillary viscometer at a temperature of 30ºC and a concentration of 0.5% wt in chloroform. g, about 0.30-0.55 dl/g, about 0.36-0.52 dl/g, about 0.40-0.58 dl/g, about 0.36-0.43 dl/g, or about 0.46-0.51 dl/g. In some embodiments, PLGA has been sterilized.

The mass ratio of risperidone to (PLGA + risperidone), expressed as a percentage of the weight of risperidone to the total weight of risperidone plus PLGA, is typically about 15-40% by weight, about 25-35% by weight, about 30 - 35%, about 31-35%, about 32-34% or about 33% wt.

The present invention also provides a kit comprising a first container and a second container, wherein a) the first container comprises DMSO; and b) the second container comprises a drug and PLGA; wherein the drug is risperidone, pars panridone or a combination thereof, and the PLGA has a particle size distribution and monomer ratio as defined herein. The LAI injectable depot composition is formed by mixing the contents of the container.

Another embodiment of the kit comprises a first container, a second container and a third container, wherein a) said first container comprises DMSO; b) said second container comprises a group selected from risperidone, paliperidone or a combination thereof; and c) said third container comprises PLGA powder having a particle size distribution and monomer ratio as defined herein. The LAI injectable depot composition is formed by mixing the contents of the container.

In some embodiments, the kit comprises about 75 mg of the drug (which is risperidone, paliperidone, or a combination thereof), about 350 mg of DMSO, and about 150 mg of PLGA having an L:G monomer moiety The ear ratio is from about 45:55 to about 55:45 (or about 50:50) and has a particle size distribution as defined herein.

In some embodiments, the kit comprises about 100 mg of the drug (which is risperidone, paliperidone, or a combination thereof), about 467 mg of DMSO, and about 200 mg of PLGA having an L:G monomer moiety The ear ratio is from about 45:55 to about 55:45 (or about 50:50) and has a particle size distribution as defined herein.

In some embodiments, the kit comprises ingredients redundant to form a LAI depot composition.

For a dose strength of 100 mg, an exemplary kit may contain about 115 mg (or about 100-130 mg or about 105-125 mg or about 110-120 mg) of a drug (which is Risperidone, Paliperid ketones or combinations thereof), about 537 mg (or about 515-560 mg or about 520-550 mg or about 530-545 mg) of DMSO and about 230 mg (or about 215-245 mg or about 220 to about 235 mg) PLGA having a L:G monomer molar ratio of from about 45:55 to about 55:45 (or about 50:50) and having a particle size distribution as defined herein.

For a dose strength of 75 mg, an exemplary kit may contain about 90 mg (or about 75-105 mg or about 80-100 mg or about 85-105 mg) of a drug (which is Risperidone, Paliperid ketones or combinations thereof), about 420 mg (or about 405-435 mg or about 415-425 mg) of DMSO and about 180 mg (or about 165-200 mg or about 170-190 mg or about 175-185 mg) of PLGA having a L:G monomer molar ratio of from about 45:55 to about 55:45 (or about 50:50) and having a particle size distribution as defined herein.

The present invention also provides a method for preparing LAI injectable depot composition, comprising mixing ingredients DMSO, drug and PLGA copolymer, thereby forming said composition, wherein the L:G monomer of PLGA (lactide monomer: glycolide monomer) molar ratio of about 45:55 to about 55:45 (or about 50:50) and have a particle size distribution as defined herein. These ingredients for mixing can be stored in multiple containers and can be placed in kits.

In some examples, we mixed DMSO and PLGA to form a polymer solution, which was then mixed with the drug to form a LAI depot composition. Polymer solutions that do not contain drugs can be sterilized by filtration through a filter medium with a nominal pore size of 0.22 microns or less or by radiation, or by a combination of filtration and radiation.

In some embodiments, the method of preparing a depot composition of LAI comprises a) mixing a powder mixture of DMSO and PLGA with the drug for 10 minutes or less, 5 minutes or less, 4 minutes or less, 3 minutes or less Short, 2 minutes or less, 1 minute or less, or 30 seconds or less, thereby forming the LAI depot composition, wherein at least 80% wt of drug is suspended in solution, and PLGA is completely dissolved therein. When using a syringe as a mixing container, the process of mixing the ingredients is accomplished by combining the syringes and repeatedly pushing and pulling the individual plungers as needed. In some embodiments, the plunger is pushed 200 times (passes) or less, 150 times or less, 100 times or less, 75 times or less, or 50 times. Pushing refers to the flow of fluid from one syringe to another.

When using PLGA grades with the particle size distribution properties described herein, there will be no or significantly reduced caking of the powder blend when mixed with DMSO compared to using a PLGA powder blend with particle size distribution properties outside the ranges described here Phenomenon. Therefore, using the PLGA described herein allows for faster and more complete dissolution than other grades of PLGA.

Prior to administration, the viscosity of the LAI depot composition typically falls within the range of about 1.0-7.0 Pa.s, about 1.5-7.0 Pa.s, or about 1.8-6.5 Pa.s.

In some embodiments, the mass ratio of DMSO to drug is about 5:1 to about 4:1, about 4.6:1 to about 4.8:1, about 4.6:1 to about 4.7:1, about 4.67:1, about 4.66 :1 or about 4.68:1 or about 4.66:1.

In some embodiments, the DMSO content of the LAI depot composition is about 55-65% wt, about 57-63% wt, about 60-62% wt, or about 61% wt compared to the total weight of the composition.

In some embodiments, the PLGA concentration in the LAI depot composition is about 24%-50% wt, about 24%-40% wt, about 25-27% wt, or about 26% wt (expressed as polymer weight relative to percentage of the total weight of the composition).

In some embodiments, the drug content in the LAI depot composition, especially risperidone, is about 10-15% wt, about 11-14% wt, about 12-14% compared to the total weight of the composition wt or about 13% wt.

The sum of all ingredients of an LAI depot composition is 100%.

In some embodiments, prior to administration, the LAI depot composition comprises about 75 mg (or about 65-85 mg or about 70-80 mg) of drug, DMSO and PLGA, wherein the drug content is about 10-15% The wt, DMSO content is about 55-65% wt, the PLGA content is about 24%-30% wt, and the L:G monomer ratio of PLGA is about 45:55 to 55:45.

In some embodiments, prior to administration, the LAI depot composition comprises about 75 mg (or about 65-85 mg or about 70-80 mg) of drug, DMSO and PLGA, wherein the drug content is about 12-14% The wt, DMSO content is about 57-63% wt, the PLGA content is about 25-27% wt, and the L:G monomer ratio of PLGA is about 45:55 to 55:45.

In some embodiments, before administration, the LAI depot composition comprises about 100 mg (or about 85-115 mg or about 90-110 mg or about 95-105 mg) of drug, DMSO and PLGA, wherein the drug content is is about 10-15% wt, DMSO content is about 55-65% wt, PLGA content is about 24%-30% wt, and the L:G monomer ratio of PLGA is about 45:55 to 55:45.

In some embodiments, before administration, the LAI depot composition comprises about 100 mg (or about 85-115 mg or about 90-110 mg or about 95-105 mg) of drug, DMSO and PLGA, wherein the drug content is is about 12-14% wt, the DMSO content is about 57-63% wt, the PLGA content is about 25-27% wt, and the L:G monomer ratio of PLGA is about 45:55 to 55:45.

The drug was partially or substantially completely insoluble in the LAI depot composition prior to administration and after mixing DMSO, drug, and PLGA. In some embodiments, a) ≤2.5%, ≤5%, ≤7.5%, ≤10%, ≤20% of the drug will dissolve in the composition prior to administration; and/or b) >0% , ≥0.5%, ≥1%, ≥5%, ≥10%, ≥15%, or up to about 20% wt of the drug will be dissolved in the composition prior to administration. All combined results of these examples have been considered.

The invention also provides a method of administering a medicament comprising administering to a subject a LAI depot composition as defined herein. The method may further comprise the step of forming said LAI depot composition by mixing the individual ingredients. The method may further comprise providing a kit as defined herein. Drug is as defined herein.

LAI depot compositions can be administered intramuscularly or subcutaneously. It can also be administered to adipose tissue. The ideal site for intramuscular administration is gluteal muscle or deltoid muscle.

The present invention also provides a stable LAI depot composition suitable for forming an in situ solid implant after administration to a subject, the implant comprising about 75 mg to about 100 mg of risperidone, PLGA and DMSO , in which risperidone and PLGA are stored in a first container and DMSO in a second container, the concentration of PLGA is 20 to 50% by weight relative to the weight of biocompatible copolymer and solvent, and laser light is used to When measured by radiation analysis, wherein the D10 particle size volume distribution of risperidone is equal to or higher than 10 microns, the D50 is between 60 and 130 microns, and the D90 is lower than or equal to 225 microns, characterized in that PLGA has been Sieve and have a particle size as defined herein.

The present invention also provides a method of treatment of a disease, condition or disorder responsive to risperidone and/or paliperidone, the method comprising administering to a subject in need thereof a LAI depot composition as defined herein. The method of treatment may include methods of preparing an LAI depot composition, and may include methods of administering an LAI depot composition.

The present invention provides a method for treating a disease, symptom or disorder responsive to risperidone and/or paliperidone, the method comprising a method of preparing an LAI depot composition, and administering LAI to a subject in need thereof Depot compositions as a method of treating said disease, disorder or condition. The method may further incorporate the step of providing a kit as described herein.

In some embodiments, the method of administration comprises a) providing a kit comprising a container containing DMSO and a container containing the drug and PLGA, wherein the PLGA has a particle size distribution as described herein; b) by mixing ingredients to prepare the LAI depot composition described herein, thereby forming the LAI depot composition; and c) administering the LAI depot composition to a subject.

In some embodiments, the method of treatment comprises a) providing a kit comprising a container containing DMSO and a container containing the drug and PLGA, wherein the PLGA has a particle size distribution as described herein; b) by mixing ingredients to prepare the LAI depot composition described herein, thereby forming the LAI depot composition; and c) administering the LAI depot composition to a subject in need.

In the methods described here, DMSO, PLGA and drug may be divided into two, three or more containers in the kit.

Exemplary illnesses, symptoms or disorders include, for example, psychosis, delusional psychosis, psychotic depression, obsessive-compulsive disorder, schizophrenia, bipolar disorder, schizoaffective disorder, non-schizophrenic psychosis, Asperger's disease, Intellectual and behavioral disorders arising from Tourette's syndrome, OCD, PTSD, ADHD, personality disorders, aggression, depression, dementia, mental retardation, and autism, autism clusters Anxiety, Eating Disorders, Nervous Anxiety, Insomnia, Primary Dystonia, Substance Abuse, and any combination of the above. Acute exacerbation episodes of the above-mentioned diseases, symptoms and disorders are within the scope of treatment of the present invention. Schizophrenia, schizoaffective disorder, bipolar disorder, and bipolar mania are ideally treated disorders.

The invention includes all combinations of the aspects, embodiments and sub-embodiments described herein.

The present invention uses a specific grade of PLGA to improve the efficacy of the kit used to prepare individual LAI depot compositions, improve the preparation effect of individual LAI depot compositions, and improve the in situ individual implantation after administration of LAI depot compositions. effect of the thing. Experiments have found that the particle size of PLGA improves the dissolution behavior of the mixture of drug and PLGA when it is mixed with DMSO.

The term "stable" as used herein means that the total level of drug-related impurities in a pharmaceutical composition or kit will not increase beyond the target level when stored at a temperature of 40°C and a relative humidity (RH) of 75% for 6 months. The word "stable" also means that the intrinsic viscosity of the PLGA copolymer in the pharmaceutical composition or kit does not decrease below the target level during the storage conditions described. The composition was stored at a temperature of 40°C and a relative humidity (RH) of 75% for 6 months and measured by liquid chromatography (HPLC) at 260 nm as an impurity target derived from the decomposition of risperidone The total content does not exceed 5% area, ideally no more than 3% area, more ideally no more than 2% area, and most ideally no more than 1% area. After 6 months of storage under the stated storage conditions, PLGA had a target minimum intrinsic viscosity of 0.20 dL/g.

As used herein, the term "loading dose" means a) a daily oral dose of drug administered to a subject over a period of more than one day, wherein the loading dose is sufficient to maintain a stable and therapeutically active moiety in the subject. and/or b) administering one or more higher doses of a drug-containing LAI depot composition prior to administration of a maintenance dose of the drug-containing LAI depot composition, wherein one or Various higher doses are sufficient to maintain plasma concentrations of the active moiety in the subject that are stable and within a therapeutic range prior to administration of the maintenance dose.

As used herein, the phrase "maintenance dose" refers to the dose of a depot composition of LAI containing the specified drug dose, from the first (initial) to subsequent administrations (about once every 28 days or about once a month) of said LAI The dose of the depot composition is administered to the subject. The maintenance dose is sufficient to maintain a plasma concentration of the active moiety in a subject that is stable and within a therapeutic range without the need to administer a loading dose of a LAI depot composition comprising risperidone and without oral supplementation Risperidone.

The term "oral supplementation" as used herein refers to the daily dose of the drug orally administered to the subject after the subject has been administered the LAI depot composition of the present invention comprising the drug.

Unless otherwise specified, the drugs or active ingredients contained in the injectable compositions used herein may exist in their free base, salt, amorphous, crystalline, anhydrous, hydrate, optically pure, optically enriched or racemic form. Combinations of these different forms are also within the scope of the present invention. Prodrugs, metabolites (paliperidone) or derivatives of the drug are also within the scope of the invention.

In some embodiments, salt forms of risperidone can be prepared according to U.S. Publication No. 20040266791, the relevant disclosure of which is hereby incorporated by reference; however, other known salts can be used.

The term "prodrug" as used herein means that the compound is administered in an inactive (or less than fully active) form and is subsequently converted to the active agent by normal metabolic processes. A prodrug is a "precursor" of a drug that is intended, such as risperidone, paliperidone, or another drug.

The term "derivative" as used herein refers to a compound obtained by chemically adjusting the parent complex such that the "derivative" has almost all or all of the chemical structure of the parent (or base) complex. A derivative is a compound formed from a similar compound, and a derivative can also be imagined as a compound produced from another compound under the condition that an atom is replaced by another atom or group of atoms. A derivative is a compound derived or obtained from another compound and containing the basic elements of the parent substance. A derivative is a chemical compound produced by one or more steps from another compound of similar structure.

As used herein, the term "dosing period" refers to the period from the first day after administration to at least about 28 days after administration, or to the number of days or weeks measured by the administration of subsequent doses. During administration, the implant will provide therapeutic plasma drug concentrations for approximately 4 weeks or more. The dosing period expires on a predetermined number of days, or ends when plasma drug concentrations fall below therapeutic concentrations.

A "treatment period" as used herein refers to a period of weeks, months or years during which the LAI depot composition of the invention is administered to a subject. A treatment period usually includes multiple dosing periods. During treatment, dosing periods can be performed sequentially or in an overlapping fashion. For example, a first dose of the injectable composition is administered, a second dose of the injectable composition can be administered each time after the first dose, so that each dose has its own corresponding dosing period, and the administration of Periods also overlap. The dosing periods are usually consecutive, or do not overlap by more than one or seven days.

Intramuscular doses can be administered to any muscle or muscle group generally recognized by the pharmaceutical industry as suitable for administration of injectable compositions. In some embodiments, we administer the composition to the gluteus and/or deltoid. The composition can also be administered to the quadriceps muscle group. The agent may be administered to a single muscle site, or the agent may be divided into two or more portions and administered separately to two or more muscle sites of the subject. For example, a first portion of the agent can be administered to a first area of the subject's gluteal muscles, and a second portion of the agent can be administered to a second area of the subject's gluteal muscles. Injectable compositions can be administered to a subject at one or more injection sites on the same day and still be considered to belong to the same administration period. For example, a portion of a medicament can be administered to a first injection site and another portion of the same medicament can be administered to another injection site. A one-piece implant is formed at each injection site. Such administration on the same day is considered a single dose administration in a single dosing period. Alternatively, the administration can be modified by inserting the needle into the subject, but with more than one injection site below the skin, by first passing the needle through the skin and muscle and administering a portion of the drug, then bringing the needle up One portion is lifted back and reinserted into another area of the muscle while keeping the needle tip under the skin, and another portion of the drug is injected into another area of the muscle. This mode of administration is still considered a single dose administration for a single dosing period.

The therapeutically effective dose of the injectable composition refers to the dose of the injectable composition containing a specific dose of drug. Therefore, the effective therapeutic dose of the 25-150 mg injectable composition is 25-150 mg of risperidone; therefore, the actual dose of the LAI depot composition will be greater than 25-150 mg, and the actual dose of the injectable composition It depends on the drugs contained in the LAI depot composition. For example, a therapeutically effective dose of a LAI depot composition containing about 13 wt % risperidone would contain a 75 mg dose of risperidone, which would equate to about 575 mg of said composition comprising DMSO, risperidone, Peridone and PLGA. Likewise, a therapeutically effective dose of a LAI depot composition containing about 13 wt % risperidone would contain a 100 mg dose of risperidone, which would equate to about 767 mg of said composition containing DMSO, risperidone, Ketones and PLGA.

Although not essential, the injectable compositions of the present invention may further comprise a base agent. Alkali agents with low water solubility, eg less than 0.02 mg/ml, may be included. The base agent can be present in a molar ratio (drug/base agent) of >2/5, which means that the base agent exceeds the drug by a molar amount. The more ideal alkaline agent is alkaline or alkaline earth hydroxide, such as magnesium hydroxide or aluminum hydroxide. Due to the limited water solubility of alkali agents, the ideal d 0,5 particle size distribution is less than 10 microns, such as magnesium hydroxide.

The methods of the invention may employ a kit suitable for forming an in situ biodegradable solid implant in a subject in need thereof. In some embodiments, the kit comprises: a first container containing risperidone; a second container containing a biocompatible PLGA copolymer; and a third container containing DMSO. The injectable composition as described herein is formed by mixing the contents of the third container with the contents of the second container to form a polymer solution, which solution is then mixed with the contents of the first container. In some embodiments, the copolymer and drug (and/or metabolites thereof and/or prodrugs thereof) are stored in a first container and DMSO is stored in a second container. In some embodiments, the container is a syringe and the mixing of the contents can be performed by directly or indirectly connecting the syringe and moving the plunger of the syringe back and forth. Embodiments of the invention include a) the drug and/or copolymer in solid form in a container prior to mixing with the solvent; b) the drug and/or copolymer in granular form or in the form of The lyophilizate is presented in a container.

The invention also provides a procedure for preparing a stable LAI depot composition comprising mixing the ingredients of the composition for about 30 seconds or less, about 1 minute or less, about 2 minutes or less, or at most Mix for about 3 minutes, preferably up to about 2 minutes prior to administration, more preferably up to about 1 minute prior to administration, to form the composition. In a preferred embodiment, the composition is prepared by mixing a solvent (DMSO) with a previous powder mixture of risperidone and biocompatible polymer (PLGA). In a more desirable embodiment, by passing the contents between two devices (preferably syringes) 200 times (passes) or less, 150 times or less, 100 times or less, 75 times or more as few, or 50, to mix the ingredients. The term "polymer solution" as used herein refers to a liquid composition containing DMSO and PLGA dissolved therein in combination. Unless otherwise stated, the viscosity of polymer solutions or injectable compositions is presented in Pa.s.

The viscosity of the polymer solution ranges from about 0.5 to about 3.0 Pa.s, from about 0.7 to about 3.0 Pa.s, from about 0.7 to about 2.0 Pa.s, from about 1.5 to about 2.5 Pa.s, from about 1.5 to about 2.3 Pa. s, about 1.5 to about 2.1 Pa.s, 1.5-2.1 ±10% Pa.s, 1.6-1.9 ±10% Pa.s, or 1.7-1.8 ±10% Pa.s. Prior to administration, the viscosity of the LAI depot composition falls within the range of about 1.0-7.0 Pa.s, about 1.5-7.0 Pa.s or about 1.8-6.5 Pa.s. In some embodiments, these values are within about ±10% of the specified limits. Viscosity can be controlled primarily based on the molecular weight of the polymer (intrinsic viscosity) and the concentration of the polymer in the injectable composition.

In some embodiments, the mass ratio of the polymer solution to the drug, expressed as the mass ratio of (polymer + solvent) to the mass of the drug, ranges from about 15:1 to about 5:1, from about 12:1 to about 5:1 , about 7:1 to about 6.5:1, about 6.5:1 to about 6.8:1, about 6.67:1, about 6.66:1 or about 6.68:1.

In some embodiments, the mass ratio of polymer to polymer solution, expressed as weight percent polymer versus weight percent polymer+solvent, is about 25-50%, about 25-35%, about 30-40%, About 28-32% or about 30%.

In some embodiments, the mass ratio of solvent (DMSO) to polymer solution, expressed in terms of solvent weight percent versus polymer+solvent weight percent, is about 50-75%, about 65-75%, about 60-70% , about 68-72% or about 70%.

The LAI depot compositions used in the methods of the invention may further comprise one or more pharmaceutically acceptable excipients suitable for intramuscular administration.

After intramuscular administration, the LAI depot composition forms an in situ solid implant in muscle tissue. In some embodiments, within about 2 hours of administration, the implant will begin releasing risperidone to provide rapid (e.g., less than 1 day, less than 18 hours, less than 12 hours, less than 6 hours, less than Works in 3 hours) and continues to provide benefits for at least about 4 weeks. Provides therapeutically effective plasma concentrations of the active moieties (risperidone + 9-OH-risperidone (paliperidone)) from the first day of administration and for a period of at least about 4 weeks .

The expression "about 50:50" used in this specification refers to the ratio of lactic acid and glycolic acid contained in the biodegradable PLGA copolymer based on lactide and glycolide dimers of individual lactic acid and glycolic acid monomers. monomer ratio. The L:G monomer molar ratio may have a standard technical error of ±10%. Known commercially available PLGA copolymer grades may be listed as having a 50:50 monomer ratio and still vary slightly in actual monomer ratio. For example, a copolymer listed as having a monomer ratio of 50:50 may actually have a monomer ratio of 45:55 to 55:45 or 48:52 to 52:48. Therefore, when referring to a monomer ratio of "50:50" or "about 50:50" in this article, all ratios within the range of 45:55 to 55:45 are considered interchangeable.

Intrinsic viscosity can be measured at 25°C or 30°C in 0.1% wt/v or 0.5% chloroform with an Ubbelhode size 0c or 0b glass capillary viscometer (RESOMER® grade), or at 30°C and chloroform at a concentration of 0.5% wt/v, measured using a No. 25 Cannon-Fenske glass capillary viscometer. Suitable grades of PLGA copolymers described herein (based on molecular weight, intrinsic viscosity, and/or molar ratio of lactic acid monomers to glycolic acid monomers) are capped (e.g., with ester groups such as laurate, methyl ester) from EVONIK® (Essen, Germany), Boehringer Ingelheim (Ingelheim am Rhein, Germany), ALKERMES (Dublin, Ireland) or SIGMA ALDRICH (ST. Louis, MO) and under the trade names RESOMER®, LAKESHORE BIOMATERIALSTM or MEDISORB® Sale. Due to the proprietary nature of certain grades of end-capped PLGA compositions, the ester-terminated components cannot be disclosed. Nevertheless, the performance properties of the PLGA copolymer grades described herein are known and are material properties.

The viscosity characteristics of PLGA polymers in LAI depot compositions fall within the range of 0.20-0.60 dl/ g, an intrinsic viscosity of about 0.30-0.55 dl/g, about 0.36-0.52 dl/g, about 0.36-0.43 dl/g, about 0.40-0.58 dl/g, or about 0.46-0.51 dl/g.

PLGA polymers can be irradiated with beta or gamma radiation at a radiation dose of about 10 to about 30 kGy at temperatures between –40°C and +35°C. Radiation irradiation can be used to reduce the molecular weight of PLGA polymers and/or to sterilize PLGA polymers. In some embodiments, the polymer is irradiated at a temperature below 35°C, preferably below 25°C and more preferably below 8°C. In one of the more desirable embodiments of the present invention, the biocompatible copolymer is irradiated with a gamma or beta dose of 10-30 kGy ±10%, measured at a temperature between -40°C and +35°C, to Its molecular weight is adjusted to a range of about 27-47 kDa, about 31-43 kDa, about 31-40 kDa, about 30-46 kDa, or about 30-36 kDa. In a more desirable embodiment, the polymer is irradiated with a radiation dose of 15-25 kGy ± 10%, measured at a temperature of 8°C.

After administration, the injectable composition forms an implant and provides a satisfactory controlled drug release profile. A "satisfactory controlled" release profile as referred to here means that the implant will exhibit an initial release profile that is not too steep (fast), which would lead to high plasma concentrations with associated toxic side effects, and exhibit Not an overly smooth (slow) initial release profile, which would result in subtherapeutic plasma concentrations. Implants exhibiting a satisfactory controlled initial release profile will release no more than 20% wt, no more than 15% wt, no more than 12% wt, no more than 10% wt within 24 hours of placement in an aqueous environment % wt, not more than 8% wt, not more than 6% wt, not more than 5% wt, not more than 4% wt, not more than 3% wt, not more than 2% wt, or not more than 1% wt of drug. It will release at least 0.1% wt, at least 0.5% wt, at least 1% wt, at least 2% wt, at least 3% wt, or at least 4% wt of drug within 24 hours of being placed in an aqueous environment. The present invention includes all combinations of the embodiments described herein.

The plasma concentration profile during dosing exhibits one, two or more maxima and one, two or more minima. The initial maximum may be due to drug dissolution in the first few days of the dosing period, followed by slow drug release, while another maximum may be due to an increased release rate for the remaining days of the dosing period. Embodiments of the present invention include: a) the plasma concentration curve exhibits a maximum during the first day to the sixth day or the first day to the third day of the administration period; b) the plasma concentration curve exhibits a maximum value after the 4-week administration period; Days 10 to 24 exhibited a maximum; c) the plasma concentration profile exhibited a maximum in the first few days of the dosing period and a maximum in the remaining days of the dosing period; d) the plasma concentration profile was basal in the dosing period levels (standard deviations within ±30%, ±25%, ±20%, ±15%, or ±10% of the mean or mean); and/or f) the plasma concentration profile exhibited a maximum during the last 10 to 28 days of the 4 to 5 week dosing period.

In humans, the average active moiety (risperidone + 9-OH- Risperidone) has plasma concentrations in the range of about 3-200, about 5-80, or about 10-60 ng/ml. When administering a dose of the injectable composition corresponding to a dose of about 25-150, about 37.5-125, or about 50-100 mg risperidone, respectively, the mean Cmin over the dosing period ranges from about 1-80, 5-50, or About 5-40 ng/ml. The mean Cmax over the dosing period ranges from about 8-300, 10-150 or 10- 120ng/ml. Some individual subjects may exhibit plasma concentrations outside the range specified herein due to poor health, advanced age, impaired metabolism, renal failure, disease, etc., based on equivalent doses. Even so, the majority of subjects in the patient population will exhibit the plasma concentrations specified herein following administration of the injectable implant.

As used herein, whenever reference is made to the plasma concentration of a drug, such plasma concentration includes the sum of the plasma concentrations of the active moiety therein (ie, the drug and its active metabolite). For example, whenever the plasma concentration of risperidone is mentioned, the plasma concentration includes the sum of the plasma concentrations of risperidone and its active metabolite, such as 9-OH-risperidone (paliperidone).

In some embodiments, the drug has a particle size distribution such that less than 10% of the total volume of the drug has a particle size of less than 10 microns (volume equivalent diameter as a function of Fraunhofer theory applied to irregularly shaped particles; measured using laser light scattering techniques, For example using Malvern Mastersizer 2000), and less than 10% of the total volume of drug particles is larger than 225 microns (or 235 microns). In addition, the drug particles have an ideal d0.5 value, approximately in the range of 60-130 microns. Therefore, in some embodiments, the particle size distribution of risperidone exhibits a wide range and can be unimodal, bimodal or trimodal.

In other embodiments, the drug exhibits one of the following particle size distributions: parameter I II III IV V VI d0.1 (micron) 27.49 <30 17.41 ≤20 ≤10 ≤10 d0.5 (micron) 79.90 40-130 51.61 40-130 40-130 40-130 d0.9 (micron) 176.66 >170 175.32 >170 >225 or >235 >200

In another embodiment of the invention, the drug has the following particle size distribution: - less than 10% of the total volume of particulates are less than 10 microns in size; - Less than 10% of the total volume of particles is greater than 225 microns (or 235 microns), or less than 10% of the total volume of particles is greater than 200 microns, and - The particle size distribution of d0.5 is in the range of about 60-130 microns, about 40-90 microns or about 40-130 microns.

Particle size distribution is measured by light scattering technique using laser light diffraction in wet mode.

Embodiments of the invention include: a) risperidone present in the container as a solid prior to mixing with the solvent; b) risperidone present in the container as microparticles or as a lyophilizate prior to mixing with the solution; c) The particle size distribution of risperidone is as follows: the particle size of the drug with less than 10% of the total volume is less than 10 microns, and the particle size of the drug with less than 10% of the total volume is greater than 225 microns (or 235 microns); d) the particle size distribution range of d0.5 is about 60-130 microns; e) the mass ratio of the dose of polymer solution (polymer + solvent) to the dose of risperidone in the injectable composition ranges from about 15:1 to 5:1; f) in the injectable composition The mass ratio of solvent dose to risperidone dose (mg solvent/mg risperidone) ranges from about 12:1 to 4:1; g) the kit also contains base; h) the molar ratio of risperidone to base The ear ratio ranges from 2/3 to 2/5; i) the solvent, polymer solution, risperidone, and/or injectable composition are sterilized prior to administration; and/or j) the kit is contained in one of the containers or The two containers further contain alkaline agents.

According to another aspect, the present invention provides a kit suitable for forming a biodegradable implant in situ in vivo following administration of a composition described herein, wherein the drug and the biocompatible polymer are deposited in a first container, while the solvent is stored in a second, different container. Preferably, at least one of the first and second containers is a syringe, vial, device or cartridge, which may be disposable or reusable, and more desirably, the first and the second container are disposable syringes. The invention in this respect relates to a kit comprising a first container, preferably a syringe, vial, device or cartridge, all of which may be disposable or non-disposable, the first container Contains a solid polymer such as PLGA and an appropriate amount of drug, and a second container, again preferably a syringe, vial, device or cartridge, all of which may be disposable or non-disposable, this second container Store water-miscible solvents. When necessary, for example by using a connector or using a male-female syringe, combine the contents of the two containers and mix with each other, for example by moving the plunger of the syringe back and forth, to reconstitute the composition according to the invention .

According to another aspect, the present invention provides a dosing regimen for administering an injectable intramuscular accumulation composition to a subject in need according to the present invention, the method comprising: a) Give the subject intramuscular injection of the first dose of LAI depot composition containing 75 mg to 100 mg risperidone; b) The patient is administered an intramuscular injection containing 75 mg to 100 mg LAI depot compositions of risperidone; and c) Repeat step b) whenever necessary.

During the treatment period, the dosage of the injectable composition is usually about the same.

Administration of a single dose is generally considered to be administered over a period of up to 24 hours, up to 12 hours, up to 6 hours, up to 3 hours, up to one hour, up to 30 minutes, up to 15 minutes, or up to 5 minutes Dosing of the injectable composition with the subject.

The agent may be administered to a single muscle site, or the agent may be divided into two or more portions and administered to two or more muscle sites of the subject. For example, a first portion of the agent can be administered to a first area of the subject's gluteal muscles, and a second portion of the agent can be administered to a second area of the subject's gluteal muscles.

As used herein, the words "initial burst" or "initial release" refer to the sum of the plasma concentration of the drug plus the plasma concentration of the active metabolite, which is also referred to throughout this specification as the "active moiety" (risperidone and Paliperidone), from the moment of injection/administration of the injectable composition to the subject in need described herein until the end of the third day after administration. For example, the drug can be risperidone, and its metabolite can be paliperidone. In some embodiments, the initial release period is within three days, within two days, within one day, within twelve hours, within 6 hours, or within 2 hours of administration.

Depot compositions of LAI containing various grades of PLGA, but otherwise identical, were prepared to determine the appropriate grade of PLGA exhibiting the improving effect. During the initial mixing of DMSO with drug and PLGA powder, the degree of clumping was determined by visual observation for 3 min. The formulations of the invention did not exhibit caking, or de-agglomerated and required less time to form a usable LAI depot composition than the control formulation. The control formulation was not adequately deagglomerated or the PLGA did not completely dissolve within the target mixing time of 3 minutes or less, or the plunger was pushed 200 times or less.

Too much PLGA in smaller particle sizes has been determined to result in excessive agglomeration of the powder mixture; however, too much PLGA in larger particle sizes can significantly increase the time required for PLGA to dissolve in DMSO.

Thus, the PLGA grades of the present invention increase the solubility of PLGA in powder mixtures of PLGA and drug, and reduce the clumping of the powder during mixing, while shortening the dissolution time of PLGA. Therefore, when the LAI depot composition is clinically prepared immediately before use, it does not take much time to mix the ingredients before administration, and avoids the situation where the agent becomes ineffective due to caking.

Next, individual LAI injectable depot compositions form implants. Then, the drug release profile of the implant was confirmed in vitro.

Implants made with PLGA 1 and 2 and mixed for less than 3 minutes showed unacceptable drug release results (Figure 1). As shown in Figure 1, the particle size mass distribution of PLGA used in this composition showed 16.8% of the particles were larger than 300 microns and 33.2% of the particles were smaller than 150 microns when measured by sieve analysis according to USP <786>. The D90 and D80 particle size volume distributions of the PLGA were 352 microns and 273 microns, respectively, as measured by laser light diffraction analysis. PLGA grades with too much larger particle size content showed incomplete dissolution during reconstitution of 3 minutes or less. Therefore, LAI depot compositions prepared from this grade of PLGA are not suitable as pharmaceuticals. However, sustained drug release from individual implants formed with PLGA 3 and 4 was satisfactory (Fig. 2). As shown in Figure 4, the PLGA particle size mass distribution used in this composition showed 1.2% of the particles were larger than 300 microns and 53.5% of the particles were smaller than 150 microns when measured by sieve analysis according to USP <786>. The D90 and D80 particle size volume distributions of the PLGA were 250 microns and 193 microns, respectively, as measured by laser light diffraction analysis.

With PLGA 5 and 6, extensive caking was observed and a suitable LAI depot composition could not be prepared within the ideal time of 3 minutes or less. Too much PLGA in the smaller particle sizes will result in excessive clumping and will not dissolve within the target 3 minutes. Therefore, these compositions are considered clinically unsuitable for use as pharmaceuticals. However, although a suitable injectable composition was not obtained, all the ingredients of the mixture were first placed in a vial, mixed by shaking the vial for 30 minutes, to be re- The composition was formulated and analyzed. An equal amount of the composition is filled into a syringe and injected to form an implant. Although PLGA 5 and 6 did not form acceptable injectable depot compositions of LAI, they still provided satisfactory drug release (Figure 3). As shown in Figure 3, the PLGA particle size mass distribution used in this composition showed 0.3% of the particles were larger than 300 microns and 77.2% of the particles were smaller than 150 microns when measured by sieve analysis according to USP <786>. The D90 and D80 particle size volume distributions of the PLGA were 168 μm and 114 μm, respectively, as measured by laser light diffraction analysis (Figure 4).

Therefore, PLGA with too large a particle size does not allow adequate drug release because PLGA cannot be completely dissolved during mixing, and the time to complete drug release from the implant is too short, three weeks instead of four. In addition, PLGA containing too much small particle size does not exert sufficient therapeutic effect due to the large amount of powder agglomeration during reconstitution, which results in neither an acceptable LAI depot composition nor an acceptable LAI depot composition. implants.

PLGA grades according to the particle size distribution provided by the present invention are capable of forming suitable implants with sustained drug release over the target 28-day period without exhibiting excessive clumping. Use of the PLGA grades of the present invention shortens the time required for complete dissolution of PLGA and avoids or significantly reduces powder clumping within the target mixing time. In some embodiments, powder blends of PLGA and drug of the present invention exhibit reduced or no clumping compared to other similar blends using PLGA grades with particle size distributions outside the desired range.

In some embodiments, the mixing time required to prepare a pharmaceutically potent LAI depot composition is 3 minutes or less, 2 minutes or less, or 1 minute or less.

The present invention also relates to a stable injectable intramuscular depot composition suitable for the formation of solid implants in situ, comprising 75 to 100 mg of risperidone, a biocompatible PLGA copolymer, and its lactide A monomer ratio of 45:55 to 55:45 to glycolide and DMSO as a solvent with risperidone and biocompatible polymer in a first container and solvent in a second container with The concentration of the biocompatible copolymer compared to the biocompatible copolymer and the solvent is 20-50% by weight. When measured by laser light diffraction analysis, the risperidone in the biocompatible copolymer and the solvent is D10 with a particle size volume distribution equal to or above 10 microns, D50 with a particle size volume distribution between 60 and 130 microns, and D90 with a particle size volume distribution below or equal to 225 microns, containing PLGA with Defined particle size distribution.

In a more desirable embodiment, the composition releases less than 20% of risperidone at day 7, based on the total amount of risperidone in the composition, as measured by the in vitro release assay described herein , and released less than 90 % of risperidone on day 21.

The present invention provides a method for treating diseases, disorders or symptoms responsive to risperidone and/or paliperidone. A more desirable applicable disease, disorder or condition is psychosis. Subjects in need thereof may be experiencing first or recurrent episodes of schizophrenia, and may have been stabilized on antipsychotic medications prior to administration of the LAI depot composition, or may not be on antipsychotic medications.

In some embodiments, the LAI accumulation composition is used for the treatment of schizophrenia, preferably for the treatment of adults, and/or the composition is used for the treatment of schizophrenia, preferably for adults with acute attacks and Treatment for maintenance of stable patients, especially for acute onset symptoms of schizophrenia in patients with moderate to severe symptoms who have not previously been stabilized with oral risperidone or paliperidone.

In a preferred embodiment, the LAI depot composition is used to treat a subject experiencing an acute episode of schizophrenia who has not previously been stabilized with an oral antipsychotic. In a particular embodiment, the subject does not have a dose setting of oral risperidone prior to administration of the composition. The term "dosage adjustment" as used herein refers to the oral administration of risperidone to determine the appropriate dosage required by the subject.

In a preferred embodiment, the LAI depot composition is used to treat moderate to severe symptoms in a subject experiencing an acute episode of schizophrenia who has not previously been stabilized by an oral antipsychotic. disease. This patient can start treatment immediately or after the drug titration is completed to ensure that risperidone is the appropriate treatment and the dose is appropriate.

In a more desirable embodiment, the LAI depot composition is used to continue (maintain) a subject who has been treated with another antipsychotic drug orally or injected with another injectable depot composition to stabilize the condition.

Other antipsychotics that subjects may be given include aripiprazole, olanzapine, blonanserin, quetiapine, haloperidol, flupenthixol, zuclopenthixol, brexiprazole, cariprazine, iloperidone, lurasidone, ziprazidone ziprasidone, chlorpromazine, fluphenazine, perphenazine, and/or clozapine. These antipsychotics can be administered before or after administration of the LAI depot composition.

All numerical values disclosed herein may have a technical measurement standard error (standard deviation) of ±10%. The word "about" is used to mean ±20%, ±15%, ±10%, ±5%, ±2.5% or ±1% of the specified value, ie "about" 20% means 20± 2%, 20±1%, 20±0.5%, or 20±0.25%. example

The following examples are for the purpose of explaining the present invention, and should not be considered as covering all content claimed in the present invention. Example 1 : Composition and its evaluation

The ingredient dosages used to prepare the various LAI depot compositions are detailed in the tables below. A control formulation was prepared by using a PLGA grade whose particle size distribution fell outside the declared range. The formulations of the present invention were prepared by using PLGA grades with particle size distributions falling within the stated ranges. PLGA and drug are stored in the first container, and DMSO is stored in the second container. Recipe 1: Element dose (mg) Lactic-co-glycolic acid copolymer (ester terminal group) 50:50 150 Dimethyl sulfoxide 350 Risperidone 75 Recipe 2: Element dose (mg) Lactic-co-glycolic acid copolymer (ester terminal group) 50:50 200 Dimethyl sulfoxide 467 Risperidone 100

Risperidone has a particle size volume distribution of d (0.1) = 33 μm, d (0.5) = 81 μm and d (0.9) = 160 μm when measured by laser light diffraction analysis (using a Malvern Mastersizer 2000 analyzer, Suspended in water until the shading rate reaches 7.4%).

Placing the ingredients in the kit is accomplished by storing DMSO in the first container, and powdered risperidone and PLGA in the second container. The preferred container is a syringe.

The assessed PLGA levels are as follows. ․ PLGA 1: PLGA is milled to have a particle size mass distribution in which more than 10% of the particles have a particle size greater than 300 microns as measured by sieve analysis according to USP<786>; ․ PLGA 2: PLGA is milled to a D90 particle size volume distribution greater than 300 microns as measured by laser light diffraction analysis; ․ PLGA 3: PLGA is milled so that in the particle size mass distribution, less than 10% of the particles are larger than 300 microns and less than 70% of the particles are smaller than 150 microns, as measured by sieve analysis according to USP<786> result; ․ PLGA 4: PLGA milled to a D90 particle size volume distribution of not greater than 300 microns and a D80 particle size volume distribution of not less than 135 microns as measured by laser light diffraction analysis; ․ PLGA 5: PLGA is milled to have a particle size mass distribution in which more than 70% of the particles are less than 150 microns in size as measured by sieve analysis according to USP<786>; ․ PLGA 6: PLGA is milled to a D80 particle size volume distribution of less than 135 microns as measured by laser light diffraction analysis.

LAI depot compositions are prepared by mixing the ingredients by connecting the syringe and pushing and pulling the individual plungers of the syringe back and forth. The degree of caking of the powder was visually observed during mixing.

Mix immediately before injection (reconstitution process). The required target top mix time is 3 minutes or less (or 200 pushes or less); however, the formulation of the present invention preferably has a target top mix time of 2 minutes or less, or 1 minute or less, or 30 seconds or less (150 pushes or less, 100 pushes or less, or 50 pushes). Determine the time required for the powder to deagglomerate and dissolve the PLGA.

Implants are formed by administering the depot composition into phosphate-buffered saline. The following in vitro drug dissolution (drug release) tests were performed on the implant: 50 rpm horizontal orbital motion; moderate: PBS pH 7.4.; temperature: 37 ± 0.5 ºC. Determine the drug concentration or dose in the test solution using HPLC with UV detection (wavelength 260 nm). Example 2 : Particle size determination Sieve analysis according to USP <786>

The following particle sizes were analyzed using the sieve stack technique to determine the PLGA particle size mass distribution: 355 > 300 > 250 > 150 > 125 > 106 > 75. The amplitude is 0.65 mm and the shaking time is 5 min. Laser Light Diffraction Analysis

The PLGA particle size distribution is expressed as a volume distribution and was determined using laser light diffraction techniques and wet dispersion methods. No sample pretreatment was used. Add the sample directly to the dispersion medium (water). The dispersion mechanism was agitation at 3,000 rpm and the samples were allowed to stabilize for 30 seconds before measurement. Example 3 : Composition

The ingredient dosages used to prepare the various LAI depot compositions are detailed in the table below. The formulations of the present invention were prepared by using PLGA grades with particle size distributions falling within the stated ranges. Individual LAI depot compositions are formed by mixing these ingredients. Recipe 3: Element dose (mg) Lactic-co-glycolic acid copolymer (ester terminal group) 75:25 150 Dimethyl sulfoxide 350 Risperidone 75 Recipe 4: Element dose (mg) Lactic-co-glycolic acid copolymer (ester terminal group) 75:25 200 Dimethyl sulfoxide 467 Risperidone 100 Recipe 5: Element dose (mg) Lactic-co-glycolic acid copolymer (ester terminal group) 50:50 50 Dimethyl sulfoxide 117 Risperidone 25 Recipe 6: Element dose (mg) Lactic-co-glycolic acid copolymer (ester terminal group) 50:50 300 Dimethyl sulfoxide 700 Risperidone 150 Recipe 7: Element dose (mg) Lactic-co-glycolic acid copolymer (carboxyl end group) 50:50 50 Dimethyl sulfoxide 117 Risperidone 25 Recipe 8: Element dose (mg) Lactic-co-glycolic acid copolymer (carboxyl end group) 50:50 300 Dimethyl sulfoxide 700 Risperidone 150 Recipe 9: Element dose (mg) Lactic-co-glycolic acid copolymer (ester terminal group) 50:50 150 Dimethyl sulfoxide 350 Paliperidone 75 Recipe 10: Element dose (mg) Lactic-co-glycolic acid copolymer (ester terminal group) 50:50 200 Dimethyl sulfoxide 467 Paliperidone 100 Recipe 11: Element dose (mg) Lactic-co-glycolic acid copolymer (ester terminal group) 50:50 120 Dimethyl sulfoxide 228 Risperidone 56 Recipe 12: Element dose (mg) Lactic-co-glycolic acid copolymer (ester terminal group) 50:50 96 Dimethyl sulfoxide 252 Risperidone 44

PLGA has an intrinsic viscosity in the range of 0.20-0.60 dl/g, about 0.30-0.55 dl/g, about 0.36 -0.52 dl/g, about 0.36-0.43 dl/g, about 0.40-0.58 dl/g, or about 0.46-0.51 dl/g.

The particle size distribution of PLGA is as follows: a) when measured by sieve analysis according to USP<786>, the mass distribution of particle sizes above 300 microns does not exceed 10%, preferably not more than 250 microns; b) when measured by laser light diffraction analysis , the particle size volume distribution of D90 is not more than 300 microns, preferably not more than 280 microns; c) when measured by sieve analysis according to USP <786>, the mass distribution of particle sizes above 300 microns does not exceed 10%, preferably not more than 10%; More than 250 microns, of which less than 70% of the particles are less than 150 microns; d) no more than 70% of the particle size mass distribution is less than 150 microns when measured by sieve analysis according to USP <786>; e) using laser light When measured by diffraction analysis, the particle size volume distribution of D90 is not more than 300 microns, preferably not more than 280 microns, and when measured by laser light diffraction analysis, the particle size volume distribution of D80 is not less than 135 microns; D80 has a particle size volume distribution of not less than 135 microns when measured by X-ray diffraction analysis; g) D50 is approximately 50-150 microns; h) D10 is approximately 10-50 microns; i) D90 is approximately 170-300 microns; and/ or j) D50 of about 50-150 microns, D10 of about 10-50 microns and D90 of about 170-300 microns.

The viscosity of the individual LAI depot compositions prepared from the above ingredients before forming the individual implants falls within the range of about 1.0-7.0 Pa.s, about 1.5-7.0 Pa.s, or about 1.8-6.5 Pa.s. Example 4 : Approaches to treating mental illness

The LAI accumulation composition prepared according to this embodiment, which contains risperidone at a dose of 75 mg or 100 mg, was intramuscularly administered to a subject suffering from schizophrenia. Evaluate and monitor the subject to determine the subject's treatment response to risperidone. If an inadequate response to treatment is determined, a higher dose of risperidone will be administered.

The same procedure can again be followed to administer the LAI depot composition subcutaneously to the subject, for example, to the adipose tissue of the subject.

The methods described above are useful in the treatment of bipolar disorder and other disorders disclosed herein that are responsive to risperidone and/or paliperidone. Example 5 : Administration method

The subject was intramuscularly administered the LAI accumulation composition prepared according to this embodiment, which contained risperidone at a dose of 75 mg or 100 mg. Evaluate and monitor subjects to determine the subject's clinical response to risperidone.

The same procedure can again be followed to administer the LAI depot composition subcutaneously to the subject, for example, to the adipose tissue of the subject.

none

We provide the following drawings to help explain the purpose of the present invention, but do not imply any limitation.

Figure 1 Cumulative percent release of risperidone obtained from an in vitro dissolution test of a control composition comprising PLGA in which PLGA exceeds 10% of its particle size mass distribution when measured by sieve analysis according to USP <786> Particle size equal to or greater than 300 microns.

Figure 2 Cumulative percent release of risperidone obtained from in vitro dissolution tests of compositions of the invention.

Figure 3 Cumulative percent release of risperidone obtained from an in vitro dissolution test of a composition comprising PLGA having at least 70% of its particle size mass distribution when measured by sieve analysis according to USP <786> The particle size is less than 150 microns.

Fig. 4 is the particle size distribution of PLGA obtained by measuring the composition of the present invention by laser light diffraction analysis. Horizontal axis: particle size in microns. Vertical axis: volume (%), indicating the volume percentage of particles of corresponding particle size, measured by the wet dispersion method carried out in water by laser light diffraction, and stirred and dispersed at 3,000 rpm.

none

Claims (21)

A powder mixture comprising a powdered drug and a powdered PLGA copolymer, wherein a) the drug is selected from the group consisting of risperidone, paliperidone or a mixture thereof; and b) The PLGA copolymer has a lactide (L) to glycolide (G) monomer ratio of 50:50 ±10% to 75:25 ±10%, 50:50 ±10% or 75:25 ±10% 10% with a particle size distribution selected from the group consisting of: i) Not more than 10% of the mass distribution of particle sizes above 300 microns, preferably not more than 250 microns, when measured by sieve analysis according to USP<786>; ii) D90 has a particle size volume distribution of not more than 300 microns, preferably not more than 280 microns, when measured by laser light diffraction analysis; iii) Not more than 10% of the particle size mass distribution above 300 microns, preferably not more than 250 microns, with less than 70% of the particles being less than 150 microns in size when measured by sieve analysis according to USP<786>; iv) Not more than 70% of the mass distribution of particle sizes under 150 microns when measured by sieve analysis according to USP<786>; v) When measured by laser light diffraction analysis, the particle size volume distribution of D90 is not more than 300 microns, preferably not more than 280 microns, and when measured by laser light diffraction analysis, the particle size volume distribution of D80 is not less than 135 microns ; vi) When measured by laser light diffraction analysis, the particle size volume distribution of D80 is not less than 135 microns; vii) D50 with a particle size volume distribution of approximately 50-150 microns; viii) D10 has a particle size volume distribution of approximately 10-50 microns; ix) D90 has a particle size volume distribution of approximately 170-300 microns; x) a particle size volume distribution of approximately 50-150 microns for D50, approximately 10-50 microns for D10, approximately 170-300 microns for D90, and xi) A combination of any of the above. A method of preparing a long-acting injectable (LAI) depot composition comprising a) Mix DMSO, PLGA copolymer and drug, where b) The drug is selected from the group consisting of risperidone, paliperidone or a mixture thereof; and the monomer ratio of lactide (L) to glycolide (G) of the PLGA copolymer is 50:50 ±10 % to 75:25 ±10%, 50:50 ±10% or 75:25 ±10%, with a particle size distribution selected from the group consisting of: i) Not more than 10% of the mass distribution of particle sizes above 300 microns, preferably not more than 250 microns, when measured by sieve analysis according to USP<786>; ii) D90 has a particle size volume distribution of not more than 300 microns, preferably not more than 280 microns, when measured by laser light diffraction analysis; iii) Not more than 10% of the particle size mass distribution above 300 microns, preferably not more than 250 microns, with less than 70% of the particles being less than 150 microns in size when measured by sieve analysis according to USP<786>; iv) Not more than 70% of the mass distribution of particle sizes under 150 microns when measured by sieve analysis according to USP<786>; v) When measured by laser light diffraction analysis, the particle size volume distribution of D90 is not more than 300 microns, preferably not more than 280 microns, and when measured by laser light diffraction analysis, the particle size volume distribution of D80 is not less than 135 microns ; vi) When measured by laser light diffraction analysis, the particle size volume distribution of D80 is not less than 135 microns; vii) D50 with a particle size volume distribution of approximately 50-150 microns; viii) D10 has a particle size volume distribution of approximately 10-50 microns; ix) D90 has a particle size volume distribution of approximately 170-300 microns; x) a particle size volume distribution of approximately 50-150 microns for D50, approximately 10-50 microns for D10, approximately 170-300 microns for D90, and xi) A combination of any of the above. A LAI storage composition prepared according to the method described in claim 2. According to the LAI storage composition described in item 3 of the patent application, wherein a) The drug is about 25 mg to about 150 mg; b) The viscosity range is about 1.0-7.0 Pa.s; c) a mass ratio of DMSO to drug of about 5:1 to about 4:1; and d) The mass ratio of drug to (PLGA+drug) (expressed as a percentage of drug weight relative to the total weight of drug plus PLGA) is approximately 15-40% by weight. According to the LAI storage composition described in item 3 of the patent application, wherein a) The drug content is about 10-15% wt; b) DMSO content of about 55-65% wt; and c) c) The PLGA content is about 24%-30% wt; said percentages are based on the total weight of the composition. A method of administering medicine to a subject, the method comprising administering to the subject the LAI storage composition according to item 3, 4 or 5 of the patent application. A method for treating a disease, disorder or symptom responsive to risperidone and/or paliperidone, the method comprising administering to a subject in need according to claim 3, 4 or 5 of the patent application The LAI depot composition. The method according to claim 7, wherein after said administration, the LAI depot composition forms an implant which continuously provides a therapeutic plasma concentration of the active moiety from the first day and Lasts for at least about 28 days. A method according to claim 7, wherein the disease, symptom or disorder is selected from the group consisting of psychosis, delusional psychosis, psychotic depression, obsessive-compulsive disorder, schizophrenia, bipolar disorder, psychotic Schizoaffective disorder, non-schizophrenic psychosis, Asperger's syndrome, Tourette's syndrome, obsessive-compulsive disorder, post-traumatic stress disorder, attention deficit hyperactivity disorder, personality disorder, Aggression, depression, dementia, mental retardation, mental retardation and behavioral disorders arising from autism, autistic group disorders, anxiety, eating disorders, nervous anxiety, insomnia, idiopathic dystonia, substance abuse and the above any combination. A method according to claim 7, wherein the disease, condition or disorder is selected from the group consisting of: schizophrenia, schizoaffective disorder, bipolar disorder and bipolar mania. The method according to claim 9 or 10, wherein said treatment is treatment of an acute exacerbation of said disease, condition or disorder. The method according to any one of claims 6-11, wherein the administration is intramuscular administration. A medical kit comprising a drug, DMSO and PLGA copolymer, wherein a) the drug is selected from the group consisting of risperidone, paliperidone or a mixture thereof; and b) The PLGA copolymer has a lactide (L) to glycolide (G) monomer ratio of 50:50 ±10% to 75:25 ±10%, 50:50 ±10% or 75:25 ± 10% with a particle size distribution selected from the group consisting of: i) Not more than 10% of the mass distribution of particle sizes above 300 microns, preferably not more than 250 microns, when measured by sieve analysis according to USP<786>; ii) When measured by laser light diffraction analysis, the particle size volume distribution of D90 is not more than 300 microns, preferably not more than 280 microns; when measured by sieve analysis according to USP<786>, the particle size mass distribution above 300 microns Not more than 10%, preferably not more than 250 microns, of which less than 70% of the particles have a particle size smaller than 150 microns; iii) Not more than 70% of the mass distribution of particle sizes under 150 microns when measured by sieve analysis according to USP <786>; iv) When measured by laser light diffraction analysis, the particle size volume distribution of D90 is not more than 300 microns, preferably not more than 280 microns, and when measured by laser light diffraction analysis, the particle size volume distribution of D80 is not less than 135 microns ; v) D80 has a particle size volume distribution of not less than 135 microns when measured by laser light diffraction analysis; vi) D50 has a particle size volume distribution of approximately 50-150 microns; vii) D10 has a particle size volume distribution of approximately 10-50 microns; viii) D90 has a particle size volume distribution of approximately 170-300 microns; ix) a particle size volume distribution of approximately 50-150 microns for D50, approximately 10-50 microns for D10, approximately 170-300 microns for D90, and x) A combination of any of the above. A set of two or more containers according to claim 13, wherein a) The DMSO is stored in the first container, and the PLGA and the drug are stored together in the second container; b) The DMSO is stored in a first container, the PLGA is stored in a second container, and the drug is stored in a third container. A kit according to claim 13 or 14, wherein a) Drug doses of about 25 mg to about 150 mg; b) The mass ratio of drug to (PLGA+drug) (expressed as a percentage of drug weight relative to the total weight of risperidone plus PLGA) is approximately 15-40% by weight; and/or c) The mass ratio of DMSO to drug is about 5:1 to about 4:1. A set according to claim 13, 14 or 15, wherein a) The drug dose is approximately 100 mg, the DMSO dose is approximately 467 mg, and the PLGA dose is approximately 200 mg; b) The drug dose is approximately 75 mg, the DMSO dose is approximately 350 mg, and the PLGA dose is approximately 150 mg; c) The drug dose is about 115 mg (or about 100-130 mg or about 105-125 mg or about 110-120 mg), the DMSO dose is about 537 mg (or about 515-560 mg or about 520-550 mg or about 530- 545 mg) with a PLGA dose of about 230 mg (or about 215-245 mg or about 220 to about 235 mg); or d) Drug dose about 90 mg (or about 75-105 mg or about 80-100 mg or about 85-105 mg), DMSO dose about 420 mg (or about 405-435 mg or about 415-425 mg) and PLGA dose About 180 mg (or about 165-200 mg or about 170-190 mg to about 175-185 mg). According to the invention described in any one of items 1-16 of the scope of application, the PLGA is sieved. According to the invention described in claim 17, the PLGA is sieved and/or pulverized. According to the invention described in claim 18 of the patent application, wherein the PLGA is micronized, milled, hammered, crushed, ground, pulverized and/or pressed into powder. According to the invention described in any one of items 1-19 of the scope of application, the PLGA is ester-terminated. According to the invention according to any one of the claims 1-19 of the patent application, wherein the drug has a D10 particle size volume distribution equal to or higher than 10 microns and a D50 of between 60 and and 130 microns and D90 is less than or equal to 225 microns.

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