Method for ensuring resuspension of paliperidone palmitate formulations

Abstract

The present invention provides a method for improving the resuspendability of a paliperidone palmitate extended release injectable suspension in a syringe, for reducing the force required to inject the paliperidone palmitate extended release injectable suspension, or for reducing the possibility of incomplete injection of the paliperidone palmitate extended release injectable suspension, the method comprising maintaining the syringe in a desired orientation different from the orientation of the syringe during storage before transportation during the syringe transportation. Also provided are a group of syringes containing the paliperidone palmitate extended release injectable suspension, each of which has been transported to a destination, and the syringes are each maintained in a desired orientation different from the orientation of the syringe during storage before transportation during the syringe transportation. The present disclosure also provides a pharmaceutical product, the pharmaceutical product comprising the paliperidone palmitate extended release injectable suspension in a syringe, for administration to a patient suffering from schizophrenia, wherein the syringe has undergone pre-transportation storage and has been transported, and wherein the syringe is maintained in an orientation different from the orientation of the syringe during storage before transportation during transportation.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 237,883 filed on August 27, 2021 and U.S. Provisional Application No. 63 / 119,305 filed on November 30, 2020. Technical Field

[0003] The present disclosure relates to methods of affecting the administration quality of a pharmaceutical suspension. Background Art

[0004] Antipsychotic drugs are the main drugs for treating schizophrenia, schizoaffective disorder and schizophreniform disorder. Antipsychotic drugs were first introduced in the mid-1950s. These typical or first-generation drugs are usually effective in controlling the positive symptoms of schizophrenia, but are less effective in alleviating the negative symptoms or cognitive impairment associated with the disease. Atypical antipsychotic drugs or second-generation drugs represented by risperidone and olanzapine were developed in the 1990s and are usually characterized by effectiveness against the positive and negative symptoms associated with schizophrenia.

[0005] Paliperidone palmitate is the palmitate ester of paliperidone (9-hydroxy-risperidone), a monoaminergic antagonist that exhibits the characteristic dopamine (D) type 2 activity of the second generation atypical antipsychotics. 2) and serotonin (5-hydroxytryptamine type 2A) antagonists. Paliperidone (9-OH risperidone) is the major active metabolite of risperidone. Paliperidone is marketed in the United States (US) as an extended release (ER) osmotic controlled release oral delivery (OROS) tablet formulation for the treatment of schizophrenia and maintenance of effect.

[0006] Paliperidone palmitate has been developed as a long-acting, intramuscular (im), injectable aqueous nanosuspension for the treatment of schizophrenia and other related diseases commonly treated with antipsychotic drugs. Due to extremely low water solubility, paliperidone esters (such as paliperidone palmitate) slowly dissolve after intramuscular injection and are then hydrolyzed into paliperidone and available in the systemic circulation.

[0007] Monthly injections of paliperidone palmitate have been developed to provide sustained paliperidone plasma concentrations, which can greatly improve compliance with dosing. Paliperidone palmitate formulated as an aqueous nanosuspension is described in U.S. Patents 6,077,843 and 6,555,544, each of which is incorporated herein by reference. In addition, dosing regimens for treating patients with paliperidone palmitate are disclosed in U.S. Patents 9,439,906 and 10,143,693, each of which is incorporated herein by reference.

[0008] Paliperidone is currently available in three formulations: oral extended-release formulation ( Extended-release [ER] tablets; also known as extended-release [PR] tablets) and two long-acting injectable (LAI) formulations (paliperidone palmitate 1-month injection [INVEGA or ] and paliperidone palmitate 3-month injection [INVEGA or Another paliperidone palmitate product (paliperidone palmitate 6-month injection) designed to be administered every 6 months has been launched in the United States [INVEGA HAFYERA TM ] and Europe Approved to further improve compliance and convenience.

[0009] Paliperidone palmitate suspension formulations are generally highly concentrated products. Therefore, an important consideration is to ensure that the product is completely suspended / resuspended prior to administration. In order to minimize the chance of incomplete administration, it is necessary to have a health care professional perform the administration and follow specific guidelines in preparation for and during administration. For example, INVEGA The label states that the syringe containing the formulation should be shaken vigorously for at least 15 seconds before administration to ensure a homogenous suspension (corresponding to the instructions for use, IFU). It is also necessary to perform the injection slowly, for example over a period of 20 seconds to 30 seconds. It is also recommended to shake the syringe while it is in the tip-up position. INVEGA HAFYERA TM The label for TRANSPORT(R) states that the syringe containing the formulation should be shaken very rapidly (with the syringe tip cap pointing upward) for at least 15 seconds, followed by a brief rest, and then shaken again for 15 seconds.

[0010] There may be some instances of deviation from the resuspension protocol due to human error, which may result in inadequate resuspension and, therefore, incomplete administration of the paliperidone palmitate suspension.There is a need for additional strategies to ensure that the desired paliperidone palmitate resuspension occurs. Summary of the invention

[0011] Provided herein is a method for improving the resuspendability of a paliperidone palmitate extended release injectable suspension in a syringe, the method comprising maintaining the syringe in a substantially horizontal orientation during syringe transportation. Also provided herein is a method for improving the resuspendability of a paliperidone palmitate extended release injectable suspension in a syringe, the method comprising maintaining the syringe in an orientation different from the orientation of the syringe during storage before transportation during transportation, such as when the orientation during storage before transportation is not substantially horizontal, maintaining a substantially horizontal orientation during syringe transportation.

[0012] Also disclosed is a method for reducing the force required to inject a paliperidone palmitate extended-release injectable suspension from a syringe, the method comprising maintaining the syringe in a substantially horizontal orientation during transport of the syringe. Also disclosed is a method for reducing the force required to inject a paliperidone palmitate extended-release injectable suspension from a syringe, the method comprising maintaining the syringe in an orientation different from the orientation of the syringe during storage prior to transport, such as maintaining the syringe in a substantially horizontal orientation during transport of the syringe when the orientation during storage prior to transport is not substantially horizontal.

[0013] The present disclosure also relates to a method for reducing the likelihood of incomplete injection of a paliperidone palmitate extended release injectable suspension from a syringe, the method comprising maintaining the syringe in a substantially horizontal orientation during transport of the syringe. The present disclosure also relates to a method for reducing the likelihood of incomplete injection of a paliperidone palmitate extended release injectable suspension from a syringe, the method comprising maintaining the syringe in an orientation different from the orientation of the syringe during storage before transport during transport, such as maintaining the syringe in a substantially horizontal orientation during transport of the syringe when the orientation during storage before transport is not substantially horizontal.

[0014] Also provided is a method for improving the resuspendability of a paliperidone palmitate extended release injectable suspension in a syringe, the method comprising maintaining the syringe in a substantially horizontal orientation during storage of the syringe. Also provided is a method for improving the resuspendability of a paliperidone palmitate extended release injectable suspension in a syringe, the method comprising maintaining the syringe in an orientation different from the orientation of the syringe during storage before transportation during transportation, such as maintaining the syringe in a substantially horizontal orientation during storage of the syringe when the orientation during storage before transportation is not substantially horizontal.

[0015] Also disclosed are syringe populations containing extended release injectable suspensions of paliperidone palmitate, each of which has been transported to a destination, and each syringe is maintained in a substantially horizontal orientation during transport of the syringe. Also disclosed are syringe populations containing extended release injectable suspensions of paliperidone palmitate, each of which has been transported to a destination, and each syringe is maintained during transport in an orientation different from the orientation of the syringe during storage before transport, such as when the orientation during storage before transport is not substantially horizontal, the syringe is maintained in a substantially horizontal orientation during transport of the syringe.

[0016] The present disclosure also provides a drug product comprising a paliperidone palmitate extended release injectable suspension in a syringe for administration to a patient suffering from schizophrenia, wherein the syringe has undergone pre-shipment storage and has been shipped, and wherein the syringe is maintained during shipping in an orientation that is different from the orientation of the syringe during pre-shipment storage.

[0017] Also disclosed are methods for treating schizophrenia, the methods comprising administering a paliperidone palmitate extended release injectable suspension from a syringe to a patient suffering from schizophrenia, wherein the syringe has undergone pre-transportation storage and has been transported, and wherein the syringe is maintained during transport in an orientation different from the orientation of the syringe during pre-transportation storage. Also disclosed are paliperidone palmitate extended release injectable suspensions for use in methods for treating schizophrenia, wherein these methods comprise administering a paliperidone palmitate extended release injectable suspension from a syringe to a patient suffering from schizophrenia, wherein the syringe has undergone pre-transportation storage and has been transported, and wherein the syringe is maintained during transport in an orientation different from the orientation of the syringe during pre-transportation storage. Also disclosed are uses of a paliperidone palmitate extended release injectable suspension in the manufacture of a medicament for treating schizophrenia, wherein the paliperidone palmitate extended release injectable suspension is prepared for administration from a syringe, wherein the syringe has undergone pre-transportation storage and has been transported, and wherein the syringe is maintained during transport in an orientation different from the orientation of the syringe during pre-transportation storage.

[0018] In an embodiment of the present disclosure, the paliperidone palmitate extended release injectable suspension is selected from the group consisting of PP3M and PP6M. In one embodiment, the paliperidone palmitate extended release injectable suspension is PP3M. In one embodiment, the paliperidone palmitate extended release injectable suspension is PP6M. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figures 1A to 1FDepicted are force injection profiles of a process performance qualification (PPQ) batch of PP6M stored in one of five different spatial orientations.

[0020] FIG. 2A to FIG. 2D Injection force curves for syringes subjected to vibration testing in either horizontal or tip-down orientations are provided. DETAILED DESCRIPTION

[0021] The inventive subject matter disclosed by the present invention may be more readily understood with reference to the following detailed description in conjunction with the accompanying examples forming a part of the present disclosure. It should be understood that these inventions are not limited to the specific formulations, methods or parameters described and / or shown herein, and the terminology used herein is only used to describe specific embodiments by way of example and is not intended to limit the invention protected by the claims.

[0022] The entire disclosure of each patent, patent application, and publication cited or described in this document is hereby incorporated by reference.

[0023] As used above and throughout this disclosure, the following terms and abbreviations shall be understood to have the following meanings, unless otherwise indicated.

[0024] In this disclosure, unless the context clearly indicates otherwise, the singular forms "a," "an," and "the" include plural referents, and references to a specific value include at least that specific value. Thus, for example, reference to "a formulation" refers to one or more such formulations, as well as equivalents of the formulation known to those skilled in the art, and so forth. In addition, when it is indicated that an element "may be" X, Y, or Z, such usage is not intended to exclude other choices of the element in all cases.

[0025] When the value is expressed as an approximate value using "about" above, it should be understood that the specific value constitutes another embodiment. Generally speaking, the use of the term "about" represents an approximate value, which can vary according to the desired characteristics that the disclosed subject matter attempts to obtain, and will be interpreted based on its function in the specific context in which the approximate value is used. In some embodiments, "about X" (where X is a numerical value) refers to the quoted value ± 10%, including the end value. For example, the phrase "about 8" can refer to a value of 7.2 to 8.8, including the end value. This value may include "just 8". Where present, all ranges include the end value and are combinable. For example, when citing a range of "1 to 5", the quoted range should be understood to optionally include ranges such as "1 to 4", "1 to 3", "1-2", "1-2 and 4-5", "1-3 and 5". In addition, when a list of alternatives is provided for sure, such a list may also include embodiments in which any of the alternatives may be excluded. For example, when describing a range of "1 to 5", such description may cover the situation where any of 1, 2, 3, 4 or 5 is excluded; thus, a reference to "1 to 5" may cover "1 and 3 to 5, but not including 2", or simply "wherein 2 is not included".

[0026] It should be understood that references herein to methods of treatment (e.g., methods of treating schizophrenia) using one or more compounds or formulations thereof (e.g., paliperidone palmitate extended release injectable suspension) should also be construed as references to:

[0027] - one or more compounds or formulations thereof (e.g. paliperidone palmitate extended release injectable suspension) for use in a method of treating, for example, schizophrenia; and / or

[0028] - Use of one or more compounds or formulations thereof (eg paliperidone palmitate extended release injectable suspension) in the manufacture of a medicament for the treatment of, for example, schizophrenia.

[0029] As described above, there is a resuspension protocol to ensure complete administration of the paliperidone palmitate injectable suspension. Although prescription paliperidone palmitate formulations include clear label instructions regarding the correct procedures for preparing the formulation for administration and the mode in which the injection itself should be performed, it is possible that the health care provider responsible for following the specified procedures may not do so in a manner that ensures adequate resuspension of the paliperidone palmitate and thereby delivery of the prescribed dose to the patient in need thereof.

[0030] The inventors have surprisingly found that changing the orientation of the syringe containing the suspension of paliperidone palmitate during the transportation process relative to the orientation of the syringe during storage before transportation affects the resuspendability of the drug product in the formulation for administration. In particular, it has been found that maintaining the syringe in an orientation different from the orientation of the syringe during storage before transportation, such as maintaining a substantially horizontal orientation during transportation, for example, in contrast to the traditional tip-down orientation when the syringe is also stored in a tip-down orientation before transportation, improves the resuspendability of paliperidone palmitate, and thus improves the possibility of complete administration of the prescribed dose. Therefore, the present discovery has the effect of alleviating human error or other causes of deviation from the prescription resuspension scheme (e.g., the type and duration of the control oscillation), which is intended to ensure sufficient resuspension of paliperidone palmitate. As a result of the improved drug resuspension, certain benefits are generated, such as reducing the amount of force required for administration, and generally, reducing the chance of incomplete administration. This can also improve resuspension by reducing the force of the oscillation required for resuspension. The fact that the chance of incomplete administration is reduced means that the risk of patients receiving less than the expected dose of paliperidone palmitate is also reduced. This means that in the event of a deviation from the prescribed resuspension regimen, a patient with schizophrenia who is administered a paliperidone palmitate extended release injectable suspension from a syringe that is maintained, for example, during transport in an orientation different from the orientation of the syringe during storage prior to transport (such as a substantially horizontal orientation during transport) is less likely to receive a lower than expected dose than a patient who is administered a paliperidone palmitate extended release injectable suspension from a syringe that is maintained, for example, in a traditional tip-down orientation during transport. Therefore, administration of a paliperidone palmitate extended release injectable suspension from a syringe that is maintained, for example, during transport in an orientation different from the orientation of the syringe during storage prior to transport (such as a substantially horizontal orientation during transport) represents an important contribution to the field of schizophrenia therapy.

[0031] Therefore, the present invention provides a method for improving the resuspendability of a paliperidone palmitate extended release injectable suspension in a syringe, the method comprising maintaining the syringe in a substantially horizontal orientation during the transportation of the syringe. The present disclosure also encompasses a method for reducing the possibility of an incomplete injection of a paliperidone palmitate extended release injectable suspension from a syringe, the method comprising maintaining the syringe in a substantially horizontal orientation during the transportation of the syringe. The present invention also provides a method for improving the resuspendability of a paliperidone palmitate extended release injectable suspension in a syringe, the method comprising maintaining the syringe in an orientation different from the orientation of the syringe during storage before transportation during transportation, such as when the orientation during storage before transportation is not substantially horizontal, maintaining a substantially horizontal orientation during the transportation of the syringe. The present invention also encompasses a method for reducing the possibility of an incomplete injection of a paliperidone palmitate extended release injectable suspension from a syringe, the method comprising maintaining the syringe in an orientation different from the orientation of the syringe during storage before transportation during transportation, such as when the orientation during storage before transportation is not substantially horizontal, maintaining a substantially horizontal orientation during the transportation of the syringe.

[0032] In an embodiment of the present disclosure, the paliperidone palmitate extended release injectable suspension is selected from the group consisting of PP3M and PP6M. In one embodiment, the paliperidone palmitate extended release injectable suspension is PP3M. In one embodiment, the paliperidone palmitate extended release injectable suspension is PP6M.

[0033] Paliperidone esters are antipsychotics belonging to the chemical class of benzisoxazole derivatives, containing a racemic mixture of (+)- and (-)-paliperidone, which is described in U.S. Pat. No. 5,254,556 (incorporated herein by reference). The chemical name of paliperidone palmitate is (±) hexadecanoic acid-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4-oxo-4H-pyrido[1,2-c]pyrimidin-9-yl ester. Its structural formula is:

[0034]

[0035] Paliperidone esters can be formulated into injectable dosage forms together with pharmaceutical excipients as described in US Pat. Nos. 5,254,556 and 6,077,843, both of which are incorporated herein by reference. Injectable preparations can be formulated in aqueous carriers.

[0036] The paliperidone palmitate extended release injectable suspension may be, for example, a commercially available formulation that is intended for administration to a subject once every three months, once every six months, or at some other interval.

[0037] Commercially available formulations that are administered every three months include INVEGA or See also U.S. Pat. No. 10,143,693, which is incorporated herein by reference. In the present disclosure, "PP3M" refers to a paliperidone palmitate extended release injectable suspension or other type of formulation having an amount of paliperidone palmitate suitable for a dosing interval of about three months. For example, "PP3M" may refer to a paliperidone palmitate extended release injectable suspension having a dosing interval of about three months.

[0038] Commercially available formulations that are administered every six months include INVEGA HAFYERA in the United States. TM The six-monthly formulation is marketed in Europe under the trade name Marketing authorization has been obtained. As used herein, "PP6M" refers to a paliperidone palmitate extended release injectable suspension or other types of preparations of paliperidone palmitate with an amount of paliperidone palmitate suitable for a dosing interval of about six months. For example, "PP6M" may refer to a paliperidone palmitate extended release injectable suspension with a dosing interval of about six months. PP6M is generally provided in a dosage ranging from about 1000 mg to about 1600 mg of paliperidone palmitate to provide a sustained paliperidone therapeutic concentration within a six-month dosing interval. Preferably, PP6M will be provided in a dosage strength of about 1092 mg or about 1560 mg of paliperidone palmitate. The drug product is hydrolyzed into the active portion paliperidone, producing a dosage strength of about 700 mg eq. or 1000 mg eq. of paliperidone, respectively.

[0039] PP6M is preferably provided in a pre-filled syringe (cyclic olefin copolymer) pre-filled with 700 mg eq. (3.5 mL) or 1000 mg eq. (5.0 mL) of paliperidone (1092 mg or 1560 mg of paliperidone palmitate, respectively) with a plunger stopper, plunger rod and tip cap (bromobutyl rubber), backstop and needle, preferably a thin wall 20 gauge (G), 1.5 inch safety needle.

[0040] PP3M is generally provided in a dosage range of about 270 mg to about 825 mg of paliperidone palmitate to provide sustained therapeutic concentrations of paliperidone over a three-month dosing interval. Preferably, PP3M will be provided in a dosage strength of about 273 mg, 410 mg, 546 mg, or 819 mg of paliperidone palmitate. The drug product is hydrolyzed into the active portion paliperidone, producing dosage strengths of about 175 mg eq., 263 mg eq., 350 mg eq., or 525 mg eq. of paliperidone, respectively.

[0041] PP3M is preferably provided in a prefilled syringe (cyclic olefin copolymer) prefilled with about 175 mg eq. to about 525 mg eq., with a plunger stopper, plunger rod and tip cap (bromobutyl rubber), backstop and needle, preferably a thin wall 20 gauge (G), 1.5 inch safety needle, or a thin wall 22 gauge (G), 1 inch safety needle.

[0042] In certain embodiments, PP3M and PP6M may have the same formulation and differ in the total volume of the suspension formulation contained in the respective syringes. The paliperidone palmitate suspension used according to the present method may contain an absolute amount of about 250 mg to about 1600 mg of paliperidone palmitate. The amount of paliperidone palmitate in the suspension may be, for example, 273 mg, 410 mg, 546 mg, or 819 mg. In certain embodiments, the amount of paliperidone palmitate in the suspension may be 1092 mg or 1560 mg.

[0043] In certain embodiments, the average particle size of the 3-month (PP3M) formulation is less than about 20 μm to about 1 μm. In other embodiments, the average particle size (d50) of the particles is about 5 μm to about 15 μm; about 3 μm to about 10 μm; or about 5 μm to about 9 μm. The d90 may be about 50 μm; about 10 μm to about 30 μm; or about 10 μm to about 20 μm. The d10 may be about 1 μm to about 10 μm, or about 1 μm to about 5 μm.

[0044] In certain embodiments, the average particle size of the 6-month (PP6M) formulation is less than about 30 μm to about 1 μm; or about 20 μm to about 1 μm. In other embodiments, the average particle size (d50) of the particles is about 3 μm to about 25 μm; about 5 μm to about 15 μm; about 3 μm to about 10 μm; or about 5 μm to about 9 μm. The d90 may be 60 μm; or about 50 μm; about 10 μm to about 30 μm; or about 10 μm to about 20 μm. The d10 may be about 1 μm to about 15 μm; about 1 μm to about 10 μm; or about 1 μm to about 5 μm.

[0045] As used herein, d10: the fraction of particles with a diameter smaller than this value is 10%; d50: the fraction of particles with a diameter smaller than this value is 50%; d90: the fraction of particles with a diameter smaller than this value is 90%; this is measured by conventional techniques known in the art (such as sedimentation field flow fractionation, photon correlation spectroscopy or disk centrifugation).

[0046] Suitable aqueous nanoparticle formulations are described in US Pat. No. 6,555,544, which is incorporated herein by reference. In some embodiments, the formulation comprises microparticles, a surfactant, a suspending agent, and optionally one or more additional ingredients selected from the group consisting of a preservative, a buffer, and an isotonic agent.

[0047] Useful surface modifiers for paliperidone palmitate formulations are considered to include those agents that physically adhere to the surface of the active agent but are not chemically bonded thereto. Suitable surface modifiers can be selected from known organic pharmaceutical excipients and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include nonionic surfactants and anionic surfactants. Representative examples of excipients include gelatin, casein, lecithin (phospholipids), gum arabic, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, cetearyl alcohol, cetomel emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., polyethylene glycol ethers, such as cetomel 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (e.g., commercially available TWEENs TM ), polyethylene glycol, polyoxyethylene stearate, colloidal silicon dioxide, phosphate esters, sodium lauryl sulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, non-crystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), poloxamer, tyloxapol and polyvinyl pyrrolidone (PVP). Most of these excipients are described in detail in the Handbook of Pharmaceutical Excipients, which is jointly published by the American Pharmaceutical Society and the British Pharmaceutical Association, Pharmaceutical Press, 1986. Surface modifiers are commercially available and / or can be prepared by techniques known in the art. Two or more surface modifiers can be used in combination.

[0048] Particularly preferred surface modifiers include polyvinylpyrrolidone; tyloxapol; poloxamers such as PLURONIC TM F68, F108 and F127, which are block copolymers of ethylene oxide and propylene oxide, available from BASF; poloxamines, such as TETRONIC TM 908 (T908), a tetrafunctional block copolymer derived from the sequential addition of ethylene oxide and propylene oxide to ethylenediamine, available from BASF; dextran; lecithin; Aerosol OT TM (AOT), which is the dioctyl ester of sodium sulfosuccinate available from Cytec Industries; DUPONOL TM P, which is sodium lauryl sulfate available from DuPont; TRITON TMX-200, which is an alkyl aryl polyether sulfonate available from Rohm and Haas; TWEEN TM 20, 40, 60 and 80, which are polyoxyethylene sorbitan fatty acid esters available from ICI Speciality Chemicals; SPAN TM 20, 40, 60 and 80, which are sorbitan esters of fatty acids; ARLACEL TM 20, 40, 60 and 80, which are sorbitan esters of fatty acids available from Hercules; CARBOWAX TM 3550 and 934, which are polyethylene glycols available from Union Carbide; CRODESTA TM F110, which is a mixture of sucrose stearate and sucrose distearate available from Croda; CRODESTA TM SL-40, available from Croda Corporation; hexyldecyltrimethylammonium chloride (CTAC); bovine serum albumin and SA90HCO, which has the following formula: 18 H 17 CH 2 (CON(CH 3 )CH 2 (CHOH) 4 CH 2 OH) 2 Surface modifiers that have been found to be particularly useful include tyloxapol and poloxamers, preferably Pluronic TM F108 and Pluronic TM F68.

[0049] Pluronic TM F108 corresponds to poloxamer 338 and is a polyoxyethylene, polyoxypropylene block copolymer, which generally conforms to the formula HO[CH 2 CH 2 O] x [CH(CH 3 )CH 2 O] y [CH 2 CH 2 O] z H, wherein the average values ​​of x, y and z are 128, 54 and 128 respectively. Other trade names of Poloxamer 338 are Hodag NONIONIC TM 1108-F and SYNPERONIC available from ICIAmericas TM PE / F108.

[0050] The optimal relative amounts of paliperidone palmitate and the surface modifier depend on various parameters. The optimal amount of surface modifier may depend, for example, on the specific surface modifier selected, the critical micelle concentration of the surface modifier (if it forms micelles), the surface area of ​​the antipsychotic agent, etc. The specific surface modifier is preferably present in an amount of about 0.1 mg to about 1 mg per square meter of paliperidone palmitate surface area. In the case of paliperidone palmitate (9-hydroxyrisperidone palmitate), it is preferred to use PLURONIC TM F108 is used as a surface modifier, and the relative amount (w / w) of the two components is preferably about 6:1.

[0051] The particles of the paliperidone palmitate suspension can be prepared by a method comprising the steps of dispersing the paliperidone palmitate in a liquid dispersion medium and applying mechanical means in the presence of a grinding medium to reduce the particle size of the antipsychotic agent to an effective average particle size. The size of the particles can be reduced in the presence of a surface modifier. Alternatively, the particles can be contacted with a surface modifier after abrasion.

[0052] A general procedure for preparing particles of a paliperidone palmitate suspension may include (a) obtaining paliperidone palmitate; (b) adding paliperidone palmitate to a liquid medium to form a premix; and (c) subjecting the premix to mechanical means in the presence of grinding media to reduce the effective average particle size.

[0053] Paliperidone palmitate may be prepared using techniques known in the art. Preferably, the particle size of paliperidone palmitate is less than about 100 μm, as determined by sieve analysis. If the particle size of paliperidone palmitate is greater than about 100 μm, it is preferred to reduce the size of the paliperidone palmitate particles to less than 100 μm.

[0054] Paliperidone palmitate can then be added to a liquid medium in which it is substantially insoluble to form a premix. The concentration (weight / weight percentage) of paliperidone palmitate in the liquid medium can vary widely and depends on the selected antipsychotic agent, the selected surface modifier and other factors. The suitable concentration of paliperidone palmitate in the composition varies from about 0.1% to about 60%, preferably from about 0.5% to about 30%, and more preferably about 7% (w / v). For PP3M, a concentration of about 200 mg eq. paliperidone / mL or about 312 mg paliperidone palmitate / mL is preferably used. For PP6M, a concentration of about 200 mg eq. paliperidone / mL or about 312 mg paliperidone palmitate / mL is preferably used.

[0055] Another exemplary procedure involves adding a surface modifier to the premix prior to subjecting the premix to mechanical means to reduce the effective average particle size. The concentration of the surface modifier (weight / weight percentage) may vary from about 0.1% to about 90%, preferably about 0.5% to about 80%, and more preferably about 7% (w / v).

[0056] The premix may be used directly by subjecting it to mechanical means to reduce the effective average particle size in the dispersion to the desired particle size. When a ball mill is used for attrition, it is preferred to use the premix directly. Alternatively, the antipsychotic agent and optional surface modifier may be dispersed in the liquid medium using suitable agitation (such as a roll mill or Cowles type mixer) until a homogeneous dispersion is obtained.

[0057] The mechanical means applied to reduce the effective average particle size of the antipsychotic drug can conveniently take the form of a dispersion mill. Suitable dispersion mills include ball mills, attritor mills, vibratory mills, planetary mills, media mills, such as sand mills and bead mills. Media mills are preferred because relatively short milling times are required to provide the desired particle size reduction. For media milling, in some embodiments, the apparent viscosity of the premix is ​​preferably any value between about 0.1 Pa·s and about 1 Pa·s. In some embodiments, for ball milling, the apparent viscosity of the premix is ​​preferably any value between about 1 mPa·s and about 100 mPa·s.

[0058] The grinding media used in the particle size reduction step can be selected from hard media, preferably in spherical or granular form, having an average size of less than about 3 mm, more preferably less than about 1 mm. Such media can ideally provide shorter processing times for the particles of the present invention and produce less wear on the grinding equipment. The choice of material for the grinding media is not considered critical. However, about 95% ZrO stabilized with magnesium oxide, zirconium silicate and glass grinding media provides acceptable particles for the preparation of pharmaceutical compositions. In addition, other media (such as polymer beads, stainless steel, titanium dioxide, aluminum oxide and about 95% ZrO stabilized with yttrium) are useful. Preferred grinding media have a particle size greater than about 2.5 g / cm 3 The density of the composite is about 95% ZrO stabilized with magnesium oxide and polymer beads.

[0059] Attrition times can vary widely and depend primarily on the specific mechanical means and processing conditions selected. For roller mills, processing times of up to two days or more may be required for smaller sized particles.

[0060] The size of the particles should be reduced at a temperature that does not significantly degrade the antipsychotic agent. Processing temperatures of less than about 30°C to about 40°C are generally preferred. If necessary, the processing equipment can be cooled with conventional cooling equipment. The method is conveniently carried out at ambient temperature and under processing pressure conditions that are safe and effective for the milling process.

[0061] If the surface modifier is not present in the premix, it is typically added to the dispersion after attrition, for example in an amount as described above for the premix. The dispersion can then be mixed, for example by vigorous shaking. Optionally, the dispersion can be subjected to an ultrasonic treatment step, for example using an ultrasonic power source.

[0062] The aqueous composition may also contain a suspending agent and a buffering agent, and optionally one or more preservatives and isotonic agents. A particular ingredient may function as two or more of these agents simultaneously, for example, behaving like a preservative and a buffering agent, or behaving like a buffering agent and an isotonic agent.

[0063] Suitable suspending agents (also referred to as physical stabilizers) for use in aqueous suspensions according to the invention are cellulose derivatives (e.g. methylcellulose, sodium carboxymethylcellulose and hydroxypropyl methylcellulose), polyvinyl pyrrolidone, alginate, chitosan, dextran, gelatin, polyethylene glycol, polyoxyethylene ether and polyoxypropylene ether. Preferably, sodium carboxymethylcellulose is used in a concentration of about 0.5% to about 2%, most preferably about 1% (w / v).

[0064] Suitable wetting agents preferred from the listed surfactants for the aqueous suspension according to the invention are polyoxyethylene derivatives of sorbitan esters (e.g. polysorbate 20 and polysorbate 80), lecithin, polyoxyethylene ethers and polyoxypropylene ethers, sodium deoxycholate. Preferably, polysorbate 20 is used in a concentration of about 0.5% to about 3%, more preferably about 0.5% to about 2%, most preferably about 1.1% (w / v).

[0065] Suitable buffers are salts of weak acids and should be used in an amount sufficient to render the pH of the dispersion from about 6.0 to alkaline. Preferably, the pH is in the range of about 6.0 to about 9.0; or in the range of about 6.0 to about 8.0; or in the range of about 6.5 to about 7.5. For example, the pH is in the range of about 6.0 to about 6.5, or about 6.5 to about 7.0, or about 7.0 to about 7.5, or about 7.5 to about 8.0, or about 8.0 to about 8.5, or about 8.5 to about 9.0. Particularly preferred is the use of a mixture of disodium hydrogen phosphate (anhydrous) (usually about 0.9% (w / v)) and sodium dihydrogen phosphate monohydrate (usually about 0.6% (w / v)). This buffer also renders the dispersion isotonic and, in addition, the ester suspended therein is less prone to flocculation.

[0066] The preservative may include an antimicrobial agent and an antioxidant, which may be selected from the group consisting of benzoic acid, benzyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, chlorobutanol, gallic acid esters, hydroxybenzoic acid esters, EDTA, phenol, chlorocresol, metacresol, benzethonium chloride, myristyl-γ-pyridinium chloride, phenylmercuric acetate, and thimerosal. In particular, benzyl alcohol may be used in a concentration of up to about 2% (w / v), preferably up to about 1.5% (w / v).

[0067] Isotonic agents are, for example, sodium chloride, glucose, mannitol, sorbitol, lactose, sodium sulfate. The suspension conveniently contains from about 0% to about 10% (w / v) of isotonic agent. Mannitol can be used in a concentration of from about 0% to about 7%, but more preferably, from about 1% to about 3% (w / v), especially from about 1.5% to about 2% (w / v), of one or more electrolytes are used to make the suspension isotonic, apparently because the ions help prevent the suspended esters from flocculating. In particular, the electrolytes of the buffer act as isotonic agents.

[0068] Particularly desirable features of injectable formulations relate to the ease with which they can be administered. In particular, such injections should be possible in the shortest possible time span using the thinnest possible needle. This can be achieved with the aqueous suspensions of the present invention by maintaining a viscosity that can be easily absorbed into a syringe (e.g., from a vial) and injected through a thin needle. For example, in some embodiments, the viscosity is less than about 75 MPa·s, or less than about 60 MPa·s at room temperature. For PP3M, 22G, 1 1 / 2 inch needle, or 22G, 1 inch needle. And for PP6M, 20G, 1 1 / 2 Inch needle.

[0069] Ideally, the aqueous suspension used according to the present method includes as much prodrug as is tolerated to keep the injection volume to a minimum, and contains as few other ingredients as possible.

[0070] In particular, for PP3M or PP6M, the composition may comprise or consist essentially of: (a) about 200 mg / mL to about 500 mg / mL of the prodrug; (b) about 2 mg / mL to about 25 mg / mL of a wetting agent; (c) about 2.5 mg / mL to about 50 mg / mL of one or more buffers; (d) about 25 mg / mL to about 150 mg / mL of a suspending agent; (e) optionally up to about 2% (w / v) of a preservative; and (f) q.s. water, which is added to 100%. Typically, the PP3M or PP6M composition has a pH of about 6.0 to about 8.0, preferably about 6.5 to about 7.5.

[0071] In other embodiments, for PP3M or PP6M, the composition may comprise or consist essentially of: (a) about 250 mg / mL to about 400 mg / mL of the prodrug; (b) about 5 mg / mL to about 20 mg / mL of a wetting agent; (c) about 5 mg / mL to about 25 mg / mL of one or more buffering agents; (d) about 50 mg / mL to about 100 mg / mL of a suspending agent; (e) optionally up to about 2% (w / v) of a preservative; and (f) water, q.s., which adds to 100%.

[0072] In other embodiments, for PP3M or PP6M, the composition may comprise or consist essentially of: (a) about 280 mg / mL to about 350 mg / mL of the prodrug; (b) about 8 mg / mL to about 12 mg / mL of a wetting agent; (c) about 5 mg / mL to about 15 mg / mL of one or more buffering agents; (d) about 65 mg / mL to about 85 mg / mL of a suspending agent; (e) optionally up to about 2% (w / v) of a preservative; and (f) water, q.s., which makes up to 100%.

[0073] The active ingredient in PP3M or PP6M comprises paliperidone palmitate (about 312 mg / mL). In certain preferred embodiments, the inactive ingredients in PP3M or PP6M are polysorbate 20 (about 10 mg / mL), polyethylene glycol 4000 (about 75 mg / mL), citric acid monohydrate (about 7.5 mg / mL), sodium dihydrogen phosphate monohydrate (about 6 mg / mL), sodium hydroxide (about 5.4 mg / mL), and water for injection. An exemplary PP3M is disclosed in Example 1. An exemplary PP6M is disclosed in Example 2.

[0074] The method includes maintaining a syringe containing paliperidone palmitate extended release injectable suspension in a substantially horizontal orientation during transport of the syringe. The method also includes maintaining a syringe containing paliperidone palmitate extended release injectable suspension in an orientation different from the orientation of the syringe during storage before transport during transport, such as maintaining a substantially horizontal orientation during transport of the syringe when the orientation during storage before transport is not substantially horizontal.

[0075] Regardless of the particular orientation of the syringe during its pre-shipment storage, according to the present method, changing the orientation of the syringe during transportation after such pre-shipment storage can mean maintaining the syringe in a shipping orientation representing an angular deviation from the orientation during storage of about 45 degrees to about 135 degrees. For example, the orientation of the syringe during transportation can be changed by about 45 degrees, 50 degrees, 55 degrees, 55 degrees, 60 degrees, 65 degrees, 70 degrees, 75 degrees, 80 degrees, 85 degrees, 90 degrees, 95 degrees, 100 degrees, 105 degrees, 110 degrees, 115 degrees, 120 degrees, 125 degrees, 130 degrees, or 135 degrees from the orientation of the syringe during pre-shipment storage.

[0076] For example, the orientation of the syringe during transport may be substantially horizontal. This is particularly appropriate when the orientation of the syringe during storage prior to transport is tip-up or tip-down (where the "tip" of the syringe refers to the portion of the syringe to which the needle is attached for injection purposes). A substantially horizontal orientation may refer to an orientation in which the angle of the syringe relative to an applicable reference point (such as the ground perpendicular to gravity, or the floor of the vehicle in which the syringe is transported) is closer to 0° than to 90°. For example, a substantially horizontal orientation can refer to an orientation of 0 degrees, 2 degrees, 3 degrees, 4 degrees, 5 degrees, 6 degrees, 7 degrees, 8 degrees, 9 degrees, 10 degrees, 11 degrees, 12 degrees, 13 degrees, 14 degrees, 15 degrees, 16 degrees, 17 degrees, 18 degrees, 19 degrees, 20 degrees, 21 degrees, 22 degrees, 23 degrees, 24 degrees, 25 degrees, 26 degrees, 27 degrees, 28 degrees, 29 degrees, 30 degrees, 31 degrees, 32 degrees, 34 degrees, 35 degrees, 36 degrees, 37 degrees, 38 degrees, 39 degrees, 40 degrees, 41 degrees, 42 degrees, 43 degrees or 44 degrees relative to a relevant reference point.

[0077] In other embodiments, the orientation of the syringe during transport may be substantially with the tip pointing upward. When the orientation of the syringe during storage prior to transport is with the tip pointing downward or substantially horizontal, this represents a suitable orientation for transport. The tip pointing upward orientation may refer to an orientation in which the angle of the syringe makes the tip closer to 90° than 0° relative to an applicable reference point (such as the ground perpendicular to gravity, or the floor of the vehicle transporting the syringe). For example, a tip-up orientation can refer to an orientation of 90 degrees, 89 degrees, 88 degrees, 87 degrees, 86 degrees, 85 degrees, 84 degrees, 83 degrees, 82 degrees, 81 degrees, 80 degrees, 79 degrees, 78 degrees, 77 degrees, 76 degrees, 75 degrees, 74 degrees, 73 degrees, 72 degrees, 71 degrees, 70 degrees, 69 degrees, 68 degrees, 67 degrees, 66 degrees, 65 degrees, 64 degrees, 63 degrees, 62 degrees, 61 degrees, 60 degrees, 59 degrees, 58 degrees, 57 degrees, 56 degrees, 55 degrees, 54 degrees, 53 degrees, 52 degrees, 51 degrees, 50 degrees, 49 degrees, 48 ​​degrees, 47 degrees, or 46 degrees relative to a relevant reference point.

[0078] In other embodiments, the orientation of the syringe during transportation may be substantially with the tip downward. When the orientation of the syringe during storage prior to transportation is with the tip downward or substantially horizontal, this represents a suitable orientation for transportation. The tip downward orientation may refer to an orientation in which the syringe is flipped 180° relative to one of the tip upward orientations described herein.

[0079] Regardless of the particular orientation during transport, "maintaining" the orientation preferably means that an acceptable angle applies most of the time during the transport process. Ideally, when a substantially horizontal orientation is desired during transport, the syringe is maintained at an angle that is always perpendicular to gravity during transport, but in practice, changes in orientation inevitably occur during transport due to changes in the orientation of the vehicle transporting the syringe. For example, when a truck loaded with syringes for transport is stationary on flat terrain, the orientation of the syringe may be perpendicular to gravity, but when the truck goes uphill or downhill during the transport process, the orientation changes. Therefore, a useful reference point may be the floor of the transport vehicle rather than gravity, and preferably, the syringe is maintained in an orientation substantially parallel to the floor of the vehicle during transport.

[0080] Maintaining a specific orientation during the transport of a syringe may include loading the syringe onto a transport vehicle with a desired orientation, monitoring the syringe during transport to confirm that the desired orientation is maintained, or both. Loading a syringe onto a transport vehicle with a desired orientation refers to placing the package containing the syringe onto the transport vehicle, with the intention that the orientation when the package is placed onto the transport vehicle is not intentionally changed during the transport process. Monitoring the syringe during transport to confirm that the desired orientation is maintained may include direct or indirect observation by a person, by an automatic system programmed to confirm compliance with the desired orientation, or a combination of these. Direct observation by a person may include visual inspection of the package containing the syringe by a person. Indirect observation may include using a sensor, which is attached to a syringe, a package containing a syringe, or both, or otherwise enables monitoring of a syringe, a package containing a syringe, or both. For example, a sensor may obtain information about the orientation of a syringe and / or a package and transmit the information to a human observer, who determines whether the transmitted information indicates that the syringe is maintained at the desired orientation during the transport process. If the orientation of a container or package has deviated from an appropriate orientation, for example, if the container / package is displaced during transport, the sensor may also transmit an alarm or some other notifications. In one embodiment, the particular orientation or desired orientation is substantially horizontal.

[0081] The human monitor or sensor that can detect the information about the orientation of syringe can directly determine the orientation of syringe, or can indirectly determine the orientation of syringe by determining the orientation of the package that holds syringe.For example, the mark on the outer side of the package can provide visual prompts to the sensor or human monitor, which indicates the corresponding orientation of the syringe contained in the package.Therefore, syringe can be contained in a container (packaging), and the container (packaging) includes an outer surface with instructions or markings, and the instructions or markings make it possible to maintain the orientation (for example, substantially horizontal orientation) of the orientation of the syringe corresponding to the desired orientation during transportation.In some embodiments, instructions can be provided in appropriate languages ​​according to the source, the personnel transported and the destination of the syringe.In some embodiments, the mark on the outer surface of the container can be an arrow, which indicates which side of the container should be appropriately oriented at the top, bottom or side.When meeting the instructions or markings, the syringe contained in the container will be correctly oriented according to this method.

[0082] The transportation of syringe can be carried out by any required conveying means, such as airship (aircraft, helicopter, etc.), truck, ship, railway, or by any combination of these means, these means can be carried out from the transportation point of the drug manufacturing facility to the health care facility for application. The total duration of transportation can be any time period required for the syringe to be transported to the second position (such as being transported to the health care facility) from the initial storage position. For example, the duration of transportation can be about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours or 15 hours. The transportation process can include the time period of transmitting the syringe, and one or more intervals of not transmitting the syringe during the period, such as in a temporary storage depot before another transmission interval. For the purpose of the present disclosure, the duration of transportation can (but not necessarily need to) refer to the total amount of time passed by the facility for application after the syringe is removed from the initial storage facility for manufacture.

[0083] The method may further include maintaining the syringe in a storage position in an intentionally selected orientation (such as in a substantially horizontal orientation) after transporting the syringe and before administering the drug suspension. In this case, because the floor of the storage facility may be horizontal and therefore perpendicular to gravity, the substantially horizontal orientation may preferably refer to an angle substantially parallel to the floor of the storage facility. This may mean that the angle between the major axis of the syringe and the floor of the storage facility is preferably less than about 20 degrees, 15 degrees, 10 degrees, 9 degrees, 8 degrees, 7 degrees, 6 degrees, 5 degrees, 4 degrees, 3 degrees, 2 degrees or 1 degree.

[0084] As mentioned above, the present method promotes and improves the resuspension of the paliperidone palmitate syringe contents. An expected result of resuspending the paliperidone palmitate particles is to reduce or remove the residue of the paliperidone palmitate that does not resuspend in the syringe tip. In the case of incomplete resuspension, the paliperidone palmitate that does not resuspend can be retained in the tip of the syringe after administration, and thus represents the medicine that is not delivered and indicates incomplete administration. Minimizing the amount of the residue of the paliperidone palmitate that represents the non-resuspended paliperidone palmitate retained in the syringe tip after administration represents the further beneficial result of the method disclosed by the present invention. For example, according to the present method, the syringe tip may contain no more than about 3mm, 2.5mm, 2mm, 1.5mm, 1 or 0.5mm of the residue of the paliperidone palmitate that does not resuspend after administration. In some embodiments, the syringe tip contains about 3 mm, 2.8 mm, 2.6 mm, 2.5 mm, 2.4 mm, 2.2. mm, 2.1 mm, 2 mm, 1.9 mm, 1.8 mm, 1.7 mm, 1.6 mm, 1.5 mm, 1.4 mm, 1.3 mm, 1.2 mm, 1.1 mm, 1 mm, 0.9 mm, 0.8 mm, 0.7 mm, 0.6 mm, 0.5 mm, 0.4 mm, 0.3 mm, 0.2 mm, 0.1 mm, or 0 mm of residue representing paliperidone palmitate that was not resuspended after administration.

[0085] Syringe can be any type and be equipped with any needle suitable for storing and using paliperidone palmitate injectable suspension.For example, syringe can have the capacity of 1mL, 1.25mL, 1.5mL, 1.75mL, 2.0mL, 2.25mL, 2.5mL, 2.75mL, 2.8mL, 3mL, 3.25mL, 3.5mL, 3.75mL, 4mL, 4.25mL, 4.5mL, 4.75mL, 5mL, 5.25mL, 5.5mL, 5.75mL, 6mL, 6.25mL, 6.5mL, 6.75mL or 7mL.In some embodiments, syringe has the capacity of 1mL, 2.25mL, 2.8mL or 3mL, and includes 1 inch or 1.5 inches long 22 gauge needle.In some embodiments, syringe has the capacity of 5mL and includes 1.5 inches long 20 gauge needle. For any of the presently disclosed inventions, the volume of the paliperidone palmitate injectable suspension with a syringe can be, for example, 1 mL, 1.25 mL, 1.5 mL, 1.75 mL, 2.0 mL, 2.25 mL, 2.5 mL, 2.75 mL, 2.8 mL, 3 mL, 3.25 mL, 3.5 mL, 3.75 mL, 4 mL, 4.25 mL, 4.5 mL, 4.75 mL, 5 mL, 5.25 mL, 5.5 mL, 5.75 mL, 6 mL, 6.25 mL, 6.5 mL, 6.75 mL, or 7 mL.

[0086] The present method may further include the step of applying the suspension from a syringe (i.e., a syringe maintained in a desired orientation during transport) to the patient. In some embodiments, the desired orientation is substantially horizontal. For example, the suspension should be applied according to the protocol described on the label of the commercially available paliperidone palmitate extended release injectable suspension product mentioned above. Although the present method alleviates certain situations in which health care personnel cannot accurately follow the recommended steps before and during the application of paliperidone palmitate extended release injectable suspension, it is still recommended to apply the suspension from a syringe according to the present method in accordance with the labeling protocol.

[0087] At the same time, the present method enables to reduce the force required for injecting paliperidone palmitate to extend the release of an injectable suspension from a syringe, which has been maintained in a substantially horizontal orientation during the transport of the syringe. Therefore, the present disclosure encompasses a method for reducing the force required for injecting paliperidone palmitate to extend the release of an injectable suspension. For example, the force required for injecting from the syringe can be less than about 5%-60% of the force required for injecting paliperidone palmitate to extend the release of an injectable suspension from a syringe that is not maintained in a substantially horizontal orientation during the transport of the syringe. The force required for injecting from the syringe can be less than, for example, about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or 60% of the force required for injecting paliperidone palmitate to extend the release of an injectable suspension from a syringe that is not maintained in a substantially horizontal orientation during the transport of the syringe. In some embodiments, the force required to inject from the syringe can be about 10%-55%, 15%-50%, 20%-50%, 25%-45% or 30%-40% less than the force required to inject the extended release injectable suspension of paliperidone palmitate from a syringe that is not maintained in a substantially horizontal orientation during the transport of the syringe. In addition and at the same time, the present method enables the reduction of the force required to inject the extended release injectable suspension of paliperidone palmitate from a syringe that is maintained in an orientation different from the orientation of the syringe during storage before transport during transport, such as when the orientation during storage before transport is not substantially horizontal, the syringe is maintained in a substantially horizontal orientation during transport. Therefore, the present disclosure encompasses a method for reducing the force required to inject the extended release injectable suspension of paliperidone palmitate. For example, the force required to inject from the syringe can be about 5%-60% less than the force required to inject the extended release injectable suspension of paliperidone palmitate from a syringe that is not maintained in an orientation different from the orientation of the syringe during storage before transport during transport. The force required to inject from the syringe may be, for example, about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50, 55, or 60% less than the force required to inject the paliperidone palmitate extended release injectable suspension from a syringe that is not maintained during transport in an orientation different from the orientation of the syringe during storage prior to transport. In some embodiments, the force required to inject from the syringe may be about 10%-55%, 15%-50%, 20%-50%, 25%-45%, or 30%-40% less than the force required to inject the paliperidone palmitate extended release injectable suspension from a syringe that is not maintained during transport in an orientation different from the orientation of the syringe during storage prior to transport.

[0088] In an absolute sense, the force required for the injection of paliperidone palmitate extended release injectable suspension from the syringe may be less than about 10 Newtons to 25 Newtons required for the injection of paliperidone palmitate extended release injectable suspension from a syringe that is not maintained in a substantially horizontal orientation during the syringe transport. The force required for the injection of paliperidone palmitate extended release injectable suspension from the syringe may be less than, for example, about 10 Newtons, 11 Newtons, 12 Newtons, 13 Newtons, 14 Newtons, 15 Newtons, 16 Newtons, 17 Newtons, 18 Newtons, 19 Newtons, 20 Newtons, 21 Newtons, 22 Newtons, 23 Newtons, 24 Newtons or 25 Newtons required for the injection of paliperidone palmitate extended release injectable suspension from a syringe that is not maintained in a substantially horizontal orientation during the syringe transport. The amount of force actually required for the injection of paliperidone palmitate extended release injectable suspension from a syringe may be, for example, about 10 Newtons to 25 Newtons. Thus, the force required to inject from the syringe may be, for example, about 10 Newtons, 11 Newtons, 12 Newtons, 13 Newtons, 14 Newtons, 15 Newtons, 16 Newtons, 17 Newtons, 18 Newtons, 19 Newtons, 20 Newtons, 21 Newtons, 22 Newtons, 23 Newtons, 24 Newtons, or 25 Newtons. Furthermore, in absolute terms, the force required to inject the paliperidone palmitate extended-release injectable suspension from the syringe may be about 5 Newtons to 25 Newtons less than the force required to inject the paliperidone palmitate extended-release injectable suspension from a syringe that is not maintained during transport in an orientation different from the orientation of the syringe during storage prior to transport. The force required to inject from the syringe can be, for example, about 5 Newtons, 6 Newtons, 7 Newtons, 8 Newtons, 9 Newtons, 10 Newtons, 11 Newtons, 12 Newtons, 13 Newtons, 14 Newtons, 15 Newtons, 16 Newtons, 17 Newtons, 18 Newtons, 19 Newtons, 20 Newtons, 21 Newtons, 22 Newtons, 23 Newtons, 24 Newtons, or 25 Newtons less than the force required to inject the paliperidone palmitate extended release injectable suspension from a syringe that is not maintained during transport in an orientation different from the orientation of the syringe during storage prior to transport. The amount of force actually required to inject the paliperidone palmitate extended release injectable suspension from a syringe can be, for example, about 10 Newtons to 25 Newtons. Thus, the force required to inject from a syringe may be, for example, about 10 Newtons, 11 Newtons, 12 Newtons, 13 Newtons, 14 Newtons, 15 Newtons, 16 Newtons, 17 Newtons, 18 Newtons, 19 Newtons, 20 Newtons, 21 Newtons, 22 Newtons, 23 Newtons, 24 Newtons, or 25 Newtons.

[0089] The method may further comprise assessing the amount of force required to complete injection of the paliperidone palmitate extended release injectable suspension from the syringe.The assessment may be performed using any available measurement technique.

[0090] The method may also or alternatively include assessing whether the injection of the extended release injectable suspension of paliperidone palmitate from the syringe is complete. The assessment may include measuring whether the amount of paliperidone palmitate not resuspended in the syringe tip exceeds a certain value, such as a length of about 4mm, 3.75mm, 3.5mm, 3.25mm, 3mm, 2.75mm, 2.5mm, 2.25mm, 2mm, 1.75mm, 1.5mm, 1.25mm, 1mm, 0.75mm, 0.5mm or 0.25mm.

[0091] Also disclosed herein is a method for improving the resuspendability of a paliperidone palmitate extended release injectable suspension in a syringe, the method comprising maintaining the syringe in a substantially horizontal orientation during syringe storage. The storage of the syringe may be performed before or after transporting the syringe. In certain embodiments, the storage of the syringe occurs after the syringe is, for example, transported, at a location corresponding to a health care facility where paliperidone palmitate is administered. These methods may be performed independently of or in conjunction with the above-mentioned method for improving resuspendability, the method comprising maintaining the syringe in a substantially horizontal orientation during transport. In other words, the syringe may be stored in a substantially horizontal orientation, transported in a substantially horizontal orientation, or transported and stored in a substantially horizontal orientation. The storage of the syringe in a substantially horizontal orientation may be promoted by markings or other instructions on the packaging or container containing the syringe, and such markings may be identical or different from markings or instructions intended to ensure that a substantially horizontal orientation is maintained during transport. As in the case of a method including maintaining a substantially horizontal orientation during transport, the present method may further include monitoring to ensure that a substantially horizontal orientation is maintained during storage. The method for monitoring may be identical to those methods described above regarding maintaining a substantially horizontal orientation during transport. Also disclosed herein is a method for improving the resuspendability of a paliperidone palmitate extended release injectable suspension in a syringe, the method comprising maintaining the syringe in an orientation different from the orientation of the syringe during storage before transportation during transportation, such as when the orientation during storage before transportation is not substantially horizontal, maintaining a substantially horizontal orientation during storage of the syringe. Storage of the syringe may be performed before or after transporting the syringe. In certain embodiments, storage of the syringe occurs after the syringe is, for example, transported, at a location corresponding to a health care facility where paliperidone palmitate is administered. These methods may be performed independently of or in conjunction with the above-mentioned method for improving resuspendability, the method comprising maintaining the syringe in an orientation different from the orientation of the syringe during storage before transportation during transportation. In other words, the syringe may be transported in a substantially horizontal orientation, then stored in a substantially horizontal orientation, or transported and stored in a substantially horizontal orientation. Storage of the syringe in a specific orientation may be promoted by markings or other instructions on the packaging or container containing the syringe, and such markings may be identical or different from markings or instructions intended to ensure that the desired orientation is maintained during transportation. As in the case of a method including maintaining a specific orientation during transportation, the method may further include monitoring to ensure that the desired orientation is maintained during storage. The methods used for monitoring may be the same as those described above with respect to maintaining a desired orientation during transport.

[0092] The present disclosure also provides a syringe population containing a prolonged release injectable suspension of paliperidone palmitate, respectively, wherein each syringe has been transported to a destination, and the syringe is maintained in a substantially horizontal orientation during the transport of the syringe. Therefore, each member of the syringe population will produce the above-mentioned benefits associated with transporting in a substantially horizontal orientation, including improved resuspendability, less residue in the syringe tip after application, less force required for application, etc. The syringe population may include about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 120, 140, 160, 180, 200, 225, 250, 275, 300, 325, 350, 360, 375, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 610, 620, 630, 640, 650, 660, 670, 680, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 811, 812, 813, 814, 815, 816, 817, 818, 819, 82 , 350, 375, 400, 425, 450, 475, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000 or more than 2000 individual syringes. Each member of the syringe population may include a syringe type and a paliperidone palmitate suspension described herein in addition according to the method disclosed in the present invention. In addition, the present disclosure also provides a syringe population containing a paliperidone palmitate extended release injectable suspension, respectively, wherein each syringe has been transported to a destination, and the syringe is maintained during transportation in an orientation different from the orientation of the syringe during storage before transportation, such as when the orientation during storage before transportation is not substantially horizontal, the syringe is maintained in a substantially horizontal orientation during transportation. Thus, each member of the syringe population will produce the above-mentioned benefits associated with shipping in an orientation different from that of the syringe during storage prior to shipping, including improved resuspendability, less residue in the syringe tip after administration, less force required for administration, etc. The syringe population may include about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 120, 140, 160, 180, 200, 225, 250, 275, 300, 325, 350, 360, 375, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 601, 611, 612, 621, 631, 640, 651 , 350, 375, 400, 425, 450, 475, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000 or more individual syringes.Each member of the syringe population may include a syringe type and a paliperidone palmitate suspension as otherwise described herein according to the methods disclosed herein.

[0093] Also provided herein is a pharmaceutical product comprising a paliperidone palmitate extended release injectable suspension in a syringe for administration to a patient suffering from schizophrenia, wherein the syringe has undergone pre-transportation storage and has been transported, and wherein the syringe is maintained during transportation in an orientation different from the orientation of the syringe during pre-transportation storage. The corresponding features of the paliperidone palmitate extended release injectable suspension, the syringe, the pre-transportation storage conditions, the orientation of the syringe during pre-transportation storage, the transport conditions, and the orientation of the syringe during transportation may be consistent with any of the embodiments described above for the method of the present invention for improving the resuspendability of the paliperidone palmitate extended release injectable suspension in the syringe and the syringe population of the present invention.

[0094] For example, the syringe may have been contained in a container including an outer surface including instructions for maintaining the container in an orientation corresponding to the desired orientation of the syringe during transport. In some embodiments, the syringe is contained in a container including an outer surface including markings indicating the orientation of the container corresponding to the desired orientation for maintaining the syringe.

[0095] After transport, the syringe may contain no more than about 1.5 mm or no more than about 1 mm of residue representing unresuspended paliperidone palmitate after injection of the suspension. For example, the syringe may contain about 1.5 mm, 1.4 mm, 1.3 mm, 1.2 mm, 1.1 mm, 1.0 mm, 0.9 mm, 0.8 mm, 0.7 mm, 0.6 mm, 0.5 mm, 0.4 mm, 0.3 mm, 0.2 mm or 0.1 mm of residue representing unresuspended paliperidone palmitate after injection of the suspension.

[0096] The extended release injectable suspension of paliperidone palmitate in a syringe may contain about 273 mg, 410 mg, 546 mg, or 819 mg of paliperidone palmitate. In other embodiments, the suspension contains about 1092 mg or 1560 mg of paliperidone palmitate.

[0097] The shipping orientation may vary from about 45 degrees to about 135 degrees from the orientation of the syringe during storage prior to shipping. For example, the orientation of the syringe during shipping may have varied from about 45 degrees, 50 degrees, 55 degrees, 55 degrees, 60 degrees, 65 degrees, 70 degrees, 75 degrees, 80 degrees, 85 degrees, 90 degrees, 95 degrees, 100 degrees, 105 degrees, 110 degrees, 115 degrees, 120 degrees, 125 degrees, 130 degrees, or 135 degrees from the orientation of the syringe during storage prior to shipping.

[0098] In some embodiments of the pharmaceutical product disclosed by the present invention, the storage orientation before transportation is pointed downward. In some embodiments of the pharmaceutical product disclosed by the present invention, the transportation orientation is substantially horizontal. In certain embodiments of the pharmaceutical product disclosed by the present invention, the storage orientation before transportation is pointed downward, and the transportation orientation is pointed upward or substantially horizontal. In other embodiments, the storage orientation before transportation is pointed downward, and the transportation orientation is substantially horizontal. In other embodiments, storage before transportation is pointed downward, and the transportation orientation is pointed upward.

[0099] The present disclosure also provides a method for treating schizophrenia, the method comprising administering a paliperidone palmitate extended release injectable suspension from a syringe to a patient suffering from schizophrenia, wherein the syringe has undergone pre-transportation storage and has been transported, and wherein the syringe is maintained during transportation in an orientation different from the orientation of the syringe during pre-transportation storage. The present disclosure also provides a paliperidone palmitate extended release injectable suspension for the method for treating schizophrenia, wherein these methods comprise administering a paliperidone palmitate extended release injectable suspension from a syringe to a patient suffering from schizophrenia, wherein the syringe has undergone pre-transportation storage and has been transported, and wherein the syringe is maintained during transportation in an orientation different from the orientation of the syringe during pre-transportation storage. For example, the suspension should be administered according to the protocol described on the label of the commercially available paliperidone palmitate extended release injectable suspension product mentioned above. Although the present method alleviates certain situations in which health care personnel cannot accurately follow the recommended steps before and during the administration of paliperidone palmitate extended release injectable suspension, it is still recommended to administer the suspension from a syringe according to the present method in accordance with the labeling protocol.

[0100] With regard to the method for treating schizophrenia disclosed in the present invention, the corresponding features of the extended release injectable suspension of paliperidone palmitate, the syringe, the storage conditions before transportation, the orientation of the syringe during storage before transportation, the transportation conditions and the orientation of the syringe during transportation can be consistent with any of the embodiments described above with regard to the method of the present invention for improving the resuspendability of the extended release injectable suspension of paliperidone palmitate in the syringe and the syringe population of the present invention.

[0101] For example, the syringe may have been contained in a container including an outer surface including instructions for maintaining the container in an orientation corresponding to the desired orientation of the syringe during transport. In some embodiments, the syringe is contained in a container including an outer surface including markings indicating the orientation of the container corresponding to the desired orientation for maintaining the syringe.

[0102] After transport, the syringe may contain no more than about 1.5 mm or no more than about 1 mm of residue representing unresuspended paliperidone palmitate after injection of the suspension. For example, the syringe may contain about 1.5 mm, 1.4 mm, 1.3 mm, 1.2 mm, 1.1 mm, 1.0 mm, 0.9 mm, 0.8 mm, 0.7 mm, 0.6 mm, 0.5 mm, 0.4 mm, 0.3 mm, 0.2 mm or 0.1 mm of residue representing unresuspended paliperidone palmitate after injection of the suspension.

[0103] The extended release injectable suspension of paliperidone palmitate in a syringe may contain about 273 mg, 410 mg, 546 mg, or 819 mg of paliperidone palmitate. In other embodiments, the suspension contains about 1092 mg or 1560 mg of paliperidone palmitate.

[0104] The shipping orientation may vary from about 45 degrees to about 135 degrees from the orientation of the syringe during storage prior to shipping. For example, the orientation of the syringe during shipping may have varied from about 45 degrees, 50 degrees, 55 degrees, 55 degrees, 60 degrees, 65 degrees, 70 degrees, 75 degrees, 80 degrees, 85 degrees, 90 degrees, 95 degrees, 100 degrees, 105 degrees, 110 degrees, 115 degrees, 120 degrees, 125 degrees, 130 degrees, or 135 degrees from the orientation of the syringe during storage prior to shipping.

[0105] In some embodiments of the method for treating schizophrenia disclosed in the present invention, the storage orientation before transport is pointed downward. In some embodiments of the method for treating schizophrenia disclosed in the present invention, the transport orientation is substantially horizontal. In certain embodiments of the method disclosed in the present invention, the storage orientation before transport is pointed downward, and the transport orientation is pointed upward or substantially horizontal. In other embodiments, the storage orientation before transport is pointed downward, and the transport orientation is substantially horizontal. In other embodiments, storage before transport is pointed downward, and the transport orientation is pointed upward.

[0106] The present disclosure also provides the use of a paliperidone palmitate extended release injectable suspension in the manufacture of a medicament for the treatment of schizophrenia, wherein the paliperidone palmitate extended release injectable suspension is prepared for administration from a syringe, wherein the syringe has been subjected to pre-transportation storage and has been transported, and wherein the syringe is maintained during transportation in an orientation different from the orientation of the syringe during pre-transportation storage. For example, the suspension should be administered according to the protocol described on the label of the commercially available paliperidone palmitate extended release injectable suspension product mentioned above. Although the use of the present invention alleviates certain situations in which health care personnel cannot accurately follow the recommended steps before and during the administration of paliperidone palmitate extended release injectable suspension, it is still recommended to administer the suspension from a syringe in accordance with the labeling protocol according to the use of the present invention.

[0107] With regard to the uses disclosed in the present invention, the corresponding features of the extended release injectable suspension of paliperidone palmitate, the syringe, the storage conditions before transport, the orientation of the syringe during storage before transport, the transport conditions and the orientation of the syringe during transport may be consistent with any of the embodiments described above with regard to the method of the present invention for improving the resuspendability of the extended release injectable suspension of paliperidone palmitate in a syringe and the syringe population of the present invention.

[0108] For example, the syringe may have been contained in a container comprising an outer surface including instructions for maintaining the container in an orientation corresponding to the desired orientation of the syringe during transport. In some embodiments, the syringe is contained in a container comprising an outer surface including markings indicating the orientation of the container corresponding to the desired orientation for maintaining the syringe.

[0109] After transport, the syringe may contain no more than about 1.5 mm or no more than about 1 mm of residue representing unresuspended paliperidone palmitate after injection of the suspension. For example, the syringe may contain about 1.5 mm, 1.4 mm, 1.3 mm, 1.2 mm, 1.1 mm, 1.0 mm, 0.9 mm, 0.8 mm, 0.7 mm, 0.6 mm, 0.5 mm, 0.4 mm, 0.3 mm, 0.2 mm or 0.1 mm of residue representing unresuspended paliperidone palmitate after injection of the suspension.

[0110] The extended release injectable suspension of paliperidone palmitate in a syringe may contain about 273 mg, 410 mg, 546 mg, or 819 mg of paliperidone palmitate. In other embodiments, the suspension contains about 1092 mg or 1560 mg of paliperidone palmitate.

[0111] The shipping orientation may vary from about 45 degrees to about 135 degrees from the orientation of the syringe during storage prior to shipping. For example, the orientation of the syringe during shipping may have varied from about 45 degrees, 50 degrees, 55 degrees, 55 degrees, 60 degrees, 65 degrees, 70 degrees, 75 degrees, 80 degrees, 85 degrees, 90 degrees, 95 degrees, 100 degrees, 105 degrees, 110 degrees, 115 degrees, 120 degrees, 125 degrees, 130 degrees, or 135 degrees from the orientation of the syringe during storage prior to shipping.

[0112] In some embodiments of the uses disclosed herein, the storage orientation before transport is pointed downward. In some embodiments of the uses disclosed herein, the transport orientation is substantially horizontal. In certain embodiments of the uses disclosed herein, the storage orientation before transport is pointed downward, and the transport orientation is pointed upward or substantially horizontal. In other embodiments, the storage orientation before transport is pointed downward, and the transport orientation is substantially horizontal. In other embodiments, storage before transport is pointed downward, and the transport orientation is pointed upward.

[0113] The present invention is further defined by reference to the following numbered clauses:

[0114] 1. A method for improving the resuspendability of a paliperidone palmitate extended release injectable suspension in a syringe, the method comprising maintaining the syringe in a substantially horizontal orientation during transport of the syringe.

[0115] 2. The method of clause 1, wherein maintaining the syringe in the substantially horizontal orientation comprises loading the syringe onto a vehicle in the substantially horizontal orientation, monitoring the syringe during transport to confirm that the substantially horizontal orientation is maintained, or both.

[0116] 3. The method of clause 1 or clause 2, further comprising housing the syringe in a container comprising an outer surface bearing instructions for maintaining the container in an orientation corresponding to the substantially horizontal orientation of the syringe during transport.

[0117] 4. A method according to any of the preceding clauses, further comprising containing the syringe in a container comprising an outer surface having markings indicating an orientation of the container, the orientation of the container corresponding to maintaining a substantially horizontal orientation of the syringe.

[0118] 5. The method according to any preceding clause, further comprising: after transporting the syringe, maintaining the syringe in a storage position in a substantially horizontal orientation.

[0119] 6. A method according to any preceding clause, wherein the syringe is transported by aircraft, truck, ship or rail.

[0120] 7. The method according to any preceding clause, wherein, after the transport, the syringe contains no more than about 1.5 mm of residue representing paliperidone palmitate that was not resuspended after administration.

[0121] 8. The method according to any preceding clause, wherein, after the transporting, the syringe contains no more than about 1 mm of residue representing un-resuspended paliperidone palmitate.

[0122] 9. A method according to any preceding clause, wherein the syringe has a capacity of 1 mL, 2.25 mL, 2.8 mL or 3 mL and comprises a 22 gauge needle that is 1 inch or 1.5 inches long.

[0123] 10. The method according to any one of clauses 1 to 13, wherein the syringe has a capacity of 5 mL and comprises a 20 gauge needle that is 1.5 inches long.

[0124] 11. The method according to any one of clauses 1 to 15, wherein the suspension contains about 273 mg, 410 mg, 546 mg or 819 mg of paliperidone palmitate.

[0125] 12. The method according to any one of clauses 1 to 15, wherein the suspension contains about 1092 mg or 1560 mg of paliperidone palmitate.

[0126] 13. The method according to any one of clauses 1 to 17, further comprising administering the suspension from the syringe to a patient.

[0127] 14. A method for reducing the force required to inject a paliperidone palmitate extended release injectable suspension from a syringe, the method comprising maintaining the syringe in a substantially horizontal orientation during transport of the syringe.

[0128] 15. The method according to clause 23, wherein the force required to inject from the syringe is about 20% to about 50% less than the force required to inject the paliperidone palmitate extended release injectable suspension from a syringe that is not maintained in a substantially horizontal orientation during syringe transport.

[0129] 16. The method according to clause 23 or clause 24, wherein the force required to inject from the syringe is about 10 Newtons to 25 Newtons less than the force required to inject the paliperidone palmitate extended release injectable suspension from a syringe that is not maintained in a substantially horizontal orientation during syringe transport.

[0130] 17. The method according to any one of clauses 23 to 25, wherein the force required to inject from the syringe is about 10 Newtons - 25 Newtons.

[0131] 18. The method according to any one of clauses 23 to 26, further comprising assessing the force required to complete injection of the paliperidone palmitate extended release injectable suspension from the syringe.

[0132] 19. A method for reducing the likelihood of incomplete injection of a paliperidone palmitate extended release injectable suspension from a syringe, the method comprising maintaining the syringe in a substantially horizontal orientation during transport of the syringe.

[0133] 20. The method according to clause 28, further comprising assessing whether injection from the syringe of the paliperidone palmitate extended release injectable suspension is complete.

[0134] 21. A method for improving the resuspendability of a paliperidone palmitate extended release injectable suspension in a syringe, the method comprising maintaining the syringe in a substantially horizontal orientation during storage of the syringe.

[0135] 22. The method according to clause 21, wherein the storage occurs after the syringe is transported.

[0136] 23. A population of syringes each containing a paliperidone palmitate extended release injectable suspension, wherein each syringe has been transported to a destination and wherein each syringe is maintained in a substantially horizontal orientation during transport of the syringes.

[0137] 24. A population according to clause 22, comprising at least 100 individual syringes.

[0138] Example

[0139] The following examples further define the present invention. It should be understood that these examples, although indicating preferred embodiments of the present invention, are given by way of illustration only and should not be construed as limiting the appended claims. Based on the above discussion and these examples, those skilled in the art can determine the essential characteristics of the present invention, and various changes and modifications can be made to the present invention to adapt it to various uses and conditions without departing from the spirit and scope of the present invention. Unless otherwise stated, the PP6M mentioned in the examples refers to the preparation in Example 2.

[0140] Example 1: Three-month extended release formulation (PP3M)

[0141] Table 1 below includes an exemplary three month extended release formulation (PP3M) of 200 mg / mL eq. paliperidone suitable for intramuscular (IM) injection.

[0142] Table 1-PP3M

[0143] Components Concentration (mg / mL) Paliperidone Palmitate 312 Polysorbate 20 10 Polyethylene glycol 4000 75 Citric acid monohydrate 7.5 Sodium dihydrogen phosphate monohydrate 6 Sodium hydroxide 5.4 Water for injection Add to 1mL

[0144] PP3M is available in pre-filled syringes with dosage strengths ranging from 175 mg eq. to 525 mg eq. obtained by filling the syringe with different volumes of 200 mg / mL eq. bulk suspension. Table 2 shows the different dosage strengths, including syringe size and nominal fill volume.

[0145] Table 2 - PP3M dosage strengths with syringe sizes and fill volumes

[0146]

[0147] Table 3 describes the syringe assembly used to package PP3M.

[0148] Table 3 - Syringe Components for PP3M

[0149]

[0150]

[0151] Example 2: Six-month extended release formulation (PP6M)

[0152] Table 4 below includes exemplary six-month extended release formulations of 200 mg / mL eq. paliperidone palmitate (PP6M) suitable for intramuscular (IM) injection.

[0153] Table 4-PP6M

[0154]

[0155] PP6M is available in pre-filled syringes with dosage strengths ranging from 700 mg eq. to 1000 mg eq. obtained by filling the syringe with different volumes of 200 mg / mL eq. bulk suspension. Table 5 shows the different dosage strengths, including syringe size and nominal fill volume.

[0156] Table 5 - PP6M dosage strengths with syringe sizes and fill volumes

[0157]

[0158] Table 6 describes the syringe assembly used to package the six month extended release formulation.

[0159] Table 6 - Syringe Assemblies for PP6M

[0160]

[0161] Example 3 - Storage conditions before transport

[0162] Prior to shipping, a stability study was conducted with a process performance qualification (PPQ) batch of PP6M in five different orientations (horizontal, tip down +45 degrees, tip up -45 degrees, tip down +45 degrees, and tip down -45 degrees). The following test results were obtained on syringes that were stored after manufacturing but not shipped prior to testing. The sensor test with oscillation for 5 seconds was conducted at two different temperatures: 25°C and 30°C. The results of this experiment are provided in Table 7:

[0163] Table 7

[0164]

[0165] Note: PPQ III level samples blister (contained in blister packs), PPQII and PPQI level samples do not blister. 9M = 9 month shelf life. NT = Not tested.

[0166] Syringability testing was performed via manual injection using a sensor on the thumb pad of the plunger rod to record force (Newtons) over time (seconds). The force injection profiles for samples in PPQ I and PPQ II after 5 seconds of vigorous shaking are described in Figures 1A to 1F middle.

[0167] The results show that product stored in any position prior to transport can be resuspended with a normal amount of force, i.e., the force required to expel the contents of the syringe is independent of the storage position prior to transport. Different storage positions gave comparable results, indicating that the position in which the syringe is stored prior to transport is not critical when oscillated for at least 5 seconds. A complete injection can be performed with acceptable injection forces.

[0168] After this experiment, it became apparent that the storage position of the product during stability testing and prior to shipping was not an important determinant of resuspendability. As described in Example 4 below, the shipping orientation was found to be much more important than the storage orientation prior to shipping.

[0169] Example 4 - Simulating Orientation During Transport

[0170] After being stored for a period of time in the tip-down orientation at the manufacturing facility, syringes containing the PP6M formulation were subjected to simulated shipping experiments with vibrations corresponding to Levels I and II defined in ASTM D4169-16 for simulating air shipping. These are the highest levels of vibration during air shipping and exceed the vibration levels defined for truck shipping. In the absence of vibration or only 5 seconds of vibration (shorter than defined in the instructions for use (IFU), which is consistent with INVEGA The resuspendability and injectability of the PP6M formulations after simulated shipping were tested to increase the sensitivity of the test to detect differences, consistent with the instructions provided on the label of the (PP3M product); the IFU of PP6M was 2 seconds x 15 seconds oscillation, and the IFU of PP3M was 1 second x 15 seconds oscillation). A summary of the residue remaining in the syringe and the maximum force required to empty the syringe to that extent is provided in Table 8 below:

[0171] Table 8 - Residue after preparation according to the instructions for use (with pull-back and degassing)

[0172]

[0173]

[0174] FIG. 2A to FIG. 2D Provided are injection force curves for syringes subjected to vibration experiments when oriented horizontally or with the tip downward. Syringability testing is performed via manual injection, using a sensor on the thumb pad of the plunger rod to record force (Newtons) over time (seconds). Oscillating conditions include two hours of Class II simulated air transport and three hours of Class I simulated air transport according to ASTM D4169. Figure 2A Corresponds to a syringe in tip-down orientation and not subjected to vibration prior to injection. Figure 2B Corresponds to a syringe in tip-down orientation and subjected to five seconds of oscillation prior to injection. Figure 2C Corresponds to a syringe in a horizontal orientation and not subjected to vibration prior to injection. Figure 2D Corresponds to a syringe in a horizontal orientation and subjected to five seconds of oscillation prior to injection.

[0175] The results of this experiment confirmed that after storage in the tip-down orientation, transporting the syringe in the tip-down position can result in very high forces being required to extrude the syringe contents, and the contents of such a syringe are not fully resuspended after 5 seconds of oscillation. In reality, a health care provider will not push as high as 30N or 35N, especially when injecting a patient.

[0176] However, when the syringes were transported in a horizontal manner after being stored in a tip-down orientation, the injection forces were in the range of 10-20 Newtons, indicating that the product required less agitation for good resuspension to occur. By comparison, the forces required to expel a one-month Paliperidone Palmitate Injectable Suspension, which represents a much less concentrated formulation (and thus a formulation that is less susceptible to impact and therefore has a lower resuspension requirement), were in the range of 7-12 Newtons.

[0177] Example 5 - Changing the orientation of the syringe during shipping relative to the orientation during storage prior to shipping reduces the injection force and reduce post-injection residue

[0178] Following initial demonstration that horizontal orientation of the PP6M syringe during transport resulted in improved resuspendability and syringeability properties compared with a tip-down orientation, further studies were initiated to more deeply evaluate the potential effects of different types and durations of transport and to monitor the behavior of the PP6M syringe for up to three months after simulated transport.

[0179] For this study, a 5 mL syringe PP6M was selected from the stability chamber. The 5 mL fill was chosen over the 3.5 mL fill as the worst case for resuspendability due to the higher product load in the same 5 mL syringe.

[0180] Before exposure to simulated shipping conditions, samples from different batches were tested for resuspendability / injectability by manually injecting the syringe into the container after 5 seconds of weak oscillation, which samples were stored in the stabilization chamber in different orientations but not yet subjected to shipping conditions. The injectability force was recorded with a sensor attached to the thumb pad and the height of the residual product in the syringe was measured. All samples resulted in a complete injection with no or acceptable product residue in the syringe, concluding that the different pre-shipment storage orientation settings did not affect the properties of the suspension per se, and the product was easily resuspendable and injectable after 9 months of storage.

[0181] After this initial test, the syringes were transported by car from Beerse, Belgium to a test facility in Diepenbeek, Belgium, and subjected to different transport simulations ranging from light exposure (1 hour truck, light) to strong exposure (4 hours air transport, high). Simulated ship tests were performed according to ASTM D4169-16. During these transport simulations, the syringes were positioned horizontally or pointed downward. During conventional manufacturing, syringes are stored in barrels with pointed ends downward after filling, usually for a month or more. When a packaging order is issued, the syringes are packaged in blister assemblies and shipped after release. Within one day after the transport simulation, samples exposed to different simulated transport conditions in different orientations were resuspended by rapid shaking for 5 seconds, and the product was manually injected into the container while measuring the injection force with a sensor attached to the thumb pad of the syringe. A shorter time for resuspending the product (5s, instead of 2×15 seconds / IFU) is used for analysis to increase the sensitivity of the test.

[0182] The remaining syringes were stored horizontally or tip-down as per protocol and were further evaluated for syringe resuspendability / syringability after one, two, or three months of storage.

[0183] As also described below, analysis showed that the orientation of the syringe prior to shipping relative to the shipping orientation is an important factor in product resuspension.

[0184] In both the single shipment and the combined truck / air shipment, maintaining the same orientation of the syringe during initial storage and shipping resulted in more difficulty resuspending the syringe, resulting in more residual product after only 5 seconds of rapid shaking.

[0185] The storage location and storage time after transport represent factors that have only a limited influence on the resuspendability of the product.

[0186] The data provided in Tables 9-11 below indicate that when the syringes were shipped horizontally after being stored horizontally prior to shipping, there was more residual product after the 5 second rapid resuspendability and injection compared to syringes stored tip down.

[0187] Similarly, syringes stored tip-up prior to shipping and oriented tip-down during shipping contained no or very limited residual product after 5 seconds of rapid resuspension and injection.

[0188] In both single and combined shipments, maintaining the same orientation of the syringes during initial storage and shipment resulted in syringes that were more difficult to resuspend, leading to more residual product after the 5-second rapid resuspendability and manual injection.

[0189] Tables 9-11 provide the results for the sample groups and allow for a head-to-head comparison between syringes that were oriented differently during initial storage and shipping and syringes that were maintained in the same orientation during storage prior to shipping and during shipping.

[0190] Experiments 1 and 2 represent two data sets from tests involving a single type of simulated transportation, while Experiment 3 provides data from a combined transportation test (ie, simulated air transportation followed by simulated truck transportation).

[0191]

[0192]

[0193]

[0194] These data indicate that syringes shipped in an orientation different from that during storage prior to shipping are more easily resuspended than syringes maintained during shipping in an orientation different from that in storage prior to shipping.

Claims

1. A method for improving the resuspendability of a six-month paliperidone palmitate extended-release injectable suspension (PP6M) in a syringe oriented with the tip downward during storage prior to transport, the method comprising transporting the syringe in a substantially horizontal orientation and maintaining the syringe in a substantially horizontal orientation during transport, wherein the syringe is transported by airplane, truck, ship or railroad or a combination thereof, and wherein the substantially horizontal orientation refers to an orientation in which the angle of the syringe relative to an applicable reference point is closer to 0° than to 90°.

2. The method of claim 1, further comprising monitoring the syringe during transport to confirm that a substantially horizontal orientation is maintained.

3. The method of claim 1 , further comprising housing the syringe in a container comprising an outer surface bearing instructions for maintaining the container in a substantially horizontal orientation during transport, the outer surface bearing indicia indicating an orientation of the container corresponding to maintaining a substantially horizontal orientation, or both.

4. The method of claim 1, further comprising maintaining the syringe in a storage position in a substantially horizontal orientation after transport.

5. The method of claim 1, wherein the syringe has a capacity of 5 mL and includes a 20-gauge needle that is 1.5 inches long.

6. The method of claim 1, wherein the PP6M contains about 1092 mg or 1560 mg of paliperidone palmitate.

7. The method of claim 6, wherein PP6M comprises 280 mg / mL to 350 mg / mL of paliperidone palmitate.

8. The method of claim 6, wherein PP6M comprises about 312 mg / mL of paliperidone palmitate.

9. The method of claim 6, wherein the PP6M comprises: 280 mg / mL to 350 mg / mL of paliperidone palmitate; 8 mg / mL to 12 mg / mL of wetting agent; one or more buffering agents; 65 mg / mL to 85 mg / mL suspension; and Add appropriate amount of water to 100%.

10. The method of claim 9, wherein the PP6M comprises: About 312 mg / mL of paliperidone palmitate; About 10 mg / mL of polysorbate 20 as a wetting agent; and About 75 mg / mL of polyethylene glycol 4000 was used as a suspending agent.

11. The method of claim 10, wherein the PP6M is at pH 6.0 to pH 8.

0.

12. The method of claim 11, wherein the one or more buffers comprise citric acid monohydrate, sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate anhydrous, or sodium hydroxide.

13. The method of claim 12, wherein the syringe has a capacity of 5 mL and includes a 20-gauge needle that is 1.5 inches long.

14. The method of claim 8, wherein the syringe has a capacity of 5 mL and includes a 20-gauge needle that is 1.5 inches long.

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