Method for ensuring resuspension of paliperidone palmitate preparations

Abstract

Provided are methods for improving the resuspension 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 likelihood of incomplete injection of the paliperidone palmitate extended-release injectable suspension, comprising maintaining the syringe in a desired orientation during shipping of the syringe that is different from the orientation of the syringe during pre-shipment storage. Also provided is a collection of syringes, each containing a paliperidone palmitate extended-release injectable suspension, each of which has been shipped to a destination, and each of which has been maintained in a desired orientation during shipping of the syringe that is different from the orientation of the syringe during pre-shipment storage. The present disclosure also provides 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-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.

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims the benefit of priority to U.S. Provisional Application No. 63 / 237,883, filed Aug. 27, 2021, and U.S. Provisional Application No. 63 / 119,305, filed Nov. 30, 2020.

[0002] (Field of the Invention) This disclosure relates to methods of affecting the quality of administration of pharmaceutical suspensions.

Background Art

[0003] Drug therapy with antipsychotics is a mainstay in the treatment of schizophrenia, schizoaffective disorder, and schizophreniform disorder. Antipsychotics were first introduced in the mid - 1950s. These typical or first - generation agents are usually effective in controlling the positive symptoms of schizophrenia but are not very effective in alleviating the negative symptoms or the cognitive dysfunction associated with the disease. Atypical antipsychotics or second - generation agents, represented by risperidone and olanzapine, were developed in the 1990s and are generally characterized by effectiveness against both the positive and negative symptoms associated with schizophrenia.

[0004] Paliperidone palmitate is a palmitic acid ester of paliperidone (9 - hydroxy - risperidone), a monoamine - acting antagonist that exhibits the characteristic dopamine type 2 (D 2) and serotonin (5 - hydroxytryptamine type 2A) antagonism. Paliperidone (9 - OH risperidone) is the major active metabolite of risperidone. Extended - release (ER) osmotic - controlled release oral delivery (OROS) paliperidone is sold in the United States as a tablet for the treatment and maintenance of schizophrenia.

[0005] Paliperidone palmitate is being developed as a long-acting, intramuscular (IM) injectable aqueous nanosuspension for the treatment of schizophrenia and other related disorders, which are typically treated with antipsychotics. Due to its very low water solubility, paliperidone esters, such as paliperidone palmitate, are hydrolyzed to paliperidone, which then slowly dissolves after intramuscular injection before becoming available in the systemic circulation.

[0006] Monthly paliperidone palmitate injections are designed to provide sustained plasma concentrations of paliperidone, which can greatly enhance administration compliance. Paliperidone palmitate formulated as an aqueous nanosuspension is described in U.S. Patents 6,077,843 and 6,555,544, which are incorporated herein by reference, respectively. In addition, dosing regimens of paliperidone palmitate for treating patients are disclosed in U.S. Patents 9,439,906 and 10,143,693, which are incorporated herein by reference, respectively.

[0007] Paliperidone is currently available for therapeutic use in the following three formulations: an oral sustained-release formulation (also known as INVEGA® Extended-Release (ER) tablets, or INVEGA® prolonged-release (PR) tablets), and two long-acting injectable (LAI) formulations (paliperidone palmitate 1-month injection [INVEGA SUSTENNA® or XEPLION®] and paliperidone palmitate 3-month injection [INVEGA TRINZA® or TREVICTA®]). Another paliperidone palmitate product intended for administration every six months (paliperidone palmitate 6-month injection) has been approved in the United States [INVEGA HAFYERA®] and Europe [BYANNLI®] to further improve adherence and convenience.

[0008] Paliperidone palmitate suspension formulations are typically highly concentrated products. Consequently, a critical consideration is ensuring complete suspension / resuspension of the product before administration. To minimize the opportunity for incomplete administration, it is necessary for a healthcare professional to administer the drug and to follow specific guidelines during preparation and administration. For example, the INVEGA TRINZA® label specifies that the syringe containing the formulation should be shaken vigorously for at least 15 seconds before administration to ensure a homogeneous suspension (corresponding to the instructions for use, IFU). Furthermore, the injection should be administered slowly, for example, over a period of 20-30 seconds. Shaking while the syringe tip is in the upward position is also recommended. The INVEGA HAFYERA® label specifies that the syringe containing the formulation should be shaken very quickly for at least 15 seconds (with the syringe tip cap facing upward), followed by a short pause, and then shaken again for 15 seconds. [Overview of the project] [Problems that the invention aims to solve]

[0009] There may be some instances where the resuspension protocol is deviated from due to human error, which can lead to insufficient resuspension and, consequently, incomplete administration of the paliperidone palmitate suspension. Further strategies are needed to ensure the necessary resuspension of paliperidone palmitate. [Means for solving the problem]

[0010] A method for improving the resuspensionability of a sustained-release injectable suspension of paliperidone palmitate in a syringe is provided herein, comprising maintaining the syringe in a substantially horizontal orientation during shipment. A method for improving the resuspensionability of a sustained-release injectable suspension of paliperidone palmitate in a syringe is also provided herein, comprising maintaining the syringe in a different orientation during shipment than that during pre-shipment storage, for example, if the pre-shipment storage orientation was not substantially horizontal, then maintaining the syringe in a substantially horizontal orientation during shipment.

[0011] Also disclosed is a method for reducing the force required to inject a sustained-release injectable suspension of paliperidone palmitate from a syringe, comprising maintaining the syringe in a substantially horizontal orientation during shipment. Also disclosed is a method for reducing the force required to inject a sustained-release injectable suspension of paliperidone palmitate from a syringe, comprising maintaining the syringe in a different orientation during shipment than the orientation of the syringe during pre-shipment storage, for example, if the orientation during pre-shipment storage was not substantially horizontal, then maintaining the syringe in a substantially horizontal orientation during shipment.

[0012] The disclosure also relates to a method for reducing the possibility of incomplete injection of a sustained-release injectable suspension of paliperidone palmitate from a syringe, comprising maintaining the syringe in a substantially horizontal orientation during shipment. The disclosure also relates to a method for reducing the possibility of incomplete injection of a sustained-release injectable suspension of paliperidone palmitate from a syringe, comprising maintaining the syringe in a different orientation during shipment than the orientation of the syringe during pre-shipment storage, for example, if the orientation during pre-shipment storage was not substantially horizontal, then during shipment the syringe is substantially horizontal.

[0013] Furthermore, a method is provided for improving the resuspensionability of a sustained-release injectable suspension of paliperidone palmitate in a syringe, comprising maintaining the syringe in a substantially horizontal orientation during storage. Furthermore, a method is provided for improving the resuspensionability of a sustained-release injectable suspension of paliperidone palmitate in a syringe, comprising maintaining the syringe in a different orientation during shipment than the orientation during pre-shipment storage, for example, in a substantially horizontal orientation during storage if the orientation during pre-shipment storage was not substantially horizontal.

[0014] Also disclosed is a syringe assembly in which each syringe contains a sustained-release injectable suspension of paliperidone palmitate, and each syringe has been shipped to its destination, and each syringe has been maintained in a substantially horizontal orientation during shipment. Also disclosed is a syringe assembly in which each syringe contains a sustained-release injectable suspension of paliperidone palmitate, and each syringe has been shipped to its destination, and during shipment each syringe has been maintained in a different orientation than the orientation of the syringe during pre-shipment storage, for example, if the orientation during pre-shipment storage was not substantially horizontal, the syringe has been maintained in a substantially horizontal orientation during shipment.

[0015] The disclosure also provides a pharmaceutical product comprising a sustained-release injectable suspension of paliperidone palmitate in a syringe for administration to a patient suffering from schizophrenia, wherein the syringe undergoes pre-shipment storage and is shipped, and the syringe is maintained during shipment in a different orientation than that of the syringe during pre-shipment storage.

[0016] Also disclosed is a method for treating schizophrenia, comprising administering a sustained-release injectable suspension of paliperidone palmitate to a patient suffering from schizophrenia from a syringe, wherein the syringe has undergone pre-shipment storage and has been shipped, and the syringe has been maintained in a different orientation during shipment than the orientation of the syringe during pre-shipment storage. Also disclosed is a sustained-release injectable suspension of paliperidone palmitate for use in a method for treating schizophrenia, wherein these methods comprise administering a sustained-release injectable suspension of paliperidone palmitate to a patient suffering from schizophrenia from a syringe, wherein the syringe has undergone pre-shipment storage and has been shipped, and the syringe has been maintained in a different orientation during shipment than the orientation of the syringe during pre-shipment storage. Furthermore, a use of paliperidone palmitate sustained-release injectable suspension in the manufacture of a pharmaceutical product for the treatment of schizophrenia is disclosed, wherein the paliperidone palmitate sustained-release injectable suspension is prepared for administration from a syringe, the syringe undergoes pre-shipment storage and is shipped, and the syringe is maintained during shipment in a different orientation than that of the syringe during pre-shipment storage.

[0017] In several embodiments of this disclosure, the sustained-release injectable suspension of paliperidone palmitate is selected from the group consisting of PP3M and PP6M. In one embodiment, the sustained-release injectable suspension of paliperidone palmitate is PP3M. In one embodiment, the sustained-release injectable suspension of paliperidone palmitate is PP6M. [Brief explanation of the drawing]

[0018] [Figure 1A] This figure shows the injection power profiles for process performance qualified (PPQ) batches of PP6M stored in one of five different spatial orientations. [Figure 1B] This figure shows the injection power profiles for process performance qualified (PPQ) batches of PP6M stored in one of five different spatial orientations. [Figure 1C] A diagram showing the ejection force profiles for PP6M Process Performance Qualification (PPQ) batches stored in one of five different spatial orientations respectively. [Figure 1D] A diagram showing the ejection force profiles for PP6M Process Performance Qualification (PPQ) batches stored in one of five different spatial orientations respectively. [Figure 1E] A diagram showing the ejection force profiles for PP6M Process Performance Qualification (PPQ) batches stored in one of five different spatial orientations respectively. [Figure 1F] A diagram showing the ejection force profiles for PP6M Process Performance Qualification (PPQ) batches stored in one of five different spatial orientations respectively. [Figure 2A] A diagram showing the ejection force curves for syringes subjected to a vibration experiment while in a horizontal or tip - downward orientation. [Figure 2B] A diagram showing the ejection force curves for syringes subjected to a vibration experiment while in a horizontal or tip - downward orientation. [Figure 2C] A diagram showing the ejection force curves for syringes subjected to a vibration experiment while in a horizontal or tip - downward orientation. [Figure 2D] A diagram showing the ejection force curves for syringes subjected to a vibration experiment while in a horizontal or tip - downward orientation.

Modes for Carrying Out the Invention

[0019] The subject matter of the invention disclosed herein can be more readily understood by referring to the following detailed description made in relation to the accompanying drawings, which form part of this disclosure. It should be understood that the invention is not limited to any particular formulation, method, condition, or parameter described and / or shown herein, and that the terminology used herein is solely for the purpose of describing specific embodiments using examples and is not intended to limit the claimed invention.

[0020] All disclosures of the respective patents, patent applications, and publications cited or referenced herein are incorporated herein by reference.

[0021] When used above, and throughout this disclosure, the following terms and abbreviations should be understood to have the following meanings unless otherwise indicated.

[0022] In this disclosure, unless otherwise explicitly stated, the singular forms “a,” “an,” and “the” encompass plural references, and references to specific numerical values ​​encompass at least that specific value. Therefore, for example, a reference to “a formulation” is a reference to one or more such formulations and their equivalents known to those skilled in the art. Furthermore, where a particular element indicates that it “may be” X, Y, or Z, such use is not intended in any way to exclude other options relating to that element.

[0023] When a value is expressed as an approximation using the antecedent “about,” it is understood that the particular value may form another embodiment. Generally, the use of the term “about” indicates an approximation that may vary depending on the desired characteristic sought by the disclosed subject matter of the invention and should be interpreted in the specific context in which it is used, based on its function. In some embodiments, “about X” (where X is a number) inclusively refers to ±10% of the stated value. For example, the phrase “about 8” may inclusively refer to a value between 7.2 and 8.8. This value may also include “exactly 8.” Where present, all ranges are inclusive and combinable. For example, when listing the range “1 to 5,” the listed range should be interpreted as including, at any choice, ranges such as “1 to 4,” “1 to 3,” “1 to 2,” “1 to 2 and 4 to 5,” “1 to 3 and 5,” etc. In addition, if a list of substitutes is explicitly provided, such a list may also include embodiments in which any of the substitutes may be excluded. For example, if the range “1 to 5” is described, such description may support a situation in which any of 1, 2, 3, 4, or 5 is excluded. Therefore, the statement "1-5" could support the interpretation of "1 and 3-5, but not 2" or simply "2 is not included."

[0024] References herein to therapeutic methods (e.g., methods for treating schizophrenia) using one or more compounds or formulations thereof (e.g., paliperidone palmitate sustained-release injectable suspension) are, - For example, one or more compounds or formulations thereof for use in methods of treating schizophrenia (e.g., paliperidone palmitate sustained-release injectable suspension), and / or -It should be understood that this should also be interpreted as a reference to the use of one or more compounds in a formulation (e.g., paliperidone palmitate sustained-release injectable suspension) in the manufacture of a medicine for the treatment of schizophrenia.

[0025] As mentioned above, resuspension protocols exist to ensure complete administration of the paliperidone palmitate injectable suspension. While prescribed paliperidone palmitate formulations include clear label instructions regarding the precise procedure for preparing the formulation for administration and the manner in which the injection itself should be administered, healthcare professionals following specific procedures may not do so in a manner that ensures sufficient resuspension of paliperidone palmitate and thereby delivers the prescribed dosage to the patient in need.

[0026] The inventors of this application have surprisingly discovered that changing the orientation of a syringe containing a paliperidone palmitate suspension during the shipping process, compared to the orientation during pre-shipment storage, affects the resuspendability of the drug product in the preparation for administration. In particular, maintaining the syringe in a different orientation than that during pre-shipment storage, for example, substantially horizontally during shipping, was found to improve the resuspendability of paliperidone palmitate, as opposed to the conventional tip-down orientation during shipping if the syringe was stored tip-down before shipping, thereby improving the likelihood of complete administration of the prescribed dosage. Therefore, this finding has the effect of mitigating human error or other causes of deviation from the prescribed resuspend protocol (e.g., controlling the type and duration of shaking) intended to ensure sufficient resuspendion of paliperidone palmitate. As a result of the improvement in drug resuspendion, certain benefits are obtained, such as a reduction in the amount of force required for administration, and, as a general problem, a reduction in the opportunity for incomplete administration. This also improves resuspension by reducing the shaking force required for resuspension. The fact that the opportunity for incomplete dosing is reduced means that the risk of the patient ingesting a lower dose of paliperidone palmitate than intended is also reduced. This means that, in the event of a deviation from the prescribed resuspension protocol, for example, a patient with schizophrenia who is administered paliperidone palmitate sustained-release injectable suspension from a syringe maintained in a different orientation during shipping than the syringe orientation during pre-shipment storage, for example, a syringe maintained in a substantially horizontal orientation during shipping, is less likely to ingest a lower dose than a patient who is administered paliperidone palmitate sustained-release injectable suspension from a syringe maintained in a conventional tip-down orientation during shipping. Therefore, for example, administration of paliperidone palmitate sustained-release injectable suspension from a syringe maintained in a different orientation during shipping than the syringe orientation during pre-shipment storage, for example, a syringe maintained in a substantially horizontal orientation during shipping, represents an important contribution to the field of schizophrenia therapy.

[0027] Accordingly, the present invention provides a method for improving the resuspensionability of a sustained-release injectable suspension of paliperidone palmitate in a syringe, comprising maintaining the syringe in a substantially horizontal orientation during shipment. The disclosure also encompasses a method for reducing the possibility of incomplete injection of a sustained-release injectable suspension of paliperidone palmitate from a syringe, comprising maintaining the syringe in a substantially horizontal orientation during shipment. Furthermore, the present invention provides a method for improving the resuspensionability of a sustained-release injectable suspension of paliperidone palmitate in a syringe, comprising maintaining the syringe in a different orientation during shipment than the orientation of the syringe during pre-shipment storage, for example, substantially horizontal during shipment if the orientation during pre-shipment storage was not substantially horizontal. The disclosure also includes a method for reducing the possibility of incomplete injection of a sustained-release injectable suspension of paliperidone palmitate from a syringe, which includes maintaining the syringe in a different orientation during shipment than the orientation of the syringe during pre-shipment storage, for example, in a substantially horizontal orientation during shipment if the orientation during pre-shipment storage was not substantially horizontal.

[0028] In several embodiments of this disclosure, the sustained-release injectable suspension of paliperidone palmitate is selected from the group consisting of PP3M and PP6M. In one embodiment, the sustained-release injectable suspension of paliperidone palmitate is PP3M. In one embodiment, the sustained-release injectable suspension of paliperidone palmitate is PP6M.

[0029] Paliperidone esters are antipsychotic agents belonging to the chemical classification of benzisoxazole derivatives, containing a racemic mixture of (+)- and (-)-paliperidone, as described in U.S. Patent No. 5,254,556 (incorporated herein by reference). The chemical name of paliperidone palmitate is (±)-3-[2-[4-(6-fluoro-1,2-benzisoxazole-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4-oxo-4H-pyrido[1,2-c]pyrimidine-9-ylhexadecanoate. Its structural formula is as follows:

[0030] [ka]

[0031] Paliperidone ester can be formulated into injectable dosage forms with pharmaceutically acceptable excipients, as described in U.S. Patents No. 5,254,556 and No. 6,077,843, both of which are incorporated herein by reference. The injectable formulations can be formulated in an aqueous carrier.

[0032] The paliperidone palmitate sustained-release injectable suspension may be a commercially available formulation intended for administration to a subject, for example, once every three months, once every six months, or at any other interval.

[0033] Examples of commercially available formulations intended for administration every three months include INVEGA TRINZA® or TREVICTA®. See also U.S. Patent No. 10,143,693 incorporated by reference. In this disclosure, “PP3M” refers to a sustained-release injectable suspension or other type of formulation of paliperidone palmitate having an amount suitable for a dosing interval of approximately three months. For example, “PP3M” may refer to a sustained-release injectable suspension of paliperidone palmitate having a dosing interval of approximately three months.

[0034] An example of a commercially available formulation for administration every six months is INVEGA HAFYERA® in the United States. A formulation for administration every six months is approved for sale in Europe under the trade name BYANNLI®. In this disclosure, “PP6M” refers to a sustained-release injectable suspension or other type of formulation of paliperidone palmitate having an amount suitable for a dosing interval of approximately six months. For example, “PP6M” may refer to a sustained-release injectable suspension of paliperidone palmitate having a dosing interval of approximately six months. PP6M is typically provided with a dose of paliperidone palmitate ranging from approximately 1000 mg to approximately 1600 mg, providing a sustained therapeutic concentration of paliperidone over a six-month dosing interval. Preferably, PP6M is provided with a dose intensity of approximately 1092 mg or approximately 1560 mg of paliperidone palmitate. The drug product is hydrolyzed to its active component, paliperidone, yielding dose strengths of approximately 700 mg equivalent or 1000 mg equivalent of paliperidone, respectively.

[0035] PP6M is preferably provided in a pre-filled syringe (cyclic olefin copolymer) having a plunger stopper, plunger rod, and tip cap (bromobutyl rubber), backstop, and needle, preferably a thin-walled 20 gauge (G) 1.5-inch safety needle, pre-filled with either 700 mg equivalent (3.5 mL) or 1000 mg equivalent (5.0 mL) of paliperidone (as 1092 mg or 1560 mg of paliperidone palmitate, respectively).

[0036] PP3M is typically supplied in doses ranging from approximately 270 mg to approximately 825 mg of paliperidone palmitate, providing a sustained therapeutic concentration of paliperidone over a 3-month dosing interval. Preferably, PP3M is supplied in dose intensities of approximately 273, 410, 546, or 819 mg of paliperidone palmitate. The drug product is hydrolyzed to the active moiety, paliperidone, yielding dose intensities of approximately 175, 263, 350, or 525 mg equivalents of paliperidone, respectively.

[0037] PP3M is preferably provided in a pre-filled syringe (cyclic olefin copolymer) having a plunger stopper, plunger rod, and tip cap (bromobutyl rubber), backstop, and needle, preferably a thin-walled 20 gauge (G) 1.5-inch safety needle or a thin-walled 22 gauge (G) 1-inch safety needle, pre-filled with approximately 175 mg equivalent to approximately 525 mg equivalent.

[0038] In certain embodiments, PP3M and PP6M may have the same formulation, differing only in the total volume of the suspension formulation contained in each syringe. The paliperidone palmitate suspension used according to this method may contain, in absolute terms, about 250 to about 1600 mg of paliperidone palmitate. The amount of paliperidone palmitate in the suspension may be, for example, 273, 410, 546, or 819 mg. In certain embodiments, the amount of paliperidone palmitate in the suspension may be 1092 or 1560 mg.

[0039] In certain embodiments, the 3-month (PP3M) formulation has an average particle size of less than about 20 μm to about 1 μm. In other embodiments, the particles have an average particle size (d50) of about 5 μm to about 15 μm, about 3 μm to about 10 μm, or about 5 μm to about 9 μm. d90 may be about 50 μm, about 10 μm to about 30 μm, or about 10 μm to about 20 μm. d10 may be about 1 μm to about 10 μm, or about 1 μm to about 5 μm.

[0040] In certain embodiments, the 6-month (PP6M) formulation has an average particle size of about less than 30 μm to about 1 μm, or about 20 μm to about 1 μm. In other embodiments, the particles have an average particle size (d50) of 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. d90 may be about 60 μm, or about 50 μm, about 10 μm to about 30 μm, or about 10 μm to about 20 μm. 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.

[0041] When used herein, if measured by prior art known in the art, such as sedimentation field flow fractionation, photon correlation spectroscopy, or disk centrifugation, d10: 10% of particles have a diameter smaller than this value. d50: 50% of particles have a diameter smaller than this value. d90: 90% of particles have a diameter smaller than this value.

[0042] Suitable aqueous nanoparticle formulations are described in U.S. Patent No. 6,555,544, which is incorporated herein by reference. In some embodiments, the formulation comprises microparticles, surfactants, suspending agents, and optionally one or more additional components selected from the group consisting of preservatives, buffers, and isotonic agents.

[0043] Surface modifiers useful for paliperidone palmitate formulations are thought to include those that physically adhere to the surface of the active agent but do not chemically bond to it. Suitable surface modifiers can be selected from known organic and inorganic pharmaceutically acceptable excipients. Such excipients include various polymers, low molecular weight oligomers, natural products, and surfactants. Suitable surface modifiers include nonionic and anionic surfactants. Typical examples of excipients include gelatin, casein, lecithin (phosphatide), acacia gum, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (e.g., commercially available TWEEN®), polyethylene glycol, polyoxyethylene stearate, colloidal silicon dioxide, phosphate, sodium dodecyl sulfate, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, amorphous cellulose, magnesium aluminosilicate, triethanolamine, and polyvinyl alcohol. Examples include alcohol (PVA), poloxamer, tyroxapol, and polyvinylpyrrolidone (PVP). Most of these excipients are described in detail in the Handbook of Pharmaceutical Excipients, the Pharmaceutical Press, 1986, jointly published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain. Surface modifiers are commercially available and / or can be prepared by techniques known in the art. Two or more surface modifiers may be used in combination.

[0044] Particularly preferred surface modifiers include polyvinylpyrrolidone; tyroxapole; poloxamers, e.g., PLURONIC® F68, F108, and F127, which are block copolymers of ethylene oxide and propylene oxide available from BASF; poloxamines, e.g., TETRONIC® 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® (AOT), a dioctyl ester of sodium sulfosuccinate available from Cytec Industries; DUPONOL® P, sodium lauryl sulfate available from DuPont; TRITON® X-200, an alkylaryl polyethersulfonate available from Rohm and Haas; and ICI Speciality. TWEEN® 20, 40, 60, and 80, polyoxyethylene sorbitan fatty acid esters available from Chemicals; SPAN® 20, 40, 60, and 80, sorbitan esters of fatty acids; ARLACEL® 20, 40, 60, and 80, sorbitan esters of fatty acids available from Hercules, Inc.; CARBOWAX® 3550 and 934, polyethylene glycol available from Union Carbide; CRODESTA® F110, a mixture of sucrose stearate and sucrose distearate available from Croda Inc.; CRODESTA® SL-40, available from Croda Inc.; Hexyldecyltrimethylammonium chloride (CTAC); Bovine serum albumin, and the following formula: C 18 H 17 SA90HCO having CH2(CON(CH3)CH2(CHOH)4CH2OH)2 is an example. Surface modifiers that have been found to be particularly useful include tyroxapol and poloxamer, preferably Pluronic® F108 and Pluronic® F68.

[0045] Pluronic(trademark) F108 is equivalent to poloxamer 338, and its formula is HO[CH2CH2O] x [CH(CH3)CH2O] y [CH2CH2O] z It is a polyoxyethylene, polyoxypropylene block copolymer that is approximately equal to H (where the mean values ​​of x, y, and z are 128, 54, and 128, respectively). Other trade names for Poloxamer 338 are Hodag NONIONIC® 1108-F, available from Hodag, and SYNPERONIC® PE / F108, available from ICI Americas.

[0046] The optimal relative amounts of paliperidone palmitate and the surface modifier depend on various parameters. The optimal amount of the surface modifier may depend, for example, on the specific surface modifier selected, the critical micelle concentration of the surface modifier if the surface modifier forms micelles, the surface area of ​​the antipsychotic, etc. The specific surface modifier is preferably present in an amount of about 0.1 to about 1 mg per square meter of surface area of ​​paliperidone palmitate. In the case of paliperidone palmitate (9-hydroxyrisperidone palmitate), it is preferable to use PLURONIC® F108 as the surface modifier, and a relative amount (w / w) of both components of about 6:1 is preferred.

[0047] Particles of a paliperidone palmitate suspension may be prepared by a method comprising the steps of dispersing paliperidone palmitate in a liquid dispersion medium and applying mechanical means to reduce the particle size of the antipsychotic agent to an effective average particle size in the presence of a grinding medium. The particles may have their dimensions reduced in the presence of a surface modifier, or the particles may come into contact with a surface modifier after abrasion.

[0048] 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 a grinding medium to reduce it to an effective average particle size.

[0049] Paliperidone palmitate can 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 exceeds about 100 μm, it is preferable to reduce the particle size of paliperidone palmitate to less than 100 μm.

[0050] Next, paliperidone palmitate can be added to a liquid medium that is essentially insoluble in order to form a premix. The concentration (by weight percentage) of paliperidone palmitate in the liquid medium can vary considerably and depends on the antipsychotic agent selected, the surface modifier selected, and other factors. A suitable concentration of paliperidone palmitate in the composition ranges from about 0.1% to about 60%, preferably about 0.5% to about 30%, and more preferably about 7% (w / v). For PP3M, it is preferable to use a concentration of about 200 mg equivalent of paliperidone per mL, or about 312 mg equivalent of paliperidone palmitate per mL. For PP6M, it is preferable to use a concentration of about 200 mg equivalent of paliperidone per mL, or about 312 mg equivalent of paliperidone palmitate per mL.

[0051] Another exemplary procedure involves adding a surface modifier to the premix before subjecting it to mechanical means to reduce the effective average particle size. The concentration of the surface modifier (by weight percentage) can range from about 0.1% to about 90%, preferably from about 0.5% to about 80%, and more preferably about 7% (w / v).

[0052] The premix can be used directly by subjecting it to mechanical means to reduce the effective average particle size in the dispersion to a desired particle size. Direct use of the premix is ​​preferable when a ball mill is used for wear. Alternatively, the antipsychotic agent and, optionally, the surface modifier can be dispersed in a liquid medium using suitable agitation, such as a roller mill or a Coreless mixer, until homogeneous dispersion is achieved.

[0053] Mechanical means applied to reduce the effective average particle size of antipsychotic drugs may, for convenience, take the form of dispersion mills. Suitable dispersion mills include medium mills such as ball mills, grinding mills, vibratory mills, planetary mills, sand mills, and bead mills. Medium mills are preferred because the milling time required to provide the desired reduction in particle size is relatively short. For medium milling, in some embodiments, the apparent viscosity of the premix is ​​preferably about 0.1 Pa·s to about 1 Pa·s. For some embodiments, for ball milling, the apparent viscosity of the premix is ​​preferably about 1 mPa·s to about 100 mPa·s.

[0054] The grinding medium for the particle size reduction step can be selected from hard media in spherical or granular form, preferably having an average diameter of less than about 3 mm, more preferably less than about 1 mm. Such media can preferably provide the particles of the present invention in a shorter processing time and reduce wear on the grinding apparatus. The choice of material for the grinding medium is not considered important. However, magnesia, zirconium silicate, and about 95% ZrO stabilized with glass grinding media provide particles acceptable for the preparation of pharmaceutical compositions. Furthermore, other media such as polymer beads, stainless steel, titania, alumina, and about 95% ZrO stabilized with yttrium are useful. A preferred grinding medium is about 2.5 g / cm³. 3 It has a density exceeding [a certain value] and contains approximately 95% ZrO stabilized with magnesia and polymer beads.

[0055] Wear times can vary considerably and depend primarily on the specific mechanical means and selected processing conditions. For rolling mills, processing times of up to two days or more may be required for small particle sizes.

[0056] The particles must be reduced in size at a temperature that does not significantly decompose the antipsychotic agent. A processing temperature of approximately 30°C to less than 40°C is usually preferred. If necessary, the processing apparatus may be cooled with a conventional cooling device. The method is conveniently carried out under ambient temperature conditions and at a processing pressure that is safe and effective for the grinding process.

[0057] If a surface modifier is not present in the premix, it is typically added to the dispersion after abrasion, for example, in the amount described above with respect to the premix. The dispersion can then be mixed, for example, by vigorous shaking. Optionally, the dispersion may be subjected to the dispersion process using, for example, ultrasonic power supply.

[0058] The aqueous composition may further contain a suspending agent and a buffering agent, and optionally one or more of a preservative and an isotonic agent. Certain components may function simultaneously as two or more of these agents, for example, acting as a preservative and a buffering agent, or as a buffering agent and an isotonic agent.

[0059] Suitable suspending agents (also called physical stabilizers) for use in aqueous suspensions according to the present invention are cellulose derivatives, such as methylcellulose, sodium carboxymethylcellulose and hydroxypropylmethylcellulose, polyvinylpyrrolidone, alginate, chitosan, dextran, gelatin, polyethylene glycol, polyoxyethylene- and polyoxypropylene ethers. Preferably, sodium carboxymethylcellulose is used at a concentration of about 0.5 to about 2%, most preferably about 1% (w / v).

[0060] Preferred wetting agents selected from the surfactants described for use in aqueous suspensions according to the present invention are polyoxyethylene derivatives of sorbitan esters, such as polysorbic acid 20 and polysorbic acid 80, lecithin, polyoxyethylene-, and polyoxypropylene ether, and sodium deoxycholate. Preferably, polysorbic acid 20 is used at a concentration of about 0.5 to about 3%, more preferably about 0.5 to about 2%, and most preferably about 1.1% (w / v).

[0061] A suitable buffer is a salt of a weak acid and should be used in an amount sufficient to bring the dispersion from about pH 6.0 to basic. Preferably, the pH is in the range of about 6.0 to about 9.0, or about 6.0 to about 8.0, or 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) (typically about 0.9% (w / v)) and sodium dihydrogen phosphate monohydrate (typically about 0.6% (w / v)). This buffer makes the dispersion isotonic and, in addition, reduces the tendency of the ester suspended therein to aggregate.

[0062] The preservative can be selected from the group consisting of benzoic acid, benzyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, chlorobutol, gallate, hydroxybenzoate, EDTA, phenol, chlorocresol, metacresol, benzethonium chloride, myristyl-gamma-picolinium chloride, phenyl acetate nitrate, and thimerosal, and may be an antimicrobial and antioxidant agent. In particular, it is benzyl alcohol, which can be used at a concentration of up to about 2% (w / v), preferably up to about 1.5% (w / v).

[0063] Isotonic agents include, for example, sodium chloride, dextrose, mannitol, sorbitol, lactose, and sodium sulfate. The suspension conveniently contains about 0% to about 10% (w / v) of the isotonic agent. Mannitol may be used at concentrations of about 0% to about 7%, but more preferably, one or more electrolytes at about 1% to about 3% (w / v), and especially about 1.5% to about 2% (w / v), are used to make the suspension isotonic, perhaps because the ions help prevent aggregation of the suspended ester. In particular, the electrolytes in buffers play an isotonic role.

[0064] A particularly desirable feature of an injectable formulation relates to the ease with which it can be administered. In particular, such injection must be possible in the shortest possible time and using the finest needle possible. This can be achieved by using the aqueous suspension of the present invention to maintain a specific viscosity that can be easily taken into a syringe (e.g., from a vial) and injected through a fine 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, a 22G 1 1 / 2-inch needle or a 22G 1-inch needle is typically used. For PP6M, a 20G 1 1 / 2-inch needle is typically used.

[0065] Ideally, the aqueous suspension for use described in this method should contain a sufficient amount of prodrugs to keep the injection volume to a minimum, and as little as possible of other components.

[0066] In particular, for PP3M or PP6M, the composition may contain, or be essentially composed of, (a) about 200 to about 500 mg / mL of a prodrug, (b) about 2 to about 25 mg / mL of a wetting agent, (c) about 2.5 to about 50 mg / mL of one or more buffering agents, (d) about 25 to about 150 mg / mL of a suspending agent, (e) optionally up to about 2% (w / v) of a preservative, and (f) the remainder of water 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.

[0067] In other embodiments, for PP3M or PP6M, the composition may contain, or essentially consist of, (a) about 250 to about 400 mg / mL of a prodrug, (b) about 5 to about 20 mg / mL of a wetting agent, (c) about 5 to about 25 mg / mL of one or more buffering agents, (d) about 50 to about 100 mg / mL of a suspending agent, (e) optionally up to about 2% (w / v) of a preservative, and (f) the remainder of water to 100%.

[0068] In other embodiments, for PP3M or PP6M, the composition may contain, or essentially consist of, (a) about 280 to about 350 mg / mL of a prodrug, (b) about 8 to about 12 mg / mL of a wetting agent, (c) about 5 to about 15 mg / mL of one or more buffering agents, (d) about 65 to about 85 mg / mL of a suspending agent, (e) optionally up to about 2% (w / v) of a preservative, and (f) the remainder of water to 100%.

[0069] The active ingredient in PP3M or PP6M is paliperidone palmitate (approximately 312 mg / mL). In certain preferred embodiments, the active ingredients in PP3M or PP6M may be polysorbate 20 (approximately 10 mg / mL), polyethylene glycol 4000 (approximately 75 mg / mL), citric acid monohydrate (approximately 7.5 mg / mL), sodium dihydrogen phosphate monohydrate (approximately 6 mg / mL), sodium hydroxide (approximately 5.4 mg / mL), and water for injection. An example of PP3M is disclosed in Example 1. An example of PP6M is disclosed in Example 2.

[0070] The method includes maintaining a syringe containing a sustained-release injectable suspension of paliperidone palmitate in a substantially horizontal orientation during shipment. The method also includes maintaining a syringe containing a sustained-release injectable suspension of paliperidone palmitate in a different orientation during shipment than the orientation of the syringe during pre-shipment storage, for example, if the orientation during pre-shipment storage was not substantially horizontal, the syringe in a substantially horizontal orientation during storage.

[0071] Regardless of the specific orientation of the syringe during pre-shipment storage, according to this method, changing the orientation of the syringe during shipment after such pre-shipment storage may mean maintaining the syringe in a shipment orientation that represents an angular deviation of approximately 45 to 135° from the storage orientation. For example, the orientation of the syringe during shipment may change by approximately 45, 50, 55, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, or 135° from the orientation of the syringe during pre-shipment storage.

[0072] For example, the orientation of a syringe during shipment may be substantially horizontal. This is particularly suitable if the syringe was oriented with its tip pointing upward or downward during storage before shipment (the “tip” of the syringe refers to the part of the syringe to which the needle is attached for the purpose of injection). A substantially horizontal orientation may mean that the syringe is oriented at an angle closer to 0° than 90° with respect to an applicable reference point, such as the ground perpendicular to gravity or the floor of the vehicle in which the syringe is shipped. For example, a substantially horizontal orientation may refer to an orientation that is 0, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 3, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, or 44° with respect to the relevant reference point.

[0073] In other embodiments, the orientation of the syringe during shipment may be substantially tip-up. This represents a suitable shipping orientation when the syringe was tip-down or substantially horizontal during pre-shipment storage. The tip-up orientation may refer to a syringe where the tip is at an angle closer to 90° than 0° with respect to an applicable reference point, such as the ground perpendicular to gravity or the floor of the vehicle in which the syringe is shipped. For example, an upward-pointing tip orientation may refer to an orientation that is 90, 89, 88, 87, 86, 85, 84, 83, 82, 81, 80, 79, 78, 77, 76, 75, 74, 73, 72, 71, 70, 69, 68, 67, 66, 65, 64, 63, 62, 61, 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, or 46° relative to the relevant reference point.

[0074] In other embodiments, the orientation of the syringe during shipping may be substantially tip-down. This represents a suitable shipping orientation when the syringe was tip-up or substantially horizontal during pre-shipment storage. The tip-down orientation may refer to an orientation in which the syringe is reversed by 180° with respect to one of the tip-up orientations described herein.

[0075] To "maintain" an orientation, regardless of the specific orientation during shipping, preferably means that an acceptable angle is applied for most of the time during the shipping process. Ideally, if a substantially horizontal orientation is desired during shipping, the syringe will always be maintained at an angle perpendicular to gravity during shipping; however, in practice, variations in orientation during shipping are inevitable due to changes in the orientation of the vehicle into which the syringe is being shipped. For example, the orientation of the syringe will be perpendicular to gravity when the truck into which the syringe is loaded for shipping is stationary on flat terrain, but this orientation will change as the truck goes uphill or downhill during the shipping process. Therefore, a useful reference point may be the floor of the shipping vehicle rather than gravity, and preferably, the syringe is maintained in an orientation substantially parallel to the floor of the vehicle during shipping.

[0076] Maintaining a specific orientation of syringes during shipment may include loading the syringes onto the shipping vehicle in the desired orientation, monitoring the syringes during shipment to ensure that the desired orientation is maintained, or both. Loading the syringes onto the shipping vehicle in the desired orientation refers to the method by which the package containing the syringes is positioned on the shipping vehicle, with the intention that the orientation of the package when it is placed on the shipping vehicle will not be intentionally changed during the shipping process. Monitoring the syringes during shipment to ensure that the desired orientation is maintained may include direct or indirect observation by a person, by an automated system programmed to verify compliance with the desired orientation, or a combination thereof. Direct observation by a person may include a visual inspection of the packaging containing the syringes by a person. Indirect observation may include the use of sensors attached to the syringes, the package containing the syringes, or both, or other means that enable such monitoring. The sensor can, for example, acquire information regarding the orientation of a syringe and / or package and transmit it to a human observer, who then determines whether the transmitted information indicates that the syringe is maintained in the required orientation during the shipping process. The sensor can also transmit an alarm or some other notification if the orientation of the container or package deviates from the appropriate orientation, for example, if the container / package moves during shipping. In one embodiment, the particular or desired orientation is substantially horizontal.

[0077] A human monitor or sensor capable of detecting information regarding the orientation of a syringe can provide a direct determination of the syringe orientation, or it can do so indirectly by determining the orientation of the package containing the syringe. For example, markings on the outside of the package can provide a sensor or human monitor with a visual cue indicating the corresponding orientation of the syringe contained within the package. Thus, the syringe may be contained within a container (package) including an outer surface, the outer surface having instructions or markings that allow the container to be maintained in an orientation corresponding to the desired syringe orientation (e.g., substantially horizontal orientation) during shipment. In some embodiments, the instructions may be provided in an appropriate language depending on the origin of the syringe, the personnel handling the shipment, and the destination of the syringe. In some embodiments, the markings on the outer surface of the container may be arrows indicating, as appropriate, which side of the container should face the top, bottom, or side. If the instructions or markings are followed, the syringe contained within the container will be in the correct orientation according to this method.

[0078] Syringe shipment may be carried out by any necessary means of transport, such as airships (airplanes, helicopters, etc.), trucks, boats, rail, or any combination of these means, which may be carried out from the time of shipment from the drug manufacturing facility to the medical facility where the drug is administered. The total duration of shipment may be any period necessary to transport the syringe from the initial storage location to a second location, such as a medical facility. For example, the duration of shipment may be approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 hours. The shipment process may include periods during which the syringe is being transported, such as one or more intervals during which the syringe is not being transported, for example, at a temporary storage location prior to further transport intervals. For the purposes of this disclosure, the duration of shipment may, but may not necessarily, refer to the total amount of time elapsed from the time the syringe is removed from the initial storage location after manufacturing until its arrival at the facility where the drug is administered.

[0079] The method may further include, after the syringe has been shipped and before the drug suspension has been administered, maintaining the syringe in a storage location in a deliberately selected orientation, for example, substantially horizontal. In this regard, since the floor of the storage facility is horizontal and therefore likely to be perpendicular to gravity, substantially horizontal orientation can preferably refer to an angle substantially parallel to the floor of the storage facility. This may mean that the angle between the long axis of the syringe and the floor of the storage facility is preferably less than about 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1°.

[0080] As described above, this method facilitates and improves the resuspension of the contents of a paliperidone palmitate syringe. One intended result of resuspending paliperidone palmitate particles is the reduction or removal of residue representing unresuspended paliperidone palmitate within the syringe tip. To some extent, if the resuspension is incomplete, unresuspended paliperidone palmitate may remain within the syringe tip after administration, thereby representing undelivered drug and an indicator of incomplete administration. Minimizing the amount of residue representing unresuspended paliperidone palmitate remaining within the syringe tip after administration represents a further beneficial result of the method disclosed herein. For example, according to this method, the syringe tip may contain residue of approximately 3, 2.5, 2, 1.5, 1, or 0.5 mm or less representing unresuspended paliperidone palmitate after administration. In some embodiments, the syringe tip contains a residue of approximately 3, 2.8, 2.6, 2.5, 2.4, 2.2, 2.1, 2, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, or 0 mm representing paliperidone palmitate that has not been resuspended after administration.

[0081] The syringe may be of any type and may be equipped with any needle suitable for storing and administering paliperidone palmitate injectable suspension. For example, the syringe may have capacities of 1, 1.25, 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, 2.8, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.25, 6.5, 6.75, or 7 mL. In some embodiments, the syringe has a capacity of 1, 2.25, 2.8, or 3 mL and includes a 22 gauge needle that is 1 or 1.5 inches long. In some embodiments, the syringe has a capacity of 5 mL and includes a 20 gauge needle that is 1.5 inches long. With respect to any of the inventions disclosed herein, the volume of a syringe-injectable suspension of paliperidone palmitate may be, for example, 1, 1.25, 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, 2.8, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.25, 6.5, 6.75, or 7 mL.

[0082] The method may further include the step of administering the suspension to the patient from a syringe (i.e., maintained in the desired orientation during shipment). In some embodiments, the desired orientation is substantially horizontal. The administration of the suspension should be carried out, for example, according to the protocol described on the label of the commercially available paliperidone palmitate sustained-release injectable suspension product described above. While the method mitigates certain instances of failure by healthcare professionals who strictly adhere to the recommended steps before and during administration of paliperidone palmitate sustained-release injectable suspension, it is still desirable that the administration of the suspension from a syringe by this method adheres to the labeling protocol.

[0083] Simultaneously, the method allows for a reduction in the force required to inject a sustained-release paliperidone palmitate injectable suspension from a syringe that is kept substantially horizontal during syringe shipment. Therefore, the disclosure encompasses a method for reducing the force required to inject a sustained-release paliperidone palmitate injectable suspension. For example, the force required to inject from a syringe may be about 5% to 60% less than the force required to inject a sustained-release paliperidone palmitate injectable suspension from a syringe that was not kept substantially horizontal during syringe shipment. The force required to inject from a 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 a sustained-release paliperidone palmitate injectable suspension from a syringe that was not kept substantially horizontal during syringe shipment. In some embodiments, the force required for injection from the syringe may be about 10–55, 15–50, 20–50, 25–45, or 30–40% less than the force required for injection of paliperidone palmitate sustained-release injectable suspension from a syringe that was not maintained in a substantially horizontal orientation during shipment. In addition, the method simultaneously allows for a reduction in the force required for injection of paliperidone palmitate sustained-release injectable suspension from a syringe that is maintained in a substantially horizontal orientation during shipment, for example, if the orientation during pre-shipment storage was not substantially horizontal. Therefore, the disclosure encompasses methods for reducing the force required for injection of paliperidone palmitate sustained-release injectable suspension. For example, the force required for injection from the syringe may be about 5–60% less than the force required for injection of paliperidone palmitate sustained-release injectable suspension from a syringe that was not maintained in a shipping orientation different from the orientation during pre-shipment storage. The force required for injection 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 for injection of paliperidone palmitate sustained-release injectable suspension from a syringe that has not been maintained in a shipping orientation different from the orientation of the syringe during pre-shipment storage.In some embodiments, the force required for injection from the syringe may be about 10–55, 15–50, 20–50, 25–45, or 30–40% less than the force required for injection of paliperidone palmitate sustained-release injectable suspension from a syringe that was not maintained in a shipping orientation different from the syringe orientation during pre-shipment storage.

[0084] From an absolute standpoint, the force required to inject a sustained-release paliperidone palmitate injectable suspension from a syringe may be about 10 to 25 Newtons less than the force required to inject a sustained-release paliperidone palmitate injectable suspension from a syringe that was not kept substantially horizontal during shipment. The force required to inject from a syringe may be, for example, about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 Newtons less than the force required to inject a sustained-release paliperidone palmitate injectable suspension from a syringe that was not kept substantially horizontal during shipment. The amount of force actually required to inject a sustained-release paliperidone palmitate injectable suspension from a syringe may be, for example, about 10 to 25 Newtons. Therefore, the force required for injection from a syringe may be, for example, about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 Newtons. In addition, in absolute terms, the force required for injection of paliperidone palmitate sustained-release injectable suspension from a syringe may be about 5 to 25 Newtons less than the force required for injection of paliperidone palmitate sustained-release injectable suspension from a syringe that has not been maintained in a shipping orientation different from the orientation of the syringe during pre-shipment storage. The force required for injection from a syringe may be about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 Newtons less than the force required for injection of paliperidone palmitate sustained-release injectable suspension from a syringe that has not been maintained in a shipping orientation different from the orientation of the syringe during pre-shipment storage. The amount of force actually required for injection of paliperidone palmitate sustained-release injectable suspension from a syringe may be, for example, about 10 to 25 Newtons. Therefore, the force required for injection from a syringe may be, for example, about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 Newtons.

[0085] This method may further include evaluating the amount of force required to complete the injection of a sustained-release paliperidone palmitate injectable suspension from a syringe. The evaluation may be performed using any available measurement technique.

[0086] The method may also include, or may not include, evaluating whether the injection of the sustained-release injectable suspension of paliperidone palmitate from the syringe is complete. The evaluation may include, for example, measuring the amount of unresuspended paliperidone palmitate in the tip of the syringe that exceeds a specific value such as approximately 4, 3.75, 3.5, 3.25, 3, 2.75, 2.5, 2.25, 2, 1.75, 1.5, 1.25, 1, 0.75, 0.5, or 0.25 mm in length.

[0087] Furthermore, methods for improving the resuspensionability of a sustained-release injectable suspension of paliperidone palmitate in a syringe are disclosed herein, including maintaining the syringe in a substantially horizontal orientation during storage. Storage of the syringe may be performed before or after shipment. In certain embodiments, storage of the syringe is performed after shipment, for example, at a location corresponding to a medical facility where paliperidone palmitate will be administered. These methods may be performed independently of or in combination with the above-described methods for improving resuspensionability, including maintaining the syringe in a substantially horizontal orientation during shipment. In other words, the syringe may be stored in a substantially horizontal orientation, shipped in a substantially horizontal orientation, or both shipped and stored in a substantially horizontal orientation. Storage of the syringe in a substantially horizontal orientation may be facilitated by markings or other instructions on the packaging or container containing the syringe, such markings may be the same as or different from markings or instructions intended to ensure that the syringe is maintained in a substantially horizontal orientation during shipment. Similar to methods that include maintaining a substantially horizontal orientation during shipment, the method may further include monitoring to ensure that a substantially horizontal orientation is maintained during storage. The approach for monitoring may be the same as that described above in relation to maintaining a substantially horizontal orientation during shipment. Also disclosed herein are methods for improving the resuspensionability of a sustained-release injectable suspension of paliperidone palmitate in a syringe, which include maintaining the syringe during shipment in an orientation different from that of the syringe during pre-shipment storage, for example, in a substantially horizontal orientation during storage if the orientation during pre-shipment storage was not substantially horizontal. Storage of the syringe may be performed before or after shipment of the syringe. In certain embodiments, storage of the syringe is performed after shipment of the syringe, for example, at a location corresponding to a medical facility where paliperidone palmitate will be administered. These methods may be performed independently of or in combination with the methods described above for improving resuspensionability, which include maintaining the syringe during shipment in an orientation different from that of the syringe during pre-shipment storage.In other words, syringes may be shipped and subsequently stored in a substantially horizontal orientation, or they may be shipped and stored in a substantially horizontal orientation. Storage of syringes in a particular orientation may be facilitated by markings or other instructions on the packaging or container containing the syringes, such markings may be the same as or different from markings or instructions intended to ensure that the desired orientation is maintained during shipment. As with methods that include maintaining a particular orientation during shipment, the method may further include monitoring to ensure that the desired orientation is maintained during storage. The approach for monitoring may be the same as those described above in relation to maintaining the desired orientation during shipment.

[0088] The disclosure also provides a syringe assembly comprising each syringe containing a sustained-release injectable suspension of paliperidone palmitate, wherein each syringe is shipped to its destination and the syringes have been maintained in a substantially horizontal orientation during shipment. Thus, each member of the syringe assembly obtains the aforementioned benefits associated with shipping in a substantially horizontal orientation, including improved resuspension, less residue in the syringe tip after administration, and less force required for administration. A syringe assembly may contain approximately 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, 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 assembly may contain a syringe type and a paliperidone palmitate suspension as otherwise described herein, in accordance with the methods disclosed herein. In addition, the disclosure also provides a syringe assembly in which each syringe contains a sustained-release injectable suspension of paliperidone palmitate, wherein each syringe is shipped to its destination and, during shipment, is maintained in a different orientation than that of the syringe during pre-shipment storage, for example, if the orientation during pre-shipment storage was not substantially horizontal, the syringe is in a substantially horizontal orientation during shipment. Thus, each member of the syringe assembly obtains the aforementioned benefits associated with shipping in a different orientation than that of the syringe during pre-shipment storage, including improved resuspension, less residue in the syringe tip after administration, and less force required for administration.A syringe assembly may contain approximately 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, 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 assembly may contain a syringe-type and a paliperidone palmitate suspension as otherwise described herein, according to the methods disclosed herein.

[0089] Furthermore, the present invention provides a pharmaceutical product comprising a paliperidone palmitate sustained-release injectable suspension for administration to a patient suffering from schizophrenia in a syringe, wherein the syringe undergoes pre-shipment storage and is shipped, and the syringe is maintained in a different orientation during shipment than the orientation of the syringe during pre-shipment storage. The characteristics of the paliperidone palmitate sustained-release injectable suspension, syringe, pre-shipment storage conditions, orientation of the syringe during pre-shipment storage, shipping conditions, and orientation of the syringe during shipment may be combined with the present invention's method for improving the resuspensionability of the paliperidone palmitate sustained-release injectable suspension in the syringe, and the syringe assembly of the present invention, according to any of the embodiments described above.

[0090] For example, the syringe may be housed in a container that includes an outer surface, the outer surface including instructions for maintaining the container in a orientation corresponding to the desired orientation of the syringe during shipping. In some embodiments, the syringe is housed in a container that includes an outer surface, the outer surface including markings indicating the orientation of the container corresponding to maintaining the desired orientation of the syringe.

[0091] After shipment, the syringe may contain residue of approximately 1.5 mm or less, or approximately 1 mm or less, representing paliperidone palmitate that has not been resuspended after injection of the suspension. For example, the syringe may contain residue of approximately 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1 mm, representing paliperidone palmitate that has not been resuspended after injection of the suspension.

[0092] The sustained-release injectable suspension of paliperidone palmitate in the syringe may contain about 273, 410, 546, or 819 mg of paliperidone palmitate. In other embodiments, the suspension contains about 1092 or 1560 mg of paliperidone palmitate.

[0093] The orientation of the syringe during shipment may vary by approximately 45° to 135° from the orientation of the syringe during storage prior to shipment. For example, the orientation of the syringe during shipment may vary by approximately 45, 50, 55, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, or 135° from the orientation of the syringe during storage prior to shipment.

[0094] In some embodiments of the pharmaceutical products disclosed herein, the pre-shipment storage orientation was tip-down. In some embodiments of the pharmaceutical products disclosed herein, the shipping orientation was substantially horizontal. In certain embodiments of the pharmaceutical products disclosed herein, the pre-shipment storage orientation was tip-down, and the shipping orientation was tip-up, or substantially horizontal. In other embodiments, the pre-shipment storage orientation was tip-down, and the shipping orientation was substantially horizontal. In other embodiments, the pre-shipment storage orientation was tip-down, and the shipping orientation was tip-up.

[0095] The Disclosure also provides a method for treating schizophrenia, comprising administering a sustained-release injectable suspension of paliperidone palmitate to a patient suffering from schizophrenia from a syringe, wherein the syringe has undergone pre-shipment storage and has been shipped, and the syringe has been maintained in a different orientation during shipping than the orientation of the syringe during pre-shipment storage. The Disclosure also provides a sustained-release injectable suspension of paliperidone palmitate for use in a method for treating schizophrenia, wherein the method comprises administering a sustained-release injectable suspension of paliperidone palmitate to a patient suffering from schizophrenia from a syringe, wherein the syringe has undergone pre-shipment storage and has been shipped, and the syringe has been maintained in a different orientation during shipping than the orientation of the syringe during pre-shipment storage. The administration of the suspension should be carried out, for example, according to the protocol described on the label of the above-mentioned commercially available sustained-release injectable suspension product. This method mitigates specific instances of failure by healthcare professionals who strictly adhere to the recommended steps before and during administration of paliperidone palmitate sustained-release injectable suspension; however, it is still desirable that the suspension be administered from a syringe using this method in accordance with the labeling protocol.

[0096] With regard to currently disclosed methods for treating schizophrenia, the characteristics of the paliperidone palmitate sustained-release injectable suspension, syringe, pre-shipment storage conditions, syringe orientation during pre-shipment storage, shipping conditions, and syringe orientation during shipping may be combined with the present invention's method for improving the resuspensionability of the paliperidone palmitate sustained-release injectable suspension in the syringe, and the syringe assembly of the present invention, to follow any of the embodiments described above.

[0097] For example, the syringe may be housed in a container that includes an outer surface, the outer surface including instructions for maintaining the container in a orientation corresponding to the desired orientation of the syringe during shipping. In some embodiments, the syringe is housed in a container that includes an outer surface, the outer surface including markings indicating the orientation of the container corresponding to maintaining the desired orientation of the syringe.

[0098] After shipment, the syringe may contain residue of approximately 1.5 mm or less, or approximately 1 mm or less, representing paliperidone palmitate that has not been resuspended after injection of the suspension. For example, the syringe may contain residue of approximately 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1 mm, representing paliperidone palmitate that has not been resuspended after injection of the suspension.

[0099] The sustained-release injectable suspension of paliperidone palmitate in the syringe may contain about 273, 410, 546, or 819 mg of paliperidone palmitate. In other embodiments, the suspension contains about 1092 or 1560 mg of paliperidone palmitate.

[0100] The orientation of the syringe during shipment may vary by approximately 45° to 135° from the orientation of the syringe during storage prior to shipment. For example, the orientation of the syringe during shipment may vary by approximately 45, 50, 55, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, or 135° from the orientation of the syringe during storage prior to shipment.

[0101] In some embodiments of the methods disclosed herein for treating schizophrenia, the pre-shipment storage orientation was tip-down. In some embodiments of the methods disclosed herein for treating schizophrenia, the shipping orientation was substantially horizontal. In certain embodiments of the methods disclosed herein, the pre-shipment storage orientation was tip-down, and the shipping orientation was tip-up, or substantially horizontal. In other embodiments, the pre-shipment storage orientation was tip-down, and the shipping orientation was substantially horizontal. In other embodiments, the pre-shipment storage orientation was tip-down, and the shipping orientation was tip-up.

[0102] This disclosure also provides a use in the manufacture of a pharmaceutical product for the treatment of schizophrenia, wherein the paliperidone palmitate sustained-release injectable suspension is prepared for administration from a syringe, the syringe has undergone pre-shipment storage and shipment, and the syringe has been maintained in a different orientation during shipment than that during pre-shipment storage. Administration of the suspension should be carried out, for example, according to the protocol described on the label of the commercially available paliperidone palmitate sustained-release injectable suspension product described above. This use mitigates certain instances of failure by healthcare professionals who strictly adhere to the recommended steps before and during administration of the paliperidone palmitate sustained-release injectable suspension, although it is still desirable that administration of the suspension from a syringe using this use adheres to the labeling protocol.

[0103] With respect to the currently disclosed uses, the characteristics of the paliperidone palmitate sustained-release injectable suspension, syringe, pre-shipment storage conditions, syringe orientation during pre-shipment storage, shipping conditions, and syringe orientation during shipping may be in combination with the present invention's method for improving the resuspensionability of the paliperidone palmitate sustained-release injectable suspension in the syringe, and the syringe assembly of the present invention, according to any of the embodiments described above.

[0104] For example, the syringe may be housed in a container that includes an outer surface, the outer surface including instructions for maintaining the container in a orientation corresponding to the desired orientation of the syringe during shipping. In some embodiments, the syringe is housed in a container that includes an outer surface, the outer surface including markings indicating the orientation of the container corresponding to maintaining the desired orientation of the syringe.

[0105] After shipment, the syringe may contain residue of approximately 1.5 mm or less, or approximately 1 mm or less, representing paliperidone palmitate that has not been resuspended after injection of the suspension. For example, the syringe may contain residue of approximately 1.5, 1.4, 1.3, 1.2, 1.1, 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or 0.1 mm, representing paliperidone palmitate that has not been resuspended after injection of the suspension.

[0106] The sustained-release injectable suspension of paliperidone palmitate in the syringe may contain about 273, 410, 546, or 819 mg of paliperidone palmitate. In other embodiments, the suspension contains about 1092 or 1560 mg of paliperidone palmitate.

[0107] The orientation of the syringe during shipment may vary by approximately 45° to 135° from the orientation of the syringe during storage prior to shipment. For example, the orientation of the syringe during shipment may vary by approximately 45, 50, 55, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, or 135° from the orientation of the syringe during storage prior to shipment.

[0108] In some embodiments of the uses disclosed herein, the pre-shipment storage orientation was tip-down. In some embodiments of the uses disclosed herein, the shipping orientation was substantially horizontal. In certain embodiments of the uses disclosed herein, the pre-shipment storage orientation was tip-down, and the shipping orientation was tip-up or substantially horizontal. In other embodiments, the pre-shipment storage orientation was tip-down, and the shipping orientation was substantially horizontal. In other embodiments, pre-shipment storage was tip-down, and the shipping orientation was tip-up.

[0109] The present invention is further defined with reference to the following numbered clauses. 1. A method for improving the resuspensionability of a sustained-release injectable suspension of paliperidone palmitate in a syringe, comprising maintaining the syringe in a substantially horizontal orientation during shipment. 2. Maintaining the syringe in a substantially horizontal orientation is the method described in paragraph 1, including loading the syringe in a substantially horizontal orientation onto the shipping vehicle, monitoring the syringe during shipping to ensure that it is maintained in a substantially horizontal orientation, or both. 3. The method of claim 1 or 2, further comprising housing a syringe in a container including an outer surface, wherein the outer surface is substantially horizontal and therefore instructions for maintaining the container in transit in an orientation corresponding to the orientation of the syringe. 4. The method according to any one of claims 1 to 3, further comprising housing a syringe in a container including an outer surface, wherein the outer surface has markings indicating the orientation of the container corresponding to maintaining the orientation of the syringe which is substantially horizontal. 5. The method according to any one of items 1 to 4, further comprising keeping the syringes in a storage location in a substantially horizontal orientation after the syringes have been shipped. 6. The method described in any one of paragraphs 1 to 5, wherein the syringe is shipped by airplane, truck, boat, or rail. 7. The method according to any one of items 1 to 6, wherein, after shipment, the syringe contains a residue of approximately 1.5 mm or less representing paliperidone palmitate that has not been resuspended after administration. 8. The method according to any one of items 1 to 7, wherein after shipment, the syringe contains a residue of approximately 1 mm or less representing unresuspended paliperidone palmitate. 9. The method according to any one of items 1 to 8, wherein the syringe has a capacity of 1 mL, 2.25 mL, 2.8 mL, or 3 mL and includes a 22 gauge needle that is 1 or 1.5 inches in length. 10. The method according to any one of items 1 to 13, wherein the syringe has a capacity of 5 mL and includes a 20 gauge needle that is 1.5 inches in length. 11. The method according to any one of items 1 to 15, wherein the suspension contains approximately 273, 410, 546, or 819 mg of paliperidone palmitate. 12. The method according to any one of items 1 to 15, wherein the suspension contains approximately 1092 or 1560 mg of paliperidone palmitate. 13. The method according to any one of items 1 to 17, further comprising administering the suspension to a patient from a syringe. 14. A method for reducing the force required to inject a sustained-release injectable suspension of paliperidone palmitate from a syringe, comprising maintaining the syringe in a substantially horizontal orientation during dispensing. 15. The method according to item 23, wherein the force required for injection from the syringe is about 20% to about 50% less than the force required for injection of paliperidone palmitate sustained-release injectable suspension from a syringe that was not kept substantially horizontal during shipment of the syringe. 16. The method according to item 23 or 24, wherein the force required for injection from the syringe is about 10 to 25 Newtons less than the force required for injection of paliperidone palmitate sustained-release injectable suspension from a syringe that was not kept substantially horizontal during shipment of the syringe. 17. The method according to any one of items 23-25, wherein the force required for injection from the syringe is approximately 10-25 Newtons. 18. The method according to any one of items 23 to 26, further comprising assessing the force required to complete the injection of a sustained-release injectable suspension of paliperidone palmitate from a syringe. 19. A method for reducing the possibility of incomplete injection of a sustained-release injectable suspension of paliperidone palmitate from a syringe, comprising maintaining the syringe in a substantially horizontal orientation during shipment. 20. The method of item 28, further comprising evaluating whether the injection of the paliperidone palmitate sustained-release injectable suspension from a syringe is complete. 21. A method for improving the resuspensionability of a sustained-release injectable suspension of paliperidone palmitate in a syringe, comprising maintaining the syringe in a substantially horizontal orientation during storage. 22. The method described in paragraph 21, wherein the storage described above is carried out after the syringe has been shipped. 23. A collection of syringes, each containing a sustained-release injectable suspension of paliperidone palmitate, wherein each syringe has been shipped to its destination, and each syringe has been maintained in a substantially horizontal orientation during shipment. 24. The assembly described in item 30, comprising at least 100 individual syringes. [Examples]

[0110] The present invention is further defined by the following embodiments. These embodiments are given merely for illustrative purposes, illustrating preferred embodiments of the invention, and should not be construed as limiting the scope of the appended claims. From the above discussion and these embodiments, those skilled in the art can identify the essential features of the invention and, without departing from its spirit and scope, make various changes and modifications to adapt the invention to various uses and conditions. Unless otherwise specified, references to PP6M in the embodiments refer to the formulation in Example 2.

[0111] Example 1: 3-month sustained-release formulation (PP3M) Table 1 below includes exemplary 3-month sustained-release formulations (PP3M) of paliperidone at a dose of 200 mg / mL suitable for intramuscular (IM) injection.

[0112] [Table 1]

[0113] PP3M can be supplied in pre-filled syringes, with dosage strengths ranging from 175 mg equivalent to 525 mg equivalent, which can be obtained by filling the syringes with different volumes of 200 mg / mL equivalent bulk suspension. Table 2 shows the different dosage strengths, including syringe sizes and nominal filling volumes.

[0114] [Table 2]

[0115] Table 3 lists the syringe components used to package PP3M.

[0116] [Table 3]

[0117] Example 2 - 6-month sustained-release formulation (PP6M) Table 4 below includes exemplary 6-month sustained-release formulations (PP6M) of paliperidone palmitate at a dose of 200 mg / mL equivalent suitable for intramuscular (IM) injection.

[0118] [Table 4]

[0119] PP6M can be supplied in pre-filled syringes, with dosage strengths ranging from 700 mg equivalent to 1000 mg equivalent, which can be achieved by filling the syringes with different volumes of 200 mg / mL equivalent bulk suspension. Table 5 shows the different dosage strengths, including syringe sizes and nominal filling volumes.

[0120] [Table 5]

[0121] Table 6 lists the syringe components used to package the 6-month sustained-release formulation.

[0122] [Table 6]

[0123] Example 3 - Storage conditions before shipment Stability testing was performed using PP6M process performance qualified (PPQ) batches in five different orientations prior to shipment (horizontal, tip downward +45°, tip upward -45°, tip downward +45°, and tip downward -45°). The following test results were obtained for syringes that were stored after manufacturing but not shipped before testing. Sensor testing by shaking for 5 seconds was performed at two different temperatures (25°C and 30°C). The results from this experiment are provided in Table 7.

[0124] [Table 7] Note: PPQIII horizontal samples are blister-packaged (contained in blister packaging), while PPQII and PPQI horizontal samples are not blister-packaged. 9M = 9-month storage period. NT = Untested.

[0125] An injection feasibility test was performed by manual injection using a sensor on the thumb pad of the plunger rod, and the force (Newtons) over time (seconds) was recorded. The injection force profiles for the samples in PPQ I and PPQ II after vigorous shaking for 5 seconds are shown in Figures 1A to 1F.

[0126] The results suggested that products stored in any location before shipment could be resuspended with a normal amount of force, meaning the force required to expel the syringe contents was independent of the storage location before shipment. Different storage locations yielded comparable results, indicating that the location where the syringe was stored before shipment was irrelevant if it had been shaken for at least 5 seconds. Complete injections could be performed with an acceptable injection force.

[0127] Following this experiment, it became clear that the storage location of the product during stability testing and before shipment was not a significant determinant of resuspendability. As described in Example 4 below, the orientation of shipment was found to be far more important than the orientation of pre-shipment storage.

[0128] Example 4 - Orientation during simulated shipment After storage in the manufacturing facility with the tip facing downwards, syringes containing the PP6M formulation were subjected to simulated shipping experiments using vibrations corresponding to Level I and Level II vibrations as defined by ASTM D4169-16 for simulated air shipment. These are the highest levels of vibration during air shipment and exceed the vibration levels defined for truck shipment. To increase the sensitivity of the tests for detecting differences, the resuspension and injectability of the PP6M formulation after simulated shipping were tested without shaking or with shaking for only 5 seconds (shorter than defined by the instructions for use (IFU), consistent with the instructions provided on the label for INVEGA TRINZA® (PP3M product); the IFU for PP6M is 2 × 15 seconds of shaking, and the IFU for PP3M is 1 × 15 seconds of shaking). A summary of the residue remaining in the syringe and the maximum force required to empty the syringe to that point is provided in Table 8 below.

[0129] [Table 8]

[0130] Figures 2A to 2D show the injection force curves for syringes subjected to vibration experiments while in a horizontal or tip-down position. Injectability tests were performed by manual injection using a sensor on the thumb pad of the plunger rod, and the force (Newtons) over time (seconds) was recorded. Vibration conditions included a 2-hour Level II simulated air shipment and a 3-hour Level I simulated air shipment, in accordance with ASTM D4169. Figure 2A corresponds to a syringe with the tip-down position and no shaking before injection. Figure 2B corresponds to a syringe with the tip-down position and 5 seconds of shaking before injection. Figure 2C corresponds to a syringe with the horizontal position and no shaking before injection. Figure 2D corresponds to a syringe with the horizontal position and 5 seconds of shaking before injection.

[0131] The results from this experiment confirm that, after storage with the tip facing downwards, dispensing the syringe in the tip-down position may require very high force to squeeze out the contents, and that the contents of such syringes may not be completely resuspended after shaking for 5 seconds. In practice, healthcare providers do not press up to 30N or 35N, especially when injecting into a patient.

[0132] However, when the syringe was stored with the tip facing downwards and then shipped in a horizontal position, the injection force was in the range of 10–20 Newtons, indicating that the product requires less shaking to achieve a good suspension. In comparison, the force required to release a one-month-old paliperidone palmitate injectable suspension, which represents a much less concentrated formulation (thus considerably less vulnerable to impact and thus less need for resuspension), is in the range of 7–12 Newtons.

[0133] Example 5 - Changing the orientation of the syringe during shipment compared to the orientation during storage before shipment reduces injection force and post-injection residue. Following initial evidence that horizontal orientation of PP6M syringes during shipment resulted in improved resuspension and injectability compared to tip-down orientation, further research was initiated to more deeply evaluate the potential effects of different types and durations of shipment and to monitor the behavior of PP6M syringes up to 3 months after simulated shipment.

[0134] For this study, PP6M in a 5 mL syringe was selected from the stability chamber. The 5 mL packing was chosen over the 3.5 mL packing as a worst-case scenario for resuspension due to the higher product load in the same 5 mL syringe.

[0135] Samples from different batches, stored in different orientations in a stability chamber but not yet subjected to shipping conditions, were tested for resuspension / injectability by manually injecting the syringe into a container after 5 seconds of insufficient shaking. Injectability was recorded using a sensor attached to a thumb pad, and the height of residual product in the syringe was measured. All samples were either completely injectable with no product residue in the syringe or with an acceptable amount of product residue. It was concluded that the different pre-shipment storage orientations did not themselves affect the suspension properties, and the product was readily resuspensionable and injectable after 9 months of storage.

[0136] Following this initial test, syringes were transported by car from Beerse (Belgium) to a testing facility in Diepenbeek (Belgium) and subjected to different shipment simulations ranging from mild exposure (1 hour truck, mild) to severe exposure (4 hours airplane, high). The simulated shipment tests were conducted according to ASTM D4169-16. During these shipment simulations, the syringes were positioned either horizontally or with the tip facing downwards. During normal manufacturing, syringes are typically stored tip-down in a tab for more than one month after filling. Once a packaging order is issued, the syringes are packaged in a blister kit and shipped after launch. Within one day of the shipment simulation, samples exposed to different simulated shipment conditions in different orientations were resuspended by shaking at high speed for 5 seconds and manually injecting the product into a container, with the injection force measured by a sensor attached to the thumb pad of the syringe. To increase the sensitivity of the test, a shorter time (5 seconds instead of 2 × 15 seconds according to IFU) was used for analysis to resuspend the product.

[0137] The remaining syringe was stored horizontally or with the tip facing downward according to the protocol, and the resuspension / injectability of the syringe was further evaluated after 1 month, 2 months, or 3 months of storage.

[0138] Furthermore, as described below, the analysis showed that the orientation of the syringe before shipment relative to the direction of shipment is an important factor in the resuspension of the product.

[0139] In both single shipments and combined truck / air shipments, maintaining the syringes in the same orientation during initial storage and shipment made resuspending the syringes more difficult, resulting in more residual product after only 5 seconds of rapid shaking.

[0140] Post-shipment storage location and storage time represented factors that had only a limited effect on the resuspendability of the product.

[0141] The data provided in Tables 9-11 (below) shows that when syringes are shipped horizontally after horizontal storage prior to shipment, they exhibit a greater amount of residual product after a rapid 5-second resuspension and injection compared to syringes stored with the tip facing downwards.

[0142] Similarly, syringes that were stored with the tip facing upward before shipment and turned with the tip facing downward during shipment contained no residual product at all or very limited residual product after rapid resuspension and injection for 5 seconds.

[0143] In both single and combined shipments, maintaining the syringes in the same orientation during initial storage and shipment made resuspension of the syringes more difficult, resulting in more residual product after rapid resuspension in 5 seconds and manual injection.

[0144] Tables 9-11 provide results for sample sets, allowing for direct comparisons between syringes whose orientation during initial storage differed from that during shipment, compared to syringes that were held in the same orientation during pre-shipment storage and during shipment.

[0145] Experiments 1 and 2 represent two datasets from trials involving a single type of simulated shipment, while Experiment 3 provides data from a combined shipment trial (i.e., simulated air shipment followed by simulated truck shipment).

[0146] [Table 9]

[0147] [Table 10]

[0148] [Table 11]

[0149] These data showed that syringes shipped in a different orientation than that used during pre-shipment storage were resuspended more easily than syringes maintained in the same orientation during shipping as they were used during pre-shipment storage. Various embodiments of the present invention are shown below. 1. A method for treating schizophrenia, comprising administering a sustained-release injectable suspension of paliperidone palmitate to a patient suffering from schizophrenia from a syringe, wherein the syringe undergoes pre-shipment storage and is shipped, and the syringe is maintained during shipment in a different orientation than that of the syringe during pre-shipment storage. 2. The treatment method according to paragraph 1 above, wherein the orientation for storage before shipment was with the tip facing downward, and the orientation for shipment was with the tip facing upward, or substantially horizontal. 3. The treatment method according to item 1 or 2 above, wherein the orientation of the product for storage before shipment was with the tip facing downward, and the orientation of the product for shipment was substantially horizontal. 4. The therapeutic method according to any one of 1 to 3 above, wherein the suspension contains approximately 273, 410, 546, or 819 mg of paliperidone palmitate. 5. The therapeutic method according to any one of items 1 to 4 above, wherein the suspension contains approximately 1092 or 1560 mg of paliperidone palmitate. 6. A method for improving the resuspensionability of a sustained-release injectable suspension of paliperidone palmitate in a syringe, comprising maintaining the syringe in a desired orientation different from the orientation of the syringe during pre-shipment storage while the syringe is being shipped. 7. The method according to 6 above, wherein maintaining the syringe in the desired shipping orientation includes loading the syringe into the shipping vehicle in the desired orientation, monitoring the syringe to ensure that the desired orientation is maintained during shipping, or both. 8. The method of 6 or 7 above, further comprising housing the syringe in a container including an outer surface, wherein the outer surface has a guide for maintaining the container in a orientation corresponding to the desired orientation of the syringe during shipping. 9. The method according to any one of 6 to 8 above, further comprising housing the syringe in a container including an outer surface, wherein the outer surface has markings indicating the orientation of the container corresponding to maintaining the desired orientation. 10. The method according to any one of 6 to 9 above, further comprising, after the syringe has been shipped, maintaining the syringe in a storage location in a substantially horizontal orientation. 11. The method according to any one of 6-10 above, wherein the syringe is shipped by airplane, truck, boat, or rail. 12. The method according to any one of 6 to 11 above, wherein, after shipment, the syringe contains a residue of approximately 1.5 mm or less representing paliperidone palmitate that has not been resuspended after administration. 13. The method according to any one of 6 to 12 above, wherein, after shipment, the syringe contains a residue of approximately 1 mm or less representing paliperidone palmitate that has not been resuspended after administration. 14. The method according to any one of 6 to 13 above, wherein the syringe has a capacity of 1 mL, 2.25 mL, 2.8 mL, or 3 mL and includes a 22 gauge needle that is 1 or 1.5 inches in length. 15. The method according to any one of 6 to 13 above, wherein the syringe has a capacity of 5 mL and includes a 20-gauge needle that is 1.5 inches in length. 16. The method according to any one of 6 to 15 above, wherein the suspension contains approximately 273, 410, 546, or 819 mg of paliperidone palmitate. 17. The method according to any one of 6 to 15 above, wherein the suspension contains about 1092 or 1560 mg of paliperidone palmitate. 18. The method according to any one of 6 to 17 above, further comprising administering the suspension to a patient from the syringe. 19. The method according to any one of 6 to 18 above, wherein the desired orientation of shipment is substantially horizontal, tip-up, or tip-down. 20. The method according to any one of 6 to 19 above, wherein the desired shipping orientation changes by approximately 45° to approximately 135° from the orientation of the syringe during storage before shipping. 21. The method according to any one of 6 to 20 above, wherein the orientation for pre-shipment storage is with the tip facing downward, and the orientation for shipment is with the tip facing upward, or substantially horizontal. 22. The method according to any one of 6 to 21 above, wherein the orientation for pre-shipment storage is with the tip facing downward, and the orientation for shipment is substantially horizontal. 23. A method for reducing the force required to inject a sustained-release injectable suspension of paliperidone palmitate from a syringe, comprising maintaining the syringe in a desired orientation during shipment, different from the orientation of the syringe during pre-shipment storage. 24. The method according to 23, wherein the force required for injection from the syringe is about 20% to about 50% less than the force required for injection of paliperidone palmitate sustained-release injectable suspension from a syringe that has been maintained in a substantially the same orientation during shipment as it was in pre-shipment storage of the syringe. 25. The method according to 23 or 24, wherein the force required for injection from the syringe is about 10 to 25 Newtons less than the force required for injection of paliperidone palmitate sustained-release injectable suspension from a syringe that was not maintained in the desired orientation during shipment of the syringe. 26. The method according to any one of the above 23 to 25, wherein the force required for injection from the syringe is approximately 10 to 25 Newtons. 27. The method according to any one of 23 to 26, further comprising evaluating the force required to complete the injection of the paliperidone palmitate sustained-release injectable suspension from the syringe. 28. A method for reducing the possibility of incomplete injection of a sustained-release injectable suspension of paliperidone palmitate from a syringe, comprising maintaining the syringe in a desired orientation different from the orientation of the syringe during pre-shipment storage while the syringe is being shipped. 29. The method according to 28, further comprising evaluating whether the injection of the sustained-release injectable suspension of paliperidone palmitate from the syringe has been completed. 30. A collection of syringes, each containing a sustained-release injectable suspension of paliperidone palmitate, wherein each syringe is stored before shipment and shipped to its destination, and each syringe is maintained during shipment in a desired orientation different from the orientation of the syringe during pre-shipment storage. 31. The assembly described in 30 above, comprising at least 100 individual syringes. 32. A pharmaceutical product comprising a syringe containing a sustained-release injectable suspension of paliperidone palmitate for administration to a patient suffering from schizophrenia, wherein the syringe undergoes pre-shipment storage and is shipped, and the syringe is maintained during shipment in a different orientation than that of the syringe during pre-shipment storage. 33. The pharmaceutical product according to 32, wherein the syringe is housed in a container including an outer surface, the outer surface including instructions for maintaining the container in a orientation corresponding to the desired orientation of the syringe during shipping. 34. The pharmaceutical product according to 32 or 33, wherein the syringe is housed in a container including an outer surface, and the outer surface includes markings indicating the orientation of the container corresponding to maintaining the desired orientation of the syringe. 35. The pharmaceutical product according to any one of 32 to 34 above, wherein, after shipment, the syringe contains a residue of approximately 1.5 mm or less representing paliperidone palmitate that has not been resuspended after injection of the suspension. 36. The pharmaceutical product according to any one of 32 to 34 above, wherein, after shipment, the syringe contains a residue of approximately 1 mm or less representing paliperidone palmitate that has not been resuspended after injection of the suspension. 37. The pharmaceutical product according to any one of 32 to 36 above, wherein the suspension contains approximately 273, 410, 546, or 819 mg of paliperidone palmitate. 38. The pharmaceutical product according to any one of 32 to 36 above, wherein the suspension contains approximately 1092 or 1560 mg of paliperidone palmitate. 39. A pharmaceutical product according to any one of the above 32 to 38, wherein the orientation of the product upon shipment has changed by approximately 45° to approximately 135° from the orientation of the syringe during storage prior to shipment. 40. A pharmaceutical product according to any one of the above 32 to 38, wherein the orientation for storage before shipment was with the tip facing downward, and the orientation for shipment was with the tip facing upward or substantially horizontal. 41. A pharmaceutical product according to any one of the above 32 to 38, wherein the orientation for storage before shipment was with the tip facing downward, and the orientation for shipment was substantially horizontal. 42. The pharmaceutical product according to any one of the above 32 to 38, wherein the orientation of the syringe during pre-shipment storage was with the tip facing downward.

Claims

1. A sustained-release injectable suspension of paliperidone palmitate for use in a method of treating schizophrenia, the method comprising administering the sustained-release injectable suspension of paliperidone palmitate to a patient suffering from schizophrenia from a syringe, wherein the syringe undergoes pre-shipment storage and is shipped, and the syringe is maintained during shipment in a different orientation than that of the syringe during pre-shipment storage, and the shipping orientation is substantially horizontal.

2. The paliperidone palmitate sustained-release injectable suspension according to claim 1, wherein the orientation for pre-shipment storage was with the tip facing downward.

3. (i) The suspension contains approximately 273, 410, 546, or 819 mg of paliperidone palmitate, (ii) The suspension contains about 1092 or 1560 mg of paliperidone palmitate. The sustained-release injectable suspension of paliperidone palmitate according to claim 1 or 2.

4. A method for improving the resuspensionability of a sustained-release injectable suspension of paliperidone palmitate in a syringe, comprising maintaining the syringe in a desired orientation during shipment that is different from the orientation of the syringe during pre-shipment storage, wherein the desired orientation is substantially horizontal.

5. The method according to claim 4, wherein maintaining the syringe in a desired shipping orientation includes loading the syringe into a shipping vehicle in the desired orientation, monitoring the syringe to ensure that the desired orientation is maintained during shipping, or both.

6. (i) further comprising housing the syringe in a container including an outer surface, wherein the outer surface has a guide for maintaining the container in a orientation corresponding to the desired orientation of the syringe during shipment, and / or (ii) further comprising housing the syringe in a container including an outer surface, wherein the outer surface has markings indicating the orientation of the container corresponding to maintaining the desired orientation, and / or (iii) After the syringe has been shipped, the syringe is to be stored in a substantially horizontal position, The method according to claim 4 or claim 5.

7. (i) The syringe is shipped by airplane, truck, boat or rail, and / or (ii) After the shipment, the syringe contains a residue of approximately 1.5 mm or less representing paliperidone palmitate that has not been resuspended after administration, and / or (iii) After the shipment, the syringe contains a residue of about 1 mm or less representing paliperidone palmitate that has not been resuspended after administration, and / or (iv) (a) the syringe having a capacity of 1 mL, 2.25 mL, 2.8 mL, or 3 mL and including a 22 gauge needle that is 1 or 1.5 inches in length, or (b) the syringe having a capacity of 5 mL and including a 20 gauge needle that is 1.5 inches in length, and / or (v) The method according to any one of claims 4 to 6, wherein (a) the suspension contains about 273, 410, 546, or 819 mg of paliperidone palmitate, or (b) the suspension contains about 1092 or 1560 mg of paliperidone palmitate.

8. The method according to any one of claims 4 to 7, wherein the syringe is for use in administering the suspension to a patient.

9. (i) The desired shipping orientation changes by approximately 45° to approximately 135° from the orientation of the syringe during storage before shipping, and / or (ii) The orientation for storage before shipment is with the tip facing downwards. The method according to any one of claims 4 to 8.

10. A method for reducing the force required to inject a sustained-release injectable suspension of paliperidone palmitate from a syringe, comprising maintaining the syringe in a desired orientation during shipment, different from the orientation of the syringe during pre-shipment storage, wherein the desired orientation is substantially horizontal.

11. (i) The force required for injection from the syringe is about 20% to about 50% less than the force required for injection of paliperidone palmitate sustained-release injectable suspension from a syringe that has been maintained in substantially the same orientation as the syringe in pre-shipment storage during shipment, and / or (ii) The force required for injection from the syringe is about 10 to 25 Newtons less than the force required for injection of the paliperidone palmitate sustained-release injectable suspension from a syringe that was not maintained in the desired orientation during shipment of the syringe, and / or (iii) The method according to claim 10, wherein the force required for injection from the syringe is about 10 to 25 Newtons.

12. The method according to claim 10 or 11, further comprising evaluating the force required to complete the injection of the sustained-release injectable suspension of paliperidone palmitate from the syringe.

13. A method for reducing the possibility of incomplete injection of a sustained-release injectable suspension of paliperidone palmitate from a syringe, comprising maintaining the syringe in a desired orientation during shipment that is different from the orientation of the syringe during pre-shipment storage, wherein the desired orientation is substantially horizontal. A method further comprising, optionally, evaluating whether the injection of the sustained-release injectable suspension of paliperidone palmitate from the syringe has been completed.

14. An assembly of syringes, each containing a sustained-release injectable suspension of paliperidone palmitate, wherein each syringe is stored before shipment and shipped to its destination, and during shipment, each syringe is maintained in a desired orientation different from the orientation of the syringe during pre-shipment storage, and the desired orientation is substantially horizontal. An assembly containing at least 100 individual syringes, of which optional.

15. A pharmaceutical product comprising a syringe containing a sustained-release injectable suspension of paliperidone palmitate for administration to a patient suffering from schizophrenia, wherein the syringe undergoes pre-shipment storage and is shipped, and the syringe is maintained during shipment in a shipping orientation different from the orientation of the syringe during pre-shipment storage, and the shipping orientation is substantially horizontal.

16. (i) The syringe is housed in a container including an outer surface, the outer surface includes instructions for maintaining the container in a orientation corresponding to the shipping orientation of the syringe, and / or (ii) The syringe is housed in a container including an outer surface, the outer surface including markings indicating the orientation of the container corresponding to maintaining the shipping orientation of the syringe, and / or (iii) (a) After the shipment, the syringe contains a residue of about 1.5 mm or less representing paliperidone palmitate that has not been resuspended after the injection of the suspension, or (b) After the aforementioned shipment, the syringe contains a residue of approximately 1 mm or less representing paliperidone palmitate that has not been resuspended after the injection of the suspension, and / or (iv) (a) the suspension contains about 273, 410, 546, or 819 mg of paliperidone palmitate, or (b) the suspension contains about 1092 or 1560 mg of paliperidone palmitate. The pharmaceutical product according to claim 15.

17. (i) The orientation of the shipment has changed by approximately 45° to approximately 135° from the orientation of the syringe during storage before shipment, (ii) The orientation of the syringe during pre-shipment storage was with the tip facing downwards. The pharmaceutical product according to claim 15 or 16.

18. A sustained-release injectable suspension of paliperidone palmitate according to any one of claims 1 to 3, an assembly of syringes according to claim 14, or a pharmaceutical product according to any one of claims 15 to 17, wherein after the shipment of the syringes, the syringes are maintained in a storage location in a substantially horizontal orientation.

19. The method according to any one of claims 4 to 13, wherein after the shipment of the syringes, the syringes are maintained in a storage place in a substantially horizontal orientation.

20. A sustained-release injectable suspension of paliperidone palmitate according to any one of claims 1 to 3, wherein the substantially horizontal orientation refers to an orientation in which the syringe is at an angle closer to 0° than 90° with respect to an applicable reference point, an assembly of syringes according to claim 14, or a pharmaceutical product according to any one of claims 15 to 17.

21. The method according to any one of claims 4 to 13, wherein the substantially horizontal orientation refers to an orientation in which the syringe is at an angle closer to 0° than 90° with respect to an applicable reference point.

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